Immune Cell Subsets Evaluation as a Predictive Tool for Hepatitis B Infection Outcome and Treatment Responsiveness.

PubMed

Kandilarova, Snezhina M; Georgieva, Atanaska I; Mihaylova, Anastasiya P; Baleva, Marta P; Atanasova, Valentina K; Petrova, Diana V; Popov, Georgi T; Naumova, Elissaveta J

2017-03-01

The patient's immune response is one of the major factors influencing HBV eradication or chronification, and it is thought to be responsible for the treatment success. Our study aimed to investigate whether cellular defense mechanisms are associated with the course of HBV infection (spontaneous recovery [SR] or chronification [CHB]) and with the therapeutic approach. A total of 139 patients (118 with CHB, 21 SR) and 29 healthy individuals (HI) were immunophenotyped by flowcytometry. Fifty-six patients were treatment-naïve, 20 were treated with interferons and 42 with nucleoside/ nucleotide analogues. Deficiency of T lymphocytes, helper-inducer (CD3+CD4+), suppressorcytotoxic (CD8+CD3+) and cytotoxic (CD8+CD11b-, CD8+CD28+) subsets, activated T cells (CD3+HLA-DR+, CD8+CD38+) and increased CD57+CD8- cells, elevated percentages of B lymphocytes and NKT cells were observed in CHB patients compared with HI. In SR patients, elevated CD8+CD11b+, NKT and activated T cells were found in comparison with controls. The higher values of T cells and their subsets in SR patients than in CHB patients reflect a recovery of cellular immunity in resolved HBV infection individuals. In both groups of treated patients, reduced T lymphocytes, CD3+CD4+ and CD8+CD38+ subsets were found in comparison with HI. Higher proportions of cytotoxic subsets were observed in treated patients compared with treatment-naïve CHB patients, more pronounced in the group with interferon therapy. Our data demonstrate that cellular immune profiles may be of prognostic value in predicting the clinical course of HBV infection, and the determination of the therapeutic response.

Decreased CD8+CD28+/CD8+CD28- T cell ratio can sensitively predict poor outcome for patients with complicated Crohn disease.

PubMed

Dai, Shi-Xue; Gu, Hong-Xiang; Lin, Qian-Yi; Wu, Yan-Kun; Wang, Xiao-Yan; Huang, Shao-Zhuo; Xing, Tiao-Si; Chen, Min-Hua; Zhang, Qing-Fang; Zheng, Zhong-Wen; Sha, Wei-Hong

2017-06-01

Crohn disease (CD) with complications such as penetrating, stricturing, and perianal disease is called complicated CD. The aim of this study is to test the efficiency with which the CD8CD28/CD8CD28 cell balance can predict a subsequent active stage in patients with newly diagnosed complicated CD.Seventeen patients with complicated CD and 48 CD patients with no complications were enrolled. Blood CD8 T cells were tested from all of the 65 newly diagnosed CD patients upon enrollment. The potential risk factors were compared between the 2 groups. A 30-week follow-up was performed, and the efficiency of the CD8 cell balance at predicting active CD was analyzed using receiver-operating characteristic curves. The cumulative remission lasting rates (CRLRs) were analyzed using the Kaplan-Meier method.Compared with the control CD group, patients with complicated CD were predominantly male and younger in age; they also had lower body mass indices (BMIs), higher Crohn disease activity indices (CDAIs), higher immunosuppressant and steroid prescription rates, and significantly higher surgical rates. The CD8CD28/CD8CD28 balance was associated with BMI, CDAI, steroids, and surgery. The CD8CD28/CD8CD28 ratios were significantly lower at week 0 and on the 6th, 22nd, and 30th week during follow-up with a shorter lasting time of remission for the complicated CD patients. The CD8CD28/CD8CD28 ratio could accurately predict the active stage for the patients with complicated CD, and the highest sensitivity (89.2%) and specificity (85.3%) were found when the ratio was 1.03. Treatment with steroids and surgery, along with a significantly lower CD8CD28/CD8CD28 ratio and lower CRLRs, was closely related to a worse outcome for the patients with complicated CD.Patients requiring steroids and surgery experience more severe disease activity and thus a disequilibrated immunological balance, which could be the main reason for a decreased CD8CD28/CD8CD28 ratio. This ratio can sensitively predict the active stage for patients with complicated CD, and more care should be taken when this ratio is <1.03.

Effects of CD4 monitoring frequency on clinical endpoints in clinically stable HIV-infected patients with viral suppression

PubMed Central

Ahn, Jin Young; Boettiger, David; Law, Matthew; Kumarasamy, Nagalingeswaran; Yunihastuti, Evy; Chaiwarith, Romanee; Lee, Man Po; Sim, Benedict LH; Oka, Shinichi; Wong, Wingwai; Kamarulzaman, Adeeba; Kantipong, Pacharee; Phanuphak, Praphan; Ng, Oon Tek; Kiertiburanakul, Sasisopin; Zhang, Fujie; Pujari, Sanjay; Ditangco, Rossana; Ratanasuwan, Winai; Merati, Tuti Parwati; Saphonn, Vonthanak; Sohn, Annette H.; Choi, Jun Yong

2015-01-01

Background Current treatment guidelines for HIV infection recommend routine CD4+ lymphocyte (CD4) count monitoring in patients with viral suppression. This may have a limited impact on influencing care as clinically meaningful CD4 decline rarely occurs during viral suppression. Methods In a regional HIV observational cohort in the Asia-Pacific, patients with viral suppression (2 consecutive viral loads <400 copies/mL) and a CD4 count ≥200 cells/μL who had CD4 testing 6 monthly were analyzed. Main study endpoints were occurrence of one CD4 count <200 cells/μL (single CD4<200) and two CD4 counts <200 cells/μL within a 6-month period (confirmed CD4<200). A comparison of time to single and confirmed CD4<200 with biannual or annual CD4 assessment was performed by generating a hypothetical group comprised of the same patients with annual CD4 testing by removing every second CD4 count. Results Among 1538 patients, the rate of single CD4<200 was 3.45/100 patient-years, and of confirmed CD4<200 was 0.77/100 patient-years. During 5 years of viral suppression, patients with baseline CD4 200-249 cells/μL were significantly more likely to experience confirmed CD4<200 compared with patients with higher baseline CD4 (hazard ratio 55.47 [95% confidence interval 7.36–418.20], p<0.001 versus baseline CD4 ≥500 cells/μL). Cumulative probabilities of confirmed CD4<200 was also higher in patients with baseline CD4 200-249 cells/μL compared with patients with higher baseline CD4. There was no significant difference in time to confirmed CD4<200 between biannual and annual CD4 measurement (p=0.336). Conclusions Annual CD4 monitoring in virally suppressed HIV patients with a baseline CD4 ≥250 cells/μL may be sufficient for clinical management. PMID:25850606

Absence of somatization in non-coeliac gluten sensitivity.

PubMed

Brottveit, Margit; Vandvik, Per Olav; Wojniusz, Slawomir; Løvik, Astrid; Lundin, Knut Ea; Boye, Birgitte

2012-07-01

In contrast to coeliac disease (CD), the mechanism behind non-coeliac gluten sensitivity (NCGS) is unclear. The aims of the study were to measure the presence of somatization, personality traits, anxiety, depression, and health-related quality of life in NCGS individuals compared with CD patients and healthy controls, and to compare the response to gluten challenge between NCGS and CD patients. We examined 22 CD patients and 31 HLA-DQ2+ NCGS patients without CD, all on a gluten-free diet. All but five CD patients were challenged orally for 3 days with gluten; symptom registration was performed during challenge. A comparison group of 40 healthy controls was included. Patients and healthy controls completed questionnaires regarding anxiety, depression, neuroticism and lie, hostility and aggression, alexithymia and health locus of control, physical complaints, and health-related quality of life. The NCGS patients reported more abdominal (p = 0.01) and non-abdominal (p < 0.01) symptoms after gluten challenge than CD patients. There were no significant differences between CD and NCGS patients regarding personality traits, level of somatization, quality of life, anxiety, and depressive symptoms. The somatization level was low in CD and NCGS groups. Symptom increase after gluten challenge was not related to personality in NCGS patients. NCGS patients did not exhibit a tendency for general somatization. Personality and quality of life did not differ between NCGS and CD patients, and were mostly at the same level as in healthy controls. NCGS patients reported more symptoms than CD patients after gluten challenge.

Enhanced CD8+ cytolytic T cell responses in the peripheral circulation of patients with sarcoidosis and non-Löfgren's disease.

PubMed

Parasa, Venkata Ramanarao; Forsslund, Helena; Enger, Tobias; Lorenz, Daniel; Kullberg, Susanna; Eklund, Anders; Sköld, Magnus; Wahlström, Jan; Grunewald, Johan; Brighenti, Susanna

2018-05-01

The role of CD4 + T cells in the immunopathogenesis of pulmonary sarcoidosis is well-established, while less is known about the phenotype and function of CD8 + cytolytic T cells (CTLs). CD8 + CTLs were explored in peripheral blood and bronchoalveolar lavage (BAL) samples obtained from up to 25 patients with sarcoidosis and 25 healthy controls. The proportion of CTLs was assessed by the expression of cytolytic effector molecules perforin, granzyme B and granulysin in CD8 + T cells, using flow cytometry. Cytolytic function in blood lymphocytes was assessed using a standard 51 Cr-release assay. Patients with Löfgren´s syndrome (LS) and an acute disease onset, were compared to non-LS patients with an insidious onset. Higher proportions of peripheral CD8 + CTLs expressing perforin and granzyme B were observed in sarcoidosis compared to healthy controls. Blood CTLs from non-LS patients had significantly higher expression of perforin, granzyme B and granulysin compared to matched BAL, while LS patients maintained lower levels of effector molecules in both compartments. Mitogen-stimulated peripheral lymphocytes from sarcoidosis patients, particularly from the non-LS group, showed a higher target cell lysis compared to controls. These results demonstrated enhanced peripheral CD8 + CTL responses in sarcoidosis, especially in non-LS patients who have an increased risk of chronic disease. Further comprehensive clinical studies are warranted to increase our understanding of CD8 + CTL responses in sarcoidosis. Copyright © 2017 Elsevier Ltd. All rights reserved.

CD38+ M-MDSC expansion characterizes a subset of advanced colorectal cancer patients.

PubMed

Karakasheva, Tatiana A; Dominguez, George A; Hashimoto, Ayumi; Lin, Eric W; Chiu, Christopher; Sasser, Kate; Lee, Jae W; Beatty, Gregory L; Gabrilovich, Dmitry I; Rustgi, Anil K

2018-03-22

Myeloid-derived suppressor cells (MDSCs) are a population of immature immune cells with several protumorigenic functions. CD38 is a transmembrane receptor-ectoenzyme expressed by MDSCs in murine models of esophageal cancer. We hypothesized that CD38 could be expressed on MDSCs in human colorectal cancer (CRC), which might allow for a new perspective on therapeutic targeting of human MDSCs with anti-CD38 monoclonal antibodies in this cancer. Blood samples were collected from 41 CRC patients and 8 healthy donors, followed by peripheral blood mononuclear cell (PBMC) separation. Polymorphonuclear (PMN-) and monocytic (M-) MDSCs and CD38 expression levels were quantified by flow cytometry. The immunosuppressive capacity of M-MDSCs from 10 CRC patients was validated in a mixed lymphocyte reaction (MLR) assay. A significant expansion of CD38+ M-MDSCs and a trend of expansion of CD38+ PMN-MDSCs (accompanied by a trend of increased CD38 expression on both M- and PMN-MDSCs) were observed in PBMCs of CRC patients when compared with healthy donors. The CD38+ M-MDSCs from CRC patients were found to be immunosuppressive when compared with mature monocytes. CD38+ M- and PMN-MDSC frequencies were significantly higher in CRC patients who previously received treatment when compared with treatment-naive patients. This study provides a rationale for an attempt to target M-MDSCs with an anti-CD38 monoclonal antibody in metastatic CRC patients. NCI P01-CA14305603, the American Cancer Society, Scott and Suzi Lustgarten Family Colon Cancer Research Fund, Hansen Foundation, and Janssen Research and Development.

Synovial features of patients with rheumatoid arthritis and psoriatic arthritis in clinical and ultrasound remission differ under anti-TNF therapy: a clue to interpret different chances of relapse after clinical remission?

PubMed

Alivernini, Stefano; Tolusso, Barbara; Petricca, Luca; Bui, Laura; Di Sante, Gabriele; Peluso, Giusy; Benvenuto, Roberta; Fedele, Anna Laura; Federico, Franco; Ferraccioli, Gianfranco; Gremese, Elisa

2017-07-01

To define the synovial characteristics of patients with rheumatoid arthritis (RA) and psoriatic arthritis (PsA) in clinical and ultrasound remission achieved by combination therapy with methotrexate (MTX) and tumour necrosis factor (TNF) blockers. Patients with RA in remission (n=25) (disease activity score (DAS)<1.6 for at least 6 months), patients with RA in low disease activity (LDA) (n=10) (1.6

Synovial features of patients with rheumatoid arthritis and psoriatic arthritis in clinical and ultrasound remission differ under anti-TNF therapy: a clue to interpret different chances of relapse after clinical remission?

PubMed Central

Alivernini, Stefano; Tolusso, Barbara; Petricca, Luca; Bui, Laura; Di Sante, Gabriele; Peluso, Giusy; Benvenuto, Roberta; Fedele, Anna Laura; Federico, Franco; Ferraccioli, Gianfranco; Gremese, Elisa

2017-01-01

Objective To define the synovial characteristics of patients with rheumatoid arthritis (RA) and psoriatic arthritis (PsA) in clinical and ultrasound remission achieved by combination therapy with methotrexate (MTX) and tumour necrosis factor (TNF) blockers. Methods Patients with RA in remission (n=25) (disease activity score (DAS)<1.6 for at least 6 months), patients with RA in low disease activity (LDA) (n=10) (1.6

Analysis of circulating CD14+/CD16+ monocyte-derived macrophages (MDMs) in the peripheral blood of patients with oral squamous cell carcinoma.

PubMed

Grimm, Martin; Feyen, Oliver; Coy, Johannes F; Hofmann, Heiko; Teriete, Peter; Reinert, Siegmar

2016-03-01

Monocytes/macrophages are regarded as the first line of defense in tumors. Therefore, analyzing monocyte subtypes in oral squamous cell carcinoma (OSCC) may be of value in disease monitoring and to explore immunotherapeutic strategies for cancer patients. Circulating peripheral blood CD14+/CD16+ monocyte-derived macrophages (MDMs) were evaluated in OSCC patients with oral squamous cell carcinoma (n = 44) compared with controls (n = 85). Moreover, epitope detection in monocytes (EDIM) technology was used to detect biomarkers Apo10 and transketolase-like-1 in CD14+/CD16+ MDMs. Compared with controls, no significant (P = .3646) difference (control group 9.8%, OSCC group 8.8%) in CD14+/CD16+ MDM were noted in OSCC. However, EDIM-Apo10 and EDIM-TKTL1 scores detected in the CD14+/CD16+ MDMs were increased in OSCC compared with controls (P < .0001). Analyzing CD14+/CD16+ MDMs represents a stable cell population for detecting biomarkers in cancer disease monitoring. Copyright © 2016 Elsevier Inc. All rights reserved.

Down-regulation of CD73 on B cells of patients with viremic HIV correlates with B cell activation and disease progression.

PubMed

Kim, Eun-Seong; Ackermann, Christin; Tóth, Ilona; Dierks, Patrick; Eberhard, Johanna M; Wroblewski, Raluca; Scherg, Felix; Geyer, Matthias; Schmidt, Reinhold E; Beisel, Claudia; Bockhorn, Maximilian; Haag, Friedrich; van Lunzen, Jan; Schulze Zur Wiesch, Julian

2017-05-01

Recently, alterations of the T cell expression of the ectonucleotidases, CD39 and CD73, during HIV infection have been described. Here, peripheral ( n = 70) and lymph nodal B cells ( n = 10) of patients with HIV at different stages of disease as well as uninfected individuals were analyzed via multicolor flow cytometry with regard to expression of CD39 and CD73 and differentiation, proliferation, and exhaustion status. Patients with chronic, untreated HIV showed a significantly decreased frequency of CD73-expressing B cells ( P < 0.001) compared with healthy controls. Decreased frequencies of CD39 + CD73 + B cells in patients with HIV correlated with low CD4 + counts ( P < 0.0256) as well as increased proliferation and exhaustion status as determined by Ki-67 and programmed death-1 expression. Down-regulation of CD73 was observed in naive and memory B cells as determined by CD27 and CD21. Neither HIV elite controller patients nor antiretroviral therapy-treated patients had significantly lower CD39 and CD73 expression on B cells compared with healthy controls. Of importance, low CD73 + expression on B cells was associated with modulated in vitro B cell function. Further in vivo studies are warranted to evaluate the in vivo role of phenotypic loss of CD73 in B cell dysregulation in HIV. © Society for Leukocyte Biology.

Sleep architecture and sleep apnea in patients with Cushing's disease.

PubMed

Shipley, J E; Schteingart, D E; Tandon, R; Starkman, M N

1992-12-01

Patients with Cushing's syndrome (CS) frequently have sleep complaints. We evaluated sleep polysomnographically in 22 patients, including 17 with pituitary-ACTH-dependent Cushing's disease (CD) and five with CS from an adrenal tumor. Data were compared to healthy controls of comparable age. Seven patients (32%) demonstrated at least mild sleep apnea (> or = 9.4 events/hour), and four of 22 (18%) had > or = 17.5 events/hour. The apneic CD and CS patients had a trend for a greater complaint of excessive daytime sleepiness. Both apneic and nonapneic groups had considerable snoring and obesity. The electroencephalographic (EEG) sleep of nonapneic patients was compared to that of normal subjects. Nonapneic CD patients differed strikingly from healthy volunteers in sleep continuity and architecture, demonstrating lighter, fragmented sleep. Rapid eye movement (REM) sleep in CD patients bore many similarities to the sleep of patients with major depression, with REM latency being significantly shortened and REM density significantly increased. Continued examination of EEG sleep in CD patients may shed light on similarities in pathophysiology between CD and major depression, disorders which are characterized by both a dysfunction of the hypothalamic-pituitary-adrenal axis and alterations in mood.

Clinical spectrum of Castleman disease–associated neuropathy

PubMed Central

Naddaf, Elie; Dispenzieri, Angela; Mandrekar, Jay

2016-01-01

Objective: To define the peripheral neuropathy phenotypes associated with Castleman disease. Methods: We conducted a retrospective chart review for patients with biopsy-proven Castleman disease evaluated between January 2003 and December 2014. Patients with associated peripheral neuropathy were identified and divided into 2 groups: those with Castleman disease without POEMS syndrome (CD-PN) and those with Castleman disease with POEMS syndrome (CD-POEMS). We used a cohort of patients with POEMS as controls. Clinical, electrodiagnostic, and laboratory characteristics were collected and compared among patient subgroups. Results: There were 7 patients with CD-PN, 20 with CD-POEMS, and 122 with POEMS. Patients with CD-PN had the mildest neuropathy characterized by predominant sensory symptoms with no pain and mild distal sensory deficits (median Neuropathy Impairment Score of 7 points). Although both patients with CD-POEMS and patients with POEMS had a severe sensory and motor neuropathy, patients with CD-POEMS were less affected (median Neuropathy Impairment Score of 33 and 66 points, respectively). The degree of severity was also reflected on electrodiagnostic testing in which patients with CD-PN demonstrated a mild degree of axonal loss, followed by patients with CD-POEMS and then those with POEMS. Demyelinating features, defined by European Federation of Neurologic Societies/Peripheral Nerve Society criteria, were present in 43% of the CD-PN, 78% of the CD-POEMS, and 86% of the POEMS group. Conclusion: There is a spectrum of demyelinating peripheral neuropathies associated with Castleman disease. CD-PN is sensory predominant and is the mildest phenotype, whereas CD-POEMS is a more severe sensory and motor neuropathy. Compared to the POEMS cohort, those with CD-POEMS neuropathy have a similar but less severe phenotype. Whether these patients respond differently to treatment deserves further study. PMID:27807187

Clinical spectrum of Castleman disease-associated neuropathy.

PubMed

Naddaf, Elie; Dispenzieri, Angela; Mandrekar, Jay; Mauermann, Michelle L

2016-12-06

To define the peripheral neuropathy phenotypes associated with Castleman disease. We conducted a retrospective chart review for patients with biopsy-proven Castleman disease evaluated between January 2003 and December 2014. Patients with associated peripheral neuropathy were identified and divided into 2 groups: those with Castleman disease without POEMS syndrome (CD-PN) and those with Castleman disease with POEMS syndrome (CD-POEMS). We used a cohort of patients with POEMS as controls. Clinical, electrodiagnostic, and laboratory characteristics were collected and compared among patient subgroups. There were 7 patients with CD-PN, 20 with CD-POEMS, and 122 with POEMS. Patients with CD-PN had the mildest neuropathy characterized by predominant sensory symptoms with no pain and mild distal sensory deficits (median Neuropathy Impairment Score of 7 points). Although both patients with CD-POEMS and patients with POEMS had a severe sensory and motor neuropathy, patients with CD-POEMS were less affected (median Neuropathy Impairment Score of 33 and 66 points, respectively). The degree of severity was also reflected on electrodiagnostic testing in which patients with CD-PN demonstrated a mild degree of axonal loss, followed by patients with CD-POEMS and then those with POEMS. Demyelinating features, defined by European Federation of Neurologic Societies/Peripheral Nerve Society criteria, were present in 43% of the CD-PN, 78% of the CD-POEMS, and 86% of the POEMS group. There is a spectrum of demyelinating peripheral neuropathies associated with Castleman disease. CD-PN is sensory predominant and is the mildest phenotype, whereas CD-POEMS is a more severe sensory and motor neuropathy. Compared to the POEMS cohort, those with CD-POEMS neuropathy have a similar but less severe phenotype. Whether these patients respond differently to treatment deserves further study. © 2016 American Academy of Neurology.

Defective circulating CD25 regulatory T cells in patients with chronic immune thrombocytopenic purpura

PubMed Central

Yu, Jin; Heck, Susanne; Patel, Vivek; Levan, Jared; Yu, Yu; Bussel, James B.

2008-01-01

Immune thrombocytopenic purpura (ITP) is characterized by the presence of antiplatelet autoantibodies as a result of loss of tolerance. CD4+CD25+ regulatory T cells (Tregs) are important for maintenance of peripheral tolerance. Decreased levels of peripheral Tregs in patients with ITP have been reported. To test whether inefficient production or reduced immunosuppressive activity of Tregs contributes to loss of tolerance in patients with chronic ITP, we investigated the frequency and function of their circulating CD4+CD25hi Tregs. We found a com-parable frequency of circulating CD4+CD25hiFoxp3+ Tregs in patients and controls (n = 16, P > .05). However, sorted CD4+CD25hi cells from patients with chronic ITP (n = 13) had a 2-fold reduction of in vitro immunosuppressive activity compared with controls (n = 10, P < .05). The impaired suppression was specific to Tregs as shown by cross-mixing experiments with T cells from controls. These data suggest that functional defects in Tregs contribute to breakdown of self-tolerance in patients with chronic ITP. PMID:18420827

CD19+ B cell subsets in the peripheral blood and skin lesions of psoriasis patients and their correlations with disease severity

PubMed Central

Lu, J.; Ding, Y.; Yi, X.; Zheng, J.

2016-01-01

T lymphocytes are important in the pathogenesis of psoriasis, and increasing evidence indicates that B cells also play an important role. The mechanisms of action, however, remain unclear. We evaluated the ratios of CD19+ B cells in peripheral blood mononuclear cells (PBMCs) from 157 patients with psoriasis (65 patients with psoriasis vulgaris, 32 patients with erythrodermic psoriasis, 30 patients with arthropathic psoriasis, and 30 patients with pustular psoriasis) and 35 healthy controls (HCs). Ratios of CD19+ B cells in skin lesions were compared with non-lesions in 7 erythrodermic psoriasis patients. The Psoriasis Area Severity Index (PASI) was used to measure disease severity. CD19+ B cell ratios in PBMCs from psoriasis vulgaris (at both the active and stationary stage) and arthropathic psoriasis patients were higher compared with HCs (P<0.01), but ratios were lower in erythrodermic and pustular psoriasis patients (P<0.01). CD19+ B cell ratios in erythrodermic psoriasis skin lesions were higher than in non-lesion areas (P<0.001). Different subsets of CD19+CD40+, CD19+CD44+, CD19+CD80+, CD19+CD86+, CD19+CD11b+, and CD19+HLA-DR+ B cells in PBMCs were observed in different psoriasis clinical subtypes. PASI scores were positively correlated with CD19+ B cell ratios in psoriasis vulgaris and arthropathic psoriasis cases (r=0.871 and r=0.692, respectively, P<0.01), but were negatively correlated in pustular psoriasis (r=-0.569, P<0.01). The results indicated that similar to T cells, B cells activation may also play important roles in different pathological stages of psoriasis. PMID:27532281

Mobilization of Peripheral Blood Stem Cells and Changes in the Concentration of Plasma Factors Influencing their Movement in Patients with Panic Disorder.

PubMed

Jabłoński, Marcin; Mazur, Jolanta Kucharska; Tarnowski, Maciej; Dołęgowska, Barbara; Pędziwiatr, Daniel; Kubiś, Ewa; Budkowska, Marta; Sałata, Daria; Wysiecka, Justyna Pełka; Kazimierczak, Arkadiusz; Reginia, Artur; Ratajczak, Mariusz Z; Samochowiec, Jerzy

2017-04-01

In this paper we examined whether stem cells and factors responsible for their movement may serve as new biological markers of anxiety disorders. The study was carried out on a group of 30 patients diagnosed with panic disorder (examined before and after treatment), compared to 30 healthy individuals forming the control group. We examined the number of circulating HSCs (hematopoetic stem cells) (Lin-/CD45 +/CD34 +) and HSCs (Lin-/CD45 +/AC133 +), the number of circulating VSELs (very small embryonic-like stem cells) (Lin-/CD45-/CD34 +) and VSELs (Lin-/CD45-/AC133 +), as well as the concentration of complement components: C3a, C5a and C5b-9, SDF-1 (stromal derived factor) and S1P (sphingosine-1-phosphate). Significantly lower levels of HSCs (Lin-/CD45 +/AC133 +) have been demonstrated in the patient group compared to the control group both before and after treatment. The level of VSELs (Lin-/CD45-/CD133 +) was significantly lower in the patient group before treatment as compared to the patient group after treatment.The levels of factors responsible for stem cell movement were significantly lower in the patient group compared to the control group before and after treatment. It was concluded that the study of stem cells and factors associated with their movement can be useful in the diagnostics of panic disorder, as well as differentiating between psychotic and anxiety disorders.

Serum sCD30 in monitoring of alloresponse in well HLA-matched cadaveric kidney transplantations.

PubMed

Matinlauri, Irma H; Kyllönen, Lauri E J; Salmela, Kaija T; Helin, Heikki; Pelzl, Steffen; Süsal, Caner

2005-12-27

In kidney transplantation, pretransplant serum sCD30 testing has been proposed in immunological risk estimation together with anti-HLA antibodies. We evaluated the risks associated with high pretransplant serum sCD30 in well HLA-matched cadaveric kidney recipients recruited in a clinical study comparing different immunosuppressive regimens. Rejection rate was similar in 37 recipients with high pretransplant serum sCD30 compared to 117 recipients with low serum sCD30 (16% vs. 15%, P=NS). Compared to pretransplant levels, the posttransplant sCD30 levels generally decreased, also in patients with rejection, although on day 21 posttransplant, rejecting patients had significantly higher relative sCD30 than nonrejecting patients (P<0.01). However, steroid-resistant rejection was associated with increasing posttransplant sCD30 levels. High pretransplant sCD30 values were associated with tubulointerstitial rejection. There was no correlation of sCD30 with delayed graft function. Good HLA matching seems to be effective in neutralizing the negative effect of a high pretransplant serum sCD30.

CD4+ CD25+ CD127low Regulatory T Cells as Indicator of Rheumatoid Arthritis Disease Activity.

PubMed

Khattab, Sahar S; El-Saied, Amany M; Mohammed, Rehab A; Mohamed, Eman E

2016-06-01

Rheumatoid arthritis (RA) is an autoimmune disease characterized by disturbed immune regulation, inducing a progressive cartilage and bone destruction. Despite enrichment of T regulatory cell (T-regs) in synovial fluid, conflicting results are reported concerning T-regs in peripheral blood (PB) of RA patients. To determine possible correlation between the frequency of PB CD4+ CD25+CD127low (T-regs) with RA disease activity. Forty females with RA, classified according to the Disease Activity Score 28 (DAS-28), as highly active, mild-moderate or low disease activity; and 20 age and sex matched healthy controls, were enrolled to study CD4+ CD25+ CD127low T- regs in PB by flow cytometry. Active RA patients had lower frequency of the CD4+ CD25+ CD127low T- regs compared to those with mild-moderate or low disease activity (P <0.001). The frequencies of the T- regs showed negative correlation with the DAS-28 (P<0.01). In conclusion, CD4+ CD25+ CD127low T-regs is significantly lower in highly active RA patients compared to patients with lower activity or controls. Copyright© by the Egyptian Association of Immunologists.

Helicobacter pylori cagA+ Is Associated with Milder Duodenal Histological Changes in Chilean Celiac Patients.

PubMed

Lucero, Yalda; Oyarzún, Amaya; O'Ryan, Miguel; Quera, Rodrigo; Espinosa, Nelly; Valenzuela, Romina; Simian, Daniela; Alcalde, Elisa; Arce, Claudio; Farfán, Mauricio J; Vergara, Alejandra F; Gajardo, Iván; Mendez, Jocelyn; Carrasco, Jorge; Errázuriz, Germán; Gonzalez, Mónica; Ossa, Juan C; Maiza, Eduardo; Perez-Bravo, Francisco; Castro, Magdalena; Araya, Magdalena

2017-01-01

HIGHLIGHTS What is already known about this subject?Celiac disease (CD) has a high clinical and histological diversity and the mechanisms underlying this phenomenon remain elusive. H. pylori is a bacterium that chronically infect gastric and duodenal mucosa activating both a Th1/Th17 and T-reg pathways.The role of H. pylori (and the effect of their virulence factors) in CD have not yet completely elucidated.What are the new findings? cagA + H. pylori strains are associated to milder histological damage in infected CD patients.In active-CD patients the presence of cagA + H. pylori is associated to an increase in T-reg markers, contrasting with a downregulation in cagA + infected potential-CD individuals.How might it impact on clinical practice in the foreseeable future?The identification of microbiological factors that could modulate inflammation and clinical expression of CD may be used in the future as preventive strategies or as supplementary treatment in patients that cannot achieve complete remission, contributing to the better care of these patients. Background: Mechanisms underlying the high clinical and histological diversity of celiac disease (CD) remain elusive. Helicobacter pylori (Hp) chronically infects gastric and duodenal mucosa and has been associated with protection against some immune-mediated conditions, but its role (specifically of cagA + strains) in CD is unclear. Objective: To assess the relationship between gastric Hp infection ( cagA + strains) and duodenal histological damage in patients with CD. Design: Case-control study including patients with active-CD, potential-CD and non-celiac individuals. Clinical presentation, HLA genotype, Hp/ cagA gene detection in gastric mucosa, duodenal histology, Foxp3 positive cells and TGF-β expression in duodenal lamina propria were analyzed. Results: We recruited 116 patients, 29 active-CD, 37 potential-CD, and 50 non-CD controls. Hp detection was similar in the three groups (~30-40%), but cagA + strains were more common in infected potential-CD than in active-CD (10/11 vs. 4/10; p = 0.020) and non-CD (10/20; p = 0.025). Among active-CD patients, Foxp3 positivity was significantly higher in subjects with cagA + Hp+ compared to cagA- Hp+ ( p < 0.01) and Hp- ( p < 0.01). In cagA+ Hp+ individuals, Foxp3 positivity was also higher comparing active- to potential-CD ( p < 0.01). TGF-β expression in duodenum was similar in active-CD with cagA + Hp+ compared to Hp- and was significantly downregulated in cagA + potential-CD subjects compared to other groups. Conclusion: Hp infection rates were similar among individuals with/without CD, but infection with cagA + strains was associated with milder histological damage in celiac patients infected by Hp, and in active-CD cases with higher expression of T-reg markers. Results suggest that infection by cagA + Hp may be protective for CD progression, or conversely, that these strains are prone to colonize intestinal mucosa with less severe damage.

Resting and Activated Natural Tregs Decrease in the Peripheral Blood of Patients with Atherosclerosis.

PubMed

Yazdani, Mohammadreza; Khosropanah, Shahdad; Hosseini, Ahmad; Doroudchi, Mehrnoosh

2016-12-01

Atherosclerosis is a chronic inflammatory disease affecting large and medium arteries. CD4+ T cells are known to play a role in the progression of the disease. CD4+CD25+Foxp3+ natural Treg (nTreg) cells seem to have a protective role in the disease and their reduction in acute coronary syndrome is recently shown. To investigate the frequency of nTreg subsets in the peripheral blood of patients with atherosclerosis. Confirmation of atherosclerosis was done by angiography and 15 ml heparinized blood was obtained from each of the 13 non-diabetic patients and 13 non-diabetic, non-smoker individuals with normal/insignificant coronary artery disease confirmed by angiography. Lipid profiles of the patients and controls were measured at the time of sampling. Mononuclear cells were used for both RNA extraction and immunophenotyping by real-time PCR and flowcytometry techniques, respectively. In natural Treg subsets, the frequency of CD4+CD45RO-CD25+Foxp3lo T-cells (resting nTregs) was greater in controls than patients (p=0.02). The frequency of CD4+CD45RO+CD25hiFoxp3hi T-cells (activated nTregs) was significantly higher in controls compared with patients (p=0.02). However, the frequency of CD4+CD25+CD45RO+Foxp3- T-cells (effector/memory T-cell) increased in patients compared with controls (p=0.01). Both the MFI and gene expression of Foxp3 were higher in control group than in patients (p=0.015 and p=0.017, respectively). Moreover, the TGF-β gene expression showed a decrease in the peripheral blood mononuclear cells of patients compared with controls (p=0.03). Decrease in both subsets of resting and activated nTregs along with a decrease in the expression of Foxp3 and TGF-β genes in patients with atherosclerosis suggests phenotypic changes in these subsets, which may as well be correlated with a more inflammatory profile in their lymphocytes.

Dysregulation of the CD4+ T cells lineage differentiation in dyslipidemic patients and impact of lipoprotein-apheresis treatment: A case study.

PubMed

Papin, J; Brennand, A; Arbore, G; Hohenstein, B; Kamvissi, V; Kemper, C; Bornstein, S R

2017-11-01

Lipoprotein-apheresis (LA) is a therapeutic approach used against severe forms of dyslipidemia in patients who are non-responders or intolerant to pharmacological treatments. However, little is known about the potential pleiotropic effects of LA, particularly regarding the immune system and its regulation. Thus, in an attempt to analyse the potential effects of dyslipidemia and LA on the regulation of CD4 + T cells activation and lineage differentiation, we compared the CD4 + T cells cytokines secretion profiles of dyslipidemic patients before and after LA with the profiles observed in healthy donors. CD4 + T cells were isolated from 5 LA patients and 5 healthy donors and activated with anti-CD3 or anti-CD3 + anti-CD46 antibodies. The supernatants were collected after 36 h incubation and levels of secreted cytokines analysed by flow cytometry. Our results revealed a deep remodelling of CD4 + T cells cytokines secretion patterns in dyslipidemic patients compared to healthy donors, as reflected by a 15 times higher IFN-γ secretion rate after CD3 + CD46 co-activation in dyslipidemic patients after LA compared to healthy subjects and 8 times higher after CD3 activation alone (p = 0.0187 and p = 0.0118 respectively). Moreover, we demonstrated that LA itself also modifies the phenotype and activation pattern of CD4 + T-cells in dyslipidemic patients. These observations could be of fundamental importance in the improvement of LA columns/systems engineering and in developing new therapeutic approaches regarding dyslipidemia and associated pathologies such as atherosclerosis and type 2 diabetes. Copyright © 2017 Elsevier B.V. All rights reserved.

Malignant and Tuberculous Pleural Effusions: Immunophenotypic Cellular Characterization

PubMed Central

de Aguiar, Lucia Maria Zanatta; Antonangelo, Leila; Vargas, Francisco S.; Zerbini, Maria Cláudia Nogueira; Sales, Maria Mirtes; Uip, David E.; Saldiva, Paulo Hilário Nascimento

2008-01-01

INTRODUCTION AND OBJECTIVES Tuberculosis and cancer are the main causes of pleural effusion. Pleural involvement is associated with migration of immune cells to the pleural cavity. We sought to characterize the immunophenotype of leukocytes in the pleural effusion and peripheral blood of patients with tuberculosis or malignancy. METHODS Thirty patients with tuberculosis (14) or malignancy (16) were studied. A control group included 20 healthy blood donors. RESULTS Malignant phycoerythrin pleural effusions showed higher percentages of CD3, CD4, CD3CD45RO, and CD20CD25 lymphocytes and lower percentages of CD3CD25 and CD20HLA-DR when compared to PB lymphocytes. Compared to PB, tuberculous effusions had a higher percentage of lymphocytes that co-expressed CD3, CD4, CD3CD45RO, CD3TCRαβ, CD3CD28, and CD20 and a lower percentage of CD14, CD8 and CD3TCRγδ-positive lymphocytes. Malignant effusions presented higher expression of CD14 whereas tuberculous effusions had higher expression of CD3 and CD3CD95L. Peripheral blood cells from tuberculosis patients showed higher expression of CD14, CD20CD25 and CD3CD95L. Compared with the control cells, tuberculosis and cancer peripheral blood cells presented a lower percentage of CD3CD4 and CD3CD28-positive cells as well as a higher percentage of CD3CD8, CD3CD25 and CD3CD80-positive cells. CONCLUSIONS Tuberculous and malignant peripheral blood is enriched with lymphocytes with a helper/inducer T cell phenotype, which are mainly of memory cells. CD14-positive cells were more frequently found in malignant effusions, while CD3-positive cells expressing Fas ligand were more frequently found in tuberculous effusions. PMID:18925324

Intracellular IL-4, IL-5, and IFN-γ as the main characteristic of CD4+CD30+ T cells after allergen stimulation in patients with vernal keratoconjunctivitis

PubMed Central

Magaña, Diana; Aguilar, Gustavo; Linares, Marisela; Ayala-Balboa, Julio; Santacruz, Concepción; Chávez, Raúl; Estrada-Parra, Sergio; Garfias, Yonathan; Lascurain, Ricardo; Jiménez-Martínez, Maria C.

2015-01-01

Background Vernal keratoconjunctivitis (VKC) is a severe form of allergic conjunctivitis, in which inflammatory infiltrates of the conjunctiva are characterized by CD3+ and CD30+ cells. Until today, the functional involvement of CD30+ T cells in VKC was unclear. Our aim was to evaluate the functional characteristics of CD30+ T cells after allergen stimulation in peripheral blood mononuclear cells obtained from patients with VKC. Methods Seventeen consecutive patients at the Institute of Ophthalmology with active forms of VKC were included. Results After allergen stimulation, we observed the frequency of CD30+ T cells increased compared with non-stimulated cells (p<0.0001). The CD30+ T cells responded to the specific allergen-inducing expression of intracellular interleukin-4 (IL-4), IL-5, and interferon-gamma (IFN-γ) compared with the CD30- T cells (p<0.0001). Increased early secretion of soluble CD30 was observed in the supernatant of the cultured cells from patients with keratoconjunctivitis, compared with healthy controls (p=0.03). Blockage with IL-4 significantly diminished CD30 frequency in the allergen-stimulated cells. Conclusions Our results suggest that after allergenic stimulation, CD4+CD30+ cells are the most important source of IL-4, IL-5, and IFN-γ. IL-4 acts as an activation loop that increases CD30 expression on T cells after specific stimulation. These findings suggest that CD4+CD30+ T cells are effector cells and play a significant role in the immune pathogenic response in patients with vernal keratoconjunctivitis. PMID:25999672

G-CSF-primed autologous and allogeneic bone marrow for transplantation in clinical oncology. Cell content and immunological characteristics

NASA Astrophysics Data System (ADS)

Grivtsova, L. Yu; Melkova, K. N.; Kupryshkina, N. A.; Vorotnikov, I. K.; Grigoryeva, T. A.; Selchuk, V. Yu; Grebennikova, O. P.; Titova, G. V.; Tupitsyn, N. N.

2018-01-01

60 samples of G-CSF-primed bone marrow (39 cancer patients and 21 healthy donors) to be used for transplantation to cancer patients were analyzed and compared by main characteristics with historical control and 13 bone marrow samples from control patient with mastopathy. Basing on morphological and multicolor flow cytometry findings certain characteristics of G-CSF-primed bone marrow were discovered, such as a significant increase in blast count in cancer patients as compared to donors and control patients (p<0.037), a higher neutrophil maturation index (p<0.001) and a lower percentage of mature lymphocytes (p<0.008) as compared to the control group. Among lymphocyte populations G-CSF-priming was associated with a significant increase in the total of mature CD3+ T-cells and CD8+ T-killers (p<0.0001) and a decrease in CD56+CD3- and/or CD16+CD3- NK-cells (p<0.006) both in cancer patients and healthy donors in comparison with the controls.

Assessment of the frequency of regulatory T cells (CD4+CD25+CD127-) in children with hemophilia A: relation to factor VIII inhibitors and disease severity.

PubMed

El-Asrar, Mohamed Abo; Hamed, Ahmed El-Saeed; Darwish, Yasser Wagih; Ismail, Eman Abdel Rahman; Ismail, Noha Ali

2016-01-01

A rapidly growing evidence showed that regulatory T cells (Tregs) play a crucial role in tolerance to coagulation factors and may be involved in the pathogenesis of inhibitor formation in patients with hemophilia. We determined the percentage of Tregs (CD4CD25CD127) in 45 children with hemophilia A compared with 45 healthy controls, and assessed their relation to the clinical characteristics of patients and factor VIII (FVIII) inhibitors. Patients were studied stressing on frequency of bleeding attacks, joint pain, history of viral hepatitis, and the received therapy (FVIII precipitate/cryotherapy). FVIII activity and FVIII inhibitors were assessed with flow cytometric analysis of CD4CD25CD127 Tregs. According to residual FVIII activity levels, 30 patients (66.7%) had mild/moderate hemophilia A, whereas 15 (33.3%) patients had severe hemophilia A. The frequency of Tregs was significantly lower among all patients with hemophilia A compared with controls (2.59 ± 1.1 versus 3.73 ± 1.12%; P = 0.002). Tregs were significantly decreased among patients with FVIII inhibitors compared with the inhibitor-negative group (P < 0.001). Patients with hematuria or severe hemophilia A had lower Tregs levels than those without (P = 0.34 and P = 0.011, respectively). A significant positive correlation was found between the percentage of Tregs and FVIII among hemophilia A patients. ROC curve analysis revealed that the cut-off value of Tregs at 1.91% could differentiate patients with and without FVIII inhibitors, with a sensitivity of 100% and a specificity of 91.3%. We suggest that alteration in the frequency of Tregs in young patients with hemophilia A may contribute to inhibitor formation and disease severity.

High pre-transplant soluble CD30 levels are predictive of the grade of rejection.

PubMed

Rajakariar, Ravindra; Jivanji, Naina; Varagunam, Mira; Rafiq, Mohammad; Gupta, Arun; Sheaff, Michael; Sinnott, Paul; Yaqoob, M M

2005-08-01

In renal transplantation, serum soluble CD30 (sCD30) levels in graft recipients are associated with increased rejection and graft loss. We investigated whether pre-transplant sCD30 concentrations are predictive of the grade of rejection. Pre-transplant sera of 51 patients with tubulointerstitial rejection (TIR), 16 patients with vascular rejection (VR) and an age-matched control group of 41 patients with no rejection (NR) were analyzed for sCD30. The transplant biopsies were immunostained for C4d. The median sCD30 level was significantly elevated in the group with VR (248 Units (U)/mL, range: 92-802) when compared with TIR (103 U/mL, range: 36-309, p<0.001) and NR (179 U/mL, range: 70-343, p<0.03). Moreover, patients with TIR had significantly lower sCD30 levels compared to NR. Based on C4d staining, a TH2 driven process, the median sCD30 levels were significantly raised in C4d+ patients compared with C4d- group (177 U/mL vs. 120 U/mL, p<0.05). sCD30 levels measured at time of transplantation correlate with the grade of rejection. High pre-transplant levels are associated with antibody-mediated rejection which carries a poorer prognosis. sCD30 could be another tool to assess immunological risk prior to transplantation and enable a patient centered approach to immunosuppression.

Serum ficolin-2 correlates worse than fecal calprotectin and CRP with endoscopic Crohn's disease activity.

PubMed

Schaffer, Thomas; Schoepfer, Alain M; Seibold, Frank

2014-09-01

Ficolin-2 is an acute phase reactant produced by the liver and targeted to recognize N-acetyl-glucosamine which is present in bacterial and fungal cell walls. We recently showed that ficolin-2 serum levels were significantly higher in CD patients compared to healthy controls. We aimed to evaluate serum ficolin-2 concentrations in CD patients regarding their correlation with endoscopic severity and to compare them with clinical activity, fecal calprotectin, and CRP. Patients provided fecal and blood samples before undergoing ileo-colonoscopy. Disease activity was scored clinically according to the Harvey-Bradshaw Index (HBI) and endoscopically according to the simplified endoscopic score for CD (SES-CD). Ficolin-2 serum levels and fecal calprotectin levels were measured by ELISA. A total of 136 CD patients were prospectively included (mean age at inclusion 41.5±15.4 years, 37.5% females). Median HBI was 3 [2-6] points, median SES-CD was 5 [2-8], median fecal calprotectin was 301 [120-703] μg/g, and median serum ficolin-2 was 2.69 [2.02-3.83] μg/mL. SES-CD correlated significantly with calprotectin (R=0.676, P<0.001), CRP (R=0.458, P<0.001), HBI (R=0.385, P<0.001), and serum ficolin-2 levels (R=0.171, P=0.047). Ficolin-2 levels were higher in CD patients with mild endoscopic disease compared to patients in endoscopic remission (P=0.015) but no difference was found between patients with mild, moderate, and severe endoscopic disease. Ficolin-2 serum levels correlate worse with endoscopic CD activity when compared to fecal calprotectin or CRP. Copyright © 2014 European Crohn's and Colitis Organisation. Published by Elsevier B.V. All rights reserved.

Soluble CD30 concentrations in ESRD patients with and without panel reactive HLA antibodies.

PubMed

Vaidya, Smita; Partlow, David; Barnes, Titus; Thomas, Phillip; Gugliuzza, Kristin

2006-01-01

In this retrospective study we compared accuracy of panel reactive antibodies (PRA) with serum soluble CD30 (sCD30) contents in predicting acute rejection crisis post-renal transplant. Pre-transplant sera from 115 patients were evaluated for their PRA and sCD30 concentrations. All patients received calcineurin inhibitor-based immunosuppressive therapy. Objective measurements for rejection were biopsy-proven acute rejection (AR) episodes within first six months of the transplant. Post-transplant sera of patients with AR were tested for the presence of donor-specific HLA antibodies (DSA). Overall AR rate was 16% (18/115). Patients positive for PRA and sCD30 tests were at significantly higher risk for AVR compared with those patients negative for both the tests (36% vs. 5%, p=0.01). Among negative PRA patients risk for AR was significantly elevated if they were also tested positive for sCD30 concentrations (21% vs. 5%, p=0.04). Of the 18 patients with AR, 14 were positive for sCD30, and 13 of them (93%) developed DSA post-transplant (p=0.001). These data showed that patients positive for sCD30 contents are at high risk for the development of DSA and AR post-transplant regardless of their pre-transplant PRA.

Helicobacter pylori cagA+ Is Associated with Milder Duodenal Histological Changes in Chilean Celiac Patients

PubMed Central

Lucero, Yalda; Oyarzún, Amaya; O'Ryan, Miguel; Quera, Rodrigo; Espinosa, Nelly; Valenzuela, Romina; Simian, Daniela; Alcalde, Elisa; Arce, Claudio; Farfán, Mauricio J.; Vergara, Alejandra F.; Gajardo, Iván; Mendez, Jocelyn; Carrasco, Jorge; Errázuriz, Germán; Gonzalez, Mónica; Ossa, Juan C.; Maiza, Eduardo; Perez-Bravo, Francisco; Castro, Magdalena; Araya, Magdalena

2017-01-01

HIGHLIGHTS What is already known about this subject?Celiac disease (CD) has a high clinical and histological diversity and the mechanisms underlying this phenomenon remain elusive.H. pylori is a bacterium that chronically infect gastric and duodenal mucosa activating both a Th1/Th17 and T-reg pathways.The role of H. pylori (and the effect of their virulence factors) in CD have not yet completely elucidated.What are the new findings?cagA+ H. pylori strains are associated to milder histological damage in infected CD patients.In active-CD patients the presence of cagA+ H. pylori is associated to an increase in T-reg markers, contrasting with a downregulation in cagA+ infected potential-CD individuals.How might it impact on clinical practice in the foreseeable future?The identification of microbiological factors that could modulate inflammation and clinical expression of CD may be used in the future as preventive strategies or as supplementary treatment in patients that cannot achieve complete remission, contributing to the better care of these patients. Background: Mechanisms underlying the high clinical and histological diversity of celiac disease (CD) remain elusive. Helicobacter pylori (Hp) chronically infects gastric and duodenal mucosa and has been associated with protection against some immune-mediated conditions, but its role (specifically of cagA+ strains) in CD is unclear. Objective: To assess the relationship between gastric Hp infection (cagA+ strains) and duodenal histological damage in patients with CD. Design: Case-control study including patients with active-CD, potential-CD and non-celiac individuals. Clinical presentation, HLA genotype, Hp/cagA gene detection in gastric mucosa, duodenal histology, Foxp3 positive cells and TGF-β expression in duodenal lamina propria were analyzed. Results: We recruited 116 patients, 29 active-CD, 37 potential-CD, and 50 non-CD controls. Hp detection was similar in the three groups (~30–40%), but cagA+ strains were more common in infected potential-CD than in active-CD (10/11 vs. 4/10; p = 0.020) and non-CD (10/20; p = 0.025). Among active-CD patients, Foxp3 positivity was significantly higher in subjects with cagA+ Hp+ compared to cagA- Hp+ (p < 0.01) and Hp- (p < 0.01). In cagA+ Hp+ individuals, Foxp3 positivity was also higher comparing active- to potential-CD (p < 0.01). TGF-β expression in duodenum was similar in active-CD with cagA+ Hp+ compared to Hp- and was significantly downregulated in cagA+ potential-CD subjects compared to other groups. Conclusion: Hp infection rates were similar among individuals with/without CD, but infection with cagA+ strains was associated with milder histological damage in celiac patients infected by Hp, and in active-CD cases with higher expression of T-reg markers. Results suggest that infection by cagA+ Hp may be protective for CD progression, or conversely, that these strains are prone to colonize intestinal mucosa with less severe damage. PMID:28879170

Is dermatitis palmaris sicca an irritant contact dermatitis?

PubMed

Chen, Fu-Juan; Liu, Zhen; Zhou, Ying; Chen, Yong-Hua; Fan, Yi-Ming

2013-01-01

Dermatitis palmaris sicca (DPS) is a common dry-fissured palmar dermatitis in Asian women. It may be an irritant contact dermatitis, but the immunophenotype of the cells in its infiltrate is unknown. The aim of this study was to evaluate the role of inflammatory cells in the pathogenesis of DPS. Patch testing was done in 68 patients with DPS, 87 subjects with hand eczema, and 31 healthy subjects. Immunophenotyping of cutaneous inflammatory cells was performed in 8 patients with DPS, 10 subjects with hand eczema, and 8 healthy individuals. Positive patch rates were higher in patients with DPS and those with hand eczema compared with healthy controls, but strong positive (++ or +++) reactions in DPS were fewer compared with hand eczema. Density of CD3, CD4, CD8, and CD68 cells in skin lesions of DPS and hand eczema was significantly higher than that in normal skin. Sparse CD20 cells were present only in hand eczema. Compared with hand eczema, the number of CD3, CD8, CD68, and dermal CD1a cells decreased, but epidermal CD1a cells and CD4/CD8 ratio increased in DPS. The absolute lack of CD20 cells and relative scarcity of dermal CD8 and CD1a cells in skin lesions might be insufficient to induce contact hypersensitivity, so DPS may be an irritant but not allergic contact dermatitis.

Circulating Endothelial Progenitor Cells Present an Inflammatory Phenotype and Function in Patients With Alcoholic Liver Cirrhosis

PubMed Central

Kaur, Savneet; Sehgal, Rashi; Shastry, Saggere M.; McCaughan, Geoffrey; McGuire, Helen M.; Fazekas St de Groth, Barbara; Sarin, Shiv; Trehanpati, Nirupma; Seth, Devanshi

2018-01-01

Background and Aim: Endothelial progenitor cells (EPCs) have been implicated in liver injury and repair. However, the phenotype and potential of these heterogenous EPCs remain elusive. In particular, their involvement in the pathogenesis of alcoholic liver cirrhosis (ALC) remains unclear. The current study extensively characterized the phenotype and functions of EPCs to understand their role in ALC pathogenesis. Methods: Circulating EPCs were identified as CD34+CD133+CD31+ cells by flow cytometer in ALC patients (n = 7) and healthy controls (HC, n = 7). A comprehensive characterization of circulating EPCs using more than 30 phenotype markers was performed by mass cytometer time of flight (CyTOF) in an independent cohort of age and gender matched ALC patients (n = 4) and controls (n = 5). Ex vivo cultures of circulating EPCs from ALC patients (n = 20) and controls (n = 18) were also tested for their functions, including colony formation, LDL uptake, lectin binding and cytokine secretion (ELISA). Results: Three distinct populations of circulating EPCs (CD34+CD133+CD31+) were identified, classified on their CD45 expression (negative: CD45−; intermediate: CD45int; high: CD45hi). CD45int and CD45hi EPCs significantly increased in ALC patients compared to controls (p-val = 0.006). CyTOF data showed that CD45hi EPCs were distinct from CD45− and CD45int EPCs, with higher expression of T cell and myeloid markers, including CD3, CD4, HLA-DR, and chemokine receptors, CCR2, CCR5, CCR7, and CX3CR1. Similar to circulating EPCs, percentage of CD45hiCD34+CD31+ EPCs in ex-vivo cultures from patients, were significantly higher compared to controls (p < 0.05). Cultured EPCs from patients also showed increased LDL uptake, lectin binding and release of TNF-alpha, RANTES, FGF-2, and VEGF. Conclusions: We report the first extensive characterization of circulating human EPCs with distinct EPC subtypes. Increase in CD45hi EPC subtype in ALC patients with enhanced functions, inflammatory cytokines and angiogenic mediators in patients suggests an inflammatory role for these cells in ALC. PMID:29872403

[An analysis of immunophenotyping of peripheral lymphocytes in adult patients with infectious mononucleosis and chronic active Epstein-Barr virus infection].

PubMed

Xie, J; Wang, H L; Qiu, Z F; Li, T S

2016-06-01

To determine the immunophenotypic features of peripheral lymphocytes in adult patients with Epstein-Barr virus(EBV)-associated infectious mononucleosis(IM) and chronic active EBV infection (CAEBV). Eighteen IM patients, 12 CAEBV patients and 18 healthy donors were included. Lymphocyte subsets including CD3(-)CD19(+) B cells, CD3(-)CD16/56(+) NK cells, CD4(+) and CD8(+) T cells in peripheral blood were measured by flow cytometry. The expression of activation markers (HLA-DR and CD38) on CD8(+) T cells and CD28 expression on T cells were also determined. Kruskal-Wallis H and Mann-Whitney U tests were used to compare variables among groups. IM patients had dramatically increased CD8(+) T cell counts than healthy donors (5.22×10(9)/L vs 0.54×10(9)/L, P<0.001). B cell counts moderately reduced in patients with IM than in healthy donors. No difference was found in absolute CD4(+) T cell and NK cell counts between IM and healthy donors. The levels of HLA-DR and CD38 on CD8(+) T cells significantly increased in IM patients compared with those in healthy controls. The intensity of CD28 on CD8(+) T cells significantly decreased, which was not seen on CD4(+) T cells. The median cell counts of B, NK, CD4(+) T and CD8(+) T subsets in CAEBV patients were 0.02×10(9)/L, 0.06×10(9)/L, 0.26×10(9)/L and 0.21×10(9)/L respectively, which were significantly lower than those in healthy donors (0.22×10(9)/L, 0.38×10(9)/L, 0.78×10(9)/L, 0.54×10(9)/L)and IM patients (0.12×10(9)/L, 0.40×10(9)/L, 0.91×10(9)/L, 5.22×10(9)/L). The positive rates of HLA-DR and CD38 on CD8(+) T cells in CAEBV patients were higher than those in healthy controls, but lower than those in IM patients. The immunophenotypic pattern in adult patients with IM is characterized by a dramatic increase of extensively activated CD8(+) T cells, a moderate reduction of CD19(+) B cells and no significant change of CD4(+) T cells and CD16/56(+) NK cells. CAEBV is featured by an immunosuppression status as demonstrated by significantly decreased B, NK, CD4(+) T and CD8(+) T subsets.

Elevated serum levels of soluble CD30 in patients with atopic dermatitis (AD).

PubMed

Bengtsson, A; Holm, L; Bäck, O; Fransson, J; Scheynius, A

1997-09-01

The immunopathology of AD is still unclear, but evidence for an immune response polarized towards Th2 activity has been provided. The CD30 molecule belongs to the tumour necrosis factor (TNF) receptor family and is expressed on activated T cells with a sustained expression in Th2 cells. This molecule also exists in a soluble form (sCD30). Elevated serum levels of sCD30 have been found in patients with Hodgkin's disease, chronic hepatitis B infection and HIV infection. Studies were undertaken to compare the serum levels of sCD30 in patients with AD (n=49) and healthy non-atopic controls (n=94). The presence of sCD30 was analysed with ELISA. A significantly higher concentration of sCD30 was noted in AD patients, median sCD30 level 29 U/ml (range 1-708 U/ml), compared with healthy non-atopic controls (P<0.001), where the median level was 11 U/ml with a range of 1-1042 U/ml. No correlation was found between sCD30 levels and total serum IgE, or between the AD patients' SCORAD values and concentration of sCD30. sCD30 levels were also analysed in 20 AD patients, which during ketoconazole treatment had improved their clinical scores and reduced their serum IgE and eosinophil cationic protein levels. However, no significant decrease in sCD30 levels was noted after treatment. The results show that patients with AD have elevated levels of sCD30, but without correlation to total serum IgE or disease activity.

Peripheral White Blood Cell Subsets in Metastatic Colorectal Cancer Patients Treated with Cetuximab: The Potential Clinical Relevance.

PubMed

Matić, Ivana Z; Kolundžija, Branka; Damjanović, Ana; Spasić, Jelena; Radosavljević, Davorin; Đorđić Crnogorac, Marija; Grozdanić, Nađa; Juranić, Zorica D

2017-01-01

It was demonstrated that cetuximab-induced tumor regression is based on the effects exerted by immune cells included mainly in the innate immune response. Therefore, the focus of this study was to explore the alterations in the percentages of CD16+, and/or CD56+ lymphocytes, which are comprised of NK cells, and minority of CD56+CD3+ cells, in patients with metastatic colorectal cancer before or 2 months after the treatment with cetuximab-based regimens associated with the response to therapy. The changes in the percentages of lymphocytes and granulocytes in these patients were evaluated as well. We enrolled 50 patients with wild-type KRAS metastatic colorectal cancer. Disease progression was observed in 11/50 patients (non-responders), while other patients achieved partial response or stable disease (responders). Control groups included up to 72 healthy individuals. A significant decrease in the percentages of CD56+ and CD16+CD56+ lymphocytes together with a significant decrease in the percentage of lymphocytes and an increase in the ratio of granulocyte to lymphocyte percentages were observed in patients with metastatic colorectal cancer before therapy, compared with those in the healthy individuals. In contrast to those in the responders, the percentage of CD16+ lymphocytes in the overall white blood cell pool was shown to be significantly decreased in the non-responders, together with a significantly decreased percentage of lymphocytes, a significantly increased percentage of granulocytes, and an increased ratio of granulocyte to lymphocyte percentages before treatment compared with those in the healthy controls. Two months after the initiation of the treatment, significantly decreased percentages of CD16+, CD56+, and CD16+CD56+ lymphocytes were observed in patients, compared with those determined in the healthy controls. The same changes in the amounts of circulating immune cells were also observed in the responder subgroup, but the percentages of CD16+, CD56+, and CD16+CD56+ lymphocytes 2 months after treatment in the non-responder group did not differ significantly in comparison with healthy individuals. Considerable alterations of immune cell percentages observed in patients with metastatic colorectal cancer with disease progression indicate that the assessment of peripheral white blood cell architecture before treatment initiation may be clinically relevant.

Increased concentrations of soluble CD40 ligand platelet in patients with primary antiphospholipidic syndrome.

PubMed

Galicia López, Aida; Olguín Ortega, Lourdes; Saavedra, Miguel A; Méndez Cruz, René; Jimenez Flores, Rafael; García de la Peña, Maximiliano

2013-01-01

To determine the concentrations of sCD40L in patients with PAPS, and establish its association with the number of thrombosis. We included patients with PAPS and healthy controls of the same age and sex. For analysis, patients with PAPS were divided into 2 groups: 1) patients with 1 thrombosis, and 2) patients with >1 thrombosis. Soluble CD40L concentrations were determined by ELISA method. sCD40L concentrations were significantly higher in patients with PAPS compared with the controls (9.72 ng ± 11.23 ng/ml vs. 4.69 ± 4.04 ng/ml) (P=.04) There was no association between serum levels of sCD40L and the number of thrombosis (1 thrombosis: 9.81 ± 9.87 ng/ml vs 9.63 ± 12.75 ng/ml in ≥ 1thrombosis (P=.13). In women with pregnancy and abortions, (13 patients) concentrations of sCD40L were higher than in those patients without a history of abortion (26 patients) but without statically significant difference (12.11 ± 16.46 ng/ml vs. 8.80 ± 8.61 ng/ml) (P=.33). There was no correlation between levels of sCD40L and the total number of thrombosis. Patients with PAPS have higher concentrations of sCD40L compared with healthy subjects, although this is not associated with a greater number of thrombosis. Among patients with PAPS, there is a tendency to higher concentrations of sCD40L in women with pregnancy and history of abortion. Since the platelet is the main cellular source of sCD40L, is possible that this pathway plays a pathogenic role in patients with PAPS. Copyright © 2012 Elsevier España, S.L. All rights reserved.

Expansion in CD39+ CD4+ Immunoregulatory T Cells and Rarity of Th17 Cells in HTLV-1 Infected Patients Is Associated with Neurological Complications

PubMed Central

Hasenkrug, Aaron M.; Bruno, Fernanda R.; Carvalho, Karina I.; Wynn-Williams, Harry; Neto, Walter K.; Sanabani, Sabri S.; Segurado, Aluisio C.; Nixon, Douglas F.; Kallas, Esper G.

2013-01-01

HTLV-1 infection is associated with several inflammatory disorders, including the neurodegenerative condition HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). It is unclear why a minority of infected subjects develops HAM/TSP. CD4+ T cells are the main target of infection and play a pivotal role in regulating immunity to HTLV and are hypothesized to participate in the pathogenesis of HAM/TSP. The CD39 ectonucleotidase receptor is expressed on CD4+ T cells and based on co-expression with CD25, marks T cells with distinct regulatory (CD39+CD25+) and effector (CD39+CD25−) function. Here, we investigated the expression of CD39 on CD4+ T cells from a cohort of HAM/TSP patients, HTLV-1 asymptomatic carriers (AC), and matched uninfected controls. The frequency of CD39+ CD4+ T cells was increased in HTLV-1 infected patients, regardless of clinical status. More importantly, the proportion of the immunostimulatory CD39+CD25− CD4+ T-cell subset was significantly elevated in HAM/TSP patients as compared to AC and phenotypically had lower levels of the immunoinhibitory receptor, PD-1. We saw no difference in the frequency of CD39+CD25+ regulatory (Treg) cells between AC and HAM/TSP patients. However, these cells transition from being anergic to displaying a polyfunctional cytokine response following HTLV-1 infection. CD39−CD25+ T cell subsets predominantly secreted the inflammatory cytokine IL-17. We found that HAM/TSP patients had significantly fewer numbers of IL-17 secreting CD4+ T cells compared to uninfected controls. Taken together, we show that the expression of CD39 is upregulated on CD4+ T cells HAM/TSP patients. This upregulation may play a role in the development of the proinflammatory milieu through pathways both distinct and separate among the different CD39 T cell subsets. CD39 upregulation may therefore serve as a surrogate diagnostic marker of progression and could potentially be a target for interventions to reduce the development of HAM/TSP. PMID:23409198

Therapeutic Efficacy of Autologous Non-Mobilized Enriched Circulating Endothelial Progenitors in Patients With Critical Limb Ischemia　- The SCELTA Trial.

PubMed

Liotta, Francesco; Annunziato, Francesco; Castellani, Sergio; Boddi, Maria; Alterini, Brunetto; Castellini, Giovanni; Mazzanti, Benedetta; Cosmi, Lorenzo; Acquafresca, Manlio; Bartalesi, Filippo; Dilaghi, Beatrice; Dorigo, Walter; Graziani, Gabriele; Bartolozzi, Benedetta; Bellandi, Guido; Carli, Giulia; Bartoloni, Alessandro; Fargion, Aaron; Fassio, Filippo; Fontanari, Paolo; Landini, Giancarlo; Lucente, Eleonora A M; Michelagnoli, Stefano; Orsi Battaglini, Carolina; Panigada, Grazia; Pigozzi, Clara; Querci, Valentina; Santarlasci, Veronica; Parronchi, Paola; Troisi, Nicola; Baggiore, Cristiana; Romagnani, Paola; Mannucci, Edoardo; Saccardi, Riccardo; Pratesi, Carlo; Gensini, Gianfranco; Romagnani, Sergio; Maggi, Enrico

2018-05-25

The therapeutic efficacy of bone marrow mononuclear cells (BM-MNC) autotransplantation in critical limb ischemia (CLI) has been reported. Variable proportions of circulating monocytes express low levels of CD34 (CD14 + CD34 low cells) and behave in vitro as endothelial progenitor cells (EPCs). The aim of the present randomized clinical trial was to compare the safety and therapeutic effects of enriched circulating EPCs (ECEPCs) with BM-MNC administration.Methods and Results:ECEPCs (obtained from non-mobilized peripheral blood by immunomagnetic selection of CD14 + and CD34 + cells) or BM-MNC were injected into the gastrocnemius of the affected limb in 23 and 17 patients, respectively. After a mean of 25.2±18.6-month follow-up, both groups showed significant and progressive improvement in muscle perfusion (primary endpoint), rest pain, consumption of analgesics, pain-free walking distance, wound healing, quality of life, ankle-brachial index, toe-brachial index, and transcutaneous PO 2 . In ECEPC-treated patients, there was a positive correlation between injected CD14 + CD34 low cell counts and the increase in muscle perfusion. The safety profile was comparable between the ECEPC and BM-MNC treatment arms. In both groups, the number of deaths and major amputations was lower compared with eligible untreated patients and historical reference patients. This study supports previous trials showing the efficacy of BM-MNC autotransplantation in CLI patients and demonstrates comparable therapeutic efficacy between BM-MNC and EPEPCs.

CD77 levels over enzyme replacement treatment in Fabry Disease Family (V269M).

PubMed

Pereira, Ester Miranda; Silva, Adalberto Socorro da; Silva, Raimundo Nonato da; Monte Neto, José Tiburcio; Nascimento, Fernando F do; Sousa, Jackeline L M; Costa Filho, Henrique César Saraiva de Arêa Leão; Sales Filho, Herton Luiz Alves; Labilloy, Anatalia; Monte, Semiramis Jamil Hadad do

2018-06-04

Fabry disease (FD) is a disorder caused by mutations in the gene encoding for lysosomal enzyme α-galactosidase A (α-GAL). Reduced α-GAL activity leads to progressive accumulation of globotriaosylceramide (Gb3), also known as CD77. The recent report of increased expression of CD77 in blood cells of patients with FD indicated that this molecule can be used as a potential marker for monitoring enzyme replacement therapy (ERT). The purpose of this study was to evaluate the CD77 levels throughout ERT in FD patients (V269M mutation). We evaluated the fluctuations in PBMC (peripheral blood mononuclear cell) membrane CD77 expression in FD patients undergoing ERT and correlated these levels with those observed in different cell types. A greater CD77 expression was found in phagocytes of patients compared to controls at baseline. Interestingly, the variability in CD77 levels is larger in patients at baseline (340 - 1619 MIF) and after 12 months of ERT (240 - 530 MIF) compared with the control group (131 - 331 MFI). Furthermore, by analyzing the levels of CD77 in phagocytes from patients throughout ERT, we found a constant decrease in CD77 levels. The increased CD77 levels in the phagocytes of Fabry carriers together with the decrease in CD77 levels throughout ERT suggest that measuring CD77 levels in phagocytes is a promising tool for monitoring the response to ERT in FD.

Peripheral CD4+ naïve/memory ratio is an independent predictor of survival in non-small cell lung cancer

PubMed Central

Yang, Peng; Ma, Junhong; Yang, Xin; Li, Wei

2017-01-01

Background To investigate the clinical significance of naïve T cells, memory T cells, CD45RA+CD45RO+ T cells, and naïve/memory ratio in non-small cell lung cancer (NSCLC) patients. Methods Pretreatment peripheral blood samples from 76 NSCLC patients and 28 age- and sex-matched healthy volunteers were collected and tested for immune cells by flow cytometry. We compared the expression of these immune cells between patients and healthy controls and evaluated their predictive roles for survival in NSCLC by cox proportional hazards model. Results Decreased naïve CD4+ T cells, naïve CD8+ T cells, CD4+ naïve/memory ratios and CD4+CD45RA+CD45RO+ T cells, and increased memory CD4+ T cells, were observed in 76 NSCLC patients compared to healthy volunteers. Univariate analysis revealed that elevated CD4+ naïve/memory ratio correlated with prolonged progression-free survival (P=0.013). Multivariate analysis confirmed its predictive role with a hazard ratio of 0.35 (95% confidence interval, 0.19-0.75, P=0.012). Conclusions Peripheral CD4+ naïve/memory ratio can be used as a predictive biomarker in NSCLC patients and used to optimize personalized treatment strategies. PMID:29137371

High serum soluble CD30 does not predict acute rejection in liver transplant patients.

PubMed

Matinlauri, I; Höckerstedt, K; Isoniemi, H

2006-12-01

Increased pre- and posttransplantation values of soluble CD30 (sCD30) have been shown to be associated with acute kidney transplant rejection. We sought to study whether high sCD30 could predict rejection early after liver transplantation. The study population included 54 consecutive liver transplant patients, whose samples were collected before liver transplantation and at discharge, which was at a mean time of 3 weeks after transplantation. During the first 6 months posttransplantation, 22 patients experienced an acute rejection episode. Serum sCD30 concentrations were measured by an enzyme-linked immunoassay; changes in serum sCD30 levels posttransplantation were also expressed as relative values compared with pretransplantation results. Liver patients before transplantation displayed higher serum sCD30 values compared with healthy controls: mean values +/- SD were 93 +/- 58 IU/mL vs 17 +/- 8 IU/mL, respectively. At 3 weeks after transplantation the mean sCD30 concentration in liver transplant patients decreased to 59 +/- 42 IU/mL (P = .005). The mean pretransplantation serum sCD30 value was slightly lower among rejecting vs nonrejecting patients: 78 +/- 43 IU/mL vs 104 +/- 65 IU/mL (P = NS). Posttransplantation values in both groups decreased significantly: 47 +/- 34 IU/mL in patients with rejection (P = .014) vs 69 +/- 45 IU/mL in patients without rejection (P = .012). The relative value at 3 weeks posttransplantation decreased slightly more among patients with vs without rejection (70% vs 88%; NS). No correlation was found between serum sCD30 and anti-HLA class I antibodies or crossmatch positivity. In conclusion, neither pre- nor posttransplantation sCD30 levels were associated with acute rejection in liver transplant patients.

CD4 T lymphocytes from patients with chronic fatigue syndrome have decreased interferon-gamma production and increased sensitivity to dexamethasone.

PubMed

Visser, J; Blauw, B; Hinloopen, B; Brommer, E; de Kloet, E R; Kluft, C; Nagelkerken, L

1998-02-01

A disturbed hypothalamus-pituitary-adrenal gland axis and alterations at the immune system level have been observed in patients with chronic fatigue syndrome (CFS). Glucocorticoids are known to modulate T cell responses; therefore, purified CD4 T cells from CFS patients were studied to determine whether they have an altered sensitivity to dexamethasone (DEX). CD4 T cells from CFS patients produced less interferon-gamma than did cells from controls; by contrast, interleukin-4 production and cell proliferation were comparable. With CD4 T cells from CFS patients (compared with cells from controls), a 10- to 20-fold lower DEX concentration was needed to achieve 50% inhibition of interleukin-4 production and proliferation, indicating an increased sensitivity to DEX in CFS patients. Surprisingly, interferon-gamma production in patients and controls was equally sensitive to DEX. A differential sensitivity of cytokines or CD4 T cell subsets to glucocorticoids might explain an altered immunologic function in CFS patients.

CD44v6 expression in patients with stage II or stage III sporadic colorectal cancer is superior to CD44 expression for predicting progression

PubMed Central

Zhao, LH; Lin, QL; Wei, J; Huai, YL; Wang, KJ; Yan, HY

2015-01-01

Background: Currently, it is difficult to predict the prognosis of patients exhibiting stage II or stage III colorectal cancer (CRC) and to identify those patients most likely to benefit from aggressive treatment. The current study was performed to examine the clinicopathological significance of CD44 and CD44v6 protein expression in these patients. Study design: We retrospectively investigated 187 consecutive patients who underwent surgery with curative intent for stage II to III CRC from 2007 to 2013 in the Beijing Civil Aviation Hospital. CD44 and CD44v6 protein expression levels were determined using immunohistochemistry and compared to the clinicopathological data. Results: Using immunohistochemical detection, CD44 expression was observed in 108 (57.75%) of the CRC patients; and its detection was significantly associated with greater invasion depth, lymph node metastasis, angiolymphatic invasion, and a more advanced pathological tumor-lymph node-metastasis (TNM) stage. CD44v6 expression was observed in 135 (72.19%) of the CRC patients; and its expression was significantly associated with a poorly differentiated histology, greater invasion depth, lymph node metastasis, angiolymphatic invasion, and a more advanced pathological TNM stage. Expression of CD44v6 was higher than that of CD44 in stage II and stage III sporadic CRC. Conclusion: CD44v6 is a more useful marker for predicting a poor prognosis in stage II and stage III sporadic CRC as compared to CD44. PMID:25755763

Prevalence of transfusion-transmitted Chagas Disease among multitransfused patients in Brazil.

PubMed

De Paula, Erich V; Goncales, Neiva S L; Xueref, Serge; Addas-Carvalho, Marcelo; Gilli, Simone C O; Angerami, Rodrigo N; Goncales, Fernando L

2008-01-16

Blood transfusion has always been an important route for Chagas Disease (CD) transmission. The high prevalence of CD in Latin America and its lifelong asymptomatic clinical picture pose a threat for the safety of the blood supply. The outcome of measures designed to improve transfusion safety can be assessed by evaluating the prevalence of CD among multitransfused patients In order to assess the impact of CD control measures on the safety of the blood supply, an observational cross-sectional study was designed to determine the prevalence of CD in 351 highly transfused patients, in which vectorial transmission was excluded. This study compared patients that received transfusion products before (n = 230) and after (n = 121) 1997, when measures to control transfusion-transmitted CD were fully implemented in Brazil. The study group consisted of 351 patients exposed to high numbers of blood products during their lifetime (median number of units transfused = 51, range 10-2086). A higher prevalence of transfusion-transmitted CD (1.30%) was observed among multitransfused patients that received their first transfusion before 1997, compared with no cases of transfusion-transmitted CD among multitransfused patients transfused after that year. The magnitude of the exposure to blood products was similar among both groups (mean number of units transfused per year of exposure = 25.00 +/- 26.46 and 23.99 +/- 30.58 respectively; P = 0.75, Mann-Whitney test). Multiple initiatives aimed to control vector and parental transmission of CD can significantly decrease transfusion-transmitted CD in Brazil. Our data suggest that mandatory donor screening for CD represents the most important measure to interrupt transmission of CD by blood transfusions.

Persistent low thymic activity and non-cardiac mortality in children with chromosome 22q11·2 microdeletion and partial DiGeorge syndrome

PubMed Central

Eberle, P; Berger, C; Junge, S; Dougoud, S; Büchel, E Valsangiacomo; Riegel, M; Schinzel, A; Seger, R; Güngör, T

2009-01-01

A subgroup of patients with 22q11·2 microdeletion and partial DiGeorge syndrome (pDGS) appears to be susceptible to non-cardiac mortality (NCM) despite sufficient overall CD4+ T cells. To detect these patients, 20 newborns with 22q11·2 microdeletion and congenital heart disease were followed prospectively for 6 years. Besides detailed clinical assessment, longitudinal monitoring of naive CD4+ and cytotoxic CD3+CD8+ T cells (CTL) was performed. To monitor thymic activity, we analysed naive platelet endothelial cell adhesion molecule-1 (CD31+) expressing CD45RA+RO−CD4+ cells containing high numbers of T cell receptor excision circle (TREC)-bearing lymphocytes and compared them with normal values of healthy children (n = 75). Comparing two age periods, low overall CD4+ and naive CD4+ T cell numbers were observed in 65%/75%, respectively, of patients in period A (< 1 year) declining to 22%/50%, respectively, of patients in period B (> 1/< 7 years). The percentage of patients with low CTLs (< P10) remained robust until school age (period A: 60%; period B: 50%). Low numbers of CTLs were associated with abnormally low naive CD45RA+RO−CD4+ T cells. A high-risk (HR) group (n = 11) and a standard-risk (SR) (n = 9) group were identified. HR patients were characterized by low numbers of both naive CD4+ and CTLs and were prone to lethal infectious and lymphoproliferative complications (NCM: four of 11; cardiac mortality: one of 11) while SR patients were not (NCM: none of nine; cardiac mortality: two of nine). Naive CD31+CD45RA+RO−CD4+, naive CD45RA+RO−CD4+ T cells as well as TRECs/106 mononuclear cells were abnormally low in HR and normal in SR patients. Longitudinal monitoring of naive CD4+ and cytotoxic T cells may help to discriminate pDGS patients at increased risk for NCM. PMID:19040613

Increased prevalence of anxiety-associated personality traits in patients with Cushing's disease: a cross-sectional study.

PubMed

Dimopoulou, C; Ising, M; Pfister, H; Schopohl, J; Stalla, G K; Sievers, C

2013-01-01

Chronic hypercortisolism in Cushing's disease (CD) has been suggested to contribute to an altered personality profile in these patients. We aimed to test this hypothesis and attempted to determine the effects of disease- and treatment-related factors that might moderate an altered personality in CD. We assessed 50 patients with CD (74% biochemically controlled) and compared them to 60 patients with non-functioning pituitary adenomas (NFPA) and 100 age- and gender-matched mentally healthy controls. Personality was measured by two standardized personality questionnaires, TPQ (Cloninger personality questionnaire) and EPQ-RK (Eysenck personality questionnaire-RK). Compared to mentally healthy controls, CD patients reported significantly less novelty-seeking behaviour, including less exploratory excitability and less extravagance. On harm avoidant subscales, they presented with more anticipatory worries and pessimism, higher fear of uncertainty, shyness with strangers, fatigability and asthenia. Moreover, CD patients appeared to be less extraverted, more neurotic and socially desirable. CD patients differed from NFPA patients in terms of higher neuroticism scores, and NFPA patients did not show altered novelty-seeking behaviour or extraversion. In the subgroup analysis, CD patients with persistent hypercortisolism displayed significantly higher fear of uncertainty, fatigability and asthenia, indicating high harm avoidance in total, than those in biochemical remission. Patients with CD showed a distinct pattern of personality traits associated with high anxiety in combination with traits of low externalizing behaviour. Such personality changes should be taken into account in the diagnosis and treatment of CD patients, as they might interfere with the patient-physician communication and/or challenge the patients' social and psychological functioning. Copyright © 2012 S. Karger AG, Basel.

Metformin plus oral contraceptive may decrease plasma sCD40 ligand in women with PCOS patients.

PubMed

Kebapcilar, Levent; Kebapcilar, Ayse Gul; Bilgir, Oktay; Taner, Cuneyt Eftal; Bozkaya, Giray; Yildiz, Yasar; Sari, Ismail

2011-02-01

To evaluate sCD40L levels in women with polycystic ovary syndrome (PCOS) who use combination therapy with metformin and oral contraceptives. Total of 60 patients with PCOS was studied to evaluate and compare with a non-PCOS group consisting of 30 subjects. A low-dose oral contraceptive containing ethinyl oestradiol-cyproterone acetate (EE/CA) and metformin (M; 850 mg metformin twice a day) were given for three cycles. Plasma sCD40L was measured before and after the treatment of 3 months. At baseline, the sCD40L levels of the patients with PCOS was significantly higher than those of control subjects (3.1 ± 2.0 vs. 2.05 ± 1.0, respectively; p=0.002). An average of 3 months of EE/CA-M therapy induced a significant decrease of sCD40L levels in the PCOS group (3.1 ± 2.0 vs. 2.5 ± 1.0; p=0.026). After having treated patients with PCOS, the sCD40L level was not completely normalised when compared to the healthy controls (2.5 ± 1.0 vs. 2.05 ± 1.0; p=0.039). PCOS is associated with elevated levels of sCD40L. Adding metformin therapy to EE/CA may decrease sCD40L levels in women PCOS. However, after the treatment for PCOS subjects, the sCD40L was not completely normalised when compared patients to healthy controls.

Impairment of Circulating CD4⁺CD25⁺GARP⁺ regulatory T cells in patients with acute coronary syndrome.

PubMed

Meng, Kai; Zhang, Wei; Zhong, Yucheng; Mao, Xiaobo; Lin, Yingzhong; Huang, Ying; Lang, Mingjian; Peng, Yudong; Zhu, Zhengfeng; Liu, Yuzhou; Zhao, Xiaoqi; Yu, Kunwu; Wu, Bangwei; Ji, Qingwei; Zeng, Qiutang

2014-01-01

Atherosclerosis (AS) is an inflammatory and immune disease. Regulatory T cells (Tregs) suppress the activation of T cells and have been shown to play a protective role during the pathogenesis of AS. However, specific markers for Tregs are lacking. Recently, glycoprotein A repetitions predominant (GARP) was discovered as a specific marker of activated Tregs, and we therefore utilized GARP as a specific surface marker for Tregs in the current study. To assess whether GARP(+) Tregs are downregulated in patients with acute coronary syndrome (ACS), we examined CD4(+)CD25(+)GARP(+) T cell frequencies as well as their associated cytokines and suppressive function. Additionally, we compared GARP expression to that of FOXP3, which may be more sensitive as a marker of activated Tregs in patients with ACS. Patients with ACS demonstrated a significant decrease in circulating CD4(+)CD25(+)GARP(+) Tregs. Moreover, the suppressive function of Tregs and levels of related cytokines were also impaired in ACS patients compared to those with stable angina (SA) or normal coronary artery (NCA). Additionally, after TCR stimulation, peripheral blood mononuclear cells (PBMCs) from patients with ACS exhibited a decrease in CD4(+)CD25(+)GARP(+) Tregs. These fnding indicate that circulating CD4(+)CD25(+)GARP(+) Tregs are impaired in patients withACS. Thus, targeting GARP may promote the protective function of Tregs in ACS. © 2014 S. Karger AG, Basel.

Gluten ataxia is better classified as non-celiac gluten sensitivity than as celiac disease: a comparative clinical study.

PubMed

Rodrigo, Luis; Hernández-Lahoz, Carlos; Lauret, Eugenia; Rodriguez-Peláez, Maria; Soucek, Miroslav; Ciccocioppo, Rachele; Kruzliak, Peter

2016-04-01

Gluten ataxia (GA) has customarily been considered to be the main neurological manifestation of celiac disease (CD). In recent years, the condition of non-celiac gluten sensitivity (NCGS) has been defined, which includes some patients who are not considered "true celiacs." We performed a comparative clinicopathological study of these three entities. We studied 31 GA, 48 CD and 37 NCGS patients, prospectively in the same center for a period of 7 years. The protocol study included two serological determinations for gluten sensitivity [anti-gliadin IgA and IgG (AGA) and anti-tissue transglutaminase IgA (TG) antibodies], HLA-DQ2 typing, and duodenal histological assessment. Demographics and investigative findings were compared. Females were 55 % in GA, 75 % in CD (p < 0.001), and 47 % in NCGS (N.S.). GA patients were older (59 ± 14 years) than CD (43 ± 13 years) and NCGS (41 ± 8 years) groups (p < 0.001). AGA positivity was higher in GA (100 %) than in CD (48 %) groups (p < 0.001), but similar to NCGS patients (89 %; N.S.); TG positivity was lower in GA (3.2 %) than in CD (33.3 %; p < 0.001), but similar to NCGS (2.7 %; N.S.). DQ2 (+) was lower in GA (32.2 %) than in CD (89.6 %; p < 0.001), but similar to NCGS (29.7 %; N.S.). Lymphocytic enteritis (Marsh type 1) was lower in GA (9.6 %) than in CD (66.7 %; p < 0.001), but similar to NCGS (10.8 %; N.S.). The other gluten sensitivity-related characteristics measured were different to CD patients, but very close to NCGS. We conclude that GA patients are better classified within the NCGS group, than within CD.

Clinical features of cytotoxic CD8+ T-lymphocyte deficiency in chronic rhinosinusitis patients: a demographic and functional study.

PubMed

Gabra, Nathalie; Alromaih, Saud; Endam, Leandra Mfuna; Brito, Rose Marie; Larivière, Françoise; Al-Mot, Sawsan; LeDeist, Françoise; Desrosiers, Martin

2014-06-01

Identification of Staphylococcus aureus intracellularly in chronic rhinosinusitis (CRS) suggests an underlying cellular immunodeficiency. Supporting this, we have previously reported low CD8+ (cytotoxic) T-lymphocyte levels in a subpopulation of CRS patients and identified polymorphisms in the CD8A gene associated with CRS. In order to better understand the role of low CD8+ in CRS, we wished to determine the phenotype for CRS/Low CD8+ in comparison to that of conventional CRS. Sixty-seven low CD8+ CRS patients identified during investigation of CRS were compared for demographics, disease evolution, and bacteriology on endoscopic culture were compared with an existing population of 480 patients with CRS with nasal polyposis previously recruited for genetic association studies. Mean level of CD8+ in the CRS/Low CD8+ population was 0.15 × 10(9)/L (range, 0.20-1.5 × 10(9)/L). There was no difference between both groups in terms of history of allergy, asthma, eczema, acetylsalicylic acid (ASA) intolerance or smoking. The bacteriology was similar between both groups (S. aureus: CRS/Low CD8+: 35%; CRS 32%, p = 0.643). Evolution of disease was somewhat milder in CRS/Low CD8+, with fewer patients requiring surgery, and first surgery performed at a more advanced age. However, antibiotic use was higher in CRS/Low CD8+. Subgroup analysis restricted to CRS with nasal polyposis (CRSwNP)/Low CD8 or CRS without nasal polyposis (CRSsNP)/Low CD8 phenotypes did not substantially alter these results. Low CD8+ levels are often identified in CRS patients; however, these patients have disease remarkably similar to those with conventional CRS. This suggests that immune deficiency, whether systemic or locally mediated, is well tolerated and may be present in other forms in CRS. CRS patients with low CD8+ levels may possibly require antibacterial therapies as part of ongoing management. © 2014 ARS-AAOA, LLC.

Characterization of lymphopenia in patients with MS treated with dimethyl fumarate and fingolimod.

PubMed

Nakhaei-Nejad, Maryam; Barilla, David; Lee, Chieh-Hsin; Blevins, Gregg; Giuliani, Fabrizio

2018-03-01

Lymphopenia is a common occurrence of disease-modifying therapies (DMTs) for relapsing-remitting MS (RRMS). The aim of this study was to dissect the prevalence of various lymphocyte subsets in patients with RRMS treated with 2 DMTs commonly associated with lymphopenia, dimethyl fumarate (DMF), and fingolimod (FTY). Multicolor flow cytometry and multiplex assays were used to identify up to 50 lymphocyte subpopulations and to examine the expression of multiple cytokines in selected patients. We compared patients untreated (NT) or treated with FTY or DMF who did (DMF-L) or did not (DMF-N) develop lymphopenia. All FTY patients developed lymphopenia in both T-cell and B-cell compartments. CD41 T cells were more affected by this treatment than CD81 cells. In the B-cell compartment, the CD271IgD2 subpopulation was reduced. T cells but not B cells were significantly reduced in DMF-L. However, within the B cells, CD271 cells were significantly lower. Both CD41 and CD81 subpopulations were reduced in DMF-L. Within the remaining CD41 and CD81 compartments, there was an expansion of the naive subpopulation and a reduction of the effector memory subpopulation. Unactivated lymphocyte from DMF-L patients had significantly higher levels of interferon-γ, interleukin (IL)-12, IL-2, IL-4, IL-6, and IL-1β compared with DMF-N. In plasma, TNFβ was significantly higher in DMF-N and DMF-L compared with NT, whereas CCL17 was significantly higher in DMF-L compared with NT and DMF-N. This study shows that different treatments can target different lymphocyte compartments and suggests that lymphopenia can induce compensatory mechanisms to maintain immune homeostasis.

Characterization of lymphopenia in patients with MS treated with dimethyl fumarate and fingolimod

PubMed Central

Nakhaei-Nejad, Maryam; Barilla, David; Lee, Chieh-Hsin; Blevins, Gregg

2017-01-01

Objective: Lymphopenia is a common occurrence of disease-modifying therapies (DMTs) for relapsing-remitting MS (RRMS). The aim of this study was to dissect the prevalence of various lymphocyte subsets in patients with RRMS treated with 2 DMTs commonly associated with lymphopenia, dimethyl fumarate (DMF), and fingolimod (FTY). Methods: Multicolor flow cytometry and multiplex assays were used to identify up to 50 lymphocyte subpopulations and to examine the expression of multiple cytokines in selected patients. We compared patients untreated (NT) or treated with FTY or DMF who did (DMF-L) or did not (DMF-N) develop lymphopenia. Results: All FTY patients developed lymphopenia in both T-cell and B-cell compartments. CD41 T cells were more affected by this treatment than CD81 cells. In the B-cell compartment, the CD271IgD2 subpopulation was reduced. T cells but not B cells were significantly reduced in DMF-L. However, within the B cells, CD271 cells were significantly lower. Both CD41 and CD81 subpopulations were reduced in DMF-L. Within the remaining CD41 and CD81 compartments, there was an expansion of the naive subpopulation and a reduction of the effector memory subpopulation. Unactivated lymphocyte from DMF-L patients had significantly higher levels of interferon-γ, interleukin (IL)-12, IL-2, IL-4, IL-6, and IL-1β compared with DMF-N. In plasma, TNFβ was significantly higher in DMF-N and DMF-L compared with NT, whereas CCL17 was significantly higher in DMF-L compared with NT and DMF-N. Conclusions: This study shows that different treatments can target different lymphocyte compartments and suggests that lymphopenia can induce compensatory mechanisms to maintain immune homeostasis. PMID:29296636

CD133+ cells derived from skeletal muscles of Duchenne muscular dystrophy patients have a compromised myogenic and muscle regenerative capability.

PubMed

Meng, Jinhong; Muntoni, Francesco; Morgan, Jennifer

2018-05-12

Cell-mediated gene therapy is a possible means to treat muscular dystrophies like Duchenne muscular dystrophy. Autologous patient stem cells can be genetically-corrected and transplanted back into the patient, without causing immunorejection problems. Regenerated muscle fibres derived from these cells will express the missing dystrophin protein, thus improving muscle function. CD133+ cells derived from normal human skeletal muscle contribute to regenerated muscle fibres and form muscle stem cells after their intra-muscular transplantation into an immunodeficient mouse model. But it is not known whether CD133+ cells derived from DMD patient muscles have compromised muscle regenerative function. To test this, we compared CD133+ cells derived from DMD and normal human muscles. DMD CD133+ cells had a reduced capacity to undergo myogenic differentiation in vitro compared with CD133+ cells derived from normal muscle. In contrast to CD133+ cells derived from normal human muscle, those derived from DMD muscle formed no satellite cells and gave rise to significantly fewer muscle fibres of donor origin, after their intra-muscular transplantation into an immunodeficient, non-dystrophic, mouse muscle. DMD CD133+ cells gave rise to more clones of smaller size and more clones that were less myogenic than did CD133+ cells derived from normal muscle. The heterogeneity of the progeny of CD133+ cells, combined with the reduced proliferation and myogenicity of DMD compared to normal CD133+ cells, may explain the reduced regenerative capacity of DMD CD133+ cells. Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.

CD4+  CD25+  GARP+ regulatory T cells display a compromised suppressive function in patients with dilated cardiomyopathy.

PubMed

Wei, Yuzhen; Yu, Kunwu; Wei, Hui; Su, Xin; Zhu, Ruirui; Shi, Huairui; Sun, Haitao; Luo, Quan; Xu, Wenbin; Xiao, Junhui; Zhong, Yucheng; Zeng, Qiutang

2017-07-01

Dilated cardiomyopathy (DCM) is a lethal inflammatory heart disease and closely connected with dysfunction of the immune system. Glycoprotein A repetitions predominant (GARP) expressed on activated CD4 + T cells with suppressive activity has been established. This study aimed to investigate the frequency and function of circulating CD4 +  CD25 +  GARP + regulatory T (Treg) cells in DCM. Forty-five DCM patients and 46 controls were enrolled in this study. There was a significant increase in peripheral T helper type 1 (Th1) and Th17 number and their related cytokines [interferon-γ (IFN-γ), interleukin (IL-17)], and an obvious decrease in Treg number, transforming growth factor-β 1 (TGF-β 1 ) levels and the expression of forkhead box P3 (FOXP3) and GARP in patients with DCM compared with controls. In addition, the suppressive function of CD4 +  CD25 +  GARP + Treg cells was impaired in DCM patients upon T-cell receptor stimulation detected using CFSE dye. Lower level of TGF-β 1 and higher levels of IFN-γ and IL-17 detected using ELISA were found in supernatants of the cultured CD4 +  CD25 +  GARP + Treg cells in DCM patients compared with controls. Together, our results indicate that CD4 +  CD25 +  GARP + Treg cells are defective in DCM patients and GARP seems to be a better molecular definition of the regulatory phenotype. Therefore, it might be an attractive stategy to pay more attention to GARP in DCM patients. © 2017 John Wiley & Sons Ltd.

The impact of mode of delivery on outcomes in patients with perianal Crohn's disease

PubMed Central

Cheng, Alice G; Oxford, Emily C; Sauk, Jenny; Nguyen, Deanna D; Yajnik, Vijay; Friedman, Sonia; Ananthakrishnan, Ashwin N

2014-01-01

Introduction Crohn's disease (CD) often affects women during the reproductive years. While several studies have examined the impact of pregnancy on luminal disease, limited literature exists in those with perianal CD. Decision regarding mode of delivery is a unique challenge in such patients due to concerns regarding the effect of pelvic floor trauma during delivery on pre-existing perianal involvement. Methods We performed a retrospective chart review of CD patients with established perianal disease undergoing either vaginal delivery or Caesarean section (C-section) at our institutions. We examined the occurrence of symptomatic perianal disease flares within 5 years after delivery in such women compared to non-pregnant CD controls. We also compared the occurrence of such flares between the two modes of delivery in women with established perianal CD. Results We identified 61 pregnant CD patients with established perianal disease (11 vaginal delivery, 50 via C-section) and 61 non-pregnant CD controls with perianal disease. One-third of the C-sections were primarily for obstetric indications. Six of the vaginal deliveries were complicated. Approximately 36% of cases had a symptomatic perianal flare within 1 year after delivery. This was similar across both modes of delivery (p=0.53), and similar to non-pregnant CD patients. There was no difference in the rates of perianal surgical intervention or luminal disease flares in our population based on mode of delivery, or between pregnant CD patients and non-pregnant CD controls. Conclusion We observed no difference in risk of symptomatic perianal flares in patients with established perianal CD delivering vaginally or via C-section. PMID:24918322

Comparative Peripheral Blood T Cells Analysis Between Adult Deceased Donor Liver Transplantation (DDLT) and Living Donor Liver Transplantation (LDLT).

PubMed

Kim, Jong Man; Kwon, Choon Hyuck David; Joh, Jae-Won; Choi, Gyu-Seong; Kang, Eun-Suk; Lee, Suk-Koo

2017-08-08

BACKGROUND T lymphocytes are an essential component of allograft rejection and tolerance. The aim of the present study was to analyze and compare the characteristics of T cell subsets in patients who underwent deceased donor liver transplantation (DDLT) versus living donor liver transplantation (LDLT). MATERIAL AND METHODS Between April 2013 and June 2014, 64 patients underwent adult liver transplantation. The distribution of peripheral blood T lymphocyte subsets before transplantation and at 4, 8, 12, and 24 weeks post-transplantation were monitored serially. RESULTS In the serial peripheral blood samples, the absolute CD3+ T cell counts in the LDLT group were higher than those in the DDLT group (p=0.037). The CD4+, CD8+, CD4/CD8, Vδ1, Vδ2, and γδ T cell counts did not change significantly over time in either group. The Vδ1/Vδ2 ratio was higher in patients with cytomegalovirus (CMV) infection than in patients without CMV infection (0.12 versus 0.26; p=0.033). The median absolute CD3+ and CD8+ T cell counts in patients with biopsy-proven acute rejection (BPAR) were 884 (range, 305-1,320) and 316 (range, 271-1,077), respectively, whereas they were 320 (range, 8-1,167) and 257 (range, 58-1,472) in patients without BPAR. The absolute CD3+ and CD8 T cell counts were higher in patients with BPAR than in patients without BPAR (p=0.007 and p=0.039, respectively). CONCLUSIONS With the exception of CD3+ T cells, T cell populations did not differ significantly between patients who received DDLT versus LDLT. In liver transplantation patients, CMV infection and BPAR were closely associated with T cell population changes.

Decreased levels of serum omentin-1 in patients with inflammatory bowel disease.

PubMed

Yin, Jian; Hou, Peng; Wu, Zhiqiang; Nie, Yanxiao

2015-01-10

Inflammation is involved in the mechanism of inflammatory bowel disease (IBD). Omentin, a newly discovered adipokine, is thought to play an anti-inflammatory role. This study aimed to determine whether serum levels of omentin-1 are associated with the presence and disease activity of IBD. This study consisted of 192 patients with IBD: 100 with Crohn's disease [CD], 92 with ulcerative colitis [UC], and 104 healthy subjects. Serum levels of omentin-1 were measured using enzyme-linked immunosorbent assay (ELISA). Serum omentin-1 levels were significantly decreased in CD and UC patients compared with healthy controls. Multivariable logistic regression analysis revealed that serum omentin-1 levels were inversely associated with the presence of CD and UC. Active CD and UC patients both had significantly decreased levels of serum omentin-1 compared with inactive CD and UC patients. In both CD and UC patients, serum omentin-1 levels were significantly associated with decreased levels of body mass index (BMI) and C-reactive protein (CRP). Decreased serum omentin-1 levels could be considered as an independent predicting marker of the presence and disease activity of IBD.

Expansion and productive HIV-1 infection of Foxp3 positive CD4 T cells at pleural sites of HIV/TB co-infection

PubMed Central

Hirsch, Christina S; Baseke, Joy; Kafuluma, John Lusiba; Nserko, Mary; Mayanja-Kizza, Harriet; Toossi, Zahra

2016-01-01

Background CD4 T-cells expressing Foxp3 are expanded systemically during active tuberculosis (TB) regardless of HIV-1 co-infection. Foxp3+ CD4 T cells are targets of HIV-1 infection. However, expansion of HIV-1 infected Foxp3+ CD4 T cells at sites of HIV/TB co-infection, and whether they contribute to promotion of HIV-1 viral activity is not known. Methods Pleural fluid mononuclear cells (PFMC) from HIV/TB co-infected patients with pleural TB were characterized by immune-staining and FACS analysis for surface markers CD4, CD127, CCR5, CXCR4, HLA-DR and intracellular expression of Foxp3, HIVp24, IFN-γ and Bcl-2. Whole PFMC and bead separated CD4+CD25+CD127− T cells were assessed for HIV-1 LTR strong stop (SS) DNA by real-time PCR, which represents viral DNA post cell entry and initiation of reverse transcription. Results High numbers of HIV-1 p24 positive Foxp3+ and Foxp3+CD127− CD4 T cells were identified in PFMC from HIV/TB co-infected subjects. CD4+Foxp3+CD127− T cells displayed high expression of the cellular activation marker, HLA-DR. Further, expression of the HIV-1 co-receptors, CCR5 and CXCR4, were higher on CD4+Foxp3+T cells compared to CD4+Foxp3− T cells. Purified CD4+CD25+CD127− T cells isolated from PFMC of HIV/TB co-infected patients, were over 90% CD4+Foxp3+T cells, and exhibited higher HIV-1 SS DNA as compared to whole PFMC, and as compared to CD4+CD25+CD127− T cells from an HIV-infected subject with pleural mesothelioma. HIV-1 p24+ Foxp3+ CD4+T cells from HIV/TB patients higher in Bcl-2 expression as compared to both HIV-1 p24+ Foxp3− CD4 T cells, and Foxp3+ CD4+T cells without HIV-p24 expression. Conclusion Foxp3+ CD4 T cells in PFMC from HIV/TB co-infected subjects are predisposed to productive HIV-1 infection and have survival advantage as compared to Foxp3 negative CD4 T cells. PMID:28124031

Human leukocyte antigen genetics and clinical features of self-treated patients on a gluten-free diet.

PubMed

Coburn, John A; Vande Voort, Jennifer L; Lahr, Brian D; Van Dyke, Carol T; Kroning, Cynthia M; Wu, Tsung-Teh; Gandhi, Manish J; Murray, Joseph A

2013-01-01

Increasingly, people start a gluten-free diet (GFD) without a clear celiac disease (CD) diagnosis. Human leukocyte antigen (HLA) genotyping is useful in ruling out CD in patients with equivocal results of serologic testing or small-bowel biopsy (SBB), but its utility and the clinical features of patients on self-treated GFD (ST-GFD) are largely unknown. Retrospective study of single tertiary care center cohort compared 137 patients on ST-GFD and 443 patients with well-defined CD. We compared HLA genotype, symptoms, serologic and SBB results, and response to GFD between the 2 groups. Analysis used univariate logistic regression modeling, adjusted for age and sex. Patients with ST-GFD presented more often with diarrhea (P<0.001), abdominal distention (P<0.001), flatulence (P=0.002), cramping (P=0.02), itchy skin (P=0.02), oral inflammation (P=0.04), and constipation (P=0.01) and less often with anemia (P<0.001) or malaise (P=0.02) than CD patients. In addition, 41% did not carry DQ2.5 and DQ8 versus 6% of CD patients (P<0.001). Only 2% of ST-GFD patients had SBB clearly consistent with CD. Family history of CD showed no difference between groups (P=0.77). Although CD patients had a statistically higher rate of GFD benefit, both groups had a high responsiveness rate (98% vs. 94%; P=0.03). HLA genotyping is useful in evaluating patients on an ST-GFD. Although confirmed CD is rare in self-treated patients, most still report benefit from GFD regardless of DQ2 and DQ8 status. Nonceliac gluten sensitivity may play a role.

Persistent high plasma levels of sCD163 and sCD14 in adult patients with measles virus infection.

PubMed

Mascia, Claudia; Pozzetto, Irene; Kertusha, Blerta; Marocco, Raffaella; Del Borgo, Cosmo; Tieghi, Tiziana; Vita, Serena; Savinelli, Stefano; Iannetta, Marco; Vullo, Vincenzo; Lichtner, Miriam; Mastroianni, Claudio Maria

2018-01-01

Measles is an infectious disease that represents a serious public health problem worldwide, being associated with increased susceptibility to secondary infections, especially in the respiratory and gastrointestinal tracts. The aim of this study was to evaluate sCD163 and sCD14 levels in measles virus (MV) infected patients, as markers of immune activation, in order to better understand their role in the pathogenesis of the disease. TNF-α plasma levels were also evaluated. sCD163, sCD14 and TNF-α were measured by ELISA in plasma samples of 27 MV infected patients and 27 healthy donors (HD) included as controls. At the time of hospital admission, sCD163 and sCD14 levels were significantly higher in MV infected patients than in HD, while a decrease in TNF-α levels were found even if without statistical significance. sCD163 and sCD14 levels were significantly decreased after two months from acute infection compared to hospital admission although they remained significantly higher compared to HD. TNF-α levels increased significantly during the follow-up period. Considering clinical parameters, sCD163 levels positively correlated with aspartate aminotransferase, white blood cell count and neutrophils rate, while negatively correlated with the lymphocyte percentage. sCD14 levels positively correlated with the neutrophil and lymphocyte percentages. These results indicate that, despite the resolution of symptoms, an important macrophage/monocyte activation persists in measles patients, even after two months from infection.

Prevalence of transfusion-transmitted Chagas disease among multitransfused patients in Brazil

PubMed Central

De Paula, Erich V; Goncales, Neiva SL; Xueref, Serge; Addas-Carvalho, Marcelo; Gilli, Simone CO; Angerami, Rodrigo N; Goncales, Fernando L

2008-01-01

Background Blood transfusion has always been an important route for Chagas Disease (CD) transmission. The high prevalence of CD in Latin America and its lifelong asymptomatic clinical picture pose a threat for the safety of the blood supply. The outcome of measures designed to improve transfusion safety can be assessed by evaluating the prevalence of CD among multitransfused patients Methods In order to assess the impact of CD control measures on the safety of the blood supply, an observational cross-sectional study was designed to determine the prevalence of CD in 351 highly transfused patients, in which vectorial transmission was excluded. This study compared patients that received transfusion products before (n = 230) and after (n = 121) 1997, when measures to control transfusion-transmitted CD were fully implemented in Brazil. Results The study group consisted of 351 patients exposed to high numbers of blood products during their lifetime (median number of units transfused = 51, range 10–2086). A higher prevalence of transfusion-transmitted CD (1.30%) was observed among multitransfused patients that received their first transfusion before 1997, compared with no cases of transfusion-transmitted CD among multitransfused patients transfused after that year. The magnitude of the exposure to blood products was similar among both groups (mean number of units transfused per year of exposure = 25.00 ± 26.46 and 23.99 ± 30.58 respectively; P = 0.75, Mann-Whitney test). Conclusion Multiple initiatives aimed to control vector and parental transmission of CD can significantly decrease transfusion-transmitted CD in Brazil. Our data suggest that mandatory donor screening for CD represents the most important measure to interrupt transmission of CD by blood transfusions. PMID:18199334

Role of CD81 and CD58 in minimal residual disease detection in pediatric B lymphoblastic leukemia.

PubMed

Tsitsikov, E; Harris, M H; Silverman, L B; Sallan, S E; Weinberg, O K

2018-06-01

Minimal residual disease (MRD) in B lymphoblastic leukemia has been demonstrated to be a powerful predictor of clinical outcome in numerous studies in both children and adults. In this study, we evaluated 86 pediatric patients with both diagnostic and remission flow cytometry studies and compared expression of CD81, CD58, CD19, CD34, CD20, and CD38 in the detection of MRD. We evaluated 86 patients with B lymphoblastic leukemia who had both diagnostic studies and remission studies for the presence of MRD using multicolor flow cytometry. We established our detection limit for identifying abnormal lymphoblasts using serial dilutions. We also compared flow cytometry findings with molecular MRD detection in a subset of patients. We found that we can resolve differences between hematogones and lymphoblasts in 85 of 86 cases using a combination of CD45, CD19, CD34, CD10, CD20, CD38, CD58, and CD81. Our detection limit using flow cytometry is 0.002% for detecting a population of abnormal B lymphoblasts. Comparison with MRD assessment by molecular methods showed a high concordance rate with flow cytometry findings. Our study highlights importance of using multiple markers to detect MRD in B lymphoblastic leukemia. Our findings indicate that including both CD58 and CD81 markers in addition to CD19, CD34, CD20, CD38, and CD10 are helpful in MRD detection by flow cytometry. © 2018 John Wiley & Sons Ltd.

Expression of CD163 in the liver of patients with viral hepatitis.

PubMed

Hiraoka, Atsushi; Horiike, Norio; Akbar, Sk Md Fazle; Michitaka, Kojiro; Matsuyama, Takami; Onji, Morikazu

2005-01-01

CD163 is a marker of activated macrophages, and increased levels of soluble CD163 have been detected in sera obtained from patients with hepatitis. The aim of this study was to detect the expression of CD163 in the liver from patients with viral hepatitis. Frozen sections of liver specimens were obtained from 5 patients with acute viral hepatitis (AH) and from 23 patients with chronic viral hepatitis (CH). The expression of CD163 in the liver was determined immunohistochemically using monoclonal antibody to human CD163. Double immunostaining was done to assess those cell types that express CD163 in the liver. The frequencies of CD163-positive cells were significantly higher both in the portal areas and in the hepatic lobules in the liver of patients with AH compared to those with CH (p < 0.05). Double immunostaining revealed that most of the CD163-positive cells were macrophages and Kupffer cells, because they expressed CD68. The expression of CD163 was very low in endothelial cells and liver stellate cells. This study shows that macrophages are activated in hepatitis liver.

Influence of uridine diphosphate glucuronosyltransferase inducers and inhibitors on the plasma lamotrigine concentration in pediatric patients with refractory epilepsy.

PubMed

Yamamoto, Yoshiaki; Takahashi, Yukitoshi; Imai, Katsumi; Ikeda, Hiroko; Takahashi, Masaaki; Nakai, Masahiko; Inoue, Yushi; Kagawa, Yoshiyuki

2015-06-01

This study evaluated the influence of concomitant antiepileptic drugs (AEDs) on the plasma concentration of lamotrigine (LTG) in pediatric patients with epilepsy. We retrospectively reviewed 1653 plasma samples from 709 patients (aged 6 months to 16 years) and compared the concentration-to-dose ratio (CD ratio) of LTG among different AED regimens. The median CD ratio of patients receiving LTG monotherapy was 1.25 μg/mL/mg/kg. In patients receiving LTG plus VPA, the CD ratio was increased by about 140%. The CD ratio was elevated from a low VPA concentration (<40 μg/mL) and the increase was VPA concentration-dependent. In contrast, the median CD ratio of patients treated with LTG plus the inducers phenytoin, phenobarbital, and carbamazepine was 0.42, 0.63, and 0.66, respectively, and phenytoin significantly reduced the CD ratio in comparison with phenobarbital or carbamazepine (p < 0.001). Pediatric patients of all ages beyond infancy showed similar susceptibility to VPA or inducers, but infants had higher CD ratios compared with the other age groups. Among other AEDs, topiramate, ethosuximide, and rufinamide reduced the CD ratio. These findings should be useful for estimating interactions between LTG and concomitant AEDs. Copyright © 2015 The Japanese Society for the Study of Xenobiotics. Published by Elsevier Ltd. All rights reserved.

Possible role of natural killer cells in pemphigus vulgaris − preliminary observations

PubMed Central

Stern, J N H; Keskin, D B; Barteneva, N; Zuniga, J; Yunis, E J; Ahmed, A R

2008-01-01

Pemphigus vulgaris (PV) is an autoimmune blistering disease that affects the skin and multiple mucous membranes, and is caused by antibodies to desmoglein (Dsg) 1 and 3. Natural killer (NK) cells have a role in autoimmunity, but their role in PV is not known. NK cells in the peripheral blood leucocytes (PBL) of 15 untreated Caucasian patients with active PV were studied and compared with healthy controls for the expression of major histocompatibility complex (MHC) class II and co-stimulatory molecules. CD56+ CD16- CD3- NK or CD56+ CD16+ CD3- NK cells from the PBL of PV patients co-express MHC class II and co-stimulatory molecule B7-H3 without exogenous stimulation. CD4+ T cells from the PBL and perilesional skin of PV patients were co-cultured with CD56+ CD3- NK cells from the PBL of the same patients; in the presence of Dsg3 peptides underwent statistically significant proliferation, indicating that NK cells functioned as antigen-presenting cells. Supernatants from these co-cultures and serum of the same patients with active PV had statistically significantly elevated levels of interleukin (IL)-6, IL-8 and interferon-γ, compared with controls indicating that the NK cells stimulated CD4+ T cells to produce proinflammatory cytokines. In these experiments, we present preliminary evidence that NK cells may play a role in the pathobiology of PV. PMID:18373702

CD40-Mediated NF-κB Activation in B Cells Is Increased in Multiple Sclerosis and Modulated by Therapeutics.

PubMed

Chen, Ding; Ireland, Sara J; Remington, Gina; Alvarez, Enrique; Racke, Michael K; Greenberg, Benjamin; Frohman, Elliot M; Monson, Nancy L

2016-12-01

CD40 interacts with CD40L and plays an essential role in immune regulation and homeostasis. Recent research findings, however, support a pathogenic role of CD40 in a number of autoimmune diseases. We previously showed that memory B cells from relapsing-remitting multiple sclerosis (RRMS) patients exhibited enhanced proliferation with CD40 stimulation compared with healthy donors. In this study, we used a multiparameter phosflow approach to analyze the phosphorylation status of NF-κB and three major MAPKs (P38, ERK, and JNK), the essential components of signaling pathways downstream of CD40 engagement in B cells from MS patients. We found that memory and naive B cells from RRMS and secondary progressive MS patients exhibited a significantly elevated level of phosphorylated NF-κB (p-P65) following CD40 stimulation compared with healthy donor controls. Combination therapy with IFN-β-1a (Avonex) and mycophenolate mofetil (Cellcept) modulated the hyperphosphorylation of P65 in B cells of RRMS patients at levels similar to healthy donor controls. Lower disease activity after the combination therapy correlated with the reduced phosphorylation of P65 following CD40 stimulation in treated patients. Additionally, glatiramer acetate treatment also significantly reduced CD40-mediated P65 phosphorylation in RRMS patients, suggesting that reducing CD40-mediated p-P65 induction may be a general mechanism by which some current therapies modulate MS disease. Copyright © 2016 by The American Association of Immunologists, Inc.

Prevalence of irritable bowel syndrome-type symptoms in patients with celiac disease: a meta-analysis.

PubMed

Sainsbury, Anita; Sanders, David S; Ford, Alexander C

2013-04-01

Patients with celiac disease (CD) often report symptoms compatible with irritable bowel syndrome (IBS). However, the prevalence of these symptoms in patients with CD and their relation to adherence to a gluten-free diet (GFD) have not been assessed systematically. We searched MEDLINE, EMBASE, and EMBASE Classic (through July 2012) to identify cross-sectional surveys or case-control studies reporting prevalence of IBS-type symptoms in adult patients (≥ 16 years old) with established CD. The number of individuals with symptoms meeting criteria for IBS was extracted for each study, according to case or control status and adherence to a GFD. Pooled prevalence and odds ratios (ORs), with 95% confidence intervals (CIs), were calculated. We analyzed data from 7 studies with 3383 participants. The pooled prevalence of IBS-type symptoms in all patients with CD was 38.0% (95% CI, 27.0%-50.0%). The pooled OR for IBS-type symptoms was higher in patients with CD than in controls (5.60; 95% CI, 3.23-9.70). In patients who were nonadherent with a GFD, the pooled OR for IBS-type symptoms, compared with those who were strictly adherent, was 2.69 (95% CI, 0.75-9.56). There was also a trend toward a higher OR for IBS-type symptoms among patients who did not adhere to the GFD, compared with controls (12.42; 95% CI, 6.84-11.75), compared with that observed for adherent CD patients vs controls (4.28; 95% CI, 1.56-11.75). IBS-type symptoms occur frequently in patients with CD and are more common than among controls. Adherence to a GFD might be associated with a reduction in symptoms. Copyright © 2013 AGA Institute. Published by Elsevier Inc. All rights reserved.

CD14+CD16+ monocytes are the main target of Zika virus infection in peripheral blood mononuclear cells in a paediatric study in Nicaragua.

PubMed

Michlmayr, Daniela; Andrade, Paulina; Gonzalez, Karla; Balmaseda, Angel; Harris, Eva

2017-11-01

The recent Zika pandemic in the Americas is linked to congenital birth defects and Guillain-Barré syndrome. White blood cells (WBCs) play an important role in host immune responses early in arboviral infection. Infected WBCs can also function as 'Trojan horses' and carry viruses into immune-sheltered spaces, including the placenta, testes and brain. Therefore, defining which WBCs are permissive to Zika virus (ZIKV) is critical. Here, we analyse ZIKV infectivity of peripheral blood mononuclear cells (PBMCs) in vitro and from Nicaraguan Zika patients and show CD14 + CD16 + monocytes are the main target of infection, with ZIKV replication detected in some dendritic cells. The frequency of CD14 + monocytes was significantly decreased, while the CD14 + CD16 + monocyte population was significantly expanded during ZIKV infection compared to uninfected controls. Viral RNA was detected in PBMCs from all patients, but in serum from only a subset, suggesting PBMCs may be a reservoir for ZIKV. In Zika patients, the frequency of infected cells was lower but the percentage of infected CD14 + CD16 + monocytes was significantly higher compared to dengue cases. The gene expression profile in monocytes isolated from ZIKV- and dengue virus-infected patients was comparable, except for significant differences in interferon-γ, CXCL12, XCL1, interleukin-6 and interleukin-10 levels. Thus, our study provides a detailed picture of the innate immune profile of ZIKV infection and highlights the important role of monocytes, and CD14 + CD16 + monocytes in particular.

Low CD1c + myeloid dendritic cell counts correlated with a high risk of rapid disease progression during early HIV-1 infection.

PubMed

Diao, Yingying; Geng, Wenqing; Fan, Xuejie; Cui, Hualu; Sun, Hong; Jiang, Yongjun; Wang, Yanan; Sun, Amy; Shang, Hong

2015-08-19

During early HIV-1 infection (EHI), the interaction between the immune response and the virus determines disease progression. Although CD1c + myeloid dendritic cells (mDCs) can trigger the immune response, the relationship between CD1c + mDC alteration and disease progression has not yet been defined. EHI changes in CD1c + mDC counts, surface marker (CD40, CD86, CD83) expression, and IL-12 secretion were assessed by flow cytometry in 29 patients. When compared with the normal controls, patients with EHI displayed significantly lower CD1c + mDC counts and IL-12 secretion and increased surface markers. CD1c + mDC counts were positively correlated with CD4+ T cell counts and inversely associated with viral loads. IL-12 secretion was only positively associated with CD4+ T cell counts. Rapid progressors had lower counts, CD86 expression, and IL-12 secretion of CD1c + mDCs comparing with typical progressors. Kaplan-Meier analysis and Cox regression models suggested patients with low CD1c + mDC counts (<10 cells/μL) had a 4-fold higher risk of rapid disease progression than those with high CD1c + mDC counts. However, no relationship was found between surface markers or IL-12 secretion and disease progression. During EHI, patients with low CD1c + mDC counts were more likely to experience rapid disease progression than those with high CD1c + mDC counts.

Activated platelets are the source of elevated levels of soluble CD40 ligand in the circulation of inflammatory bowel disease patients.

PubMed

Danese, S; Katz, J A; Saibeni, S; Papa, A; Gasbarrini, A; Vecchi, M; Fiocchi, C

2003-10-01

The CD40/CD40L system, a key regulator and amplifier of immune reactivity, is activated in inflammatory bowel disease (IBD) mucosa. To determine whether plasma levels of sCD40L are elevated in Crohn's disease (CD) and ulcerative colitis (UC) patients compared with normal controls, to investigate the cellular source of sCD40L, and to explore CD40L induction mechanisms. CD, UC, and normal control subjects were studied. The concentration of sCD40L in plasma and supernatants of freshly isolated platelets and autologous peripheral blood T cells (PBT) was measured by ELISA. Surface CD40L expression level was measured by flow cytometry in resting and thrombin activated platelets, and unstimulated and CD3/CD28 stimulated PBT before and after coculture with human intestinal microvascular endothelial cells (HIMEC). Compared with normal controls, plasma sCD40L levels were significantly higher in both CD and UC patients and proportional to the extent of mucosal inflammation. Platelets from IBD patients displayed a significantly higher surface CD40L expression than those from control subjects, and released greater amounts of sCD40L than autologous PBT. Contact with IL-1beta activated HIMEC induced significant upregulation of CD40L surface expression and release by platelets. Elevated levels of sCD40L in the circulation of IBD patients reflect enhanced surface expression and release of CD40L by platelets. This phenomenon translates to an increased platelet activation state apparently induced by passage through an inflamed mucosal microvascular bed, a conclusion supported by the positive correlation of plasma sCD40L levels with the extent of anatomical involvement by IBD. These results suggest that platelet-endothelial interactions critically contribute to activation of the CD40 pathway in IBD.

Evaluation of pretransplant immunologic status in kidney-transplant recipients by panel reactive antibody and soluble CD30 determinations.

PubMed

Cinti, Paola; Pretagostini, Renzo; Arpino, Alessia; Tamburro, Maria Luisa; Mengasini, Sonia; Lattanzi, Roberto; De Simone, Paolo; Berloco, Pasquale; Molajoni, Elvira Renna

2005-05-15

To retrospectively compare the accuracy of pretransplant panel of reactivity antibodies (PRA) and serum level of soluble CD30 (sCD30) in predicting early (<6 months) acute rejection (AR) in living-donor and deceased-donor kidney-transplant (KT) patients. Pretransplant sera of 24 KT recipients were retrospectively tested for sCD30 and compared with PRA. Inclusion criteria were de novo graft patients on calcineurin-inhibitor-based immunosuppression, minimum follow-up of 1 year, alive with a functioning graft, and stable renal function over the last 12 months. Objective measures were incidence of biopsy-proven AR (BPAR) within 6 months of KT and sCD30 and PRA diagnostic indexes. The relative risk (RR) of BPAR for each test was also obtained. Fourteen (58.3%) patients presented at least one episode of BPAR within 6 months of KT. All rejection episodes were responsive to steroid treatment. PRA was positive in six (25%) patients, and four (66.7%) of them presented at least one episode of BPAR. sCD30 tested positive in nine (37.5%) patients, and all these later presented at least one episode of BPAR. sCD30 and PRA diagnostic indexes in predicting early (< 6months) BPAR were sensitivity 64.2% versus 28.5%; specificity 100% versus 80%; accuracy 79.1% versus 50%; positive predictive value 100% versus 66.6%; and negative predictive value 66.6% versus 44.4%. The RR of early AR was 1.4 in PRA-positive patients and extremely higher in the sCD30-positive group. Pretransplant sCD30 is a more accurate predictor of AR when compared with PRA. These results support its use in the pretransplant work-up of kidney-graft recipients.

Evaluation of pretransplant immunologic status in kidney-transplant recipients by panel reactive antibody and soluble CD30 determinations.

PubMed

Cinti, Paola; Pretagostini, Renzo; Arpino, Alessia; Tamburro, Maria Luisa; Mengasini, Sonia; Lattanzi, Roberto; De Simone, Paolo; Berloco, Pasquale; Molajoni, Elvira Renna

2005-03-15

To retrospectively compare the accuracy of pretransplant panel of reactivity antibodies (PRA) and serum level of soluble CD30 (sCD30) in predicting early (< 6 months) acute rejection (AR) in living-donor and deceased-donor kidney-transplant (KT) patients. Pretransplant sera of 24 KT recipients were retrospectively tested for sCD30 and compared with PRA. Inclusion criteria were de novo graft patients on calcineurin-inhibitor-based immunosuppression, minimum follow-up of 1 year, alive with a functioning graft, and stable renal function over the last 12 months. Objective measures were incidence of biopsy-proven AR (BPAR) within 6 months of KT and sCD30 and PRA diagnostic indexes. The relative risk (RR) of BPAR for each test was also obtained. Fourteen (58.3%) patients presented at least one episode of BPAR within 6 months of KT. All rejection episodes were responsive to steroid treatment. PRA was positive in six (25%) patients, and four (66.7%) of them presented at least one episode of BPAR. sCD30 tested positive in nine (37.5%) patients, and all these later presented at least one episode of BPAR. sCD30 and PRA diagnostic indexes in predicting early (< 6 months) BPAR were sensitivity 64.2% versus 28.5%; specificity 100% versus 80%; accuracy 79.1% versus 50%; positive predictive value 100% versus 66.6%; and negative predictive value 66.6% versus 44.4%. The RR of early AR was 1.4 in PRA-positive patients and extremely higher in the sCD30-positive group. Pretransplant sCD30 is a more accurate predictor of AR when compared with PRA. These results support its use in the pretransplant work-up of kidney-graft recipients.

Association between vascular access failure and microparticles in hemodialysis patients

PubMed Central

Ryu, Jung-Hwa; Lim, Su-Young; Ryu, Dong-Ryeol; Kang, Duk-Hee; Choi, Kyu Bok; Kim, Seung-Jung

2012-01-01

Background Vascular access failure, a major cause of morbidity in hemodialysis (HD) patients, occurs mainly at stenotic endothelium following an acute thrombotic event. Microparticles (MPs) are fragments derived from injured cell membrane and are closely associated with coagulation and vascular inflammatory responses. Methods We investigated the relationship between levels of circulating MPs and vascular access patency in HD patients. A total of 82 HD patients and 28 healthy patients were enrolled. We used flow cytometry to measure endothelial MPs (EMPs) identified by CD31+CD42− or CD51+ and platelet-derived MPs (PMPs) identified by CD31+CD42+ in plasma samples of participants. Vascular access patency was defined as an interval from the time of access formation to the time of first access stenosis in each patient. MP counts were compared according to access patent duration. Results The levels of EMP (both CD31+CD42− and CD51+) and CD31+CD42+PMP were significantly higher in patients than in healthy participants. Levels of CD31+CD42−EMP and CD31+CD42+PMP showed a positive correlation. In non-diabetic HD patients, CD31+CD42−EMPs and CD31+CD42+PMPs were more elevated in the shorter access survival group (access survival <1 year) than in the longer survival group (access survival ≥ 4 years). Conclusion Elevated circulating EMP or PMP counts are influenced by end-stage renal disease and increased levels of EMP and PMP may be associated with vascular access failure in HD patients. PMID:26889407

Anomalies of the CD8+ T cell pool in haemochromatosis: HLA-A3-linked expansions of CD8+CD28- T cells.

PubMed

Arosa, F A; Oliveira, L; Porto, G; da Silva, B M; Kruijer, W; Veltman, J; de Sousa, M

1997-03-01

The present study consists of a phenotypic and functional characterization of peripheral blood T lymphocytes in a group of 21 patients with hereditary haemochromatosis (HH), an MHC class I-linked genetic disease resulting in iron overload, and a group of 30 healthy individuals, both HLA-phenotyped. The HH patients studied showed an increased percentage of CD8+ CD28- T cells with a corresponding reduction in the percentage of CD8+ CD28+ T cells in peripheral blood relative to healthy blood donors. No anomalies of CD28 expression were found in the CD4+ subset. The presence of the HLA-A3 antigen but not age accounted for these imbalances. Thus, an apparent failure of the CD8+ CD28+ T cell population 'to expand', coinciding with an 'expansion' of CD8+ CD28- T cells in peripheral blood of HLA-A3+ but not HLA-A3- HH patients was observed when compared with the respective HLA-A3-matched control group. A significantly higher percentage of HLA-DR+ but not CD45RO+ cells was also found within the peripheral CD8+ T cell subset in HH patients relative to controls. Phytohaemagglutinin (PHA) stimulation of peripheral blood mononuclear cells (PBMC) for 5 days showed: (i) that CD8+ CD28+ T cells both in controls and HH were able to expand in vitro; (ii) that CD8+ CD28- T cells decreased markedly after activation in controls but not in HH patients. Moreover, functional studies showed that CD8+ cytotoxic T lymphocytes (CTL) from HH patients exhibited a diminished cytotoxic activity (approx. two-fold) in standard 51Cr-release assays when compared with CD8+ CTL from healthy controls. The present results provide additional evidence for the existence of phenotypic and functional anomalies of the peripheral CD8+ T cell pool that may underlie the clinical heterogeneity of this iron overload disease. They are of particular relevance given the recent discovery of a novel mutated MHC class I-like gene in HH.

Anomalies of the CD8+ T cell pool in haemochromatosis: HLA-A3-linked expansions of CD8+CD28− T cells

PubMed Central

AROSA, F A; OLIVEIRA, L; PORTO, G; DA SILVA, B M; KRUIJER, W; VELTMAN, J; DE SOUSA, M

1997-01-01

The present study consists of a phenotypic and functional characterization of peripheral blood T lymphocytes in a group of 21 patients with hereditary haemochromatosis (HH), an MHC class I-linked genetic disease resulting in iron overload, and a group of 30 healthy individuals, both HLA-phenotyped. The HH patients studied showed an increased percentage of CD8+ CD28− T cells with a corresponding reduction in the percentage of CD8+ CD28+ T cells in peripheral blood relative to healthy blood donors. No anomalies of CD28 expression were found in the CD4+ subset. The presence of the HLA-A3 antigen but not age accounted for these imbalances. Thus, an apparent failure of the CD8+ CD28+ T cell population ‘to expand’, coinciding with an ‘expansion’ of CD8+ CD28− T cells in peripheral blood of HLA-A3+ but not HLA-A3− HH patients was observed when compared with the respective HLA-A3-matched control group. A significantly higher percentage of HLA-DR+ but not CD45RO+ cells was also found within the peripheral CD8+ T cell subset in HH patients relative to controls. Phytohaemagglutinin (PHA) stimulation of peripheral blood mononuclear cells (PBMC) for 5 days showed: (i) that CD8+ CD28+ T cells both in controls and HH were able to expand in vitro; (ii) that CD8+ CD28− T cells decreased markedly after activation in controls but not in HH patients. Moreover, functional studies showed that CD8+ cytotoxic T lymphocytes (CTL) from HH patients exhibited a diminished cytotoxic activity (approx. two-fold) in standard 51Cr-release assays when compared with CD8+ CTL from healthy controls. The present results provide additional evidence for the existence of phenotypic and functional anomalies of the peripheral CD8+ T cell pool that may underlie the clinical heterogeneity of this iron overload disease. They are of particular relevance given the recent discovery of a novel mutated MHC class I-like gene in HH. PMID:9067531

Granzyme B as a diagnostic marker of tuberculosis in patients with and without HIV coinfection.

PubMed

Sarkar, Pronoti; Mitra, Soumik; Pant, Priyannk; Kotwal, Aarti; Kakati, Barnali; Masih, Victor; Sindhwani, Girish; Biswas, Debasis

2016-05-01

Immunodiagnostic tests for tuberculosis (TB) are based on the estimation of interferon γ (IFN-γ) or IFN-γ-secreting CD4(+) T cells following ex vivo stimulation with ESAT6 and CFP-10. Sensitivity of these tests is likely to be compromised in CD4(+) T-cell-depleted situations, like HIV-TB coinfection. CD4(+) and CD8(+) T cells, isolated from 3 groups, viz., HIV-negative patients with active TB, HIV-TB coinfected patients, and healthy household contacts (HHCs) were cocultivated with autologous dendritic cells, and the cytokine response to rESAT6 stimulation was compared between groups in supernatants. While CD4(+) T-cell stimulation yielded significantly elevated levels of IFN-γ and interleukin 4 in HIV-negative TB patients, compared to HHCs, the levels of both these cytokines were nondiscriminatory between HIV-positive TB patients and HHCs. However, CD8(+) T-cell stimulation yielded significantly elevated granzyme B titers in both groups of patients, irrespective of HIV coinfection status. Hence, contrary to IFN-γ, granzyme B might be a useful diagnostic marker for Mycobacterium tuberculosis infection particularly in HIV coinfected patients. Copyright © 2016 Elsevier Inc. All rights reserved.

Clinical and pathological characteristics of HIV- and HHV-8–negative Castleman disease

PubMed Central

Yu, Li; Tu, Meifeng; Cortes, Jorge; Xu-Monette, Zijun Y.; Miranda, Roberto N.; Zhang, Jun; Orlowski, Robert Z.; Neelapu, Sattva; Boddu, Prajwal C.; Akosile, Mary A.; Uldrick, Thomas S.; Yarchoan, Robert; Medeiros, L. Jeffrey; Li, Yong; Fajgenbaum, David C.

2017-01-01

Castleman disease (CD) comprises 3 poorly understood lymphoproliferative variants sharing several common histopathological features. Unicentric CD (UCD) is localized to a single region of lymph nodes. Multicentric CD (MCD) manifests with systemic inflammatory symptoms and organ dysfunction due to cytokine dysregulation and involves multiple lymph node regions. Human herpesvirus 8 (HHV-8) causes MCD (HHV-8–associated MCD) in immunocompromised individuals, such as HIV-infected patients. However, >50% of MCD cases are HIV and HHV-8 negative (defined as idiopathic [iMCD]). The clinical and biological behavior of CD remains poorly elucidated. Here, we analyzed the clinicopathologic features of 74 patients (43 with UCD and 31 with iMCD) and therapeutic response of 96 patients (43 with UCD and 53 with iMCD) with HIV-/HHV-8–negative CD compared with 51 HIV-/HHV-8–positive patients. Systemic inflammatory symptoms and elevated inflammatory factors were more common in iMCD patients than UCD patients. Abnormal bone marrow features were more frequent in iMCD (77.0%) than UCD (45%); the most frequent was plasmacytosis, which was seen in 3% to 30.4% of marrow cells. In the lymph nodes, higher numbers of CD3+ lymphocytes (median, 58.88 ± 20.57) and lower frequency of CD19+/CD5+ (median, 5.88 ± 6.52) were observed in iMCD patients compared with UCD patients (median CD3+ cells, 43.19 ± 17.37; median CD19+/CD5+ cells, 17.37 ± 15.80). Complete surgical resection is a better option for patients with UCD. Siltuximab had a greater proportion of complete responses and longer progression-free survival (PFS) for iMCD than rituximab. Centricity, histopathological type, and anemia significantly impacted PFS. This study reveals that CD represents a heterogeneous group of diseases with differential immunophenotypic profiling and treatment response. PMID:28100459

Effect of Concomitant Medications on the Safety and Efficacy of Extended-Release Carbidopa-Levodopa (IPX066) in Patients With Advanced Parkinson Disease: A Post Hoc Analysis.

PubMed

LeWitt, Peter A; Verhagen Metman, Leo; Rubens, Robert; Khanna, Sarita; Kell, Sherron; Gupta, Suneel

Extended-release (ER) carbidopa-levodopa (CD-LD) (IPX066/RYTARY/NUMIENT) produces improvements in "off" time, "on" time without troublesome dyskinesia, and Unified Parkinson Disease Rating Scale scores compared with immediate-release (IR) CD-LD or IR CD-LD plus entacapone (CLE). Post hoc analyses of 2 ER CD-LD phase 3 trials evaluated whether the efficacy and safety of ER CD-LD relative to the respective active comparators were altered by concomitant medications (dopaminergic agonists, monoamine oxidase B [MAO-B] inhibitors, or amantadine). ADVANCE-PD (n = 393) assessed safety and efficacy of ER CD-LD versus IR CD-LD. ASCEND-PD (n = 91) evaluated ER CD-LD versus CLE. In both studies, IR- and CLE-experienced patients underwent a 6-week, open-label dose-conversion period to ER CD-LD prior to randomization. For analysis, the randomized population was divided into 3 subgroups: dopaminergic agonists, rasagiline or selegiline, and amantadine. For each subgroup, changes from baseline in PD diary measures ("off" time and "on" time with and without troublesome dyskinesia), Unified Parkinson Disease Rating Scale Parts II + III scores, and adverse events were analyzed, comparing ER CD-LD with the active comparator. Concomitant dopaminergic agonist or MAO-B inhibitor use did not diminish the efficacy (improvement in "off" time and "on" time without troublesome dyskinesia) of ER CD-LD compared with IR CD-LD or CLE, whereas the improvement with concomitant amantadine failed to reach significance. Safety and tolerability were similar among the subgroups, and ER CD-LD did not increase troublesome dyskinesia. For patients on oral LD regimens and taking a dopaminergic agonist, and/or a MAO-B inhibitor, changing from an IR to an ER CD-LD formulation provides approximately an additional hour of "good" on time.

Effect of Concomitant Medications on the Safety and Efficacy of Extended-Release Carbidopa-Levodopa (IPX066) in Patients With Advanced Parkinson Disease: A Post Hoc Analysis

PubMed Central

LeWitt, Peter A.; Verhagen Metman, Leo; Rubens, Robert; Khanna, Sarita; Kell, Sherron; Gupta, Suneel

2018-01-01

Objectives Extended-release (ER) carbidopa-levodopa (CD-LD) (IPX066/RYTARY/NUMIENT) produces improvements in “off” time, “on” time without troublesome dyskinesia, and Unified Parkinson Disease Rating Scale scores compared with immediate-release (IR) CD-LD or IR CD-LD plus entacapone (CLE). Post hoc analyses of 2 ER CD-LD phase 3 trials evaluated whether the efficacy and safety of ER CD-LD relative to the respective active comparators were altered by concomitant medications (dopaminergic agonists, monoamine oxidase B [MAO-B] inhibitors, or amantadine). Methods ADVANCE-PD (n = 393) assessed safety and efficacy of ER CD-LD versus IR CD-LD. ASCEND-PD (n = 91) evaluated ER CD-LD versus CLE. In both studies, IR- and CLE-experienced patients underwent a 6-week, open-label dose-conversion period to ER CD-LD prior to randomization. For analysis, the randomized population was divided into 3 subgroups: dopaminergic agonists, rasagiline or selegiline, and amantadine. For each subgroup, changes from baseline in PD diary measures (“off” time and “on” time with and without troublesome dyskinesia), Unified Parkinson Disease Rating Scale Parts II + III scores, and adverse events were analyzed, comparing ER CD-LD with the active comparator. Results and Conclusions Concomitant dopaminergic agonist or MAO-B inhibitor use did not diminish the efficacy (improvement in “off” time and “on” time without troublesome dyskinesia) of ER CD-LD compared with IR CD-LD or CLE, whereas the improvement with concomitant amantadine failed to reach significance. Safety and tolerability were similar among the subgroups, and ER CD-LD did not increase troublesome dyskinesia. For patients on oral LD regimens and taking a dopaminergic agonist, and/or a MAO-B inhibitor, changing from an IR to an ER CD-LD formulation provides approximately an additional hour of “good” on time. PMID:29432286

The Use of Vedolizumab in Preventing Postoperative Recurrence of Crohn's Disease.

PubMed

Yamada, Akihiro; Komaki, Yuga; Patel, Nayan; Komaki, Fukiko; Pekow, Joel; Dalal, Sushila; Cohen, Russell D; Cannon, Lisa; Umanskiy, Konstantin; Smith, Radhika; Hurst, Roger; Hyman, Neil; Rubin, David T; Sakuraba, Atsushi

2018-02-15

Clinical and endoscopic recurrence are common after surgery in Crohn's disease (CD). Vedolizumab has been increasingly used to treat CD, however, its effectiveness in preventing postoperative recurrence remains unknown. We aimed to investigate the use of vedolizumab in the postoperative setting and compare the risk of recurrence between patients receiving vedolizumab and anti-tumor necrosis factor (TNF)-α agents. Medical records of CD patients who underwent surgery between April 2014 and June 2016 were reviewed. We first analyzed how frequently vedolizumab is used to prevent postoperative recurrence and compared the patient characteristics with those being treated with other therapies. Furthermore, the rates of endoscopic remission, defined as a simple endoscopic score for CD of 0, at 6-12 months after surgery were compared between patients receiving vedolizumab and anti-TNF-α agents. Clinical, biological, and histologic outcomes such as Harvey-Bradshaw index, C-reactive protein, and histologic inflammation also were compared between the 2 groups. Risks of recurrence were assessed by univariate, multivariate, and propensity score-matched analyses. Among 203 patients that underwent a CD related surgery, 22 patients received vedolizumab as postoperative treatment. There were 58, 38, and 16 patients who received anti-TNF-α agents, immunomodulators, and metronidazole, respectively, whereas 69 patients were monitored without any medication. Patients receiving vedolizumab were young and frequently had perianal disease. Patients postoperatively treated with vedolizumab or anti-TNF-α agents were mostly treated with the same agent pre- and postoperatively. Rate of endoscopic remission at 6-12 months in the vedolizumab group was 25%, which was significantly lower as compared to anti-TNF-α agent group (66%, P = 0.01). Vedolizumab use was the only factor that was associated with an increased risk of endoscopic recurrence on both univariate (odds ratio (OR) 5.58, 95% confidence interval (CI) 1.51-24.3, P = 0.005) and multivariate analysis (OR 5.77, 95%CI 1.71-19.4, P = 0.005). The results were supported by a propensity score-matched analysis demonstrating lower rates of endoscopic remission (25 vs 69%, P = 0.03) in patients treated with vedolizumab as compared to anti-TNF-α agents. In the present retrospective cohort study of real-world experience, vedolizumab was shown to be commonly used as postoperative treatment for CD especially in high risk patients. Multivariate and propensity score-matched analyses showed that postoperative endoscopic recurrence in CD was higher with vedolizumab than with anti-TNF-α agents, but further investigation including controlled trials is required before determining the utility of vedolizumab in preventing postoperative recurrence of CD.

Low-level viremia and proviral DNA impede immune reconstitution in HIV-1-infected patients receiving highly active antiretroviral therapy.

PubMed

Ostrowski, Sisse R; Katzenstein, Terese L; Thim, Per T; Pedersen, Bente K; Gerstoft, Jan; Ullum, Henrik

2005-02-01

Immunological and virological consequences of low-level viremia in human immunodeficiency virus (HIV) type 1-infected patients receiving highly active antiretroviral therapy (HAART) remain to be determined. For 24 months, 101 HAART-treated, HIV-1-infected patients with HIV RNA levels 20 copies/mL at >/=1 visit (dVL patients) (median increase, 81 copies/mL [interquartile range, 37-480 copies/mL]). dVL patients had higher concentrations of CD8 cells, activated and memory T cells, and proviral DNA, compared with uVL patients (P<.05). A higher HIV RNA level was independently associated with reduced CD4 gain (P<.001). A higher HIV RNA level also was associated with increases in activated CD8(+)CD38(+) and CD8(+)HLA-DR(+) cells (P<.05), and a higher level of activated CD8(+)CD38(+) cells was independently associated with reduced CD4 gain (P<.05). A higher proviral DNA level was associated with increases in CD4(+)CD45RA(-)CD28(-) effector cells and reductions in naive CD4(+)CD45RA(+)CD62L(+) and CD8(+)CD45RA(+)CD62L(+) cells (P<.05). Higher levels of activated CD4(+)HLA-DR(+) and early differentiated CD4(+)CD45RA(-)CD28(+) cells predicted increased risk of subsequent detectable viremia in patients with undetectable HIV RNA (P<.05). These findings indicate that low-level viremia and proviral DNA are intimately associated with the immunological and virological equilibrium in patients receiving HAART.

Killer cell immunoglobulin receptor profile on CD4+ CD28− T cells and their pathogenic role in non-dialysis-dependent and dialysis-dependent chronic kidney disease patients

PubMed Central

Zal, Behnam; Chitalia, Nihil; Ng, Yin Sing; Trieu, Verna; Javed, Sana; Warrington, Rachelle; Kaski, Juan Carlos; Banerjee, Debasish; Baboonian, Christina

2015-01-01

There is a progressive increase in cardiovascular disease with declining renal function, unexplained by traditional risk factors. A CD4+ T-cell subpopulation (CD4+ CD28−), activated by human heat-shock protein 60 (hHSP 60), expands in patients with acute coronary syndrome and is associated with vascular damage. These cells exhibit cytotoxicity via expression of activating killer cell-immunoglobulin-like receptor KIR2DS2, mainly in the absence of inhibitory KIR2DL3. We investigated expansion of these cells and the pathogenic role of the KIR in non-dialysis-dependent chronic kidney disease (NDD-CKD) and end-stage haemodialysis-dependent renal disease (HD-ESRD) patients. CD4+ CD28− cells were present in 27% of the NDD-CKD and HD-ESRD patients (8–11% and 10–11% of CD4+ compartment, respectively). CD4+ CD28− cells were phenotyped for KIR and DAP12 expression. Cytotoxicity was assessed by perforin and pro-inflammatory function by interferon-γ expression on CD4+ CD28− clones (NDD-CKD n = 97, HD-ESRD n = 262). Thirty-four per cent of the CD4+ CD28− cells from NDD-CKD expressed KIR2DS2 compared with 56% in HD-ESRD patients (P = 0·03). However, 20% of clones expressed KIR2DL3 in NDD-CKD compared with 7% in HD-ESRD patients (P = 0·004). DAP12 expression in CD28− 2DS2+ clones was more prevalent in HD-ESRD than NDD-CKD (92% versus 60%; P < 0·001). Only 2DS2+ 2DL3− DAP12+ clones were cytotoxic in response to hHSP 60. CD4+ CD28− cells exhibited increased KIR2DS2, reduced KIR2DL3 and increased DAP12 expression in HD-ESRD compared with NDD-CKD patients. These findings suggest a gradual loss of expression, functionality and protective role of inhibitory KIR2DL3 as well as increased cytotoxic potential of CD4+ C28− cells with progressive renal impairment. Clonal expansion of these T cells may contribute to heightened cardiovascular events in HD-ESRD. PMID:25484131

CD4+, CD8+, CD3+ cell counts and CD4+/CD8+ ratio among patients with mycobacterial diseases (leprosy, tuberculosis), HIV infections, and normal healthy adults: a comparative analysis of studies in different regions of India.

PubMed

Hussain, Tahziba; Kulshreshtha, K K; Yadav, V S; Katoch, Kiran

2015-01-01

In this study, we estimated the CD4+, CD8+, CD3+ cell counts and the CD4/CD8 ratio among normal healthy controls (adults and children), leprosy patients (without any complications and during reactional states), TB patients (with and without HIV), and HIV-positive patients (early infection and full-blown AIDS) and correlated the changes with disease progression. In our study, it was observed that among adults, CD4+ cell counts ranged from 518-1098, CD8+ from 312-952, whereas CD4/CD8 ratio from 0.75-2.30. Among children, both CD4+ and CD8+ cells were more and the CD4/CD8 ratio varied from 0.91-3.17. With regard to leprosy patients, we observed that CD4+ and CD8+ cell counts were lower among PB (pauci-bacillary) and MB (multi-bacillary) patients. CD4/CD8 ratio was 0.99 ± 0.28 among PB patients while the ratio was lower, 0.78 ± 0.20, among MB patients. CD4+ cell counts were raised during RR (reversal reactions) and ENL (erythema nodosum leprosum) among the PB and MB patients whereas the CD8+ cell counts were lower among PB and MB patients. CD4/CD8 ratio doubled during reactional episodes of RR and ENL. Among the HIV-negative tuberculosis (TB) patients, both the CD4+ and CD8+ cell counts were found to be less and the CD4/CD8 ratio varied between 0.53-1.75. Among the HIV-positive TB patients and HIV-positive patients, both the CD4+ and CD8+ cells were very less and ratio drops significantly. In the initial stages of infection, as CD4+ counts drop, an increase in the CD8+ cell counts was observed and the ratio declines. In full-blown cases, CD4+ cell counts were very low, 3-4 to 54 cells, CD8+ cells from 12-211 and the ratio drops too low. This study is the first of its kind in this region of the country and assumes importance since no other study has reported the values of CD4+ and CD8+ T-lymphocyte counts among patients with mycobacterial diseases (leprosy and TB), HIV infections along with normal healthy individuals of the region, and correlation with clinical presentations of patients.

CD4+CD28null T Cells are related to previous cytomegalovirus infection but not to accelerated atherosclerosis in ANCA-associated vasculitis.

PubMed

Slot, Marjan C; Kroon, Abraham A; Damoiseaux, Jan G M C; Theunissen, Ruud; Houben, Alfons J H M; de Leeuw, Peter W; Tervaert, Jan Willem Cohen

2017-05-01

Previous studies have suggested an increased risk for cardiovascular events in antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV). We analyzed the presence of atherosclerotic damage in patients with AAV in relation to the presence of CD4 + CD28 null T cells and antibodies against cytomegalovirus (CMV) and human Heat-Shock Protein 60 (hHSP60). In this cross-sectional study, patients with inactive AAV were compared with healthy controls (HC). Carotid intima-media thickness (IMT) and aortic pulse-wave velocity (PWV) were measured. In addition, CD4 + CD28 null T cells, anti-CMV, and anti-hHSP60 levels were determined. Forty patients with AAV were included. Patients' spouses were recruited as HC (N = 38). CD4 + CD28 null T cells are present in patients with AAV in a higher percentage (median 3.1, range 0.01-85) than in HC (0.28, 0-36, P < 0.0001). No significant difference in IMT (mm) between patients and controls was detected (mean 0.77 ± standard deviation 0.15 and 0.73 ± 0.11, respectively, P = 0.20). PWV standardized for MAP was increased in AAV patients (9.80 ± 2.50 m/s, compared to 8.72 ± 1.68 in HC, P = 0.04). There was a strong association between a previous CMV infection and the presence and percentage of CD4 + CD28 null T cells (0.33 vs 13.8, P < 0.001). There was no relationship between CD4 + CD28 null T cells and/or a previous CMV infection and IMT or PWV. There was no relation between anti-hHSP60 and CD4 + CD28 null T cells. Increased PWV values suggest atherosclerotic damage in patients with AAV. Plaque size, as determined by IMT, did not differ. CD4 + CD28 null T cells are increased in AAV and related to the previous CMV infection.

The CD4/CD8 ratio is associated with coronary artery disease (CAD) in elderly Chinese patients.

PubMed

Gao, Pan; Rong, Hong-Hui; Lu, Ting; Tang, Gang; Si, Liang-Yi; Lederer, James A; Xiong, Wei

2017-01-01

The aim of this study was to investigate the relationship between number of circulating T cells and coronary artery disease (CAD) in an elderly Chinese population. A total of 295 elderly inpatients (age≥60) were included in this cross-sectional study. Their clinical and biochemical characteristics were recorded. Patients were divided to two groups: control patients and CAD patients. The risk factors of CAD were explored by binary logistic regression analysis. Compared with control patients, the ratio of CD4 to CD8 T cells was significantly increased in CAD patients. There was no difference in the number of CD3, CD4, and CD8 T cells between the two groups. Multiple logistic regression analysis showed that CAD was independently associated with age, gender, body mass index (BMI), systolic blood pressure (SBP), chronic heart failure (CHF) and the CD4/CD8 ratio. In addition, after adjusting for different clinical parameters (including gender, age, CHF, hypertension, arrhythmia, SBP, and BMI), the risk of CAD was significantly increased in patients with a CD4/CD8 ratio>1.5. There was a strong and independent association between the ratio of CD4/CD8 and CAD in elderly Chinese population. Copyright © 2016. Published by Elsevier B.V.

Lymphocyte integrin expression differences between SIRS and sepsis patients.

PubMed

Heffernan, D S; Monaghan, S F; Ayala, Alfred

2017-11-01

Systemic Inflammatory Response Syndrome (SIRS) and sepsis remain leading causes of death. Despite many similarities, the two entities are very distinct clinically and immunologically. T-Lymphocytes play a key pivotal role in the pathogenesis and ultimately outcome following both SIRS and sepsis. Integrins are essential in the trafficking and migration of lymphocytes. They also serve vital roles in efficient wound healing and clearance of infections. Here, we investigate whether integrin expression, specifically β1 (CD29) and β2 (CD18), are disrupted in SIRS and sepsis, and assess differences in integrin expression between these two critically ill clinical categories. T-Lymphocytes were isolated from whole blood collected from ICU patients exhibiting SIRS or sepsis. Samples were analyzed for CD18 (β2) and CD29 (β1) on CD3 + T cells through flow cytometry. Septic patients were stratified into either exclusively abdominal or non-abdominal sources of sepsis. CD18 was almost ubiquitously expressed on CD3 + T cells irrespective of clinical condition. However, CD29 (β1 integrin) was lowest in SIRS patients (20.4% of CD3 + T cells) when compared with either septic patients (35.5%) or healthy volunteers (54.1%). Furthermore, there was evidence of compartmentalization in septic patients, where abdominal sources had a greater percentage of CD3 + CD29 + T cells (41.7%) when compared with those with non-abdominal sources (29.5%). Distinct differences in T-cell integrin expression exists between patients in SIRS versus sepsis, as well as relative to the source of sepsis. Further work is needed to understand cause and effect relative to the progression from SIRS into sepsis.

Significant differences in B-cell subpopulations characterize patients with chronic graft-versus-host disease-associated dysgammaglobulinemia.

PubMed

Kuzmina, Zoya; Greinix, Hildegard T; Weigl, Roman; Körmöczi, Ulrike; Rottal, Arno; Frantal, Sophie; Eder, Sandra; Pickl, Winfried F

2011-02-17

Manifestations of chronic graft-versus-host disease (cGVHD) can resemble those seen in immunodeficiency states and autoimmune disorders. Reports by us and others suggest an involvement of B cells in the pathogenesis of cGVHD. We investigated B-lymphocyte subpopulations in cGVHD cohorts defined by serum immunoglobulin G (IgG) levels to characterize novel biomarkers for impairment of humoral immunity after allogeneic hematopoietic stem cell transplantation. Seventy-six patients were enrolled a median of 46 months after hematopoietic stem cell transplantation. The hypogammaglobulinemia group had significantly diminished CD19(+) B cells (165 vs 454 vs 417 × 10⁶L) with elevated CD19(+)CD21(low) immature (16.5%, 7.7%, and 9.1%) and CD19(+)CD21(int-high)CD38(high)IgM(high) transitional (10.5% vs 4.2% vs 6.3%) B-cell proportions compared with the normogammaglobulinemia and hypergammaglobulinemia groups. CD19(+)CD10(-)CD27(-)CD21(high) naive B cells were highly elevated in all patients with cGVHD. CD19(+)CD27(+)IgD(+) non-class-switched (4 vs 12 vs 11 × 10⁶/L) and class-switched (7 vs 35 vs 42 × 10⁶/L) memory B cells were significantly lower in the hypogammaglobulinemia group compared with the others. Besides significantly higher B-cell activation factor/B-cell ratios, significantly more cGVHD patients with hypergammaglobulinemia had autoantibodies compared with the hypogammaglobulinemia subgroup (68% vs 24%, P = .024). In conclusion, B-cell subpopulations can serve as novel cellular biomarkers for immunodeficiency and autoimmunity indicating different pathogenetic mechanisms of cGVHD and encouraging future prospective longitudinal studies.

Pruritic papular eruption and eosinophilic folliculitis associated with human immunodeficiency virus (HIV) infection: a histopathological and immunohistochemical comparative study.

PubMed

Afonso, João Paulo Junqueira Magalhães; Tomimori, Jane; Michalany, Nilceo Schwery; Nonogaki, Suely; Porro, Adriana Maria

2012-08-01

Among the papular-pruriginous dermatoses related to human immunodeficiency (HIV) infection, two entities remain poorly differentiated leading to confusion in their diagnosis: HIV-related pruritic papular eruption (HIV-PPE or prurigo) and eosinophilic folliculitis (HIV-EF). To establish histopathological and immunohistochemical parameters to differentiate between two conditions associated with HIV infection, the pruritic papular eruption (HIV-PPE) and eosinophilic folliculitis (HIV-EF). Clinically typical HIV-PPE (18 cases) and HIV-EF (10 cases) cases were compared with each other in terms of the following topics: clinical and laboratory features (gender, age, CD4+ cell and eosinophil count), histopathological features (hematoxylin-eosin and toluidine blue staining) and immunohistochemical features (anti-CD1a, anti-CD4, anti-CD7, anti-CD8, anti-CD15, anti-CD20, anti-CD30, anti-CD68/macrophage and anti-S-100 reactions). Among the HIV-EF patients, we found an intense perivascular and diffuse inflammatory infiltration compared with those patients with HIV-PPE. The tissue mast cell count by toluidine staining was higher in the HIV-EF patients, who also presented higher expression levels of CD15 (for eosinophils), CD4 (T helper), and CD7 (pan-T lymphocytes) than the HIV-PPE patients. Only quantitative differences and not qualitative differences were found. These data indicate that HIV-related PPE and EF could possibly be differentiated by histopathological and immunohistochemical findings in addition to clinical characteristics. In fact, these two inflammatory manifestations could be within the spectrum of the same disease because only quantitative, and not qualitative, differences were found. Copyright © 2011 American Academy of Dermatology, Inc. Published by Mosby, Inc. All rights reserved.

The prevalence of abnormal celiac antibodies and celiac disease in patients with suspected irritable bowel syndrome: a prospective multi-center US study

PubMed Central

Cash, Brooks D.; Rubenstein, Joel H.; Young, Patrick E.; Gentry, Andrew; Nojkov, Borko; Lee, Dong; Andrews, A. Hirsohi; Dobhan, Richard; Chey, William D.

2011-01-01

Background & Aims Guidelines recommend that patients with symptoms of non-constipated inflammatory bowel syndrome (NC-IBS) undergo testing for celiac disease (CD). We evaluated the prevalence of CD antibodies and biopsy confirmed CD among patients with NC-IBS in a large US population. Methods In a study conducted at 4 sites, from 2003 to 2008, we compared data from 492 patients with symptoms of NC-IBS to 458 asymptomatic individuals who underwent colonoscopy examinations for cancer screening or polyp surveillance (controls). All participants provided blood samples for specific and non-specific CD-associated antibodies. Additionally, patients with IBS were analyzed for complete blood cell counts, metabolic factors, erythrocyte sedimentation rates, and levels of C-reactive protein and thyroid-stimulating hormone. Any subjects found to have CD-associated antibodies were offered esophagogastroduodenoscopy and duodenal biopsy analysis. Results Of patients with NC-IBS, 7.3% had abnormal results in tests for CD-associated antibodies, compared to 4.8% of controls (adjusted odds ratio=1.49; 95% confidence interval, 0.76–2.90. P=.25). Within the NC-IBS group, 6.51% had antibodies against gliadin, 1.22% against tissue transglutaminase, and 0.61% against endomysium (P>.05 vs controls for all antibodies tested). CD was confirmed in 0.41% of patients in the NC-IBS group and 0.44% of controls (P>0.99). Conclusions Although CD-associated antibodies are relatively common, the prevalence of CD among patients with NC-IBS is similar to that among controls in a large US population. These findings challenge recommendations to routinely screen patients with NC-IBS for CD. More than 7% of patients with NC-IBS had CD-associated antibodies, indicating that gluten sensitivity might mediate IBS symptoms; further studies are needed. PMID:21762658

Task-shifting point-of-care CD4+ testing to lay health workers in HIV care and treatment services in Namibia.

PubMed

Kaindjee-Tjituka, Francina; Sawadogo, Souleymane; Mutandi, Graham; Maher, Andrew D; Salomo, Natanael; Mbapaha, Claudia; Neo, Marytha; Beukes, Anita; Gweshe, Justice; Muadinohamba, Alexinah; Lowrance, David W

2017-01-01

Access to CD4+ testing remains a common barrier to early initiation of antiretroviral therapy among persons living with HIV/AIDS in low- and middle-income countries. The feasibility of task-shifting of point-of-care (POC) CD4+ testing to lay health workers in Namibia has not been evaluated. From July to August 2011, Pima CD4+ analysers were used to improve access to CD4+ testing at 10 selected public health facilities in Namibia. POC Pima CD4+ testing was performed by nurses or lay health workers. Venous blood samples were collected from 10% of patients and sent to centralised laboratories for CD4+ testing with standard methods. Outcomes for POC Pima CD4+ testing and patient receipt of results were compared between nurses and lay health workers and between the POC method and standard laboratory CD4+ testing methods. Overall, 1429 patients received a Pima CD4+ test; 500 (35.0%) tests were performed by nurses and 929 (65.0%) were performed by lay health workers. When Pima CD4+ testing was performed by a nurse or a lay health worker, 93.2% and 95.2% of results were valid ( p = 0.1); 95.6% and 98.1% of results were received by the patient ( p = 0.007); 96.2% and 94.0% of results were received by the patient on the same day ( p = 0.08). Overall, 97.2% of Pima CD4+ results were received by patients, compared to 55.4% of standard laboratory CD4+ results ( p < 0.001). POC CD4+ testing was feasible and effective when task-shifted to lay health workers. Rollout of POC CD4+ testing via task-shifting can improve access to CD4+ testing and retention in care between HIV diagnosis and antiretroviral therapy initiation in low- and middle-income countries.

Dissection of a circulating CD3+ CD20+ T cell subpopulation in patients with psoriasis.

PubMed

Niu, J; Zhai, Z; Hao, F; Zhang, Y; Song, Z; Zhong, H

2018-05-01

CD3 + CD20 + T cells are a population of CD3 + T cells that express CD20 and identified in healthy donors and autoimmune diseases. However, the nature and role of these cells in patients with psoriasis remain unclear. In this study, we aimed to investigate the level, phenotype, functional and clinical relevance of CD3 + CD20 + T cells in the peripheral blood of patients with psoriasis. We found that a small subset of CD3 + T cells expressed CD20 molecule in the peripheral blood of patients with psoriasis, and their levels were similar to those in healthy donors. Circulating CD3 + CD20 + T cells in patients with psoriasis were enriched in CD4 + cells and displayed an activated effector phenotype, as these cells contained fewer CD45RA + -naive and CCR7 + cells with increased activity than those of CD3 + T cells lacking CD20. In addition, compared with healthy donors, circulating CD3 + CD20 + T cells in patients with psoriasis produced more cytokines, interleukin (IL)-17A, tumour necrosis factor (TNF)-α and IL-21, but not IL-4 and IFN-γ. Furthermore, a significantly positive correlation was found between the levels of IL-17A, TNF-α and IL-21-production CD3 + CD20 + T cells with Psoriasis Area and Severity Index scores. Our findings suggest that CD3 + CD20 + T cells may play a role in the pathogenesis of psoriasis. © 2018 British Society for Immunology.

Refractory celiac disease and EATL patients show severe malnutrition and malabsorption at diagnosis.

PubMed

Wierdsma, Nicolette J; Nijeboer, Petula; de van der Schueren, Marian A E; Berkenpas, Marijke; van Bodegraven, Ad A; Mulder, Chris J J

2016-06-01

Refractory celiac disease type II (RCDII) and EATL (Enteropathy Associated T-cell Lymphoma) are (pre)malignant complications of celiac disease (CD). Data on malnutrition and intestinal absorption is lacking in these patients. Therefore, the aim of the study is to comprehensively assess nutritional status and intestinal absorption capacity of patients with RCDII and EATL, compared with data of newly diagnosed CD patients. Observational study in tertiary care setting in RCDII (n = 24, 63.8 ± 8.2 y), EATL (n = 25, 62.3 ± 5.7 y) and CD patients (n = 43, 45.6 ± 14.8 y). At diagnosis, anthropometry (BMI, unintentional weight loss, fat-free mass index (FFMI), handgrip strength (HGS), nutritional intake, fecal losses and Resting Energy Expenditure (REE)) were assessed. Low BMI (<18.5) was more often observed in RCDII patients than in CD or EATL patients (in 33%, 12% and 12%, respectively, p = 0.029). EATL patients more frequently had unintentional weight loss (>10%) than CD or RCDII patients (in 58%, 19% and 39% of patients, respectively; p = 0.005/0.082). Energy malabsorption (<85%) was detected in 44% and 33% of RCDII and EATL patients, vs 21.6% in CD (NS). Fecal energy losses were higher in RCDII than in CD patients (589 ± 451 vs 277 ± 137 kcal/d, p = 0.017). REE was underestimated by predicted-REE with>10% in 60% of RCDII, 89% of EATL, and 38% of CD patients (p = 0.006). Low FFMI and HGS were detected in one third and two thirds of all patients, respectively. The nutritional status of patients with RCDII and EATL is inferior compared with untreated naïve CD patients at presentation. Both malabsorption as well as hypermetabolism contribute to malnutrition. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

Microvessel density in head and neck squamous cell carcinoma.

PubMed

Szafarowski, Tomasz; Sierdzinski, Janusz; Szczepanski, Miroslaw J; Whiteside, Theresa L; Ludwig, Nils; Krzeski, Antoni

2018-05-10

Microvessel density (MVD) corresponds to the intensity of neo-angiogenesis. MVD assessments are based on the expression levels of the vascular endothelium markers such as, e.g., CD34 or CD105. The goal of this study was to assess MVD among patients with head and neck squamous cell carcinoma (HNSCC), and to evaluate the predictive value of MVD in head and neck cancers. The study included 49 patients treated for HNSCC and 11 patients with dysplasia of the upper respiratory tract epithelium. Control tissues consisted of 12 normal mucous membranes of the throat. Expression levels of MVD markers were assessed by immunohistochemistry (IHC) using tissue microarrays (TMA). Clinicopathological factors and patients' survival over the 5-year follow-up period were analyzed. The MVD/CD34 values were found to be significantly elevated in the HNSCCs compared to the non-malignant control tissues (p = 0.001) and to dysplastic tissues. (p = 0.02). Significantly higher MVD/CD105 values were also seen in the tumor compared to the control tissues (p = 0.001) or the dysplastic tissues (p = 0.001). Unexpectedly, significantly lower MVD/CD34 values were seen in the tumor tissues of patients with the T3-T4 tumors compared to those with T1-T2 tumors (p = 0.01). HNSCCs have statistically higher MVD values compared to dysplasia of the upper respiratory tract epithelium. However, the MVD/CD34 values did not correlate with local invasiveness (the T feature) of HNSCCs. This counterintuitive observation suggests that assessments of MVD as performed on TMA by IHC using anti-CD34 or anti-CD105 antibodies considered to be specific for endothelial cell markers might underestimate the extent of the tumor vascularity in HNSCC.

Meta-Analysis of the Changes of Peripheral Blood T Cell Subsets in Patients with Brucellosis

PubMed Central

Zheng, Rongjiong; Xie, Songsong; Niyazi, Shaniya; Lu, Xiaobo; Zhou, Yan

2018-01-01

Brucellosis is one of the most prevalent zoonotic diseases in the world, but its pathogenesis is not very clear. At present, it is thought that it may be related to the immunity of T cells. The conclusions of related studies are inconsistent, and its clinical significance is not explicit. We searched published articles in electronic databases up to December 2017 identified as relating to the clinical features of human brucellosis in China. Only eight studies had sufficient quality for data extraction. Meta-analysis showed a significantly decreased proportion of CD4+ T cells in human brucellosis patients compared to healthy subject individuals. The frequency of CD8+ T cells was significantly higher in human brucellosis patients than that in the healthy control group. The pooled analysis presented a significant decrease of the CD4+/CD8+ ratio in human brucellosis patients compared to healthy subjects. There is immunologic dysfunction of T lymphocyte in patients with human brucellosis, the CD4+ and CD8+ T cells might be the important factors affecting the progress of brucellosis. PMID:29888294

Decreased frequency of peripheral CD4(+) CD161(+) Th(17) -precursor cells in kidney transplant recipients on long-term therapy with Belatacept.

PubMed

Vondran, Florian Wolfgang Rudolf; Timrott, Kai; Kollrich, Sonja; Klempnauer, Juergen; Schwinzer, Reinhard; Becker, Thomas

2012-04-01

Clinical trials have pointed out the promising role of co-stimulation blocker Belatacept for improvement of graft function and avoidance of undesired side-effects associated with calcineurin-inhibitors (CNI). However, due to the worldwide limited availability of appropriate patients, almost no data exist to assess the effects of sustained application of this immunomodulator on the recipient's immune system. The aim of this study was to reveal specific alterations in the composition of immunologic subpopulations potentially involved in development of tolerance or chronic graft rejection following long-term Belatacept therapy. For this, peripheral lymphocyte subsets of kidney recipients treated with Belatacept (n=5; average 7.8years) were determined by flow-cytometry and compared with cells from matched patients on CNI (n=9) and healthy controls (n=10). T cells capable of producing IL-17 and serum levels of soluble CD30 were quantified. Patients on CNI showed a higher frequency of CD4(+) CD161(+) Th(17) -precursors and IL-17-producing CD4(+) T cells than Belatacept patients and controls. Significantly higher serum levels of soluble CD30 were observed in CNI patients, indicating a possible involvement of the CD30/CD30L-system in Th(17) -differentiation. No differences were found concerning CD4(+) CD25(+) CD127(low) FoxP3(+) regulatory T cells. In conclusion, patients on therapy with Belatacept did not show a comparable Th(17) -profile to that seen in individuals with chronic intake of CNI. The distinct effects of Belatacept on Th(17) -immunity might prove beneficial for the long-term outcome following kidney transplantation. © 2012 The Authors. Transplant International © 2012 European Society for Organ Transplantation.

Increase of CD69, CD161 and CD94 on NK cells in women with recurrent spontaneous abortion and in vitro fertilization failure.

PubMed

Ghafourian, Mehri; Karami, Najmeh; Khodadadi, Ali; Nikbakht, Roshan

2014-06-01

Recurrent spontaneous abortion (RSA) and in vitro fertilization (IVF) failure with unknown causes are the controversial issues that are probably related to the immune system. To compare circulating NK cells expressing activation and inhibition surface markers between patients with RSA and IVF failure with those of healthy multiparous and successful IVF control women, respectively. In this case-control study peripheral blood samples were collected from 43 patients who included 23 women with RSA and 20 with IVF failure, plus 43 healthy control women comprising of 36 normal multiparous women and seven women with successful IVF. The expression of CD69, CD94 and CD161 surface markers on CD56+NK cells were assessed using specific monoclonal antibodies by flowcytometry. The percentage of NK cells increased significantly in patients with RSA and in women with IVF failure in comparison to healthy multiparous and successful IVF control groups (p<0.001). The overall expression of CD69, CD94, CD161 were also increased significantly on NK cells in both patient groups compared to control groups (p<0.001). Elevated expression of CD69 and CD161 on NK cells can be considered as immunological risk markers in RSA and IVF failure. However, it is not clear if high expression of CD94 on peripheral blood NK cells is related to abnormal activity of endometrial NK cells.

Paradoxical arthritis occurring during anti-TNF in patients with inflammatory bowel disease: histological and immunological features of a complex synovitis.

PubMed

Alivernini, Stefano; Pugliese, Daniela; Tolusso, Barbara; Bui, Laura; Petricca, Luca; Guidi, Luisa; Mirone, Luisa; Rapaccini, Gian Ludovico; Federico, Francesco; Ferraccioli, Gianfranco; Armuzzi, Alessandro; Gremese, Elisa

2018-01-01

Paradoxical arthritis under tumour necrosis factor inhibitor (TNF-i) for inflammatory bowel disease (IBD) has been described. This study aims to evaluate the histological features of paired synovial tissue (ST) and colonic mucosa (CM) tissue in patients with IBD developing paradoxical arthritis under TNF-i. Patients with IBD without history of coexisting joint involvement who developed arthritis under TNF-i were enrolled. Each patient underwent ST biopsy and ileocolonoscopy with CM biopsies. ST and CM paired samples were stained through immunohistochemistry (IHC) for CD68, CD21, CD20, CD3 and CD117. Clinical and immunological parameters (anticitrullinated peptides antibodies (ACPA)-immunoglobulin (Ig)M/IgA rheumatoid factor (RF)) were collected. Psoriatic arthritis (PsA) and ACPA/IgM-RF/IgA-RF negative rheumatoid arthritis (RA) were enrolled as comparison. 10 patients with IBD (age 46.0±9.7 years, 13.2±9.9 years of disease duration, 2.5±1.6 years of TNF-i exposure, six with Crohn's disease and four with ulcerative colitis, respectively) were studied. At ST level, IHC revealed that patients with IBD with paradoxical arthritis showed more similar histological findings in terms of synovial CD68 + , CD21 + , CD20 + , CD3 + and CD117 + cells compared with PsA than ACPA/IgM-RF/IgA-RF negative RA. Analysing the CM specimens, patients with IBD showed the presence of CD68 + , CD3 + , CD117 + and CD20 + cells in 100%, 70%, 60% and 50% of cases, respectively, despite endoscopic remission. Finally, addition of conventional disease-modifying antirheumatic drugs and switch to ustekinumab were more effective than swapping into different TNF-i in patients with IBD with paradoxical arthritis. Patients with IBD may develop histologically proven synovitis during TNF-i, comparable to PsA. The inhibition of inflammatory pathways alternative to TNF (IL12/1L23) may be an effective therapeutic option for severe paradoxical articular manifestations.

Paradoxical arthritis occurring during anti-TNF in patients with inflammatory bowel disease: histological and immunological features of a complex synovitis

PubMed Central

Alivernini, Stefano; Pugliese, Daniela; Tolusso, Barbara; Bui, Laura; Petricca, Luca; Guidi, Luisa; Mirone, Luisa; Rapaccini, Gian Ludovico; Federico, Francesco; Ferraccioli, Gianfranco; Armuzzi, Alessandro; Gremese, Elisa

2018-01-01

Objective Paradoxical arthritis under tumour necrosis factor inhibitor (TNF-i) for inflammatory bowel disease (IBD) has been described. This study aims to evaluate the histological features of paired synovial tissue (ST) and colonic mucosa (CM) tissue in patients with IBD developing paradoxical arthritis under TNF-i. Methods Patients with IBD without history of coexisting joint involvement who developed arthritis under TNF-i were enrolled. Each patient underwent ST biopsy and ileocolonoscopy with CM biopsies. ST and CM paired samples were stained through immunohistochemistry (IHC) for CD68, CD21, CD20, CD3 and CD117. Clinical and immunological parameters (anticitrullinated peptides antibodies (ACPA)-immunoglobulin (Ig)M/IgA rheumatoid factor (RF)) were collected. Psoriatic arthritis (PsA) and ACPA/IgM-RF/IgA-RF negative rheumatoid arthritis (RA) were enrolled as comparison. Results 10 patients with IBD (age 46.0±9.7 years, 13.2±9.9 years of disease duration, 2.5±1.6 years of TNF-i exposure, six with Crohn’s disease and four with ulcerative colitis, respectively) were studied. At ST level, IHC revealed that patients with IBD with paradoxical arthritis showed more similar histological findings in terms of synovial CD68+, CD21+, CD20+, CD3+ and CD117+ cells compared with PsA than ACPA/IgM-RF/IgA-RF negative RA. Analysing the CM specimens, patients with IBD showed the presence of CD68+, CD3+, CD117+ and CD20+ cells in 100%, 70%, 60% and 50% of cases, respectively, despite endoscopic remission. Finally, addition of conventional disease-modifying antirheumatic drugs and switch to ustekinumab were more effective than swapping into different TNF-i in patients with IBD with paradoxical arthritis. Conclusion Patients with IBD may develop histologically proven synovitis during TNF-i, comparable to PsA. The inhibition of inflammatory pathways alternative to TNF (IL12/1L23) may be an effective therapeutic option for severe paradoxical articular manifestations. PMID:29657833

Balance of CD8+ CD28+ / CD8+ CD28- T lymphocytes is vital for patients with ulcerative colitis.

PubMed

Dai, Shi-Xue; Wu, Gang; Zou, Ying; Feng, Yan-Ling; Liu, Hong-Bo; Feng, Jin-Shan; Chi, Hong-Gang; Lv, Ru-Xi; Zheng, Xue-Bao

2013-01-01

Immune balances are important for many diseases including ulcerative colitis (UC). This study aimed to explore the role of the balance between CD8+ CD28+ and CD8+ CD28- T lymphocytes for the immunological pathogenesis of UC. Sixteen patients with UC, 16 patients with irritable bowel syndrome (IBS) and 15 healthy volunteers were enrolled. The frequencies of CD8+ CD28+ and CD8+CD28- T lymphocytes in peripheral blood and colon tissue were tested using flow cytometry and immunofluorescent, respectively. The cytokines of the two lymphocytes were detected by protein chips and ELISA. The expression of the signal transducers, the JAK3 and STAT6, as well the transcription factors, the NFATc2 and GATA3, was all detected by both western blot and immunohistochemistry. For UC patients, the frequencies of CD8+ CD28+ T lymphocytes, together with the ratios of CD8+ CD28+ / CD8+ CD28- T lymphocytes in blood and colon tissue, were significantly lower than those in both IBS patients and healthy volunteers. But the frequencies of CD8+ CD28- T lymphocytes in blood and colon tissue of the UC patients were significantly higher than the other two groups. The concentration of IL-7 and -13, and the expression of JAK3 and STAT6 in UC patients, were significantly lower when compared with the other two groups. Conversely, the concentration of IL-12p40 and -15, and the expression of GATA3 and NFATc2 in UC patients, were significantly higher than both IBS and control group. The balance of CD8+ CD28+ / CD8+ CD28- T lymphocytes plays a vital role in UC, while the balance tilt towards CD8+ CD28+ T lymphocytes is beneficial for patients with UC.

Altered intestinal microbiota and blood T cell phenotype are shared by patients with Crohn's disease and their unaffected siblings.

PubMed

Hedin, Charlotte R; McCarthy, Neil E; Louis, Petra; Farquharson, Freda M; McCartney, Sara; Taylor, Kirstin; Prescott, Natalie J; Murrells, Trevor; Stagg, Andrew J; Whelan, Kevin; Lindsay, James O

2014-10-01

Crohn's disease (CD) is associated with intestinal dysbiosis, altered blood T cell populations, elevated faecal calprotectin (FC) and increased intestinal permeability (IP). CD-associated features present in siblings (increased risk of CD) but not in healthy controls, provide insight into early CD pathogenesis. We aimed to (1) Delineate the genetic, immune and microbiological profile of patients with CD, their siblings and controls and (2) Determine which factors discriminate between groups. Faecal microbiology was analysed by quantitative PCR targeting 16S ribosomal RNA, FC by ELISA, blood T cell phenotype by flow cytometry and IP by differential lactulose-rhamnose absorption in 22 patients with inactive CD, 21 of their healthy siblings and 25 controls. Subject's genotype relative risk was determined by Illumina Immuno BeadChip. Strikingly, siblings shared aspects of intestinal dysbiosis with patients with CD (lower concentrations of Faecalibacterium prausnitzii (p=0.048), Clostridia cluster IV (p=0.003) and Roseburia spp. (p=0.09) compared with controls). As in CD, siblings demonstrated a predominance of memory T cells (p=0.002) and elevated naïve CD4 T cell β7 integrin expression (p=0.01) compared with controls. FC was elevated (>50 μg/g) in 8/21 (38%) siblings compared with 2/25 (8%) controls (p=0.028); whereas IP did not differ between siblings and controls. Discriminant function analysis determined that combinations of these factors significantly discriminated between groups (χ(2)=80.4, df=20, p<0.001). Siblings were separated from controls by immunological and microbiological variables. Healthy siblings of patients with CD manifest immune and microbiological abnormalities associated with CD distinct from their genotype-related risk and provide an excellent model in which to investigate early CD pathogenesis. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Enteropathy-associated T-cell lymphoma--a clinicopathologic and array comparative genomic hybridization study.

PubMed

Ko, Young Hyeh; Karnan, Sivasundaram; Kim, Kyeong Mee; Park, Cheol Keun; Kang, Eun Suk; Kim, Young Ho; Kang, Won Ki; Kim, Seok Jin; Kim, Won Seog; Lee, Woo Yong; Chun, Ho Kyung; Seto, Masao

2010-09-01

According to the new World Health Organization classification system, there are 2 types of enteropathy-associated T-cell lymphoma. Type 1 is associated with celiac disease and accounts for the majority of cases in Western countries, whereas type 2 is not associated with celiac disease. To characterize enteropathy-associated T-cell lymphoma types in Korea, we carried out clinicopathologic and immunophenotypic analyses of 8 Koreans with enteropathy-associated T-cell lymphoma and investigated genomic profile using array comparative genomic hybridization. The tumors involved the small intestine in 5 patients and the colorectum in 3 patients. Two patients carried an HLA DQB10302 allele that corresponds to HLA DQ8. None of the patients had gluten-sensitive malabsorption syndrome. Intraepithelial lymphocytosis was observed in all patients. The sizes of the tumor cells were small or small-to-medium in 7 cases and medium-to-large in 1 case. The immunophenotypes of the tumor cells were CD4-CD8+CD56+ in 4 cases, CD4-CD8+CD56- in 1 case, CD4-CD8-CD56+ in 2 cases, and CD4-CD8-CD56- in 1 case. Array comparative genomic hybridization analysis showed that chromosome 9q33-q34.1 gain was present in 4 (80%) of the 5 cases examined. Other recurrent genomic alterations were gain of 6p21.1-21.31 (3/5, 60%), gain of 19q (2/5), and the loss of 3p12.1-p12.2 (2/5) and 3q26.31 (2/5). These results suggest that the most prevalent type of enteropathy-associated T-cell lymphoma in this geographic region is type 2, and the genetic changes associated with it are similar to those in Western countries. Copyright 2010 Elsevier Inc. All rights reserved.

The immunological response of HIV-positive patients initiating HAART at the Komfo Anokye Teaching Hospital, Kumasi, Ghana.

PubMed

Annison, L; Dompreh, A; Adu-Sarkodie, Y

2013-12-01

The study sought to document the experience of immunological improvement among Ghanaian PLHIV on HAART comparing different categories of patients. Serology Unit, Komfo Anokye Teaching Hospital, Kumasi, Ghana. The study comprised a convenient sample of 303 treatment naïve HIV patients due to start HAART. Questionnaires were used to collect patient demographic and clinical data. Four CD4 counts were measured at six-monthly intervals to determine rates of CD4 change. These were pre-therapy, 1(st) post-therapy, 2(nd) post-therapy, and 3(rd) post-therapy counts. The rates of CD4 change among the different categories of patients were also compared. At baseline, women had higher CD4 count (mean of 77.4 cells/μl), and mean age of participants was 40 years. The CD4 count increased from a mean baseline of 70.2 cells/μl to 229.2, 270.0, and 297.6 cells/μl at 6, 12, and 18 months of treatment respectively (P < 0.0001 at each time point). There were no gender (P=0.46) and age (P=0.96) differences in treatment response. There was no difference (P=0.18) in treatment response comparing those with CD4 <250 cells/μl and those whose CD4 count was between 250 and 350 cells/μl at baseline although patients with baseline CD4 count <250 cells/μl showed larger increases after 12 months of treatment. Out of 282 patients with pre-therapy CD4 count ≤250 cells/μl, 241 (85.5%) and 41 (14.5%) were adherents and nonadherents respectively. Mean rate of increase was 15.2 and 8.4 cells/μl/month in adherent and non-adherent patients respectively (p=0.2). The study suggests that a sustained CD4 increase could be achieved in adherent patients commencing therapy with baseline CD4 count ≤250 cells/μl, and that these patients have greater ability for immunological recovery during 12 months of treatment The study, therefore, concludes that significant immunological improvement is possible among Ghanaian PLHIV on HAART as long as a high level of treatment adherence is observed.

Reduced CD5(+) CD24(hi) CD38(hi) and interleukin-10(+) regulatory B cells in active anti-neutrophil cytoplasmic autoantibody-associated vasculitis permit increased circulating autoantibodies.

PubMed

Aybar, L T; McGregor, J G; Hogan, S L; Hu, Y; Mendoza, C E; Brant, E J; Poulton, C J; Henderson, C D; Falk, R J; Bunch, D O

2015-05-01

Pathogenesis of anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis is B cell-dependent, although how particular B cell subsets modulate immunopathogenesis remains unknown. Although their phenotype remains controversial, regulatory B cells (Bregs ), play a role in immunological tolerance via interleukin (IL)-10. Putative CD19(+) CD24(hi) CD38(hi) and CD19(+) CD24(hi) CD27(+) Bregs were evaluated in addition to their CD5(+) subsets in 69 patients with ANCA-associated vasculitis (AAV). B cell IL-10 was verified by flow cytometry following culture with CD40 ligand and cytosine-phosphate-guanosine (CpG) DNA. Patients with active disease had decreased levels of CD5(+) CD24(hi) CD38(hi) B cells and IL-10(+) B cells compared to patients in remission and healthy controls (HCs). As IL-10(+) and CD5(+) CD24(hi) CD38(hi) B cells normalized in remission within an individual, ANCA titres decreased. The CD5(+) subset of CD24(hi) CD38(hi) B cells decreases in active disease and rebounds during remission similarly to IL-10-producing B cells. Moreover, CD5(+) B cells are enriched in the ability to produce IL-10 compared to CD5(neg) B cells. Together these results suggest that CD5 may identify functional IL-10-producing Bregs . The malfunction of Bregs during active disease due to reduced IL-10 expression may thus permit ANCA production. © 2014 British Society for Immunology.

Soluble CD30 and Cd27 levels in patients undergoing HLA antibody-incompatible renal transplantation.

PubMed

Hamer, Rizwan; Roche, Laura; Smillie, David; Harmer, Andrea; Mitchell, Daniel; Molostvov, Guerman; Lam, For T; Kashi, Habib; Tan, Lam Chin; Imray, Chris; Fletcher, Simon; Briggs, David; Lowe, David; Zehnder, Daniel; Higgins, Rob

2010-08-01

HLA antibody-incompatible transplantation has a higher risk of rejection when compared to standard renal transplantation. Soluble CD30 (sCD30) has been shown in many, but not all, studies to be a biomarker for risk of rejection in standard renal transplant recipients. We sought to define the value of sCD30 and soluble CD27 (sCD27) in patients receiving HLA antibody-incompatible transplants. Serum taken at different time points from 32 HLA antibody-incompatible transplant recipients was retrospectively assessed for sCD30 and sCD27 levels by enzyme-linked immunosorbent assay (ELISA). This was compared to episodes of acute rejection, post-transplant donor-specific antibody (DSA) levels and 12 month serum creatinine levels. No association was found between sCD27 and sCD30 levels and risk of acute rejection or DSA levels. Higher sCD30 levels at 4-6 weeks post-transplantation were associated with a higher serum creatinine at 12 months. Conclusion patients undergoing HLA antibody-incompatible transplantation are at a high risk of rejection but neither sCD30 (unlike in standard transplantation) nor sCD27 was found to be a risk factor. High sCD30 levels measured at 4-6 weeks post-transplantation was associated with poorer graft function at one year. Copyright © 2010 Elsevier B.V. All rights reserved.

Intestinal alkaline phosphatase in the colonic mucosa of children with inflammatory bowel disease

PubMed Central

Molnár, Kriszta; Vannay, Ádám; Szebeni, Beáta; Bánki, Nóra Fanni; Sziksz, Erna; Cseh, Áron; Győrffy, Hajnalka; Lakatos, Péter László; Papp, Mária; Arató, András; Veres, Gábor

2012-01-01

AIM: To investigate intestinal alkaline phosphatase (iAP) in the intestinal mucosa of children with inflammatory bowel disease (IBD). METHODS: Colonic biopsy samples were taken from 15 newly diagnosed IBD patients and from 10 healthy controls. In IBD patients, specimens were obtained both from inflamed and non-inflamed areas. The iAP mRNA and protein expression was determined by reverse transcription-polymerase chain reaction and Western blotting analysis, respectively. Tissue localization of iAP and Toll-like receptor (TLR) 4 was investigated by immunofluorescent staining. RESULTS: The iAP protein level in the inflamed mucosa of children with Crohn’s disease (CD) and ulcerative colitis (UC) was significantly decreased when compared with controls (both P < 0.05). Similarly, we found a significantly decreased level of iAP protein in the inflamed mucosa in CD compared with non-inflamed mucosa in CD (P < 0.05). In addition, the iAP protein level in inflamed colonic mucosa in patients with UC was decreased compared with non-inflamed mucosa in patients with CD (P < 0.05). iAP protein levels in the non-inflamed mucosa of patients with CD were similar to controls. iAP mRNA expression in inflamed colonic mucosa of children with CD and UC was not significantly different from that in non-inflamed colonic mucosa with CD. Expression of iAP mRNA in patients with non-inflamed mucosa and in controls were similar. Co-localization of iAP with TLR4 showed intense staining with a dotted-like pattern. iAP was present in the inflamed and non-inflamed mucosa of patients with CD, UC, and in control biopsy specimens, irrespective of whether it was present in the terminal ileum or in the colon. However, the fluorescent signal of TLR4 was more pronounced in the colon compared with the terminal ileum in all groups studied. CONCLUSION: Lower than normal iAP protein levels in inflamed mucosa of IBD patients may indicate a role for iAP in inflammatory lesions in IBD. Based on our results, administration of exogenous iAP enzyme to patients with the active form of IBD may be a therapeutic option. PMID:22783049

Down-regulation of microRNA-451a facilitates the activation and proliferation of CD4+ T cells by targeting Myc in patients with dilated cardiomyopathy.

PubMed

Zeng, Zhipeng; Wang, Ke; Li, Yuanyuan; Xia, Ni; Nie, Shaofang; Lv, Bingjie; Zhang, Min; Tu, Xin; Li, Qianqian; Tang, Tingting; Cheng, Xiang

2017-04-07

CD4 + T cells are abnormally activated in patients with dilated cardiomyopathy (DCM) and might be associated with the immunopathogenesis of the disease. However, the underlying mechanisms of CD4 + T cell activation remain largely undefined. Our aim was to investigate whether the dysregulation of microRNAs (miRNAs) was associated with CD4 + T cell activation in DCM. CD4 + T cells from DCM patients showed increased expression levels of CD25 and CD69 and enhanced proliferation in response to anti-CD3/28, indicating an activated state. miRNA profiling analysis of magnetically sorted CD4 + T cells revealed a distinct pattern of miRNA expression in CD4 + T cells from DCM patients compared with controls. The level of miRNA-451a (miR-451a) was significantly decreased in the CD4 + T cells of DCM patients compared with that of the controls. The transfection of T cells with an miR-451a mimic inhibited their activation and proliferation, whereas an miR-451a inhibitor produced the opposite effects. Myc was directly inhibited by miR-451a via interaction with its 3'-UTR, thus identifying it as an miR-451a target in T cells. The knockdown of Myc suppressed the activation and proliferation of T cells, and the expression of Myc was significantly up-regulated at the mRNA level in CD4 + T cells from patients with DCM. A strong inverse correlation was observed between the Myc mRNA expression and miR-451a transcription level. Our data suggest that the down-regulation of miR-451a contributes to the activation and proliferation of CD4 + T cells by targeting the transcription factor Myc in DCM patients and may contribute to the immunopathogenesis of DCM. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

Ex-vivo characterization of regulatory T cells in pulmonary tuberculosis patients, latently infected persons, and healthy endemic controls.

PubMed

Zewdie, Martha; Howe, Rawleigh; Hoff, Søren T; Doherty, T Mark; Getachew, Nahom; Tarekegne, Azeb; Tessema, Bamlak; Yamuah, Lawrence; Aseffa, Abraham; Abebe, Markos

2016-09-01

Regulatory T cells (Treg) are an essential arm of adaptive immunity not only in tolerance and autoimmunity but also in infectious diseases. In Tuberculosis (TB), it has been suggested that the frequency of Tregs is higher in the blood of TB patients when compared to healthy controls with subsequent decline after treatment. However, with the discovery that FOXP3, the hallmark marker of Tregs, is not exclusive to Tregs and the lack of specific markers for Tregs, it has been a challenge to fully understand the role of Tregs in TB. We isolated PBMC from smear positive TB patients (TB, N = 13) before and after treatment, latent TB infected participants (LTBI, N = 8), and healthy endemic controls (EC, N = 9) and evaluated the frequency of different populations of Tregs and expression of FOXP3 by flowcytometry using six markers. The findings in this study showed that the association of Treg frequency with TB disease depends on the phenotypic markers used. While the frequency of CD4(+)CD25(+/hi) T cells was higher in TB patients compared to LTBI individuals, there was no difference in the frequency of CD4(+)CD25(+)FOXP3(+)CD127(lo) Treg among TB, LTBI, or EC. However, delineation of Tregs into active and naïve subsets revealed a significant increase in FOXP3 expression in active primed Tregs (CD4(+)CD25(+)FOXP3(+)CD127(lo)CD45RO(+)Ki-67(+)) of TB patients compared to LTBI and EC; and a significantly higher frequency of resting primed (CD45RO(+)Ki-67(-)) Treg in QuantiFERON negative EC compared to TB patients. After treatment completion, there was a significant decline in the frequency of active primed Treg, median (IQR) from 12.4% (9.5-21.9) of Tregs to 9.3% (7.0-12.2); P = 0.003 Wilcoxon signed rank test. We conclude that Treg subsets may be differentially regulated and expressed in TB disease, cure, and infection. Copyright © 2016 Elsevier Ltd. All rights reserved.

Ex-vivo characterization of regulatory T cells in pulmonary tuberculosis patients, latently infected persons, and healthy endemic controls

PubMed Central

Zewdie, Martha; Howe, Rawleigh; Hoff, Søren T.; Doherty, T. Mark; Getachew, Nahom; Tarekegne, Azeb; Tessema, Bamlak; Yamuah, Lawrence; Aseffa, Abraham; Abebe, Markos

2016-01-01

SUMMARY Background Regulatory T cells (Treg) are an essential arm of adaptive immunity not only in tolerance and autoimmunity but also in infectious diseases. In Tuberculosis (TB), it has been suggested that the frequency of Tregs is higher in the blood of TB patients when compared to healthy controls with subsequent decline after treatment. However, with the discovery that FOXP3, the hallmark marker of Tregs, is not exclusive to Tregs and the lack of specific markers for Tregs, it has been a challenge to fully understand the role of Tregs in TB. Method We isolated PBMC from smear positive TB patients (TB, N = 13) before and after treatment, latent TB infected participants (LTBI, N = 8), and healthy endemic controls (EC, N = 9) and evaluated the frequency of different populations of Tregs and expression of FOXP3 by flowcytometry using six markers. Results The findings in this study showed that the association of Treg frequency with TB disease depends on the phenotypic markers used. While the frequency of CD4+CD25+/hi T cells was higher in TB patients compared to LTBI individuals, there was no difference in the frequency of CD4+CD25+FOXP3+CD127lo Treg among TB, LTBI, or EC. However, delineation of Tregs into active and naïve subsets revealed a significant increase in FOXP3 expression in active primed Tregs (CD4+CD25+FOXP3+CD127loCD45RO+Ki-67+) of TB patients compared to LTBI and EC; and a significantly higher frequency of resting primed (CD45RO+Ki-67−) Treg in QuantiFERON negative EC compared to TB patients. After treatment completion, there was a significant decline in the frequency of active primed Treg, median (IQR) from 12.4% (9.5–21.9) of Tregs to 9.3% (7.0–12.2); P = 0.003 Wilcoxon signed rank test. We conclude that Treg subsets may be differentially regulated and expressed in TB disease, cure, and infection. PMID:27553411

Autoantibody-mediated regulation of B cell responses by functional anti-CD22 autoantibodies in patients with systemic sclerosis.

PubMed

Odaka, M; Hasegawa, M; Hamaguchi, Y; Ishiura, N; Kumada, S; Matsushita, T; Komura, K; Sato, S; Takehara, K; Fujimoto, M

2010-02-01

Studies have demonstrated that B cells play important roles in systemic sclerosis (SSc), especially through the CD19/CD22 autoimmune loop. CD22 is a B cell-specific inhibitory receptor that dampens B cell antigen receptor (BCR) signalling via tyrosine phosphorylation-dependent mechanism. In this study, we examined the presence and functional property of circulating autoantibodies reacting with CD22 in systemic sclerosis. Serum samples from 10 tight skin (TSK/+) mice and 50 SSc patients were assessed for anti-CD22 autoantibodies by enzyme-linked immunosorbent assays using recombinant mouse or human CD22. The association between anti-CD22 antibodies and clinical features was also investigated in SSc patients. Furthermore, the influence of SSc serum including anti-CD22 autoantibodies for CD22 tyrosine phosphorylation was examined by Western blotting using phosphotyrosine-specific antibodies reacting with four major tyrosine motifs of CD22 cytoplasmic domain. Anti-CD22 autoantibodies were positive in 80% of TSK/+ mice and in 22% of SSc patients. Patients positive for anti-CD22 antibodies showed significantly higher modified Rodnan skin thickness score compared with patients negative for anti-CD22 antibodies. Furthermore, anti-CD22 antibodies from patients' sera were capable of reducing phosphorylation of all four CD22 tyrosine motifs, while sera negative for anti-CD22 antibodies did not affect CD22 phosphorylation. Thus, a subset of SSc patients possessed autoantibodies reacting with a major inhibitory B cell response regulator, CD22. Because these antibodies can interfere CD22-mediated suppression onto B cell activation in vitro, SSc B cells produce functional autoantibodies that can enhance their own activation. This unique regulation may contribute to the autoimmune aspect of SSc.

Readressing the role of Toll-like receptor-4 alleles in inflammatory bowel disease: colitis, smoking, and seroreactivity.

PubMed

Manolakis, Anastassios C; Kapsoritakis, Andreas N; Kapsoritaki, Anastasia; Tiaka, Elisavet K; Oikonomou, Konstantinos A; Lotis, Vassilis; Vamvakopoulou, Dimitra; Davidi, Ioanna; Vamvakopoulos, Nikolaos; Potamianos, Spyros P

2013-02-01

Toll-like receptor (TLR) polymorphisms, and especially TLR-4 Asp299Gly and TLR-4 Thr399Ile, have been linked with Crohn's disease (CD) and to a lesser extent with ulcerative colitis (UC), CD behavior, and compromised seroreactivity to microbial antigens. Available data, however, are conflicting. To address these issues, the distribution of TLR-4 polymorphic alleles was assessed in patients with UC, CD, and healthy controls (HC), considering patient and disease characteristics as well as related serological markers. TLR-4 Asp299Gly and TLR-4 Thr399Ile polymorphisms were determined in 187 UC and 163 CD patients and 274 randomly selected HC. C reactive protein, anti-Saccharomyces cerevisiae mannan antibodies, anti-mannobioside carbohydrate antibodies, anti-laminariobioside carbohydrate antibodies IgG, and anti-chitobioside carbohydrate antibodies (ACCA) IgA levels were also assessed. UC and especially pancolitis patients carried the mutant alleles more frequently compared to CD patients and HC or UC patients with different disease extents (P = 0.002 and P < 0.0001, respectively). Involvement of the colon was more frequent in CD patients with mutant TLR-4 compared to those with wild-type alleles (P = 0.004). Levels and positivity rates of ACCA IgA were lower in inflammatory bowel disease (IBD) patients carrying the mutant compared to those with wild-type alleles (0.075 < P < 0.05). Despite the mutant TLR-4 predisposition for UC pancolitis, smoking was associated with more limited disease (P < 0.001). The presence of TLR-4 Asp299Gly and TLR-4 Thr399Ile polymorphisms is related to UC pancolitis, involvement of the colon in CD, and lower ACCA IgA levels. Smoking reduces the extent of UC, even in the presence of mutant alleles.

The postoperative clinical outcomes and safety of early enteral nutrition in operated gastric cancer patients.

PubMed

Li, Bing; Liu, Hong-Yi; Guo, Shao-Hua; Sun, Peng; Gong, Fang-Ming; Jia, Bao-Qing

2015-01-01

This study investigated the impact of early enteral nutrition (EEN) on the clinical outcomes of gastric cancer patients after radical gastrectomy. Four hundred gastric cancer patients undergoing radical gastrectomy of any extend with D2 nodal dissection were randomly divided into an experimental and a control group with 200 cases in each group. Patients in the control group received postoperative parenteral nutrition (PN), while patients in the experimental group received postoperative EEN. After treatment, the clinical outcomes, postoperative immune function, and nutritional status of the two groups were evaluated. The postoperative fever time, intestinal function recovery time, anal exhaust time, and the length of hospital stay for patients in the experimental group were significantly shorter than those of the control group. We did not find significant differences in anastomotic leak, postoperative ileus and regurgitation between the two groups. The activities of multiple immune cell types, including CD3⁺, CD4⁺, CD4⁺/CD8⁺, and natural killer (NK) cells, were significantly lower in both groups on postoperative day 1 when compared with the preoperative levels (p<0.05). The level of CD8⁺ was not significantly different between the two groups (p>0.05). After treatment, levels of CD3⁺, CD4⁺, CD4⁺/CD8⁺, and NK cells in the experimental group patients were 35.6 ± 4.2, 42.2 ± 3.0, 1.7 ± 0.3, and 27.3 ± 5.3%, respectively, on postoperative day 7, which were similar to the preoperative levels. The immune cell levels from the control group patients remained significantly lower when compared with preoperative values; in addition, these values were also significantly lower when compared with the EEN patients (p<0.05) CONCLUSION: For gastric cancer patients undergoing radical gastrectomy, the clinical outcome, immune function and nutritional status after EEN were significantly improved. These data suggest the widespread use of EEN in clinical practice.

Elevated soluble CD30 correlates with development of bronchiolitis obliterans syndrome following lung transplantation.

PubMed

Fields, Ryan C; Bharat, Ankit; Steward, Nancy; Aloush, Aviva; Meyers, Brian F; Trulock, Elbert P; Chapman, William C; Patterson, G Alexander; Mohanakumar, Thalachallour

2006-12-27

The long-term function of lung transplants is limited by chronic rejection (bronchiolitis obliterans syndrome, BOS). Due to lack of specific markers, BOS is diagnosed clinically. Because there is strong evidence that alloimmunity plays a significant role in the pathogenesis of BOS, we investigated whether soluble CD30 (sCD30), a T-cell activation marker, would correlate with BOS. Sera collected serially from BOS+ (n = 20) and matched BOS- (n = 20) lung transplant (LT) patients were analyzed for sCD30 by enzyme-linked immunosorbent assay. Pretransplant sera and sera from normal donors were also analyzed. PreLT levels were comparable to normal subjects. However, posttransplant there was a significant elevation in sCD30 levels during BOS development in all BOS+ patients, compared to BOS- (mean 139.8+/-10.7 vs. 14.8+/-2.7 U/ml, P < 0.001). sCD30 levels declined in the BOS+ patients but were still elevated compared to BOS- (48.52+/-5.04 vs. 7.19+/-2.9, P < 0.0001). We conclude that sCD30 may represent a novel marker to monitor the development of BOS.

Characterization of CD4+ T cell-mediated cytotoxicity in patients with multiple myeloma.

PubMed

Zhang, Xiaole; Gao, Lei; Meng, Kai; Han, Chunting; Li, Qiang; Feng, Zhenjun; Chen, Lei

2018-05-01

Multiple myeloma (MM) is an incurable cancer characterized by the development of malignant plasma cells. The CD8 T cell-mediated cytotoxicity is considered a major player in antitumor immunity, but in MM patients, the CD8 T cells displayed senescence markers and were functionally impaired. To investigate whether cytotoxic CD4 T cells could act as a treatment alternative in MM, we examined the frequency and function of naturally occurring cytotoxic CD4 T cells in MM patients. The cytotoxic CD4 T cells were identified as granzyme-A, granzyme B-, and perforin-expressing CD4 T cells, and their frequencies were significantly upregulated in MM patients when compared with healthy controls. The frequencies of cytotoxic CD4 T cells in MM patients were not associated with the frequencies of cytotoxic CD8 T cells, but were negatively associated with disease severity. Interestingly, the expression levels of inhibitory molecules, including PD-1 and CTLA-4, were significantly lower in cytotoxic CD4 T cells than in cytotoxic CD8 T cells. When co-incubated with autologous CD38 + CD138 + plasma cells, CD4 T cells were capable of eliminating plasma cells with varying degrees of efficacy. In MM patients, the frequency of circulating plasma cells was negatively correlated with the frequency of cytotoxic CD4 T cells. Therefore, CD4 T cell-mediated cytotoxicity existed naturally in MM patients and could potentially act as an option in antitumor therapies. Copyright © 2018 Elsevier Inc. All rights reserved.

Increased numbers of CD38 molecules on bright CD8+ T lymphocytes in infectious mononucleosis caused by Epstein–Barr virus infection

PubMed Central

ŽIDOVEC LEPEJ, S; VINCE, A; ÐAKOVIĆ RODE, O; REMENAR, A; JEREN, T

2003-01-01

The aim of this study was to quantify the expression of CD38 on CD8+ T lymphocytes of patients with infectious mononucleosis (IM) caused by Epstein–Barr virus (EBV) and cytomegalovirus (CMV). CD38 quantification technique chosen for this study was based on the enumeration of CD38 antibody binding sites in comparison to the quantification standards rather than determining relative fluorescence, which is difficult to standardize. The study enrolled 19 patients with typical clinical and laboratory parameters compatible with EBV-induced IM as well as 10 patients with atypical clinical presentation of this disease. Furthermore, CD38 expression was analysed in a group of 13 patients with IM caused by CMV infection. CD38 quantification was performed within 6 days of the presentation of symptoms. All three groups of IM patients showed a statistically significant increase in the number of anti-CD38 antibody binding sites (which correspond to the number of CD38 molecules) on bright CD8+ T lymphocytes compared to healthy controls. The numbers of CD38 molecules expressed on CD8+ T lymphocytes did not differ significantly between IM patients with typical and atypical clinical presentation of the disease. Patients with CMV-induced IM had significantly lower numbers of CD38 molecules expressed on CD8+ T lymphocytes. Therefore, we conclude that CD38 quantification could be helpful in differential diagnostics of IM cases with atypical clinical presentation. PMID:12930365

Hospital revisit rate after a diagnosis of conversion disorder.

PubMed

Merkler, Alexander E; Parikh, Neal S; Chaudhry, Simriti; Chait, Alanna; Allen, Nicole C; Navi, Babak B; Kamel, Hooman

2016-04-01

To estimate the hospital revisit rate of patients diagnosed with conversion disorder (CD). Using administrative data, we identified all patients discharged from California, Florida and New York emergency departments (EDs) and acute care hospitals between 2005 and 2011 with a primary discharge diagnosis of CD. Patients discharged with a primary diagnosis of seizure or transient global amnesia (TGA) served as control groups. Our primary outcome was the rate of repeat ED visits and hospital admissions after initial presentation. Poisson regression was used to compare rates between diagnosis groups while adjusting for demographic characteristics. We identified 7946 patients discharged with a primary diagnosis of CD. During a mean follow-up of 3.0 (±1.6) years, patients with CD had a median of three (IQR, 1-9) ED or inpatient revisits, compared with 0 (IQR, 0-2) in patients with TGA and 3 (IQR, 1-7) in those with seizures. Revisit rates were 18.25 (95% CI, 18.10 to 18.40) visits per 100 patients per month in those with CD, 3.90 (95% CI, 3.84 to 3.95) in those with TGA and 17.78 (95% CI, 17.75 to 17.81) in those with seizures. As compared to CD, the incidence rate ratio for repeat ED visits or hospitalisations was 0.89 (95% CI, 0.86 to 0.93) for seizure disorder and 0.32 (95% CI 0.31 to 0.34) for TGA. CD is associated with a substantial hospital revisit rate. Our findings suggest that CD is not an acute, time-limited response to stress, but rather that CD is a manifestation of a broader pattern of chronic neuropsychiatric disease. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

miR-29b and miR-198 overexpression in CD8+ T cells of renal cell carcinoma patients down-modulates JAK3 and MCL-1 leading to immune dysfunction.

PubMed

Gigante, Margherita; Pontrelli, Paola; Herr, Wolfgang; Gigante, Maddalena; D'Avenia, Morena; Zaza, Gianluigi; Cavalcanti, Elisabetta; Accetturo, Matteo; Lucarelli, Giuseppe; Carrieri, Giuseppe; Battaglia, Michele; Storkus, Walter J; Gesualdo, Loreto; Ranieri, Elena

2016-04-11

Mammalian microRNAs (miR) regulate the expression of genes relevant for the development of adaptive and innate immunity against cancer. Since T cell dysfunction has previously been reported in patients with renal cell carcinoma (RCC; clear cell type), we aimed to analyze these immune cells for genetic and protein differences when compared to normal donor T cells freshly after isolation and 35 days after in vitro stimulation (IVS) with HLA-matched RCC tumor cells. We investigated gene expression profiles of tumor-reactive CD8(+) T cells obtained from RCC patient and compared with their HLA-matched healthy sibling donors using a microarray approach. In addition, miRNAs analysis was performed in a validation cohort of peripheral blood CD8(+) T cells from 25 RCC patients compared to 15 healthy volunteers. We observed that CD8(+) T cells from RCC patients expressed reduced levels of anti-apoptotic and proliferation-associated gene products when compared with normal donor T cells both pre- and post-IVS. In particular, JAK3 and MCL-1 were down-regulated in patient CD8(+) T cells versus their normal counterparts, likely due to defective suppressor activity of miR-29b and miR-198 in RCC CD8(+) T cells. Indeed, specific inhibition of miR-29b or miR-198 in peripheral blood mononuclear cells (PBMCs) isolated from RCC patients, resulted in the up-regulation of JAK3 and MCL-1 proteins and significant improvement of cell survival in vitro. Our results suggest that miR-29b and miR-198 dysregulation in RCC patient CD8(+) T cells is associated with dysfunctional immunity and foreshadow the development of miR-targeted therapeutics to correct such T cell defects in vivo.

Investigation of celiac disease followed by immune thrombocytopenic purpura diagnosis in patients and comparison with literature

PubMed Central

Sarbay, Hakan; Kocamaz, Halil; Akin, Mehmet; Ozhan, Bayram

2017-01-01

OBJECTIVE: Celiac disease (CD) and Immune thrombocytopenic purpura (ITP) may occur together as a result of similar autoimmune mechanisms. The aim of this study was to assess the frequency of CD in a group of ITP patients and in the literature. METHODS: A total of 29 patients in Pamukkale University Faculty of Medicine Hospital Pediatric Hematology and Oncology Department with ITP were included in the study. Test was performed for the antibodies related to CD. Positive result for celiac antibodies was confirmed with biopsy. The results were compared with the literature. RESULTS: Of the study group, 13 patients (44.8%) were female and 16 (55.2%) were male. The mean age was 7.2±4.7 years and mean platelet count at the time of admission was 13,440±11,110/mm3 (range: 2000-41,000/mm3). Twelve patients (41.4%) were diagnosed as acute ITP, 6 patients (20.7%) as persistent ITP, and 11 patients (37.9%) as chronic ITP, according to the duration of thrombocytopenia. Antibody positivity was detected in 1 patient. Histological evaluation was compatible with CD. Results were compared with studies regarding the prevalence of CD in the population. No significant difference was found. CONCLUSION: Although it is not necessary to perform CD test in every case of ITP, the presence of differential diagnosis of CD is important to prevent unnecessary treatment, especially in ITP patients with growth retardation or malabsorption findings. PMID:28971174

Higher constitutive IL15Rα expression and lower IL-15 response threshold in coeliac disease patients

PubMed Central

Bernardo, D; Garrote, J A; Allegretti, Y; León, A; Gómez, E; Bermejo-Martin, J F; Calvo, C; Riestra, S; Fernández-Salazar, L; Blanco-Quirós, A; Chirdo, F; Arranz, E

2008-01-01

The IL-15 triggering effect of gliadin is not exclusive to coeliac disease (CD) patients, whereas the secondary response is CD specific. We have studied the expression of the IL-15 receptor, and the IL-15 response upon stimulation, in non-CD and CD patients, and the possible existence of a lower immunological threshold in the latter. Forty-two CD patients (20 on a gluten-containing diet, GCD, and 22 on gluten-free diet, GFD) and 24 non-CD healthy individuals were studied. IL15Rα mRNA expression, and tissue characterization, were assayed in the duodenum. Biopsies from six CD patients on GFD and 10 non-CD individuals were studied in vitro using organ culture in basal conditions, as well as after IL-15 stimulation discarding basal IL-15 production. Secretion of immune mediators was measured in the culture supernatants. IL15Rα mRNA expression was increased in CD patients, as compared with non-CD controls (on GFD P = 0·0334, on GCD P = 0·0062, respectively), and confirmed also by immunofluorescence. No differences were found between CD patients on GFD and on GCD. After in vitro IL-15 stimulation, IL15Rα expression was only triggered in non-CD controls (P = 0·0313), though it remained increased in CD patients. Moreover, IL-15 induced a more intense immunological response in CD patients after triggering the production of both nitrites and IFNγ (P = 0·0313, P = 0·0313, respectively). Gliadin-induced IL15 has a lower response threshold in CD patients, leading to the production of other immune mediators and the development of the intestinal lesion, and thus magnifying its effects within the CD intestine. PMID:18821940

An evaluation of serum soluble CD30 levels and serum CD26 (DPPIV) enzyme activity as markers of type 2 and type 1 cytokines in HIV patients receiving highly active antiretroviral therapy

PubMed Central

Keane, N M; Price, P; Lee, S; Stone, S F; French, M A

2001-01-01

This study evaluates serum CD26 (dipeptidyl peptidase IV, DPPIV) enzyme activity and serum levels of soluble CD30 as markers of T1 and T2 cytokine environments in HIV patients who achieved immune reconstitution after highly active antiretroviral therapy (HAART). Patients who had experienced inflammatory disease associated with pre-existent opportunistic infections after HAART (immune restoration diseases, IRD) were considered separately. Serum sCD30 levels and CD26 (DPPIV) enzyme activity were compared with IFN-γ production by PBMC cultured with cytomegalovirus (CMV) antigen in controls and patient groups. High sCD30 levels were associated with low IFN-γ production after antigenic stimulation in control subjects and, to a lesser extent, in immune reconstituted HIV patients. There was no association between serum CD26 (DPPIV) enzyme activity and IFN-γ production or sCD30 levels. Serum sCD30 levels and CD26 (DPPIV) enzyme activity were significantly increased in immune reconstituted patients with high HIV viral loads. Patients who had experienced CMV retinitis as an IRD had significantly higher sCD30 levels than all other patient groups. Hence, high sCD30 levels may be a marker of a T2 cytokine environment in HIV patients with immune reconstitution and are associated with higher HIV viral loads and a history of CMV associated IRD. PMID:11678906

Interleukin 27 is up-regulated in patients with active inflammatory bowel disease.

PubMed

Furuzawa Carballeda, Janette; Fonseca Camarillo, Gabriela; Yamamoto-Furusho, Jesús K

2016-08-01

The aim of the study was to characterize and quantify tissue gene and protein expression of IL-27 in ulcerative colitis (UC) and Crohn's disease (CD) patients. This is an observational and cross-sectional study. Fifty-four patients with IBD were studied: 27 active UC, 12 inactive UC, 10 active CD, and 5 inactive CD. All patients belonged to the Inflammatory Bowel Disease Clinic at the Instituto Nacional de Ciencias Médicas y Nutrición. We found that IL-27 gene expression was significantly higher in active UC versus inactive UC group (P = 0.015). The IL-27 mRNA expression was increased in patients with active CD compared with inactive CD disease (P = 0.035). The percentage of IL-27 immunoreactive cells was higher in active UC versus active CD patients and non-inflamed tissue controls. The IL-27 was significantly elevated in active UC and CD patients, and it was associated with disease severity.

Identification of patients at risk of acute rejection by pretransplantation and posttransplantation monitoring of soluble CD30 levels in kidney transplantation.

PubMed

Sengul, Sule; Keven, Kenan; Gormez, Ulku; Kutlay, Sim; Erturk, Sehsuvar; Erbay, Bulent

2006-04-27

In this study, we investigated the impact of pre- and posttransplantation sCD30 monitoring on early (<6 months) acute rejection (AR) risk and analyzed the effect of different immunosuppressive regimens on posttransplantation sCD30 levels in kidney recipients. Fifty patients receiving kidney allograft and 10 healthy donors were included in this retrospective cohort study. Eight patients developed biopsy-proven AR (19%). In pretransplantation samples, patients showed a significantly higher sCD30 than healthy controls. The pretransplantation and posttransplantation (day-15) sCD30 levels were significantly elevated in rejecting patients compared to non-rejecting patients. No significant differences among immunosuppressive regimens were found in posttransplantation sCD30 levels. High pretransplantation and posttransplantation (day 15) sCD30 levels are associated with increased risk of early AR, and sCD30 can be another tool to evaluate immunological risk prior to kidney transplantation. There was no difference in immunosuppressive regimens used in this study on posttransplantation sCD30 levels at the first month.

Immune responses induced by T-cell vaccination in patients with rheumatoid arthritis

PubMed Central

Ivanova, Irina; Seledtsova, Galina; Mamaev, Sergey; Shishkov, Alexey; Seledtsov, Viktor

2014-01-01

Patients with rheumatoid arthritis (RA) were treated with a cellular vaccine, which consisted of autologous collagen-reactive T-cells. This study showed that antigen-specific proliferative activity of the peripheral blood mononuclear cells was significantly downregulated after T-cell vaccination in RA patients. T-cell vaccination resulted in a statistically significant decrease in plasma IFNγ levels and a concomitant increase in IL-4 levels in treated patients. Accordingly, following T-cell vaccination the number of IFNγ-producing CD4+ and CD8+ T-cells was decreased by 1.6–1.8-fold, which was paralleled by 1.7-fold increases in IL-4-producing CD4+ T-cells. In addition, the present study showed 5–7-fold increase in the CD8+CD45RO+CD62L– effector memory T-cells and central memory T-cells (both CD4+ CD45RO+CD62L+ T-cells and CD8+CD45RO+CD62L+ T-cells) in RA patients, as compared with healthy individuals. We observed significant reduction in CD4+ and CD8+ central memory T-cells, as well as reduction in CD8+ effector memory T-cells in vaccinated patients in the course of the treatment. We also demonstrated that CD4+CD25+FoxP3+ regulatory T-cell levels were significantly up-regulated in the peripheral blood of RA patients following T-cell vaccination. However, CD4+CD25-FoxP3+ Т-cell levels did not significantly change during the entire T-cell vaccination course. In conclusion, the T-cell immunotherapy regimen used resulted in the clinical improvement, which was achieved in 87% patients. PMID:24633313

CD34 cells from patients with trisomy 8 myelodysplastic syndrome (MDS) express early apoptotic markers but avoid programmed cell death by up-regulation of antiapoptotic proteins

PubMed Central

Pfannes, Loretta; Chen, Gubin; Shah, Simant; Solomou, Elena E.; Barrett, John; Young, Neal S.

2007-01-01

CD34 cells from patients with trisomy 8 myelodysplastic syndrome (MDS) are distinguished from other MDS cells and from normal hematopoietic cells by their pronounced expression of apoptotic markers. Paradoxically, trisomy 8 clones can persist in patients with bone marrow failure and expand following immunosuppression. We previously demonstrated up-regulation of c-myc and CD1 by microarray analysis. Here, we confirmed these findings by real-time polymerase chain reaction (PCR), demonstrated up-regulation of survivin, c-myc, and CD1 protein expression, and documented comparable colony formation by annexin+ trisomy 8− CD34+ and annexin− CD34 cells. There were low levels of DNA degradation in annexin+ trisomy 8 CD34 cells, which were comparable with annexin− CD34 cells. Trisomy 8 cells were resistant to apoptosis induced by gamma irradiation. Knock-down of survivin by siRNA resulted in preferential loss of trisomy 8 cells. These results suggest that trisomy 8 cells undergo incomplete apoptosis and are nonetheless capable of colony formation and growth. PMID:17090657

Serum levels of the soluble form of CD30 molecule as a tumor marker in CD30+ anaplastic large-cell lymphoma.

PubMed

Nadali, G; Vinante, F; Stein, H; Todeschini, G; Tecchio, C; Morosato, L; Chilosi, M; Menestrina, F; Kinney, M C; Greer, J P

1995-06-01

To determine serum levels of the soluble form of CD30 molecule (sCD30) in patients with Ki-1/CD30+ anaplastic large-cell lymphoma (ALCL), and to evaluate its correlation with clinical features at presentation and its possible role as a tumor marker to monitor response to treatment and subsequent follow-up. sCD30 serum levels were measured with an improved commercial sandwich enzyme-linked immunosorbent assay (ELISA) test kit in 24 patients with CD30+ ALCL at diagnosis and in 13 after treatment. Increased values (> 20 U/mL) at diagnosis were observed in 23 of 24 cases (median, 842.5 U/mL; range, 16 to 37,250) as compared with controls (P < .0001). These values were greater than those of 60 stage-matched cases of Hodgkin's disease (HD) (P < .0001). The highest median value was observed in patients with T-cell-type ALCL (1,690 U/mL), with a significant overall difference as compared with B- and null-cell types (P = .004). Phenotype maintained its significance when results were corrected for other parameters, such as age, sex, and stage (P = .03). sCD30 values returned to the normal range in complete remission (CR), but remained increased in one patient who only partially responded to treatment. Subsequent increases of sCD30 levels were recorded in four of four patients after relapse. sCD30 appears to be a new biologic serum tumor marker of possible use in the clinical setting of CD30+ ALCL.

Co-expression of LAG3 and TIM3 identifies a potent Treg population that suppresses macrophage functions in colorectal cancer patients.

PubMed

Ma, Qiang; Liu, Junning; Wu, Guoliang; Teng, Mujian; Wang, Shaoxuan; Cui, Meng; Li, Yuantao

2018-06-15

Regulatory T (Treg) cells are critical suppressors of inflammation and are thought to exert mainly deleterious effects in cancers. In colorectal cancer (CRC), Foxp3 +  Treg accumulation in the tumor was associated with poor prognosis. Hence, we examined the circulating Treg cells in CRC patients. Compared to controls, CRC patients presented mild upregulations in CD4 + CD25 +/hi T cells and in the more canonical CD4 + CD25 +/hi Foxp3 + Treg cells in peripheral blood mononuclear cells. Both of these Treg populations could be roughly divided into LAG3 - TIM3 - and LAG3 + TIM3 + subsets. In CRC patients, the LAG3 + TIM3 + subset represented approximately half of CD4 + CD25 +/hi T cells and greater than 60% of CD4 + CD25 +/hi Foxp3 + Treg cells, which was significantly more frequent than in healthy controls. Compared to the LAG3 - TIM3 - CD4 + CD25 +/hi T cells, the LAG3 + TIM3 + CD4 + CD25 +/hi T cells presented considerably higher transforming growth factor (TGF)-β and slightly higher interleukin (IL)-10 secretion, together with higher CTLA-4 and Foxp3 expression levels. Notably, macrophages following incubation with LAG3 - TIM3 - CD4 + CD25 +/hi T cells and LAG3 + TIM3 + CD4 + CD25 +/hi T cells displayed different characteristics. Macrophages incubated with LAG3 + TIM3 + CD4 + CD25 +/hi T cells presented lower expression of MHC class II, CD80, CD86, and tumor necrosis factor alpha (TNFα) but higher expression of IL-10, than macrophages incubated with LAG3 - TIM3 - CD4 + CD25 +/hi T cells. Together, our investigations demonstrated that CRC patients presented an enrichment of circulating Treg cells, in which the LAG3 + TIM3 + subset exhibited more potent expression of inhibitory molecules, and furthermore, the LAG3 + TIM3 + Treg cells could suppress the proinflammatory activation of macrophages more potently than the LAG3 - TIM3 - Treg cells. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Increased Prevalence of Luminal Narrowing and Stricturing Identified by Enterography in Pediatric Crohn Disease Patients with Elevated Granulocyte-Macrophage Colony Stimulating Factor Auto-antibodies

PubMed Central

Dykes, Dana M.H.; Towbin, Alexander J.; Bonkowski, Erin; Chalk, Claudia; Bezold, Ramona; Lake, Kathleen; Kim, Mi-Ok; Heubi, James E.; Trapnell, Bruce C.; Podberesky, Daniel J.; Denson, Lee A.

2013-01-01

Background Crohn disease (CD) patients with elevated Granulocyte-Macrophage Colony-Stimulating Factor auto-antibodies (GM-CSF Ab) are more likely to develop stricturing behavior requiring surgery. Computed Tomography or Magnetic Resonance Enterography (CTE or MRE) may detect luminal narrowing (LN) prior to stricture development. Objective To determine whether CD patients with elevated GM-CSF Ab (≥ 1.6 mcg/mL) have a higher prevalence of LN and stricturing on CTE or MRE. Methods A single center, cross-sectional study of 153 pediatric CD patients and controls undergoing CTE or MRE. A novel scoring system evaluated for disease activity, presence of LN, stricture, intra-abdominal abscess, or fistulae Ouutcomes were compared with respect to antibody status using Fisher's exact test, logistic regression, and the unpaired t-test. Results GM-CSF Ab were elevated in CD patients (n=114) with a median (IQR) GM-CSF Ab level of 2.3 mcg/mL (0.5, 6.6) compared with healthy and disease controls, p=0.001. Ileal disease location was more common in CD patients with high GM-CSF Ab, p<0.001. Luminal narrowing increased from 39% in CD patients with low GM-CSF Ab to 71% in those with high levels (p=0.004). High GM-CSF Ab remained significantly associated with LN in a multivariate logistic model. Stricturing increased from 4% in CD patients with low GM-CSF Ab to 19% in those with high GM-CSF Ab (p=0.03). Conclusions Pediatric CD patients with high GM-CSF Ab levels have a higher prevalence of LN on CTE or MRE. Further study will be needed to determine whether medical therapy will reduce progression to stricturing behavior in these patients. PMID:23893081

Do implant-supported dentures facilitate efficacy of eating more healthily?

PubMed

Moynihan, P J; Elfeky, A; Ellis, J S; Seal, C J; Hyland, R M; Thomason, J M

2012-10-01

Edentulous persons have poor diet quality demonstrating a need for dietary intervention. Implant-supported mandibular overdentures (IODs) have functional advantages over conventional dentures (CD), but whether they enhance the ability to eat more healthily following dietary advice is unknown. This study aimed to compare the effectiveness of dietary intervention between IODs and CD patients. Edentulous adults (28 IOD and 26 CD) received customised dietary advice. The percentage contribution of dietary fats, carbohydrate and protein to energy (kcal) intake, dietary intakes of fibre, fruits, vegetables and antioxidants, and plasma antioxidants were assessed pre- and at 3 and 6 months post-dietary intervention. Both groups increased fruit and vegetable intake at 3 and 6 months following dietary intervention but intakes between groups did not differ. The IOD group had reduced % energy from total fat at 3 and 6 months and from saturated fat at 3 months. The CD group had reduced % energy from saturated by 6 months. The IOD group had a significantly lower % energy intake from saturated fat at 3 months and higher intake of non-starch polysaccharide (NSP) compared with the CD group. Both groups showed improvements in serum antioxidant status but the IOD group had significantly higher plasma antioxidant capacity post intervention compared with the CD group. Dietary intervention benefits denture patients. IOD patients showed moderately greater dietary improvements compared with conventional denture patients. Crown Copyright © 2012. Published by Elsevier Ltd. All rights reserved.

Differences in Peripheral Blood Lymphocytes between Brand-Name and Generic Tacrolimus Used in Stable Liver Transplant Recipients.

PubMed

Kim, Jong Man; Kwon, Choon Hyuck David; Joh, Jae-Won; Sinn, Dong Hyun; Choi, Gyu-Seong; Park, Jae Berm; Kang, Eun-Suk; Lee, Suk-Koo

2017-01-01

In this study, peripheral blood lymphocytes were compared between a brand-name and a generic tacrolimus group in stable liver transplant recipients. Sixteen patients who underwent ABO-compatible living donor liver transplants between 2012 and 2013 and had stable graft function were included in this study. Ten patients received brand-name tacrolimus and 6 patients received generic tacrolimus. CD3, CD4, CD8, γδ, CD4+FoxP3+, and CD3-CD56+ T cells were analyzed in peripheral blood obtained preoperatively and 4, 8, 12, and 24 weeks after liver transplantation. Categorical variables were compared using a χ2 test or Fisher exact test, and continuous variables were compared using the Mann-Whitney U test. Regarding the baseline and perioperative characteristics, there were no statistically significant differences between the 2 groups. Immunosuppression also was not different. Subtype analysis of T-cell populations carried out in parallel showed similar levels of CD3, CD4, CD8, and γδT cells with brand-name tacrolimus and generic tacrolimus in stable liver transplant recipients. However, the levels of CD4+Foxp3+ and CD3-CD56+ T cells were higher in the brand-name tacrolimus group than in the generic tacrolimus group 8 weeks after transplantation (p < 0.05). The level of CD4+Foxp3+ T cells was higher in the brand-name tacrolimus group than in the generic tacrolimus group after transplantation. This finding showed that brand-name tacrolimus could have more potential immunosuppressive activity than generic tacrolimus regarding the contribution of CD4+Foxp3+ T cells to graft tolerance in liver transplant recipients. © 2017 S. Karger AG, Basel.

Immune system alterations in lung cancer patients.

PubMed

Mazzoccoli, G; Grilli, M; Carughi, S; Puzzolante, F; De Cata, A; La Viola, M; Giuliani, A; Urbano, N; Tarquini, R; Perfetto, F

2003-01-01

The immune system plays an important role in the defense against neoplastic disease and immune responses show temporal changes related to circadian variations of antibodies, total lymphocytes in the peripheral blood and cell mediated immune responses. In this study we evaluate. lymphocyte subpopulations and interleukin-2 (IL-2) serum levels in peripheral blood samples collected at four-hour intervals for 24-hours starting at 06.00 h from ten healthy subjects aged 65-79 years (mean age +/- s.e. 67.28 +/- 3.11) and from ten subjects suffering from untreated non small cell lung cancer aged 65-78 years (mean age +/- s.e. 68.57 +/- 1.81). Areas under the curve, mean diurnal levels (mean of 06.00-10.00-14.00 h) and mean nocturnal levels (mean of 18.00-22.00-02.00 h) were calculated, and the presence of circadian rhythmicity was evaluate. When we compared AUC values there was a decrease in CD8bright (T suppressor subset) and an increase in CD16 (natural killer cells) and of IL-2 serum levels in cancer patients. When we compared mean diurnal levels, CD8 (T suppressor/cytotoxic subset) and CD8bright levels were lower, and CD16 levels were higher in cancer patients. When we compared mean nocturnal levels, CD16 and CD25 (T and B activated lymphocytes with expression of the a chain of IL-2 receptor) levels were higher, while CD8, CD8bright, CD20 (total B-cells), TcRd1 (epitope of the constant domain of d chain of T-cell receptor 1) and dTcS1 (epitope of the variable domain of d chain of T-cell receptor1) levels were lower in cancer patients. A clear circadian rhythm was validated for the time-qualified changes in CD4, CD20, HLA-DR with acrophase at night, and CD8, CD8 bright, CD8 dim, CD16, TcRd1 and dTcS1 with acrophase in the morning in the control group. A clear circadian rhythm was validated for the time-qualified changes in CD4 with acrophase at night, in the group of cancer patients. Results obtained in our study show that lung cancer is associated with anomalies of proportion and circadian variations of lymphocyte subsets that must be considered when adoptive immunotherapy has to be planned.

Identification of CD34+ and CD34− leukemia-initiating cells in MLL-rearranged human acute lymphoblastic leukemia

PubMed Central

Aoki, Yuki; Watanabe, Takashi; Saito, Yoriko; Kuroki, Yoko; Hijikata, Atsushi; Takagi, Masatoshi; Tomizawa, Daisuke; Eguchi, Mariko; Eguchi-Ishimae, Minenori; Kaneko, Akiko; Ono, Rintaro; Sato, Kaori; Suzuki, Nahoko; Fujiki, Saera; Koh, Katsuyoshi; Ishii, Eiichi; Shultz, Leonard D.; Ohara, Osamu; Mizutani, Shuki

2015-01-01

Translocation of the mixed-lineage leukemia (MLL) gene with AF4, AF9, or ENL results in acute leukemia with both lymphoid and myeloid involvement. We characterized leukemia-initiating cells (LICs) in primary infant MLL-rearranged leukemia using a xenotransplantation model. In MLL-AF4 patients, CD34+CD38+CD19+ and CD34−CD19+ cells initiated leukemia, and in MLL-AF9 patients, CD34−CD19+ cells were LICs. In MLL-ENL patients, either CD34+ or CD34− cells were LICs, depending on the pattern of CD34 expression. In contrast, in patients with these MLL translocations, CD34+CD38−CD19−CD33− cells were enriched for normal hematopoietic stem cells (HSCs) with in vivo long-term multilineage hematopoietic repopulation capacity. Although LICs developed leukemic cells with clonal immunoglobulin heavy-chain (IGH) rearrangement in vivo, CD34+CD38−CD19−CD33− cells repopulated recipient bone marrow and spleen with B cells, showing broad polyclonal IGH rearrangement and recipient thymus with CD4+ single positive (SP), CD8+ SP, and CD4+CD8+ double-positive (DP) T cells. Global gene expression profiling revealed that CD9, CD32, and CD24 were over-represented in MLL-AF4, MLL-AF9, and MLL-ENL LICs compared with normal HSCs. In patient samples, these molecules were expressed in CD34+CD38+ and CD34− LICs but not in CD34+CD38−CD19−CD33− HSCs. Identification of LICs and LIC-specific molecules in primary human MLL-rearranged acute lymphoblastic leukemia may lead to improved therapeutic strategies for MLL-rearranged leukemia. PMID:25538041

T-lymphocyte Subsets as a Prognostic Factor in a Clinical Course of Chickenpox

PubMed Central

Baljic, Rusmir; Konjo, Hadzan; Hrustemovic, Dzenana; Gazibera, Belma; Katica, Amela; Hukic, Mirsada

2017-01-01

Objective: To investigate possible prognostic values of CD4+, CD8+ T-lymphocytes, CD4/CD8 ratio to clinical course of chickenpox in immunocompetent hosts. Materials and methods: We performed a prospective study which included 69 immunocompetent patients with chickenpox who were addmited to Clinic for infectious disease, Clinical Center University of Sarajevo, in a 18 month period. All patients were divided into two groups depending on clinical presentation on admission. Patients with mild clinical form were dedicated to „outpatient” group, and patients with moderate, severe or life-threatening clinical forms were dedicated to „hospitalized” group. Also 30 healthy volunteers are included in study as a control group. We analyzed values of CD4+, CD8+ percentage, CD4/CD8 ratio with comparison to clinical course of chickenpox. All specimens were taken in acute phase of illness. Results: Values of CD4+ percentage were significantly declined in a group of hospitalized patients, compared to group of outpatients and control group. Values of CD8+ percentage were higher in a group of hospitalized patients, while CD4/CD8 values were lower in comparison to a group of outpatients and control group. Conclusion: We found significant correlation between these parameters and clinical course of chickenpox. PMID:28484347

[Immunological balance of CD8+CD28+/CD8+CD28- T lymphocytes can predict gastrointestinal hemorrhage in patients with inflammatory bowel disease].

PubMed

Dai, Shi-Xue; Gu, Hong-Xiang; Wu, Gang; Zhong, Tao; Jian, Hong-Jian; Zhan, Yong-le; Zhang, Min-Hai; Gao, Yong; Xu, Jun; Chen, Dong-Sheng; Liao, Guang-Jie; Feng, Yan-Ling; Liu, Hong-Bo; Zou, Ying; Chi, Hong-Gang

2016-12-20

To evaluate the sensitivity and specificity of CD8 + CD28 + /CD8 + CD28 - T lymphocyte balance in predicting the gastrointestinal hemorrhage (GH) in patients with inflammatory bowel disease (IBD). Forty-nine IBD patients, including 30 with ulcerous colitis (UC) and 19 with Crohn's disease (CD), were enrolled to test peripheral blood CD8 + CD28 + and CD8 + CD28 - T cells using flow cytometry. All the patients were followed up for one year. The receiver-operating characteristic (ROC) curves were used to test the efficiency of CD8 + CD28 + /CD8 + CD28 - T lymphocyte balance to predict GH. The differences in lasting time of remission (LTR) under different factors were compared using Kaplan-Meier survival analysis, and the correlation between CD8 + T lymphocytes and the factors were analyzed. The utilization rates of immunosuppressant, steroids, and biological agent (BA) were significantly higher in CD patients than in UC patients (P=0.003, 0.043 and 0.002, respectively). The frequencies of CD8 + CD28 + T cells were obviously higher in UC patients than those in CD patients (t=3.022, P=0.004). CD8 + CD28 + T cells, CD8 + CD28 - T cells, and especially CD8 + CD28 + /CD8 + CD28 - ratio (area under curve of 0.977, P=0.000; cut-off value of 1.14 [13.95%/12.24%] with a sensitivity of 93.3% and a specificity of 91.2%) showed good efficiencies in predicting GH (P<0.01). The mean and median of LTR of IBD patients who did not receive BA or surgical treatment were significantly longer (Χ 2 =9.730, P=0.002; Χ 2 =15.981, P=0.000). CD8 + CD28 + /CD8 + CD28 - ratio was significantly related to both BA (P=0.009) and surgery (P=0.038). Both decreased CD8 + CD28 + T cells and elevated CD8 + CD28 - T cells are closely correlated with GH, and their ratio can predict the occurrence of GH with a high sensitivity and specificity and is correlated with BA and surgery at the cut-off value of 1.14.

Upregulation of CD19⁺CD24(hi)CD38(hi) regulatory B cells is associated with a reduced risk of acute lung injury in elderly pneumonia patients.

PubMed

Song, Haihan; Xi, Jianjun; Li, Guang-Gang; Xu, Shumin; Wang, Chunmei; Cheng, Tingting; Li, Hongqiang; Zhang, Ying; Liu, Xiandong; Bai, Jianwen

2016-04-01

Acute lung injury (ALI) is a common complication in elderly pneumonia patients who have a rapid progression, and is accompanied by a high mortality rate. Because the treatment options of ALI are limited to supportive care, identifying pneumonia patients who are at higher risk of ALI development is the emphasis of many studies. Here, we approach this problem from an immunological perspective by examining CD19(+)CD24(hi)CD38(hi) B cells, an important participant in acute and chronic inflammation. We find that elderly pneumonia patients have elevated CD19(+)CD24(hi)CD38(hi) B cell frequency compared to healthy individuals. This B cell population may express a higher level of IL-10, which has been was shown to suppress CD4(+) T cell-mediated proinflammatory cytokine interferon gamma (IFNg) and tumor necrosis factor alpha (TNFa) production, through an IL-10-dependent mechanism. We also observe that the frequency of CD19(+)CD24(hi)CD38(hi) B cell is positively correlated with the frequency of CD4(+)CD25(+)Foxp3(+)Tregs in peripheral blood. Moreover, consistent with CD19(+)CD24(hi)CD38(hi) B cell's anti-inflammatory role, we find that pneumonia patients who later developed ALI have reduced level of CD19(+)CD24(hi)CD38(hi) B cells. Together, our results demonstrated that CD19(+)CD24(hi)CD38(hi) B cells in pneumonia patients possess regulatory function in vivo, and are associated with a reduced ALI risk.

Prevention strategies differentially modulate the impact of cytomegalovirus replication on CD8(+) T-cell differentiation in high-risk solid organ transplant patients.

PubMed

Cantisán, Sara; Páez-Vega, Aurora; Pérez-Romero, Pilar; Montejo, Miguel; Cordero, Elisa; Gracia-Ahufinger, Irene; Martín-Gandul, Cecilia; Maruri, Naroa; Aguado, Rocío; Solana, Rafael; Torre-Cisneros, Julián

2016-08-01

The present study aimed to determine whether antiviral prevention strategies against cytomegalovirus (CMV) infection used in high-risk D+R- solid organ transplanted patients can modulate the impact of CMV replication on CD8(+) T-cell differentiation. The different CD8(+) T-cell subpopulations were measured at a single point when at least one year had elapsed since transplantation. A total of 68 D+R- patients were included, of which 33 underwent pre-emptive therapy and 35 received prophylaxis. Multivariate analysis showed that CMV replication was associated with the expansion of CD28־ EMRA CD8(+) T cells in patients managed pre-emptively but not in patients under prophylaxis (21.4% vs. 3.6%). This finding is likely related to the higher frequency of CMV recurrence observed in patients under pre-emptive therapy compared to those under prophylaxis (75% vs. 14.3%; p < 0.001). In fact, multivariate analysis showed that having more than one replication episode was associated with a 17.2% increase (p = 0.001) in the percentage of CD28־ EMRA CD8(+) T cells compared to "no episode" and with a 10.9% increase with respect to "single episodes" (p = 0.025). Additionally, patients with IFNγ response to CMV (QuantiFERON-CMV Reactive) had a higher percentage of late-differentiated CD8(+) T cells than patients lacking this response. In summary, recurrent CMV replication in D+R- patients under pre-emptive therapy was associated with the expansion of CD28־ EMRA CD8(+) T cells, which might have a short-term beneficial effect related to the high functionality of this T-cell subpopulation. Nevertheless, we cannot rule out that this accumulation might have a long-term detrimental effect related to immunosenescence and inflammation. Copyright © 2016 Elsevier B.V. All rights reserved.

Regulatory T cells and other lymphocyte subpopulations in patients with melanoma developing interferon-induced thyroiditis during high-dose interferon-α2b treatment.

PubMed

Soldevila, Berta; Alonso, Núria; Martínez-Arconada, Maria J; Granada, Maria L; Boada, Aram; Vallejos, Virginia; Fraile, Manuel; Fernández-Sanmartín, Marco A; Pujol-Borrell, Ricardo; Puig-Domingo, Manel; Sanmartí, Anna; Martínez-Cáceres, Eva M

2013-04-01

One of the side effects of interferon-alpha therapy is interferon-induced thyroiditis (IIT). The role of lymphocyte subpopulations in IIT melanoma patients remains to be defined. Our objective was to assess different peripheral blood lymphocyte subpopulations, mainly regulatory T cells (Tregs), in melanoma patients who developed IIT. From 30 melanoma patients receiving high-dose interferon (HDI)-alpha 2b (IFN-α2b) treatment, those who developed IIT (IIT patients) were selected and compared with patients who did not develop IIT (Co-MM) and healthy controls (Co-H). Peripheral blood mononuclear cells were obtained before treatment (BT), mid-treatment (MT), end of treatment (ET), 24 weeks post-treatment and at appearance of IIT (TT). Nine patients developed IIT (30%): four Hashimoto's thyroiditis and five destructive thyroiditis. An increase in Tregs was observed in both melanoma groups during HDI treatment. A decrease in CD3(+) , NKT lymphocyte subpopulations and Bcl2 expression on B cells was also observed in both groups. However, no changes were observed in the percentage of CD4(+) , CD8(+) , CD3(+) γδ(+) , CD19(+) , transitional B cells (CD24(high) CD38(high) CD19(+) CD27(-) ), natural killer (NK), invariant NKT (iNKT) lymphocytes and Th1/Th2 balance when BT was compared with ET. At TT, IIT patients had a higher Tregs percentage than Co-MM (P = 0·012) and Co-H (P = 0·004), a higher iNKT percentage than Co-MM (P = 0·011), a higher transitional B cells percentage than Co-H (P = 0·015), a lower CD3(+) percentage than Co-H (P = 0·001) and a lower Bcl2 expression on B cells than Co-H (P < 0·001). Our results point to the immunomodulatory effects of IFN-α on different lymphocyte subpopulations and a possible role of Tregs in melanoma patients who developed IIT. © 2012 Blackwell Publishing Ltd.

Effects of combined general-epidural anesthesia and total intravenous anesthesia on cellular immunity and prognosis in patients with non‑small cell lung cancer: A comparative study.

PubMed

Xu, Qiang; Shi, Nian-Jun; Zhang, Hao; Zhu, Yan-Mei

2017-10-01

The aim of the present study was to investigate the effects of combined general‑epidural anesthesia (CGEA) and total intravenous anesthesia (TIVA) on cellular immunity and prognosis in patients with non‑small cell lung cancer (NSCLC) in a Chinese population. One‑hundred and twenty NSCLC patients were randomly divided into a TIVA group (n=60) and a CGEA group (n=60) using a random number table. All patients underwent video‑assisted thoracoscopic surgery for radical resection. Blood pressure (BP) and peripheral oxygen saturation (SpO2) were measured. Post‑operative analgesic effects were evaluated with a visual analog scale pain score. Flow cytometry was applied to measure T lymphocyte subsets [cluster of differentiation (CD)3+, CD4+, CD8+ and CD4+/CD8+] and natural killer cell CD56+. A 3‑year follow‑up was conducted to observe the prognosis. The analgesic effects of CGEA were identified to be better than those of TIVA. Compared with the TIVA group, the CGEA group demonstrated a shorter time of spontaneous breathing recovery, eyes opening, and extubation, lower heart rate, blood pressure and mean arterial pressure, and higher SpO2. At 24 and 48 h after surgery, CD3+, CD4+, CD4+/CD8+ and CD56+ in the CGEA group were higher than those in the TIVA group. At 72 h after surgery, CD3+, CD4+, CD4+/CD8+ in the CGEA group were higher than those in the TIVA group. These results indicate that CGEA and TIVA effected cellular immunity, and CGEA had a reduced effect on cellular immunity and improved postoperative analgesic effects.

The obestatin/ghrelin ratio and ghrelin genetics in adult celiac patients before and after a gluten-free diet, in irritable bowel syndrome patients and healthy individuals.

PubMed

Russo, Francesco; Chimienti, Guglielmina; Linsalata, Michele; Clemente, Caterina; Orlando, Antonella; Riezzo, Giuseppe

2017-02-01

Ghrelin levels and obestatin/ghrelin ratio have been proposed as activity markers in ulcerative colitis, but no data are available in celiac disease (CD) and irritable bowel syndrome (IBS). Our aims were as follows: (a) to assess obestatin and ghrelin concentrations in adult active CD patients, diarrhea-predominant IBS (IBS-d), and healthy controls (HC) in relation to intestinal permeability; (b) to evaluate the ghrelin-obestatin profile in CD patients after a 1-year gluten-free diet (GFD); and (c) to establish the impact of ghrelin genetics. The study included 31 CD patients, 28 IBS-d patients, and 19 HC. Intestinal permeability, assayed by high-performance liquid chromatography determination of urinary lactulose (La)/mannitol (Ma), and circulating concentrations of obestatin, ghrelin, and their ratio were evaluated at enrollment and after GFD. The ghrelin single nucleotide polymorphisms Arg51Gln (rs34911341), Leu72Met (rs696217), and Gln90Leu (rs4684677) were analyzed. Intestinal permeability was impaired in CD patients and ameliorated after GFD. Ghrelin was significantly (P=0.048) higher and the obestatin/ghrelin ratio was significantly (P=0.034) lower in CD patients compared with both IBS-d and HC, and GFD reduced the peptide levels, but without reaching the concentrations in HC. Significant differences (P<0.05) were found in the Leu72Met polymorphism among groups, with the reduction of the GT genotype and the T allele in both CD and IBS-d patients compared with HC. Intestinal permeability is altered in CD, but not in IBS-d patients, and ghrelin levels increase in CD patients as observed in other inflammatory conditions. Moreover, a role for ghrelin genetics is hypothesized in sustaining the many pathogenetic components of these different pathologies, but with a similar symptom profile.

The Heterogeneity Between Lynch-Associated and Sporadic MMR Deficiency in Colorectal Cancers.

PubMed

Liu, Guo-Chen; Liu, Ran-Yi; Yan, Jun-Ping; An, Xin; Jiang, Wu; Ling, Yi-Hong; Chen, Jie-Wei; Bei, Jin-Xin; Zuo, Xiao-Yu; Cai, Mu-Yan; Liu, Ze-Xian; Zuo, Zhi-Xiang; Liu, Ji-Hong; Pan, Zhi-Zhong; Ding, Pei-Rong

2018-02-20

Previous studies demonstrated that prognosis of germline deficiency in mismatch repair protein (dMMR) was different from that of sporadic dMMR. The underlying mechanism has not been studied. From a prospectively maintained database, we collected dMMR colorectal cancer (CRC) patients identified by postoperative immunohistochemistry screening. According to genetic test, patients were grouped as Lynch-associated or sporadic dMMR. We compared the clinical-pathological features, prognosis, and immunoreactive differences between the two groups. By whole-exome sequencing and neoantigen detection pipeline, mutational frequencies and neoantigen burdens were also compared. All statistical tests were two-sided. Sixty-seven sporadic dMMR and 85 Lynch-associated CRC patients were included in the study. Sporadic dMMR patients were older (P < .001) and their tumors were poorly differentiated (P = .03). The survival was better in the Lynch-associated group (P = .001). After adjustment, the difference still remained statistically significant (hazard ratio = 0.29, 95% confidence interval = 0.09 to 0.95, P = .04). The scores of Crohn's-like reaction (CRO; P < .001), immunoreactions in the invasive margin (IM; P = .01), tumor stroma (TS; P = .009), and cancer nest (CN; P = .02) of the Lynch-associated group were statistically significantly higher. The numbers of CD3+, CD8+, Foxp3+ tumor-infiltrating lymphocytes (TILs) in IM; CD3+, CD4+ TILs in TS; and CD3+, CD4+, CD8+ TILs in CN were statistically significantly higher in Lynch-associated dMMR patients. Based on the 16 patients who under went whole-exome sequencing, there were also more somatic mutations and neoantigen burdens in the Lynch-associated group compared with the sporadic dMMR group (439/pt vs 68/pt, P = .006; 628/pt vs 97/pt, P = .009). There are heterogeneities in dMMR CRCs. Lynch-associated dMMR patients present with more somatic mutations and neoantigens compared with sporadic dMMR, which probably results in stronger immunoreactions and survival improvement.

An Evil Backstage Manipulator: Psychological Factors Correlated with Health-Related Quality of Life in Chinese Patients with Crohn's Disease

PubMed Central

Liu, Song; Hong, Zhiwu; Li, Xiaoting; Yao, Min; Yan, Dongsheng; Ren, Huajian; Wu, Xiuwen; Wang, Gefei; Gu, Guosheng; Xia, Qiuyuan; Han, Gang; Li, Jieshou

2013-01-01

Health-related quality of life (HRQoL) is recommended as one of essential parameters to evaluate treatment effect and clinical outcome in patients with Crohn's disease (CD). Recent studies reported that psychological factors might play a role in HRQoL in Western and American CD patients. Sufficient evidences in Chinese CD patients are still unavailable. This study is dedicated to investigate the correlation of various psychological factors with HRQoL in Chinese CD patients. We prospectively collected 40 active and 40 quiescent CD patients in China and found that psychological factors, especially neuroticism and anxiety, significantly correlate with and affect HRQoL in both active and quiescent CD groups. This is the first report revealing correlation between psychological factors and HRQoL in Chinese CD patients. Therefore, we assume that our results can contribute to a better understanding of etiology and tailoring of management in Chinese patients with Crohn's disease and are beneficial to our colleagues to compare the heterogeneous characteristics of Crohn's disease in different ethnic groups. PMID:24453858

Comparative study of CD4 and CD45RO T cells and CD20 B cells in cerebrospinal fluid of syphilitic meningitis and tuberculous meningitis patients.

PubMed

Yu, Nian; Zhang, Qiao-Quan; Zhang, Kang; Xie, Yuan; Zhu, Hai-Qing; Lin, Xing-Jian; Di, Qing

2016-09-01

This study was to investigate the differences of lymphocyte in the cerebrospinal fluid (CSF) of patients with syphilis meningitis (SM) and tuberculous meningitis (TBM) for new diagnostic insights. Totally, 79 cases of SM and 45 cases of TBM were enrolled. In the CSF, the CD4, CD45RO or CD20 positive lymphocytes were detected by immunohistochemistry. The proportion of CD4 T cells in the CSF lymphocytes in patients with SM was significantly higher than that in patients with TBM (p < 0.05). After medical therapy, there was a significantly decline trend of the CD4 T-cell proportion in both groups (p < 0.05). The proportion of CD45RO T cells in CSF lymphocytes of patients with SM was less than that of patients with TBM (p < 0.05). After medical therapy, the positive ratio of CD45RO T cells was increased in the CSF of both group patients (p < 0.05). The proportion of CD20B cells in the CSF lymphocytes was not obviously different between the two groups during every stage. In conclusion, there are strong differences of CD4 and CD45RO T-cell ratio, but not the CD20 B cells in the meningitis. CD4 and CD45RO T cells in CSF are a useful complement in differentially diagnosing SM and TBM; it contributes to further understand the pathogenesis and prognosis of SM and TBM. © 2016 APMIS. Published by John Wiley & Sons Ltd.

FcγRIIIa Expression on Monocytes in Rheumatoid Arthritis: Role in Immune-Complex Stimulated TNF Production and Non-Response to Methotrexate Therapy

PubMed Central

Cooper, Dawn L.; Martin, Stephen G.; Robinson, James I.; Mackie, Sarah L.; Charles, Christopher J.; Nam, Jackie; Consortium, YEAR; Isaacs, John D.; Emery, Paul; Morgan, Ann W.

2012-01-01

Objective The expression of FcγRIIIa/CD16 may render monocytes targets for activation by IgG-containing immune complexes (IC). We investigated whether FcγRIIIa/CD16 was upregulated in rheumatoid arthritis (RA), associated with TNF production in response to IC-stimulation, and if this predicted response to methotrexate therapy. Methods FcγRIIIa/CD16 expression on CD14low and CD14++ monocytes was measured by flow cytometry in healthy controls and RA patients (early and long-standing disease). Intracellular TNF-staining was carried out after in vitro LPS or heat-aggregated immunoglobulin (HAG) activation. FcγRIIIa/CD16 expression pre- and post-steroid/methotrexate treatment was examined. Results Increased FcγRIIIa/CD16 expression on CD14++ monocytes in long-standing RA patients compared to controls was demonstrated (p = 0.002) with intermediate levels in early-RA patients. HAG-induced TNF-production in RA patients was correlated with the percentage of CD14++ monocytes expressing FcγRIIIa/CD16 (p<0.001). The percentage of CD14++ monocytes expressing FcγRIIIa/CD16 at baseline in early DMARD-naïve RA patients was negatively correlated with DAS28-ESR improvement 14-weeks post-methotrexate therapy (p = 0.003) and was significantly increased in EULAR non-responders compared to moderate (p = 0.01) or good responders (p = 0.003). FcγRIIIa/CD16 expression was not correlated with age, presence of systemic inflammation or autoantibody titers. Conclusion Increased FcγRIIIa/CD16 expression on CD14++ monocytes in RA may result in a cell that has increased responsiveness to IC-stimulation. This monocyte subset may contribute to non-response to methotrexate therapy. PMID:22235253

Gastroesophageal reflux symptoms in patients with celiac disease and the effects of a gluten-free diet.

PubMed

Nachman, Fabio; Vázquez, Horacio; González, Andrea; Andrenacci, Paola; Compagni, Liliana; Reyes, Hugo; Sugai, Emilia; Moreno, María Laura; Smecuol, Edgardo; Hwang, Hui Jer; Sánchez, Inés Pinto; Mauriño, Eduardo; Bai, Julio César

2011-03-01

Celiac disease (CD) patients often complain of symptoms consistent with gastroesophageal reflux disease (GERD). We aimed to assess the prevalence of GERD symptoms at diagnosis and to determine the impact of the gluten-free diet (GFD). We evaluated 133 adult CD patients at diagnosis and 70 healthy controls. Fifty-three patients completed questionnaires every 3 months during the first year and more than 4 years after diagnosis. GERD symptoms were evaluated using a subdimension of the Gastrointestinal Symptoms Rating Scale for heartburn and regurgitation domains. At diagnosis, celiac patients had a significantly higher reflux symptom mean score than healthy controls (P < .001). At baseline, 30.1% of CD patients had moderate to severe GERD (score >3) compared with 5.7% of controls (P < .01). Moderate to severe symptoms were significantly associated with the classical clinical presentation of CD (35.0%) compared with atypical/silent cases (15.2%; P < .03). A rapid improvement was evidenced at 3 months after initial treatment with a GFD (P < .0001) with reflux scores comparable to healthy controls from this time point onward. GERD symptoms are common in classically symptomatic untreated CD patients. The GFD is associated with a rapid and persistent improvement in reflux symptoms that resembles the healthy population. Copyright © 2011 AGA Institute. Published by Elsevier Inc. All rights reserved.

In vitro cytotoxicity of CD8+ T cells in multi-drug-resistant tuberculosis. A preliminary report.

PubMed

Sada-Ovalle, Isabel; Torre-Bouscoulet, Luis; Valdez-Vázquez, Rafael; Lascurain, Ricardo

2009-05-01

Specific CD8+ T-cell cytotoxicity has been recognized as being involved in the elimination of drug-susceptible tuberculosis (DS-TB). Given that there is currently no information on the cytotoxic effector functions of CD8+ T cells in multi-drug-resistant tuberculosis (MDR-TB), our objective was to analyse the cytotoxic activity, both basal and stimulated, of CD8+ T cells from MDR-TB patients and compare it with that of DS-TB patients, as well as purified protein derivative (PPD)+ and PPD- subjects. Cytotoxic activity of CD8+ T cells from MDR-TB patients, DS-TB patients, PPD+ and PPD- subjects was measured by a colorimetric assay, using H37Rv culture filtrate protein as the antigenic stimulus. Twenty-eight subjects were studied (7 MDR-TB patients, 7 DS-TB patients, 7 PPD+ subjects and 7 PPD- subjects). In the presence of the antigenic stimulus, the cytotoxic activity of CD8+ T cells from MDR-TB patients (% lysis) increased from 6.7% to 59.6% (P < 0.001). In DS-TB patients lysis increased from 3.2% to 22.5% (P < 0.001), whereas in PPD+ subjects it increased from 2.7% to 12.0% (P < 0.001) and in PPD- subjects from 1.3% to 3.2% (P < 0.001). Basal cytotoxic activity was significantly higher for MDR-TB patients than PPD+ and PPD- subjects (P = 0.003), but not compared with that for DS-TB patients (P = 0.05). Stimulated cytotoxic activity was highest for MDR-TB patients. CD8+ T cells from MDR-TB patients showed an exaggerated cytotoxic activity after antigenic stimulation. Further studies are required to elucidate the role of this response in the immunopathogenesis of MDR-TB.

Distinct alterations in the distribution of CD45RO+ T-cell subsets in HIV-2 compared with HIV-1 infection.

PubMed

Jaleco, A C; Covas, M J; Pinto, L A; Victorino, R M

1994-12-01

Some clinical studies indicate that disease progression in HIV-2-infected subjects may be slower than in HIV-1. We investigated whether there were differences in the distribution of CD45RO+ (memory) and CD45RA+ (naive) T-cell subsets between HIV-1 and HIV-2 infection. Analysis of lymphocyte subsets was performed by flow cytometry in peripheral blood mononuclear cells from healthy controls, HIV-1-(n = 49) and HIV-2-infected (n = 47) individuals divided into two groups: asymptomatic (ASY)/persistent generalized lymphadenopathy (PGL) and AIDS-related complex (ARC)/AIDS. Both HIV-1- and HIV-2-infected patients had significant reductions in the absolute number and percentage of CD4+ lymphocytes compared with seronegative individuals. No significant differences were found between HIV-2- and HIV-1-infected subjects in the same clinical stage. CD4+CD45RA+ cells were significantly reduced in HIV-1 and HIV-2 ARC/AIDS patients and mildly reduced in ASY/PGL HIV-1 and HIV-2 patients. There were no differences in the degree of reduction of CD4+CD45RO+ cells in ASY/PGL HIV-1 versus HIV-2 patients. However, in HIV-1-infected ARC/AIDS individuals the reduction in the percentage of this subset was more pronounced than in HIV-2 infection and this difference reached statistical significance. The increase in CD8+ lymphocytes (percentage and absolute number) was more pronounced in HIV-1 and the differences between HIV-1- and HIV-2-infected patients were statistically significant. CD8+CD45RO+ cells were significantly increased both in ASY/PGL and ARC/AIDS HIV-1-infected patients, whereas HIV-2-infected ASY/PGL patients had normal levels of these cells and HIV-2-infected ARC/AIDS patients had increases that were much less pronounced than that observed in HIV-1-infected ARC/AIDS patients. Significant differences in the absolute number and percentage of this subset between HIV-1- and HIV-2-infected individuals in similar clinical stages were found. HIV-2-infected individuals exhibit a lesser degree of depletion of memory CD4+ cells and a more limited expansion of CD8+CD45RO+ subset, which could be related to the putative lower immunopathogenicity of HIV-2.

Anti-CD74 antibodies have no diagnostic value in early axial spondyloarthritis: data from the spondyloarthritis caught early (SPACE) cohort.

PubMed

de Winter, Janneke J; van de Sande, Marleen G; Baerlecken, Niklas; Berg, Inger; Ramonda, Roberta; van der Heijde, Désirée; van Gaalen, Floris A; Witte, Torsten; Baeten, Dominique L

2018-03-01

Anti-CD74 IgG antibodies are reported to be elevated in patients with axial spondyloarthritis (axSpA). This study assessed the diagnostic value of anti-CD74 antibodies in patients with early axSpA. Anti-CD74 IgG and IgA antibodies were first measured in an exploratory cohort of patients with radiographic axSpA (138 patients with ankylosing spondyloarthritis (AS)) and 57 healthy controls and then were measured in patients with early axSpA (n = 274) and with non-SpA chronic back pain (CBP) (n = 319), participating in the spondyloarthritis caught early (SPACE) prospective cohort study of patients under 45 years old with early back pain (for ≥ 3 months, but ≤ 2 years). In the exploratory cohort, anti-CD74 IgG antibodies were present in 79.7% of patients with AS vs. 43.9% of healthy controls (p < 0.001). Anti-CD74 IgA antibodies were present in 28.5% of patients with AS vs. 5.3% of healthy controls (p < 0.001). In the SPACE cohort, anti-CD74 IgG antibody levels were present in 46.4% of the patients with axSpA vs. 47.9% of the patients with CBP (p = 0.71). Anti-CD74 IgA antibodies were present in 54.7% of the patients with axSpA and 37.0% of the patients with CBP (p < 0.001). This resulted in a positive predictive value of 58.8% (compared to a prior probability of 46.2%) and a negative predictive value of 59.1% (compared to a prior probability of 53.8%). In a regression model, total serum IgA was associated with axSpA odds ratio (OR) 1.19, p < 0.001) whereas anti-CD74 IgA was not (OR) 1.01, p = 0.33). Furthermore, anti-CD74 IgA was associated with sacroiliitis on magnetic resonance imaging (MRI) (OR) = 2.50, p = 0.005) and heel enthesitis (OR) = 2.56, p = 0.002). Albeit anti-CD74 IgA is elevated in patients with early axSpA, this elevation is not sufficiently specific to yield significant diagnostic value in patients under 45 years old presenting with early back pain.

Tumor Necrosis Factor-producing T-regulatory Cells Are Associated With Severe Liver Injury in Patients With Acute Hepatitis A.

PubMed

Choi, Yoon Seok; Jung, Min Kyung; Lee, Jeewon; Choi, Seong Jin; Choi, Sung Hoon; Lee, Hyun Woong; Lee, Jong-Joo; Kim, Hyung Joon; Ahn, Sang Hoon; Lee, Dong Hyeon; Kim, Won; Park, Su-Hyung; Huh, Jun R; Kim, Hyoung-Pyo; Park, Jun Yong; Shin, Eui-Cheol

2018-03-01

CD4 + CD25 + Foxp3 + T-regulatory (Treg) cells control immune responses and maintain immune homeostasis. However, under inflammatory conditions, Treg cells produce cytokines that promote inflammation. We investigated production of tumor necrosis factor (TNF) by Treg cells in patients with acute hepatitis A (AHA), and examined the characteristics of these cells and association with clinical factors. We analyzed blood samples collected from 63 patients with AHA at the time of hospitalization (and some at later time points) and 19 healthy donors in South Korea. Liver tissues were collected from patients with fulminant AHA during liver transplantation. Peripheral blood mononuclear cells were isolated from whole blood and lymphocytes were isolated from liver tissues and analyzed by flow cytometry. Cytokine production from Treg cells (CD4 + CD25 + Foxp3 + ) was measured by immunofluorescence levels following stimulation with anti-CD3 and anti-CD28. Epigenetic stability of Treg cells was determined based on DNA methylation patterns. Phenotypes of Treg cells were analyzed by flow cytometry and an RORγt inhibitor, ML-209, was used to inhibit TNF production. Treg cell suppression assay was performed by co-culture of Treg-depleted peripheral blood mononuclear cells s and isolated Treg cells. A higher proportion of CD4 + CD25 + Foxp3 + Treg cells from patients with AHA compared with controls produced TNF upon stimulation with anti-CD3 and anti-CD28 (11.2% vs 2.8%). DNA methylation analysis confirmed the identity of the Treg cells. TNF-producing Treg cells had features of T-helper 17 cells, including up-regulation of RORγt, which was required for TNF production. The Treg cells had reduced suppressive functions compared with Treg cells from controls. The frequency of TNF-producing Treg cells in AHA patients' blood correlated with their serum level of alanine aminotransferase. Treg cells from patients with AHA have altered functions compared with Treg cells from healthy individuals. Treg cells from patients with AHA produce higher levels of TNF, gain features of T-helper 17 cells, and have reduced suppressive activity. The presence of these cells is associated with severe liver injury in patients with AHA. Copyright © 2018 AGA Institute. Published by Elsevier Inc. All rights reserved.

The role of ABO blood groups in Crohn's disease and in monitoring response to infliximab treatment.

PubMed

Yu, Qiao; Wang, Lingyun; Zhang, Shenghong; Feng, Ting; Li, Li; Chen, Baili; Chen, Minhu

2016-09-01

The variation in ABO blood groups is reported to be associated with multiple diseases. Infliximab (IFX) has been widely used in the treatment of Crohn's disease (CD). We aim to investigate the distribution of ABO blood groups in Chinese patients with CD and to explore its impact on response to IFX. Patients with CD were consecutively recruited to the study between 2007 and 2014. CD patients receiving IFX therapy were followed for at least two years. In 293 patients with CD, most patients (40.6%) had blood type O (119/293). The odds ratio (OR) of CD in blood type O patients was 1.06 (95%CI: 0.6-1.86; p=0.84) compared to all other blood types. Among those CD patients, 107 patients received IFX treatment. One year after the first course of IFX, a significant association was found between the overall ABO system and outcomes of IFX treatment (p<0.001). CD patients with blood type AB (OR=4.42, 95% CI: 1.04-18.76; p=0.044) were more likely to achieve mucosal healing, while CD patients with blood type A had a high risk of losing response (OR=0.38, 95% CI: 0.15-0.96; p=0.040). ABO blood groups are not associated with prevalence of CD. Patients with blood type AB had a better response to IFX while those with blood type A appeared to have a risk of losing response to IFX.

Comparison of high-sensitivity C-reactive protein and fetuin-A levels before and after treatment for subjects with subclinical hyperthyroidism.

PubMed

Bilgir, Oktay; Bilgir, Ferda; Topcuoglu, Tuba; Calan, Mehmet; Calan, Ozlem

2014-03-01

This study was designed to show the effect of propylthiouracil treatment on sCD40L, high-sensitivity C-reactive protein, and fetuin-A levels on subjects with subclinical hyperthyroidism. After checking sCD40L, high-sensitivity C-reactive protein, and fetuin-A levels of 35 patients with subclinical hyperthyroidism, each was given 50 mg tablets of propylthiouracil three times daily. After 3 months, sCD40L, high-sensitivity C-reactive protein, and fetuin-A levels were then compared to the levels before treatment. Although high-sensitivity C-reactive protein and sCD40L levels were normal in the subclinical hyperthyroidism patients compared to the healthy controls, fetuin-A levels were statistically significantly higher (*p = 0.022). After treatment, fetuin-A levels of subclinical hyperthyroidism patients decreased statistically significantly compared to the levels before treatment (**p = 0.026). sCD40L and high-sensitivity C-reactive protein levels did not have a statistically significant difference compared to the control group and post-propylthiouracil treatment. In subclinical hyperthyroidism patients, high fetuin-A levels before propylthiouracil treatment and decreases in these levels after treatment in cases with subclinical hyperthyroidism indicated the possibility of preventing long-term cardiac complications with propylthiouracil treatment.

CD45RA, a specific marker for leukaemia stem cell sub-populations in acute myeloid leukaemia.

PubMed

Kersten, Bas; Valkering, Matthijs; Wouters, Rolf; van Amerongen, Rosa; Hanekamp, Diana; Kwidama, Zinia; Valk, Peter; Ossenkoppele, Gert; Zeijlemaker, Wendelien; Kaspers, Gertjan; Cloos, Jacqueline; Schuurhuis, Gerrit J

2016-04-01

Chemotherapy resistant leukaemic stem cells (LSC) are thought to be responsible for relapses after therapy in acute myeloid leukaemia (AML). Flow cytometry can discriminate CD34(+) CD38(-) LSC and normal haematopoietic stem cells (HSC) by using aberrant expression of markers and scatter properties. However, not all LSC can be identified using currently available markers, so new markers are needed. CD45RA is expressed on leukaemic cells in the majority of AML patients. We investigated the potency of CD45RA to specifically identify LSC and HSC and improve LSC quantification. Compared to our best other markers (CLL-1, also termed CLEC12A, CD33 and CD123), CD45RA was the most reliable marker. Patients with high percentages (>90%) of CD45RA on CD34(+) CD38(-) LSC have 1·69-fold higher scatter values compared to HSC (P < 0·001), indicating a more mature CD34(+) CD38(-) phenotype. Patients with low (<10%) or intermediate (10-90%) CD45RA expression on LSC showed no significant differences to HSC (1·12- and 1·15-fold higher, P = 0·31 and P = 0·44, respectively). CD45RA-positive LSC tended to represent more favourable cytogenetic/molecular markers. In conclusion, CD45RA contributes to more accurate LSC detection and is recommended for inclusion in stem cell tracking panels. CD45RA may contribute to define new LSC-specific therapies and to monitor effects of anti-LSC treatment. © 2016 John Wiley & Sons Ltd.

Mucin Genes Expression in the Intestine of Crohn's Disease Patients: a Systematic Review and Meta-analysis.

PubMed

Niv, Yaron

2016-09-01

The mucus layer of the intestinal tract is the main barrier between luminal microbes and the mucosa, and has an essential role in the body defense mechanisms. Previous research could not establish consistent results for mucin genes expression in Crohn's disease (CD) patients. In this meta-analysis we looked at the mucin expression in CD patients and compared it with healthy controls. English medical literature searches were conducted for mucin expression in the mucosa of the ileum and colon of CD patients and compared it with normal mucosa. Case-control studies were included. Meta-analysis was performed by using Comprehensive meta-anaslysis software. Pooled odds ratios and 95% confidence intervals were calculated. We found 160 eligible studies. Twenty studies were rejected because they have been performed in animals or did not have full text, and 134 studies were excluded because of language, being editorials, review articles, or because of duplications. We were left with 6 case-control studies from 4 countries that fulfilled the inclusion criteria, published till 31.12.2015. No significant heterogeneity was demonstrated: Q = 149.256, df (Q) = 40.00, I2= 73.2% (less than 75%). We found a decrease of 34% in the total mucin expression in CD patients (Odds Ratio 0.660, 95% CI 0.486-0.897, P = 0.008). We also found a significantly decreased expression in CD patients for MUC5AC, MUC5B and MUC7. We demonstrated a global decrease in mucin expression in CD patients when compared with healthy controls.

Serology of Patients with Ulcerative Colitis After Pouch Surgery Is More Comparable with that of Patients with Crohn's Disease.

PubMed

Goren, Idan; Yahav, Lior; Tulchinsky, Hagit; Dotan, Iris

2015-10-01

The serologic status of patients with ulcerative colitis (UC) who develop postoperative pouchitis was compared with that of patients with Crohn's disease (CD) and unoperated patients with UC. Pouch patients were stratified into normal pouch, acute/recurrent acute pouchitis, and chronic pouchitis/Crohn's-like disease of the pouch groups. Antibodies against glycans associated with CD (anti-Saccharomyces cerevisiae, anti-laminaribioside, anti-chitobioside, and anti-mannobioside carbohydrate antibodies [ASCA, ALCA, ACCA, and AMCA, respectively]) were detected and correlated with type of inflammatory bowel disease and pouch behavior. A total of 501 patients with inflammatory bowel diseases were recruited: 250 (50%) CD, 124 (24.7%) unoperated UC, and 127 (25.3%) UC-pouch. At least 1 positive antibody was detected in 77.6% CD, 52.0% UC-pouch and 33.1% unoperated UC (P < 0.0001 for all). ACCA and AMCA prevalence in CD, UC-pouch and unoperated patients with UC were 33.2%, 24.4%, and 16.9% (P = 0.003 for all) and 35.2%, 26.8%, and 7.3%, respectively (P < 0.0001 for all). ALCA and ASCA were more prevalent in patients with CD than unoperated UC and UC-pouch patients. A longer interval since pouch surgery was associated with inflammatory pouch behavior: 12.45, 11.39, and 8.5 years for acute/recurrent acute pouchitis, chronic pouchitis/Crohn's-like disease of the pouch, and normal pouch, respectively, P = 0.01 for all. The prevalence of the CD-associated anti-glycan antibodies ACCA and AMCA is significantly increased in UC-pouch patients, suggesting that pouch surgery may trigger differential immune responses to glycans. The finding that the serology of UC-pouch patients shares similarities with that of patients with CD supports the notion that those 2 inflammatory bowel diseases share a common pathogenic pathway.

Integrative analysis reveals CD38 as a therapeutic target for plasma cell-rich pre-disease and established rheumatoid arthritis and systemic lupus erythematosus.

PubMed

Cole, Suzanne; Walsh, Alice; Yin, Xuefeng; Wechalekar, Mihir D; Smith, Malcolm D; Proudman, Susanna M; Veale, Douglas J; Fearon, Ursula; Pitzalis, Costantino; Humby, Frances; Bombardieri, Michele; Axel, Amy; Adams, Homer; Chiu, Christopher; Sharp, Michael; Alvarez, John; Anderson, Ian; Madakamutil, Loui; Nagpal, Sunil; Guo, Yanxia

2018-05-02

Plasmablasts and plasma cells play a key role in many autoimmune diseases, such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). This study was undertaken to evaluate the potential of targeting CD38 as a plasma cell/plasmablast depletion mechanism by daratumumab in the treatment of patients with RA and SLE. RNA-sequencing analysis of synovial biopsies from various stages of RA disease progression, flow cytometry analysis of peripheral blood mononuclear cells (PBMC) from patients with RA or SLE and healthy donors, immunohistochemistry assessment (IHC) of synovial biopsies from patients with early RA, and ex vivo immune cell depletion assays using daratumumab (an anti-CD38 monoclonal antibody) were used to assess CD38 as a therapeutic target. We demonstrated that the plasma cell/plasmablast-related genes CD38, XBP1, IRF4, PRDM1, IGJ and TNFSF13B are significantly up-regulated in synovial biopsies from patients with arthralgia, undifferentiated arthritis (UA), early RA and established RA as compared to healthy controls and control patients with osteoarthritis. In addition, the highest CD38 expression was observed on plasma cells and plasmablasts compared to natural killer (NK) cells, classical dendritic cells (DCs), plasmacytoid DCs (pDCs) and T cells, in blood from healthy controls and patients with SLE and RA. Furthermore, IHC showed CD38 staining in the same region as CD3 and CD138 staining in synovial tissue biopsies from patients with early RA. Most importantly, our data show for the first time that daratumumab effectively depletes plasma cells/plasmablasts in PBMC from patients with SLE and RA in a dose-dependent manner ex vivo. These results indicate that CD38 may be a potential target for RA disease interception and daratumumab should be evaluated clinically for the treatment of both RA and SLE.

CD38 expression and immunoglobulin variable region mutations are independent prognostic variables in chronic lymphocytic leukemia, but CD38 expression may vary during the course of the disease.

PubMed

Hamblin, Terry J; Orchard, Jenny A; Ibbotson, Rachel E; Davis, Zadie; Thomas, Peter W; Stevenson, Freda K; Oscier, David G

2002-02-01

Although the presence or absence of somatic mutations in the immunoglobulin variable region (IgV(H)) genes in chronic lymphocytic leukemia (B-CLL) identifies subtypes with very different prognoses, the assay is technically complex and unavailable to most laboratories. CD38 expression has been suggested as a surrogate marker for the 2 subtypes. IgV(H) mutations and CD38 expression in 145 patients with B-CLL with a long follow-up were compared. The 2 assays gave discordant results in 41 patients (28.3%). Multivariate analysis demonstrated that Binet stage, IgV(H) mutations and CD38 were independent prognostic indicators. Median survival time in patients whose cells had unmutated IgV(H) genes and expressed CD38 was 8 years; in those with mutated IgV(H) genes not expressing CD38, it was 26 years. For those with discordant results, median survival time was 15 years. Thus, although CD38 expression does not identify the same 2 subsets as IgV(H) mutations in CLL, it is an independent risk factor that can be used with IgV(H) mutations and clinical stage to select patients with B-CLL with the worst prognoses. Using cryopreserved cells taken at intervals during the course of the disease, however, changes of CD38 expression over time were demonstrated in 10 of 41 patients. Causes of the variation of CD38 expression require further study. Additional prospective studies are required for comparing CD38 expression with other prognostic factors and for taking sequential measurements during the course of the disease.

Role of flow-cytometric immunophenotyping in prediction of BCR/ABL1 gene rearrangement in adult B-cell acute lymphoblastic leukemia.

PubMed

Corrente, Francesco; Bellesi, Silvia; Metafuni, Elisabetta; Puggioni, Pier Luigi; Marietti, Sara; Ciminello, Angela Maria; Za, Tommaso; Sorà, Federica; Fianchi, Luana; Sica, Simona; De Stefano, Valerio; Chiusolo, Patrizia

2018-05-01

We performed a retrospective analysis of 88 adult patients with B-ALL diagnosed in our center by a flow-cytometric assessment. Immunophenotypic expression of leukemic cells was explored by simultaneous evaluation of positivity, percentage of expressing cells and median fluorescence intensity (MFI). BCR/ABL1 fusion transcripts were assessed by RT-PCR analysis and were identified in 36 patients (40.9%). CD10 and CD34 were positive in the totality of BCR/ABL1-positive cases. Patients with gene rearrangement had a greater frequency of CD66c, CD13 and CD33 positivity compared with BCR/ABL1-negative cases. Moreover, BCR/ABL1-positive cases exhibited a greater median percentage and MFI values of CD13, CD33, CD66c, CD10, CD34 and CD25 expressions, but a lower median percentage and MFI values of CD38 and CD22 expressions than patients without gene rearrangement. Multivariate logistic regression analysis showed that CD10, CD38 and CD13 expressions were independent predictors for the presence of BCR/ABL1 rearrangement. Predictive probabilities of molecular occurrence based on these markers are proposed. © 2017 International Clinical Cytometry Society. © 2017 International Clinical Cytometry Society.

Early elevation of soluble CD14 may help identify trauma patients at high risk for infection.

PubMed

Carrillo, E H; Gordon, L; Goode, E; Davis, E; Polk, H C

2001-05-01

Elevated levels of soluble CD14 (sCD14) have been implicated in both gram-positive and gram-negative sepsis, and it has been associated with high mortality in trauma patients who become infected. Eleven healthy volunteers and 25 adult trauma patients with multiple injuries and a mean Injury Severity Score of 32 participated. Whole blood was obtained at intervals. Immunohistochemistry was used to quantify membrane CD14 (mCD14), by flow cytometry and plasma levels of sCD14 by enzyme-linked immunosorbent assay. Analysis of variance and Student's T test with Mann-Whitney posttest were used to determine significance at p < 0.05. On posttrauma day 1, sCD14 was significantly different in the plasma of infected patients compared with normal controls (7.16 +/- 1.87 microg/mL vs. 4.4 +/- 0.92 microg/mL, p < 0.01), but not significantly different from noninfected patients. The percentage of monocytes expressing mCD14 in trauma patients did not differentiate them from normal controls; however, mCD14 receptor density did demonstrate significance in septic trauma patients (n = 15) versus normal controls on posttrauma day 3 (p = 0.0065). On the basis of our data, mCD14 did not differentiate infected and noninfected trauma patients, although trauma in general reduced mCD14 and elevated sCD14. Interestingly, 100% of patients who exceeded plasma levels of 8 microg/mL of sCD14 on day 1 after injury developed infections. Therefore, early high expressers of sCD14 may be at higher risk for infectious complications after trauma.

Association of BAFF, APRIL serum levels, BAFF-R, TACI and BCMA expression on peripheral B-cell subsets with clinical manifestations in systemic lupus erythematosus.

PubMed

Salazar-Camarena, D C; Ortiz-Lazareno, P C; Cruz, A; Oregon-Romero, E; Machado-Contreras, J R; Muñoz-Valle, J F; Orozco-López, M; Marín-Rosales, M; Palafox-Sánchez, C A

2016-05-01

B-cell-activating factor (BAFF) and a proliferation-inducing ligand (APRIL) signaling pathways regulate B-cell survival through interactions with their receptors BAFF-R, TACI and BCMA. We evaluated the association of these ligands/receptors on B-cell subsets according to clinical manifestations of systemic lupus erythematosus (SLE). BAFF and APRIL serum concentrations were measured in 30 SLE patients by enzyme-linked immunosorbent assay. The BAFF-R, TACI and BCMA expression was analyzed on each B cell subset (CD19 + CD27-CD38-/ + naïve; CD19 + CD27 + CD38-/ + memory; CD19 + CD27-CD38 + + immature and CD19 + CD27 + CD38 + + plasma cells) by flow cytometry, and compared among patients with different clinical manifestations as well as healthy controls (HCs). Serum BAFF and APRIL levels were high in SLE patients and correlated with the Mex-SLEDAI disease activity index (r = 0.584; p = 0.001 and r = 0.456; p = 0.011, respectively). The SLE patients showed an increased proportion of memory and plasma B cells (p < 0.05). BAFF-R, TACI and BCMA expression in SLE patients was decreased in almost all B cell subsets compared to HCs (p < 0.05). A lower BCMA expression was associated with severe disease activity, glomerulonephritis, serositis and hemolytic anemia (p < 0.01). BCMA expression showed a negative correlation with Mex-SLEDAI score (r = -0.494, p = 0.006). Decreased BCMA expression on peripheral B cells according to severe disease activity suggests that BCMA plays an important regulating role in B-cell hyperactivity and immune tolerance homeostasis in SLE patients. © The Author(s) 2015.

AZT Impairs Immunological Recovery on First-line ART: Collaborative analysis of cohort studies in Southern Africa

PubMed Central

WANDELER, Gilles; GSPONER, Thomas; MULENGA, Lloyd; GARONE, Daniela; WOOD, Robin; MASKEW, Mhairi; PROZESKY, Hans; HOFFMANN, Christopher; EHMER, Jochen; DICKINSON, Diana; DAVIES, Mary-Ann; EGGER, Matthias; KEISER, Olivia

2013-01-01

Objectives Zidovudine (AZT) is recommended for first-line antiretroviral therapy (ART) in resource limited settings. AZT may, however, lead to anemia and impaired immunological response. We compared CD4 counts over 5 years between patients starting ART with and without AZT in Southern Africa. Design Cohort study Methods Patients aged ≥16 years who started first-line ART in South Africa, Botswana, Zambia or Lesotho were included. We used linear mixed-effect models to compare CD4 cell count trajectories between patients on AZT-containing regimens and patients on other regimens, censoring follow-up at first treatment change. Impaired immunological recovery, defined as a CD4 count below 100 cells/μl at 1 year, was assessed in logistic regression. Analyses were adjusted for baseline CD4 count and haemoglobin level, age, gender, type of regimen, viral load monitoring and calendar year. Results 72,597 patients starting ART, including 19,758 (27.2%) on AZT, were analysed. Patients on AZT had higher CD4 cell counts (150 vs.128 cells/μl) and haemoglobin level (12.0 vs. 11.0 g/dl) at baseline, and were less likely to be female than those on other regimens. Adjusted differences in CD4 counts between regimens containing and not containing AZT were −16 cells/μl (95% CI −18 to −14) at 1 year and −56 cells/μl (95% CI −59 to −52) at 5 years. Impaired immunological recovery was more likely with AZT compared to other regimens (odds ratio 1.40, 95% CI 1.22–1.61). Conclusions In Southern Africa AZT is associated with inferior immunological recovery compared to other backbones. Replacing AZT with another NRTI could avoid unnecessary switches to second-line ART. PMID:23660577

Skin-infiltrating, interleukin-22-producing T cells differentiate pediatric psoriasis from adult psoriasis.

PubMed

Cordoro, Kelly M; Hitraya-Low, Maria; Taravati, Keyon; Sandoval, Priscila Munoz; Kim, Esther; Sugarman, Jeffrey; Pauli, Mariela L; Liao, Wilson; Rosenblum, Michael D

2017-09-01

Evidence from adult psoriasis studies implicates an imbalance between regulatory and effector T cells, particularly T H -17-producing T cells, in the pathogenesis of psoriasis. Little is known about the immunopathology of psoriasis in children. We sought to functionally characterize the inflammatory cell profiles of psoriatic plaques from pediatric patients and compare them with healthy, age-matched controls and adult psoriasis patients. Skin samples from pediatric psoriasis patients and healthy controls were analyzed by multiparameter flow cytometry to determine the dominant immune cell subsets present and cytokines produced. Lesional tissue from pediatric psoriasis patients had significantly increased interleukin (IL) 22 derived from CD4 + and CD8 + cells compared with the tissues from healthy pediatric controls and adult psoriasis patients. Tissue from pediatric psoriasis patients had significantly less elevation of IL-17 derived from CD4 + and CD8 + cells compared with the tissue from adult psoriasis patients. In contrast with the lesions from adult patients, lesional skin in pediatric patients with psoriasis did not have increases in regulatory T cells. This is a pilot study, thus the sample size is small. Significant differences in IL-17 and IL-22 expression were observed in the pediatric psoriasis patients compared with pediatric healthy controls and adult psoriasis patients. IL-22 might be relevant in the pathogenesis of pediatric psoriasis and represents a potential treatment target unique to pediatric psoriasis. Copyright © 2017 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.

Is tremor related to celiac disease?

PubMed

Ameghino, Lucia; Rossi, Malco Damian; Cerquetti, Daniel; Merello, Marcelo

2017-06-14

Neurological features in celiac disease (CD) are not rare (5%-36%), but tremor is scarcely described. Subjects with CD and healthy controls completed an online survey using WHIGET tremor rating scale. One thousand five hundred and twelve subjects completed the survey, finally 674 CD patients and 290 healthy subjects were included. A higher prevalence of tremor in CD patients was observed in comparison to controls (28% vs 14%, P < 0.001). Frequency of family history of tremor in CD patients with and without tremor was 25% and 20% ( P = 0.2), while in the control group it was 41% and 10% ( P < 0.001). Controls with tremor showed a higher frequency of family history of tremor when compared to CD patients with tremor (41.5% vs 24.6%, P = 0.03). The results suggested that tremor in CD might be more frequent and possibly related to the disease itself and not due to associated essential tremor.

B cell subsets and dysfunction of regulatory B cells in IgG4-related diseases and primary Sjögren's syndrome: the similarities and differences.

PubMed

Lin, Wei; Jin, Lixia; Chen, Hua; Wu, Qingjun; Fei, Yunyun; Zheng, Wenjie; Wang, Qian; Li, Ping; Li, Yongzhe; Zhang, Wen; Zhao, Yan; Zeng, Xiaofeng; Zhang, Fengchun

2014-05-29

IgG4-related disease (IgG4-RD) is a multisystem-involved autoimmune disease. Abnormally activated and differentiated B cells may play important roles. Regulatory B cells (Breg) are newly defined B cell subgroups with immunosuppressive functions. In this study, we investigated the differences of B cell subsets, the expressions of co-stimulatory molecules on B cells, and the function of Breg cells in patients with IgG4-RD, primary Sjögren's syndrome (pSS) as well as in healthy controls (HC). Newly diagnosed IgG4-RD patients (n = 48) were enrolled, 38 untreated pSS patients and 30 healthy volunteers were recruited as disease and healthy controls. To analyze B cell subsets and B cell activity, PBMCs were surface stained and detected by flow cytometry. The function of Breg cells was tested by coculturing isolated CD19 + CD24(hi)CD38(hi) Breg cells with purified CD4 + CD25- T cells. Serum cytokines were measured by ELISA and cytometric bead array. Relationship between clinical data and laboratory findings were analyzed as well. Compared with pSS patients and HC, IgG4-RD patients had a lower frequency of peripheral Breg cells. Interestingly, CD19 + CD24-CD38(hi) B cell subsets were significantly higher in peripheral B cells from IgG4-RD patients than in pSS patients and HC, which correlated with serum IgG4 levels. The expression of BAFF-R and CD40 on B cells was significantly lower in IgG4-RD patients compared with those in pSS patients and HC. Unlike HC, Breg cells from pSS patients lacked suppressive functions. B cells in patients with IgG4-RD and pSS display a variety of abnormalities, including disturbed B cell subpopulations, abnormal expression of key signaling molecules, co-stimulatory molecules, and inflammatory cytokines. In addition, a significantly increased B cell subset, CD19 + CD24-CD38(hi) B cells, may play an important role in the pathogenesis of IgG4-RD.

[Effect of Yishen capsule on serum vascular endothelial growth factor and cell immunity in patients with chronic glomerulonephritis].

PubMed

Wu, Xi-li; Sun, Wan-sen; Zhang, Wang-gang; Qiao, Cheng-lin; Wang, Zhu; Wang, Juan

2007-11-01

To explore the effect of Yishen capsule on the serum vascular endothelial growth factor (VEGF), the cell immunity and the theraphic. Serum VEGF and T cell subsets were studied in 30 normal subjects and 83 patients before and after treatment. Compare with normal subjects, CD3, CD4, CD4/CD8 were decreased, CD8 and serum VEGF were increased obviously (P <0. 05 or P <0. 01). After three months treatment with YiShen capsule, CD4/CD8 was increased, CD8 and serum VEGF were decreased significantly (P <0.05 or P <0.01). Yishen capsule can reduce the proteinuria, increase the function of immunity and improve the clinical symptom of patients with chronic glomerulonephritis, achieved the effects of allevating chronic glomerular sclerosis ultimately.

Autonomic Dysfunction Correlates with Clinical and Inflammatory Activity in Patients with Crohn's Disease.

PubMed

Engel, Tal; Ben-Horin, Shomron; Beer-Gabel, Marc

2015-10-01

Autonomic dysfunction has been implicated in Crohn's disease (CD). We aimed to investigate heart rate variability (HRV) as a marker of possible autonomic imbalance in patients with CD. Thirty patients with CD and 30 age- and gender-matched healthy controls were enrolled in a prospective cohort study and underwent HRV study. Anxiety level was scored using the STAI questionnaire and CD clinical activity was assessed by Harvey-Bradshaw index. Blood tests including inflammatory markers were obtained for all participants. CD subjects had lower mean blood pressure (85.51 ± 11.07 mm Hg, 91.51 ± 6.99, P = 0.015) and albumin and significantly higher CRP and IL-6 compared with controls (P < 0.002 for all comparisons). Mean HRV values of very low-frequency power and low-frequency power components were significantly lower among CD subjects (P = 0.038 and 0.027, respectively), implying a predominant sympathetic tone. Anxiety level scores were significantly higher among patients with CD for both state anxiety (P = 0.001) and trait anxiety (P < 0.0001). However, patients with active disease had similar anxiety scores as patients in remission, yet had a significantly lower BMI, lower albumin level, and higher CRP and IL-6 levels (P < 0.05 for all comparisons). Moreover, despite similar anxiety scores, patients with active disease had higher pulse rate (P = 0.02) and lower HRV indexes, which correlated with albumin levels(r = 0.7, P = 0.001). Although patients with CD have higher anxiety levels compared with controls, they exhibit depressed HRV independent of this anxiety state and in direct correlation with disease activity and inflammatory markers. These observations suggest an inherent imbalance of autonomic function associated with active inflammation.

Functional characterization of CD4 and CD8 T cell responses among human papillomavirus infected patients with ano-genital warts.

PubMed

Singh, Manjula; Thakral, Deepshi; Rishi, Narayan; Kar, Hemanta Kumar; Mitra, Dipendra Kumar

2017-06-01

Ano-genital warts are considered one of the commonest and highly infectious sexually transmitted infections. These warts are primarily caused by the human papillomavirus (HPV) of the family Papillomaviridae , genus alpha - papillomavirus , species 10 and types 6 and 11. However the high recurrence rate of warts is a matter of serious concern to the patients and a challenge for the treating physician. The conventional treatment options are targeted only to the local site of warts. There is no systemic treatment modality as there is limited understanding of the disease immune-pathogenesis. The role of cell-mediated immunity in combating HPV infection is not clearly defined. Hence the present study is aimed at investigating the CD4 + T helper (Th1 and Th2) and CD8 + T cell responses among wart patients. In this study, we compared HPV6 and HPV11 antigen-specific T cell responses among venereal wart patients relative to healthy controls. Significant decrease in percent frequencies of IFN-γ producing CD4 + and CD8 + T cells were observed in HPV infected wart patients. On the other hand, the frequency of CD4 + T cells expressing IL-4 was significantly increased in these patients as compared to healthy controls. The observed functional skewing of HPV specific T cells from Th1 to Th2 response in patients indicated suppressed immunity against the HPV. Moreover, decrease in CD8 T cell function correlated with poor wart clearance. Our findings open future avenues for exploring potential immunomodulation strategies as an adjunct to standard treatment for better management of these patients and prevention of recurrence.

Stimulatory role of interleukin 10 in CD8+ T cells through STATs in gastric cancer.

PubMed

Xi, Jianjun; Xu, Mingzheng; Song, Zongchang; Li, Hongqiang; Xu, Shumin; Wang, Chunmei; Song, Haihan; Bai, Jianwen

2017-05-01

CD8 + T cells are considered to be critical in tumor surveillance and elimination. Increased CD8 + T cell frequency and function is associated with better prognosis in cancer patients. Interleukin 10 is a cytokine with controversial roles in CD8 + T cell-mediated anti-tumor immunity. We therefore examined the interleukin 10 expression and consumption in CD8 + T cells harvested from the peripheral blood and resected tumors of gastric cancer patients of stages II-IV. We found that the gastric cancer patients presented significantly elevated frequencies of interleukin 10-expressing cells in both CD4 + and CD8 + T cells compared to healthy controls. But distinctive from the interleukin 10-expressing CD4 + T cells, which increased in frequency in advanced cancer, the interleukin 10-expressing CD8 + T cells did not increase with cancer stage in the peripheral blood and actually decreased with cancer stage in resected tumor. Interleukin 10 and interleukin 10 receptor expression was also enriched in interferon gamma-expressing activated CD8 + T cells. Compared to interleukin 10-nonexpressing CD8 + T cells, interleukin 10 receptor-expressing CD8 + T cells secreted significantly elevated interferon gamma levels. Treatment of anti-CD3/CD28-stimulated, purified CD8 + T cells with interleukin 10 alone could significantly enhance CD8 + T cell survival, an effect dependent on interleukin 10 receptor expression. Interleukin 10 also increased CD8 + T cell proliferation synergistically with interferon gamma but not alone. Analysis of downstream signal transducer and activator of transcription molecules showed that interleukin 10 treatment significantly increased the phosphorylation of signal transducer and activator of transcription 3 and signal transducer and activator of transcription 1 to lesser extent. Together, these results demonstrate that interleukin 10 possessed stimulatory roles in activated CD8 + T cells from gastric cancer patients.

Analysis of fat and muscle mass in patients with inflammatory bowel disease during remission and active phase.

PubMed

Rocha, Raquel; Santana, Genoile Oliveira; Almeida, Neogélia; Lyra, Andre Castro

2009-03-01

Inflammatory bowel disease (IBD) is often associated with malnutrition. The aim of this study was to compare the body composition of outpatients with IBD during remission and active phase. In order to evaluate disease activity we used Crohn's Disease Activity Index for Crohn's disease (CD) patients and Lichtiger's Index for ulcerative colitis (UC) patients. All patients underwent the analysis of BMI, arm muscle area (AMA) and triceps plus subscapula skinfold thickness (TST+SST) to identify total, muscle and fat mass, respectively. In total 102 patients were evaluated (CD, n 50; UC, n 52) and the majority was young women. Malnutrition according to BMI was found in 14.0 % of patients with CD and 5.7 % of UC patients. Muscle mass depletion was detected in more than half of the CD and UC patients. The BMI, TST+SST and AMA values were lower in the active phase only in CD patients (P < 0.05). Fat mass depletion was associated with active phase in both CD and UC patients. Body composition parameters obtained using BMI, TST+SST and AMA were not correlated with the presence of fistula in CD patients (P>0.05). In conclusion, patients without signs of malnutrition had fat mass depletion especially in the active phase and muscle mass depletion occurred both in CD and UC patients.

CD20+ T cell numbers are decreased in untreated HIV-1 patients and recover after HAART.

PubMed

Förster, Friederike; Singla, Anuj; Arora, Sunil K; Schmidt, Reinhold E; Jacobs, Roland

2012-08-30

To elucidate if CD20(+) T cells are affected by HIV-1 infection and may have a prognostic value for the course of disease, numbers of CD20(+) T cells were determined in healthy controls, untreated and HAART-treated HIV-1 patients. Coexpression patterns of CD4, CD8, and CD38 were analysed on CD3(+)CD20(+) and CD3(+)CD20(-) T cells. We found a significant decrease of CD20(+) T cell numbers in untreated HIV-1 patients (1.4%) as compared to healthy controls (2.5%) which recovered under HAART (1.9%). Particularly, the CD8(+) T cell compartment was affected revealing significant differences between healthy controls (3.4%) and both treated (1.7%) and untreated (1.1%) patients. CD38 was expressed on a few CD20(+) T cells but preferentially on CD20(-) cells in all three groups. IFN-γ production was measured upon cell activation using PMA alone or in combination with ionomycin in order to assess functional capacities of the cells. PMA alone was much more effective in CD20(+) cells regardless of CD38 coexpression, indicating a supportive role of CD20 but not CD38 in T cell activation. Here we present data showing that CD3(+)CD20(+) T cells are decreased in untreated HIV-1 patients and normal numbers are restored under HAART. Expression of CD20 and CD38 is independently regulated on T cells. Contrary to CD38, CD20 can substitute ionophores for Ca(2+) flux in early T cell activation and also strongly amplify cell stimulation in the presence of Ca(2+) ionophores, indicating that CD20 contributes to T cell activation. Copyright © 2012 Elsevier B.V. All rights reserved.

COMPARE CPM-RMI Trial: Intramyocardial Transplantation of Autologous Bone Marrow-Derived CD133+ Cells and MNCs during CABG in Patients with Recent MI: A Phase II/III, Multicenter, Placebo-Controlled, Randomized, Double-Blind Clinical Trial.

PubMed

Naseri, Mohammad Hassan; Madani, Hoda; Ahmadi Tafti, Seyed Hossein; Moshkani Farahani, Maryam; Kazemi Saleh, Davood; Hosseinnejad, Hossein; Hosseini, Saeid; Hekmat, Sepideh; Hossein Ahmadi, Zargham; Dehghani, Majid; Saadat, Alireza; Mardpour, Soura; Hosseini, Seyedeh Esmat; Esmaeilzadeh, Maryam; Sadeghian, Hakimeh; Bahoush, Gholamreza; Bassi, Ali; Amin, Ahmad; Fazeli, Roghayeh; Sharafi, Yaser; Arab, Leila; Movahhed, Mansour; Davaran, Saeid; Ramezanzadeh, Narges; Kouhkan, Azam; Hezavehei, Ali; Namiri, Mehrnaz; Kashfi, Fahimeh; Akhlaghi, Ali; Sotoodehnejadnematalahi, Fattah; Vosough Dizaji, Ahmad; Gourabi, Hamid; Syedi, Naeema; Shahverdi, Abdol Hosein; Baharvand, Hossein; Aghdami, Nasser

2018-07-01

The regenerative potential of bone marrow-derived mononuclear cells (MNCs) and CD133+ stem cells in the heart varies in terms of their pro-angiogenic effects. This phase II/III, multicenter and double-blind trial is designed to compare the functional effects of intramyocardial autologous transplantation of both cell types and placebo in patients with recent myocardial infarction (RMI) post-coronary artery bypass graft. This was a phase II/III, randomized, double-blind, placebo-controlled trial COMPARE CPM-RMI (CD133, Placebo, MNCs - recent myocardial infarction) conducted in accordance with the Declaration of Helsinki that assessed the safety and efficacy of CD133 and MNCs compared to placebo in patients with RMI. We randomly assigned 77 eligible RMI patients selected from 5 hospitals to receive CD133+ cells, MNC, or a placebo. Patients underwent gated single photon emission computed tomography assessments at 6 and 18 months post-intramyocardial transplantation. We tested the normally distributed efficacy outcomes with a mixed analysis of variance model that used the entire data set of baseline and between-group comparisons as well as within subject (time) and group×time interaction terms. There were no related serious adverse events reported. The intramyocardial transplantation of both cell types increased left ventricular ejection fraction by 9% [95% confidence intervals (CI): 2.14% to 15.78%, P=0.01] and improved decreased systolic wall thickening by -3.7 (95% CI: -7.07 to -0.42, P=0.03). The CD133 group showed significantly decreased non-viable segments by 75% (P=0.001) compared to the placebo and 60% (P=0.01) compared to the MNC group. We observed this improvement at both the 6- and 18-month time points. Intramyocardial injections of CD133+ cells or MNCs appeared to be safe and efficient with superiority of CD133+ cells for patients with RMI. Although the sample size precluded a definitive statement about clinical outcomes, these results have provided the basis for larger studies to confirm definitive evidence about the efficacy of these cell types (Registration Number: NCT01167751). Copyright© by Royan Institute. All rights reserved.

[Therapeutic effect of autologous cytokine-induced killer cells on patients with liver cirrhosis caused by HBV infection].

PubMed

Su, Hai-bin; Li, Han-wei; Zhao, Hong-lan; Shi, Ming; Zhang, Bing; Tang, Zi-rong; Lei, Zhou-yun; Wang, Hui-fen; Wang, Fu-sheng

2007-03-01

To observe the therapeutic effect of autologous cytokine-induced killer cells (CIK) on HBV DNA positive patients with liver cirrhosis. HBV DNA positive 33 patients with cirrhosis were treated with CIK. Before and after cultured in vitro and post-treatment, CD3+, CD3+CD4+, CD3+CD8+, CD3+CD56+ cells, mDC and pDC were detected by flow cytometry. The indexes of virus and liver function were compared between pre- and post-treatment. CD3+, CD3+CD8+ cells and CD3+CD56+ cells were higher after cultured in vitro and after transfused back than those before culture (91.5 +/- 10.3, 74.4 +/- 9.9 vs. 67.9 +/- 12.8; 60.9 +/- 15.5, 37.3 +/- 15.1 vs. 27.9 +/- 10.9; 18.4 +/- 11.7, 14.5 +/- 7.5 vs. 10.6 +/- 7.1). The percentages of mDC and pDC also increased after-treatment vs. pre-treatment (0.54 +/- 0.18 vs. 0.70 +/- 0.29; 0.26 +/- 0.13 vs. 0.41 +/- 0.25). HBV DNA became undetectable in 12 patients and decrease exceeded 100 times in 4 patients after treatment. HBeAg became undetectable in 10 of 14 patients who were HBeAg positive pretreatment patients, among them 2 patients had HBeAb sero conversion. The liver function was improved after treatment. All patients tolerated the treatment. CIK treatment can increase immune effector cells and has some antiviral effect and is safe.

Clinical value of Pro-GRP and T lymphocyte subpopulation for the assessment of immune functions of lung cancer patients after DC-CIK biological therapy.

PubMed

He, Lijie; Wang, Jing; Chang, Dandan; Lv, Dandan; Li, Haina; Zhang, Heping

2018-02-01

The present study investigated the aptness of assessing the levels of progastrin-releasing peptide (Pro-GRP) in addition to the T lymphocyte subpopulation in lung cancer patients prior to and after therapy for determining immune function. A total of 45 patients with lung cancer were recruited and stratified in to a non-small cell lung cancer (NSCLC) and an SCLC group. Prior to and after treatment by combined biological therapy comprising chemotherapy or chemoradiotherapy followed by three cycles of retransformation of autologous dendritic cells-cytokine-induced killer cells (DC-CIK), the peripheral blood was assessed for populations of CD3 + , CD4 + , CD8 + and regulatory T cells (Treg) by flow cytometry, and for the levels of pro-GRP, carcinoembryonic antigen, neuron-specific enolase and Cyfra 21-1. The results revealed that in NSCLC patients, CD8 + T lymphocytes and Treg populations were decreased, and that CD3 + and CD4 + T lymphocytes as well as the CD4 + /CD8 + ratio were increased after therapy; in SCLC patients, CD3 + , CD4 + and CD8 + T lymphocytes were increased, while Treg cells were decreased after treatment compared with those at baseline. In each group, Pro-GRP was decreased compared with that prior to treatment, and in the SCLC group only, an obvious negative correlation was identified between Pro-GRP and the T lymphocyte subpopulation. Furthermore, a significant correlation between Pro-GRP and Tregs was identified in each group. In conclusion, the present study revealed that the immune function of the patients was improved after biological therapy. The results suggested a significant correlation between Pro-GRP and the T lymphocyte subpopulation in SCLC patients. Detection of Pro-GRP may assist the early clinical diagnosis of SCLC and may also be used to assess the immune regulatory function of patients along with the T lymphocyte subpopulation. Biological therapy with retransformed autologous DC-CIK was indicated to enhance the specific elimination of tumor cells and improve the immune surveillance function in cancer patients, and also restrained the immune evasion of the tumor, leading to decreased Pro-GRP levels.

Circulating and tumor-infiltrating Tim-3 in patients with colorectal cancer

PubMed Central

Gao, Quanli; Yuan, Peng; Zhao, Peng; Yuan, Huijuan; Fan, Huijie; Li, Tiepeng; Qin, Peng; Han, Lu; Fang, Weijia; Suo, Zhenhe

2015-01-01

T-cell exhaustion represents a progressive loss of T-cell function. The inhibitory receptor PD-1 is known to negatively regulate CD8+ T cell responses directed against tumor antigen, but the blockades of PD-1 pathway didn't show the objective responses in patients with colorectal cancer (CRC). Thus, further exploring the molecular mechanism responsible for inducing T-cell dysfunction in CRC patients may reveal effective strategies for immune therapy. This study aims to characterize co-inhibitory receptors on T cells in CRC patients to identify novel targets for immunotherapy. In this study, peripheral blood samples from 20 healthy controls and 54 consented CRC patients, and tumor and matched paraneoplastic tissues from 7 patients with advanced CRC, subjected to multicolor flow cytometric analysis of the expression of PD-1 and Tim-3 receptors on CD8+ T cells. It was found that CRC patients presented with significantly higher levels of circulating Tim-3+PD-1+CD8+ T cells compared to the healthy controls (medians of 3.12% and 1.99%, respectively, p = 0.0403). A similar increase of Tim-3+PD-1+CD8+ T cells was also observed in the tumor tissues compared to paraneoplastic tussues. Tim-3+PD-1+CD8+ T cells in tumor tissues produced even less cytokine than that in paraneoplastic tissues. Functional ex vivo experiments showed that Tim-3+PD-1+CD8+ T cells produced significantly less IFN-γ than Tim-3−PD-1−CD8+ T cells, followed by Tim-3+PD-1−CD8+ T cells, and Tim-3−PD-1+CD8+ T cells, indicating a stronger inhibition of IFN-γ production of Tim-3+CD8+ T cells. It is also found in this study that Tim-3+PD-1+CD8+ T cell increase in circulation was correlated with clinical cancer stage but not histologic grade and serum concentrations of cancer biomarker CEA. Our results indicate that upregulation of the inhibitory receptor Tim-3 may restrict T cell responses in CRC patients, and therefore blockage of Tim-3 and thus restoring T cell responses may be a potential therapeutic approach for CRC patients. PMID:26008981

Graded versus Intermittent Exercise Effects on Lymphocytes in Chronic Fatigue Syndrome.

PubMed

Broadbent, Suzanne; Coutts, Rosanne

2016-09-01

There is increasing evidence of immune system dysfunction in chronic fatigue syndrome (CFS), but little is known of the regular exercise effects on immune cell parameters. This pilot study investigated the effects of graded and intermittent exercise on CD4 lymphocyte subset counts and activation compared with usual care. Twenty-four CFS patients (50.2 ± 10 yr) were randomized to graded exercise (GE), intermittent exercise (IE), or usual care (UC) groups; 18 sedentary non-CFS participants (50.6 ± 10 yr) were controls (CTL) for blood and immunological comparisons. Outcome measures were pre- and postintervention flow cytometric analyses of circulating lymphocyte subset cell counts; expression of CD3, CD4, CD25, and CD134; full blood counts; and V˙O2peak. Preintervention, CD3 cell counts, and expression of CD4, CD25, CD134, and CD4CD25CD134 were significantly lower in GE, IE, and UC compared with CTL (P < 0.05). Total lymphocyte concentration was significantly lower in GE and IE groups compared with CTL. There were significant postintervention increases in i) expression of CD4 and CD4CD25CD134 for GE and IE, but CD25 and CD134 for IE only; ii) circulating counts of CD3 and CD4 for GE, and CD3, CD4, CD8, CD3CD4CD8, CD3CD16CD56, CD19, and CD45 for IE; iii) neutrophil concentration for GE; and iv) V˙O2peak and elapsed test time for IE and GE, V˙Epeak for IE. Twelve weeks of GE and IE training significantly improved CD4 lymphocyte activation and aerobic capacity without exacerbating CFS symptoms. IE may be a more effective exercise modality with regard to enhanced CD4 activation in CFS patients.

Anal skin tags in inflammatory bowel disease: new observations and a clinical review.

PubMed

Bonheur, Jennifer L; Braunstein, Jared; Korelitz, Burton I; Panagopoulos, Georgia

2008-09-01

The association between intestinal Crohn's disease (CD) and specific perianal abnormalities called anal skin tags (AST) has been recognized but not well defined. Skin tags have been classified into 2 types: 1) raised, broad, or narrow, single or multiple, soft or firm, and painless, often referred to as "elephant ears"; or 2) edematous, hard, often cyanotic, tender or not, and typically arising from a healed anal fissure, ulcer, or hemorrhoid. The aims of this study were to i) better characterize those skin tags identified by the term "elephant ears" and differentiate them from other types of AST; ii) compare their prevalence in patients with CD and ulcerative colitis (UC); iii) observe the relationship of the skin tags to the location of the primary bowel disease; and iv) to discuss the value of these typical AST in making an early diagnosis of CD. Photographs of all AST were taken when present at lower endoscopy in 170 consecutive patients with inflammatory bowel disease (IBD) seen in the private office of the senior investigator and Lenox Hill Hospital. Data was gathered with respect to major differences between the 2 types of AST. The location of the primary bowel disease for these patients was obtained from an extensive IBD computer database and review of details from charts. Specific features of AST were described and served to favor type 1 versus type 2. AST were found more frequently in patients with CD (75.4%) as compared to patients with UC (24.6%), confirming previous observations that they are more diagnostic of CD (P = 0.005). Subset analysis revealed a trend with a greater incidence of AST in patients with colitis (46.9%) as compared to patients with ileitis (36.7%) and ileocolitis (16.3%) (P = 0.067). We provide photographs with the most characteristic features of AST and attempt to separate elephant ears (type 1) from less typical AST (type 2) in CD. Our study confirms previous reports that AST are more commonly found in association with CD as compared with UC and more so in the presence of disease limited to the colon as compared to disease elsewhere in the bowel. Our observations support the diagnostic significance of AST heralding the diagnosis of CD when they are discovered on physical exam, especially in young people with diarrhea, abdominal pain, and/or growth retardation.

CD133+CD54+CD44+ circulating tumor cells as a biomarker of treatment selection and liver metastasis in patients with colorectal cancer

PubMed Central

Wang, Cun; Huang, Qiaorong; Meng, Wentong; Yu, Yongyang; Yang, Lie; Peng, Zhihai; Hu, Jiankun; Li, Yuan; Mo, Xianming; Zhou, Zongguang

2016-01-01

Introduction Liver is the most common site of distant metastasis in colorectal cancer (CRC). Early diagnosis and appropriate treatment selection decides overall prognosis of patients. However, current diagnostic measures were basically imaging but not functional. Circulating tumor cells (CTCs) known as hold the key to understand the biology of metastatic mechanism provide a novel and auxiliary diagnostic strategy for CRC with liver metastasis (CRC-LM). Results The expression of CD133+ and CD133+CD54+CD44+ cellular subpopulations were higher in the peripheral blood of CRC-LM patients when compared with those without metastasis (P<0.001). Multivariate analysis proved the association between the expression of CD133+CD44+CD54+ cellular subpopulation and the existence of CRC-LM (P<0.001). The combination of abdominal CT/MRI, CEA and the CD133+CD44+CD54+ cellular subpopulation showed increased detection and discrimination rate for liver metastasis, with a sensitivity of 88.2% and a specificity of 92.4%. Meanwhile, it also show accurate predictive value for liver metastasis (OR=2.898, 95% C.I.1.374–6.110). Materials and Method Flow cytometry and multivariate analysis was performed to detect the expression of cancer initiating cells the correlation between cellular subpopulations and liver metastasis in patients with CRC. The receiver operating characteristic curves combined with the area under the curve were generated to compare the predictive ability of the cellular subpopulation for liver metastasis with current CT and MRI images. Conclusions The identification, expression and application of CTC subpopulations will provide an ideal cellular predictive marker for CRC liver metastasis and a potential marker for further investigation. PMID:27764803

Rapid response to vedolizumab therapy in biologic-naïve patients with inflammatory bowel diseases.

PubMed

Feagan, Brian G; Lasch, Karen; Lissoos, Trevor; Cao, Charlie; Wojtowicz, Abigail M; Khalid, Javaria Mona; Colombel, Jean-Frédéric

2018-05-29

Vedolizumab, a humanized monoclonal antibody against α4β7 integrin, is used to treat adults with moderately to severely active ulcerative colitis (UC) and Crohn's disease (CD). We investigated the time course of clinical response to vedolizumab in patients who were and were not previously treated with tumor necrosis factor (TNF) antagonists. We performed a post-hoc analysis of data from phase 3, randomized, controlled trials of vedolizumab vs placebo in adult patients with UC (n=374) or CD (n=784). We collected data on patient-reported symptoms (rectal bleeding and stool frequency for patients with UC, abdominal pain and loose stool frequency for patients with CD) reported at weeks 2, 4, and 6 of treatment. We reported mean percentage score changes from baseline and proportions of patients who achieved predefined scores. We performed multivariate logistic regression analysis to identify factors associated with an early response (at week 2). In patients with UC (overall or naïve to TNF antagonist therapy), a significantly greater percentage of patients given vedolizumab achieved the predefined composite symptom score at weeks 2, 4, and 6 compared to those given placebo. In patients with CD who were naïve to TNF antagonists, a significantly greater percentage of patients given vedolizumab achieved the predefined score at weeks 2 and 4 compared to those given placebo. Among patients with UC given vedolizumab, 19.1% (overall) and 22.3% (TNF antagonist naïve) achieved a composite score of rectal bleeding of 0 and stool frequency ≤1 at week 2 compared to 10% (overall) and 6.6% (TNF antagonist naïve) of those receiving placebo. Among TNF antagonist-naïve patients with CD, 15.0% of those given vedolizumab achieved an average daily composite score of abdominal pain ≤1 and loose stool frequency ≤3 at week 2 (compared to 7.9% given placebo), and 23.8% of those given vedolizumab achieved these by week 4 (compared to 10.3% given placebo). In a post-hoc analysis of data from phase 3 clinical trials, vedolizumab significantly improved patient-reported symptoms of UC and CD as early as week 2 of treatment, continuing through the first 6 weeks-especially when given as first-line biologic therapy. Copyright © 2018 AGA Institute. Published by Elsevier Inc. All rights reserved.

Immune Responses in Acute and Convalescent Patients with Mild, Moderate and Severe Disease during the 2009 Influenza Pandemic in Norway

PubMed Central

Mohn, Kristin G.-I.; Cox, Rebecca Jane; Tunheim, Gro; Berdal, Jan Erik; Hauge, Anna Germundsson; Jul-Larsen, Åsne; Peters, Bjoern; Oftung, Fredrik

2015-01-01

Increased understanding of immune responses influencing clinical severity during pandemic influenza infection is important for improved treatment and vaccine development. In this study we recruited 46 adult patients during the 2009 influenza pandemic and characterized humoral and cellular immune responses. Those included were either acute hospitalized or convalescent patients with different disease severities (mild, moderate or severe). In general, protective antibody responses increased with enhanced disease severity. In the acute patients, we found higher levels of TNF-α single-producing CD4+T-cells in the severely ill as compared to patients with moderate disease. Stimulation of peripheral blood mononuclear cells (PBMC) from a subset of acute patients with peptide T-cell epitopes showed significantly lower frequencies of influenza specific CD8+ compared with CD4+ IFN-γ T-cells in acute patients. Both T-cell subsets were predominantly directed against the envelope antigens (HA and NA). However, in the convalescent patients we found high levels of both CD4+ and CD8+ T-cells directed against conserved core antigens (NP, PA, PB, and M). The results indicate that the antigen targets recognized by the T-cell subsets may vary according to the phase of infection. The apparent low levels of cross-reactive CD8+ T-cells recognizing internal antigens in acute hospitalized patients suggest an important role for this T-cell subset in protective immunity against influenza. PMID:26606759

Protective Cytomegalovirus (CMV)-Specific T-Cell Immunity Is Frequent in Kidney Transplant Patients without Serum Anti-CMV Antibodies

PubMed Central

Litjens, Nicolle H. R.; Huang, Ling; Dedeoglu, Burç; Meijers, Ruud W. J.; Kwekkeboom, Jaap; Betjes, Michiel G. H.

2017-01-01

The absence of anti-cytomegalovirus (CMV) immunoglobulin G (IgG) is used to classify pretransplant patients as naïve for CMV infection (CMVneg patients). This study assessed whether pretransplant CMV-specific T-cell immunity exists in CMVneg patients and whether it protects against CMV infection after kidney transplantation. The results show that CMV-specific CD137+IFNγ+CD4+ and CD137+IFNγ+CD8+ memory T cells were present in 46 and 39% of CMVneg patients (n = 28) although at much lower frequencies compared to CMVpos patients (median 0.01 versus 0.58% for CD4+ and 0.05 versus 0.64% for CD8+ T cells) with a less differentiated CD28-expressing phenotype. In line with these data, CMV-specific proliferative CD4+ and CD8+ T cells were observed in CMVneg patients, which significantly correlated with the frequency of CMV-specific T cells. CMV-specific IgG antibody-secreting cells (ASC) could be detected at low frequency in 36% of CMVneg patients (1 versus 45 ASC/105 cells in CMVpos patients). CMVneg patients with pretransplant CMV-specific CD137+IFNγ+CD4+ T cells had a lower risk to develop CMV viremia after transplantation with a CMVpos donor kidney (relative risk: 0.43, P = 0.03). In conclusion, a solitary CMV-specific T-cell response without detectable anti-CMV antibodies is frequent and clinically relevant as it is associated with protection to CMV infection following transplantation with a kidney from a CMVpos donor. PMID:28955345

Expression of CD30 in patients with acute graft-versus-host disease.

PubMed

Chen, Yi-Bin; McDonough, Sean; Hasserjian, Robert; Chen, Heidi; Coughlin, Erin; Illiano, Christina; Park, In Sun; Jagasia, Madan; Spitzer, Thomas R; Cutler, Corey S; Soiffer, Robert J; Ritz, Jerome

2012-07-19

Acute GVHD (aGVHD) remains a major source of morbidity after allogeneic hematopoietic cell transplantation. CD30 is a cell-surface protein expressed on certain activated T cells. We analyzed CD30 expression on peripheral blood T-cell subsets and soluble CD30 levels in 26 patients at the time of presentation of aGVHD, before the initiation of treatment, compared with 27 patients after hematopoietic cell transplantation without aGVHD (NONE). Analysis by flow cytometry showed that patients with aGVHD had a greater percentage of CD30 expressing CD8(+) T cells with the difference especially pronounced in the central memory subset (CD8(+)CD45RO(+)CD62L(+)): GVHD median 12.4% (range, 0.8%-33.4%) versus NONE 2.1% (0.7%, 17.5%), P < .001. There were similar levels of CD30 expression in naive T cells, CD4(+) T cells, and regulatory (CD4(+)CD127(low)CD25(+)) T cells. Plasma levels of soluble CD30 were significantly greater in patients with GVHD: median 61.7 ng/mL (range, 9.8-357.1 ng/mL) versus 17.4 (range, 3.7-142.4 ng/mL) in NONE (P < .001). Immunohistochemical analysis of affected intestinal tissue showed many CD30(+) infiltrating lymphocytes present. These results suggest that CD30 expression on CD8(+) T-cell subsets or plasma levels of soluble CD30 may be a potential biomarker for aGVHD. CD30 may also represent a target for novel therapeutic approaches for aGVHD.

Expression of CD30 in patients with acute graft-versus-host disease

PubMed Central

McDonough, Sean; Hasserjian, Robert; Chen, Heidi; Coughlin, Erin; Illiano, Christina; Park, In Sun; Jagasia, Madan; Spitzer, Thomas R.; Cutler, Corey S.; Soiffer, Robert J.; Ritz, Jerome

2012-01-01

Acute GVHD (aGVHD) remains a major source of morbidity after allogeneic hematopoietic cell transplantation. CD30 is a cell-surface protein expressed on certain activated T cells. We analyzed CD30 expression on peripheral blood T-cell subsets and soluble CD30 levels in 26 patients at the time of presentation of aGVHD, before the initiation of treatment, compared with 27 patients after hematopoietic cell transplantation without aGVHD (NONE). Analysis by flow cytometry showed that patients with aGVHD had a greater percentage of CD30 expressing CD8+ T cells with the difference especially pronounced in the central memory subset (CD8+CD45RO+CD62L+): GVHD median 12.4% (range, 0.8%-33.4%) versus NONE 2.1% (0.7%, 17.5%), P < .001. There were similar levels of CD30 expression in naive T cells, CD4+ T cells, and regulatory (CD4+CD127lowCD25+) T cells. Plasma levels of soluble CD30 were significantly greater in patients with GVHD: median 61.7 ng/mL (range, 9.8-357.1 ng/mL) versus 17.4 (range, 3.7-142.4 ng/mL) in NONE (P < .001). Immunohistochemical analysis of affected intestinal tissue showed many CD30+ infiltrating lymphocytes present. These results suggest that CD30 expression on CD8+ T-cell subsets or plasma levels of soluble CD30 may be a potential biomarker for aGVHD. CD30 may also represent a target for novel therapeutic approaches for aGVHD. PMID:22661699

Regulatory T Cells in Patients with Idiopathic Thrombocytopenic Purpura.

PubMed

Akyol Erikçi, Alev; Karagöz, Bülent; Bilgi, Oğuz

2016-06-05

Immune thrombocytopenic purpura (ITP) is an immune-mediated bleeding disorder in which platelets are opsonized by autoantibodies and destroyed by an Fc receptor-mediated phagocytosis by the reticuloendothelial system within the spleen. Autoimmune processes are also considered in the pathogenesis of this disorder. CD4+CD25+FoxP3+ regulatory T (Treg) cells and CD8+CD28- Treg cells have roles in autoimmune diseases. We investigated these regulatory cells in ITP patients. We included 22 ITP patients and 16 age-matched healthy subjects. CD4+CD25+FoxP3+ Treg cells and CD8+CD28- cells were investigated by three-color flow cytometry. The ratios of these cell populations to total lymphocytes were calculated. Statistical analysis was carried out with the Mann-Whitney U test. CD4+CD25+ Treg cells were 9.69±3.70% and 12.99±5.58% in patients with ITP and controls, respectively. CD4+CD25highFoxP3+ cells were 27.72±19.74% and 27.55±23.98% in ITP patients and controls, respectively. The percentages of both of these cell types were not statistically significant when compared to the control group. We did not find any differences in ratios of CD4+CD25+FoxP3+ Treg cells or CD8+CD28- T cells in lymphocytes between patients and healthy subjects. We conclude that these circulatory cells are not different in ITP, but further studies are needed to explore the putative roles of these regulatory cells.

Transient expansion of activated CD8+ T cells characterizes tuberculosis-associated immune reconstitution inflammatory syndrome in patients with HIV: a case control study

PubMed Central

2013-01-01

Background CD4+ T cell activation indicators have been reported to be a common phenomenon underlying diverse manifestations of immune reconstitution inflammatory syndrome (IRIS). However, we have found that a high frequency of circulating CD8+ T cells is a specific risk factor for mycobacterial IRIS. Therefore, we investigated whether CD8+ T cells from patients who develop TB IRIS were specifically activated. Methods We obtained PBMCs from HIV+ patients prior to and 4, 8, 12, 24, 52 and 104 weeks after initiating antiretroviral therapy. CD38 and HLADR expression on naive, central memory and effector memory CD8+ and CD4+ T cells were determined by flow cytometry. Absolute counts and frequencies of CD8+ T cell subsets were compared between patients who developed TB IRIS, who developed other IRIS forms and who remained IRIS-free. Results TB IRIS patients showed significantly higher counts of naive CD8+ T cells than the other groups at most time points, with a contraction of the effector memory subpopulation occurring later in the follow-up period. Activated (CD38+ HLADR+) CD8+ T cells from all groups decreased with treatment but transiently peaked in TB IRIS patients. This increase was due to an increase in activated naive CD8+ T cell counts during IRIS. Additionally, the CD8+ T cell subpopulations of TB IRIS patients expressed HLADR without CD38 more frequently and expressed CD38 without HLADR less frequently than cells from other groups. Conclusions CD8+ T cell activation is specifically relevant to TB IRIS. Different IRIS forms may involve different alterations in T cell subsets, suggesting different underlying inflammatory processes. PMID:23688318

Immunophenotyping of Monocytes During Human Sepsis Shows Impairment in Antigen Presentation: A Shift Toward Nonclassical Differentiation and Upregulation of FcγRi-Receptor.

PubMed

Ferreira da Mota, Nadijane Valeria; Brunialti, Milena Karina Colo; Santos, Sidneia Sousa; Machado, Flavia Ribeiro; Assunçao, Murillo; de Azevedo, Luciano Cesar Pontes; Salomao, Reinaldo

2017-12-05

Monocytes and macrophages are pivotal in the host response to sepsis, recognizing the infecting microorganism and triggering an inflammatory response. These functions are, at least in part, modulated by the expression of cell surface receptors. We aimed to characterize the monocyte phenotype from septic patients during an ongoing sepsis process and its association with clinical outcomes. Sixty-one septic patients and 31 healthy volunteers (HVs) were enrolled in the study. Samples were obtained from patients at baseline (D0, N = 61), and after 7 (D7, N = 36) and 14 days of therapy (D14, N = 22). Monocytes from septic patients presented decreased expression of CD86, HLA-DR, CD200R, CCR2, CXCR2, and CD163 compared with HV monocytes. In contrast, the PD-1, PD-L1, CD206, CD64, and CD16 expression levels were upregulated in patients. HLA-DR, CD64, PD-1, and PD-L1 expression levels were higher in survivors than in nonsurvivors. Increased CD86, HLA-DR, and CXCR2 expression levels were observed in follow-up samples; in contrast, CD64 and CD16 GMFI decreased over time. In conclusion, monocytes from septic patients show antigen presentation impairment as characterized by decreased HLA-DR and costimulatory CD86 expression and increased PD-1 and PD-L1 expression. On the contrary, increased monocyte inflammatory and phagocytic activities may be inferred by the increased CD16 and CD64 expression. We found conflicting results regarding differentiation toward the M2 phenotype, with increased CD206 expression and decreased CD163 expression on monocytes from septic patients, whereas the subset of nonclassical monocytes was demonstrated by increased CD16.

Soluble CD163 is increased in patients with acute pancreatitis independent of disease severity.

PubMed

Karrasch, Thomas; Brünnler, Tanja; Hamer, Okka W; Schmid, Karin; Voelk, Markus; Herfarth, Hans; Buechler, Christa

2015-10-01

Macrophages are crucially involved in the pathophysiology of acute pancreatitis. Soluble CD163 (sCD163) is specifically released from macrophages and systemic levels are increased in inflammatory diseases. Here, sCD163 was measured in serum of 50 patients with acute pancreatitis to find out possible associations with disease activity. Admission levels of systemic sCD163 were nearly three-fold higher in patients with acute pancreatitis compared to controls. In patients sCD163 did not correlate with C-reactive protein and leukocyte count as established markers of inflammation. Levels were not associated with disease severity assessed by the Schroeder score, Balthazar score, Acute Physiology, Age, and Chronic Health Evaluation (Apache) II score and peripancreatic necrosis score. Soluble CD163 was not related to complications of acute pancreatitis. These data show that serum sCD163 is increased in acute pancreatitis indicating activation of macrophages but is not associated with disease severity and outcome. Copyright © 2015 Elsevier Inc. All rights reserved.

Response to rituximab and timeframe to relapse in rheumatoid arthritis patients: association with B-cell markers.

PubMed

Pyrpasopoulou, Athina; Douma, Stella; Triantafyllou, Areti; Simoulidou, Elisavet; Samara, Magda; Parapanisiou, Efthymia; Aslanidis, Spyros

2010-02-01

Rituximab is used to deplete B cells and control disease activity, mainly in patients with rheumatoid arthritis (RA) who have not responded to anti-tumor necrosis factor (TNF) therapy. Response rates and time to relapse vary significantly among treated individuals. The objective of this study was to monitor the response of seropositive and seronegative RA patients to rituximab and correlate relapse with B-cell markers in the two groups. Seventeen RA patients (eight seropositive for rheumatoid factor [RF+] and nine seronegative [RF-]) were treated with two cycles of rituximab. After treatment, all patients were re-evaluated at the outpatient clinic, and rituximab was readministered when disease relapse was confirmed by clinical-laboratory measures (Disease Activity Score [DAS]-28). CD20+ cells and CD20 receptor expression levels were estimated at initiation, relapse, and re-evaluation timepoints, and were compared between the two groups. Seropositive patients responded favorably to treatment compared with the seronegative group. The mean time to relapse was 337.5 +/- 127.0 days for the RF+ patients versus 233.3 +/- 59.6 days for the RF- patients (p = 0.043), despite more aggressive concomitant treatment in the seronegative group. The DAS28 decrease 3 months after treatment was 1.695 +/- 1.076 in seropositive patients versus 0.94 +/- 1.62 in seronegative patients. At relapse, CD20 receptor expression (molecules/cell) was higher in RF+ patients than in their RF- counterparts, despite a significantly lower percentage of CD20+ cells. Rituximab treatment is efficient in both seropositive and seronegative RA. However, seropositive RA patients tend to respond favorably compared with seronegative patients. The differential CD20 receptor expression in the two groups at relapse potentially suggests a different pathogenetic mechanism of relapse and merits further investigation.

Pretransplant soluble CD30 is a better predictor of posttransplant development of donor-specific antibodies and acute vascular rejection than panel reactive antibodies.

PubMed

Vaidya, Smita; Partlow, David; Barnes, Titus; Gugliuzza, Kristine

2006-12-27

This study tests a hypothesis that pretransplant concentration of soluble CD30 (sCD30) is a better predictor of posttransplant development of donor-specific HLA antibodies (DSA) and acute vascular rejection (AVR) than panel reactive HLA antibodies (PRA). Pretransplant sera from 115 patients were evaluated for their PRA and sCD30 concentrations. All patients received calcineurin-inhibitor based immunosuppressive therapy. Objective measurements for rejection were biopsy-proven AVR episodes within first 6 months of the transplant. Posttransplant sera of patients with or without AVR were tested for the presence of DSA. AVR rate was 16% (18/115). Patients positive for PRA and sCD30 tests were at significantly higher risk for AVR compared to those patients negative for both tests (36% versus 5%, p = 0.01). Among negative PRA patients risk for AR was significantly elevated if they were also tested positive for sCD30 concentrations (21% versus 5%, p = 0.04). Of the 18 patients with AVR, 14 were positive for sCD30, and 13 of them (93%) developed DSA posttransplant (p = 0.001) Nineteen patients without AVR were tested for DSA and sCD30 concentrations. Only two of these 19 patients were positive for sCD30 and DSA. AVR was strongly associated with the patients tested positive for both the tests: DSA and sCD30 (p = 0.00007). Furthermore, patients with AVR are more likely to produce DSA than those without AVR (p = 0.02). These data support our hypothesis that patients positive for sCD30 contents are at high risk the development of DSA and AVR posttransplant regardless of their pretransplant PRA.

Nationwide population-based cohort study of celiac disease and risk of Ehlers-Danlos syndrome and joint hypermobility syndrome.

PubMed

Laszkowska, Monika; Roy, Abhik; Lebwohl, Benjamin; Green, Peter H R; Sundelin, Heléne E K; Ludvigsson, Jonas F

2016-09-01

Patients with celiac disease (CD) often have articular complaints, and small prior studies suggest an association with Ehlers-Danlos syndrome (EDS)/joint hypermobility syndrome (JHS). This study examines the risks of EDS/JHS in patients with CD. This cohort study compared all individuals in Sweden diagnosed with CD based on small intestinal biopsy between 1969-2008 (n=28,631) to 139,832 matched reference individuals, and to a second reference group undergoing biopsy without having CD (n=16,104). Rates of EDS/JHS were determined based on diagnostic codes in the Swedish Patient Register. Hazard ratios (HRs) for EDS/JHS were estimated through Cox regression. There are 45 and 148 cases of EDS/JHS in patients with CD and reference individuals, respectively. This corresponds to a 49% increased risk of EDS/JHS in CD (95%CI=1.07-2.07). The HR for EDS was 2.43 (95%CI=1.20-4.91) and for JHS 1.34 (95%CI=0.93-1.95). Compared to reference individuals undergoing intestinal biopsy, CD was not a risk factor for EDS/JHS. A stronger association was seen in patients initially diagnosed with EDS/JHS and subsequently diagnosed with CD (odds ratio=2.29; 95%CI=1.21-4.34). Individuals with CD have higher risk of EDS/JHS than the general population, which may be due to surveillance bias or factors intrinsic to celiac development. Copyright © 2016 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

The CD200-tolerance signaling molecule associated with pregnancy success is present in patients with early-stage breast cancer but does not favor nodal metastasis.

PubMed

Clark, David A; Dhesy-Thind, Sukhbinder; Ellis, Peter; Ramsay, Jennifer

2014-11-01

The CD200-tolerance signaling molecule prevents pregnancy failure and is also expressed by a wide variety of malignant tumors. The effect of CD200 mRNA expression on progression of human tumors has been variable. A cross-sectional study was performed to examine the correlation between CD200 protein expression in the primary tumors from postoperative Stage I-IIIA human breast cancer and the likelihood of regional lymph node metastasis. Fifty-eight percentage of patients had strong CD200(+) tumor staining (71% of Stage I and 53% Stage II-IIIA). Strong staining was associated with large T2-3 primary tumors compared to T1 tumors (64 versus 50%) and T2-3 N(+) versus T1 N(-) tumors (70 versus 63%), but this was not statistically significant. Nodal metastases were not more frequent in patients with strong CD200(+) staining (57% compared to 58% for weak/negative staining cases), and the metastatic tumor cells in regional lymph nodes were often CD200(-) when the primary tumor was CD200(+). CD200 expression by early-stage human breast cancer cells in primary tumors did not correlate with increased regional lymph node metastasis. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

CD147 expression predicts biochemical recurrence after prostatectomy independent of histologic and pathologic features.

PubMed

Bauman, Tyler M; Ewald, Jonathan A; Huang, Wei; Ricke, William A

2015-07-25

CD147 is an MMP-inducing protein often implicated in cancer progression. The purpose of this study was to investigate the expression of CD147 in prostate cancer (PCa) progression and the prognostic ability of CD147 in predicting biochemical recurrence after prostatectomy. Plasma membrane-localized CD147 protein expression was quantified in patient samples using immunohistochemistry and multispectral imaging, and expression was compared to clinico-pathological features (pathologic stage, Gleason score, tumor volume, preoperative PSA, lymph node status, surgical margins, biochemical recurrence status). CD147 specificity and expression were confirmed with immunoblotting of prostate cell lines, and CD147 mRNA expression was evaluated in public expression microarray datasets of patient prostate tumors. Expression of CD147 protein was significantly decreased in localized tumors (pT2; p = 0.02) and aggressive PCa (≥pT3; p = 0.004), and metastases (p = 0.001) compared to benign prostatic tissue. Decreased CD147 was associated with advanced pathologic stage (p = 0.009) and high Gleason score (p = 0.02), and low CD147 expression predicted biochemical recurrence (HR 0.55; 95 % CI 0.31-0.97; p = 0.04) independent of clinico-pathologic features. Immunoblot bands were detected at 44 kDa and 66 kDa, representing non-glycosylated and glycosylated forms of CD147 protein, and CD147 expression was lower in tumorigenic T10 cells than non-tumorigenic BPH-1 cells (p = 0.02). Decreased CD147 mRNA expression was associated with increased Gleason score and pathologic stage in patient tumors but is not associated with recurrence status. Membrane-associated CD147 expression is significantly decreased in PCa compared to non-malignant prostate tissue and is associated with tumor progression, and low CD147 expression predicts biochemical recurrence after prostatectomy independent of pathologic stage, Gleason score, lymph node status, surgical margins, and tumor volume in multivariable analysis.

CD142+/CD61+, CD146+ and CD45+ microparticles predict cardiovascular events in high risk patients following a Mediterranean diet supplemented with nuts.

PubMed

Chiva-Blanch, Gemma; Crespo, Javier; Suades, Rosa; Arderiu, Gemma; Padro, Teresa; Vilahur, Gemma; Cubedo, Judith; Corella, Dolores; Salas-Salvadó, Jordi; Arós, Fernando; Martínez-González, Miguel-Angel; Ros, Emilio; Fitó, Montse; Estruch, Ramon; Badimon, Lina

2016-07-04

Circulating microparticles (cMPs) are small phospholipid-rich microvesicles shed by activated cells that play a pivotal role in cell signalling related to the pathogenesis of atherothrombosis. We aimed to investigate the prognostic value of cMPs released from different vascular cells for cardiovascular event (CVE) presentation in asymptomatic patients at high cardiovascular risk factors under nutritional and pharmacologic treatment. This is a nested case-control study of 50 patients from the five-year follow-up prospective PREDIMED trial enrolled in the nuts arm of the Mediterranean diet (MedDiet-nuts). We randomly selected 25 patients who had suffered a CVE during follow-up and pair-matched them for sex, age, and classical CV risk factors to 25 patients who remained asymptomatic (no-CVE). Total Annexin V-(AV)+ cMPs and cMPs from cells of the vascular compartment were quantified by flow cytometry at baseline and after one year follow-up. MedDiet-nuts and pharmacological treatment neither modified levels nor source of MP shedding in CVE patients. However, no-CVE patients showed 40-86 % decreased total AV+, PAC-1+/AV+, CD61+/AV+, CD142+/CD61+/AV+, CD62P+/AV+, CD146+/AV+, CD63+/AV+ and CD11a+/AV+ cMPs at one year follow-up (p≤0.046, all). CD142+/CD61+/AV+, CD146+/AV+ and CD45+/AV+ cMPs were decreased in no-CVE patients compared to CVE patients. A ROC-curve clustered model for CD142+/CD61+/AV+, CD45+/AV+ and CD146+/AV+ cMPs predicted a future CVE [p<0.0001, AUC=0.805 (0.672 to 0.938)]. In patients at high CV risk profile treated with a controlled MedDiet supplemented with nuts and receiving up-to-date CV drug treatment, reduced cMPs derived from activated platelets, leukocytes and endothelial cells are predictive of protection against CVE within the next four years.

Duodenal intraepithelial T lymphocytes in patients with functional dyspepsia

PubMed Central

Gargala, Gilles; Lecleire, Stéphane; François, Arnaud; Jacquot, Serge; Déchelotte, Pierre; Ballet, Jean Jacques; Favennec, Loic; Ducrotté, Philippe

2007-01-01

AIM: To quantify the intraepithelial lymphocytes (IELs) and to document the membrane expression of CD4, CD8, TCRγδ and adhesion and/or activation-associated molecules (CD103, CD28, CD44, CD69, HLA-DR, CD95/Fas) in the duodenal mucosa of patients with functional dyspepsia (FD) in order to provide arguments for an immunological process in FD. METHODS: Twenty-six FD patients according to Rome II criteria (20 were H pylori negative) were studied and compared to 12 healthy adults. IELs were isolated from five duodenal biopsy samples, then quantified by microscopy and flow cytometry while the membrane phenotypes were determined by cytofluorometry. RESULTS: Duodenal histological examination was normal. In H pylori negative patients, the number of IELs was not different from that in healthy controls. Median percentage expression of CD4, CD8, or TCRγδ and CD103, CD44, CD28, CD69 on CD3+ IELs, among the adhesion/activation associated molecules tested, was not different from that in healthy controls. In contrast, the median percentage expression of CD95/Fas [22 (9-65) vs 45 (19-88), P = 0.03] and HLA-DR expressing CD3+ IELs [4 (0-30) vs 13 (4-42), P = 0.04] was significantly lower in the H pylori negative FD group than in healthy controls, respectively. The number of IELs was significantly greater in H pylori positive FD patients than in healthy controls [median ratiofor 100 enterocytes 27.5 (6.7-62.5) vs 10.8 (3-33.3), P = 0.02] due to a higher number of CD8+ CD3+ IELs. CONCLUSION: In H pylori negative FD patients, the phenotypic characterization of IELs suggests that we cannot exclude a role of IELs in FD. PMID:17511033

CD147-CD98hc complex contributes to poor prognosis of non-small cell lung cancer patients through promoting cell proliferation via the PI3K/Akt signaling pathway.

PubMed

Fei, Fei; Li, Xiaofei; Xu, Li; Li, Deyang; Zhang, Zhipei; Guo, Xu; Yang, Hushan; Chen, Zhinan; Xing, Jinliang

2014-12-01

It has been reported that CD147 and CD98 heavy chain (CD98hc) form a complex on the cell plasma membrane of several cancers; however, whether this complex exists in non-small cell lung cancer (NSCLC) cells and affects the prognosis of patients remains to be elucidated. The expression of CD147 and CD98hc was assessed in tissue samples from 241 NSCLC patients and NSCLC cell lines. The correlation between CD147 and CD98hc expression and their association with the prognosis of NSCLC patients were analyzed. We also evaluated the impact of CD147 and CD98hc on the growth of NSCLC cells as well as Akt phosphorylation. Both CD147 and CD98hc were significantly upregulated in NSCLC cells, and their expression levels were significantly correlated (p < 0.001). Immunoflurenece staining and co-immunoprecipitation demonstrated that CD147 and CD98hc could form a complex on NSCLC cells. Compared with NSCLC patients with CD147-/CD98hc-, those with CD147+/CD98hc+ exhibited a significantly poor overall survival (OS) with a hazard ratio (HR) of 1.92 (p = 0.010), and a significantly increased risk of recurrence with a HR of 1.97 (p = 0.004). Also, we demonstrated that the proliferation of lung cancer cell lines was significantly affected by knockdown and force-expression of the CD147-CD98hc complex. Western blot analysis indicated that the phosphorylation of Akt in NSCLC cells was significantly affected by knockdown and overexpression of either or both CD147 and CD98hc. Our findings indicate that the CD147-CD98hc complex significantly contributes to poor prognosis of NSCLC patients through promoting cell proliferation via the PI3K/Akt pathway.

Comparison of circulating and intratumoral regulatory T cells in patients with renal cell carcinoma.

PubMed

Asma, Gati; Amal, Gorrab; Raja, Marrakchi; Amine, Derouiche; Mohammed, Chebil; Amel, Ben Ammar Elgaaied

2015-05-01

The clear evidence that tumor-infiltrating lymphocytes (TIL) exists in the tumor microenvironment raises the question why renal cell carcinoma (RCC) progresses. Numerous studies support the implication of CD4(+)CD25(high) regulatory T (Treg) cells in RCC development. We aimed in this study to characterize the phenotype and function of circulating and intratumoral Treg cells of RCC patient in order to evaluate their implication in the inhibition of the local antitumor immune response. Our results demonstrate that the proportion of Treg in TIL was, in average, similar to that found in circulating CD4(+) T cells of patients or healthy donors. However, intratumoral Treg exhibit a marked different phenotype when compared with the autologous circulating Treg. A higher CD25 mean level, HLA-DR, Fas, and GITR, and a lower CD45RA expression were observed in intratumoral Treg, suggesting therefore that these cells are effector in the tumor microenvironment. Additionally, intratumoral Treg showed a higher inhibitory function on autologous CD4(+)CD25(-) T cells when compared with circulating Treg that may be explained by an overexpression of FoxP3 transcription factor. These findings suggest that intratumoral Treg could be major actors in the impairment of local antitumor immune response for RCC patients.

Paediatric Crohn disease patients with stricturing behaviour exhibit ileal granulocyte–macrophage colony-stimulating factor (GM-CSF) autoantibody production and reduced neutrophil bacterial killing and GM-CSF bioactivity

PubMed Central

Jurickova, I; Collins, M H; Chalk, C; Seese, A; Bezold, R; Lake, K; Allmen, D; Frischer, J S; Falcone, R A; Trapnell, B C; Denson, L A

2013-01-01

Granulocyte–macrophage colony-stimulating factor (GM-CSF) autoantibodies are associated with stricturing behaviour in Crohn disease (CD). We hypothesized that CD ileal lamina propria mononuclear cells (LPMC) would produce GM-CSF autoantibodies and peripheral blood (PB) samples would contain GM-CSF neutralizing capacity (NC). Paediatric CD and control PBMC and ileal biopsies or LPMC were isolated and cultured and GM-CSF, immunoglobulin (Ig)G and GM-CSF autoantibodies production were measured by enzyme-linked immunosorbent assay (ELISA). Basal and GM-CSF-primed neutrophil bacterial killing and signal transducer and activator of transcription 5 (STAT5) tyrosine phosphorylation (pSTAT5) were measured by flow cytometry. GM-CSF autoantibodies were enriched within total IgG for LPMC isolated from CD ileal strictures and proximal margins compared to control ileum. Neutrophil bacterial killing was reduced in CD patients compared to controls. Within CD, neutrophil GM-CSF-dependent STAT5 activation and bacterial killing were reduced as GM-CSF autoantibodies increased. GM-CSF stimulation of pSTAT5 did not vary between controls and CD patients in washed PB granulocytes in which serum was removed. However, GM-CSF stimulation of pSTAT5 was reduced in whole PB samples from CD patients. These data were used to calculate the GM-CSF NC. CD patients with GM-CSF NC greater than 25% exhibited a fourfold higher rate of stricturing behaviour and surgery. The likelihood ratio (95% confidence interval) for stricturing behaviour for patients with elevation in both GM-CSF autoantibodies and GM-CSF NC was equal to 5 (2, 11). GM-CSF autoantibodies are produced by LPMC isolated from CD ileal resection specimens and are associated with reduced neutrophil bacterial killing. CD peripheral blood contains GM-CSF NC, which is associated with increased rates of stricturing behaviour. PMID:23600834

Eating Disorders in Adolescents with Celiac Disease: Influence of Personality Characteristics and Coping.

PubMed

Wagner, Gudrun; Zeiler, Michael; Berger, Gabriele; Huber, Wolf-Dietrich; Favaro, Angela; Santonastaso, Paolo; Karwautz, Andreas

2015-09-01

Patients suffering from celiac disease (CD) have a higher risk of developing disturbed eating behaviour. In a multi-centre study, 259 female adolescents with CD and without a chronic condition were analysed regarding their eating disorder (ED) status, depression, personality, coping strategies and quality of life. Patients with CD and comorbid EDs were older and more often non-compliant with their diet and had a higher body mass index (BMI) and higher levels of depression. Differences in personality features disappear when controlling for age and depression. Higher ill-being and lower joy in life were reported by patients with CD and ED compared with patients without EDs, even when controlling for age and depression levels. No differences between patients (with CD) with and without EDs in coping strategies were found. BMI and lower self-directedness predicted ED status. Early identification of EDs in patients with CD is suggested and should include BMI and personality factors. Copyright © 2015 John Wiley & Sons, Ltd and Eating Disorders Association.

CD4 cell count response to first-line combination ART in HIV-2+ patients compared with HIV-1+ patients: a multinational, multicohort European study.

PubMed

Wittkop, Linda; Arsandaux, Julie; Trevino, Ana; Schim van der Loeff, Maarten; Anderson, Jane; van Sighem, Ard; Böni, Jürg; Brun-Vezinet, Françoise; Soriano, Vicente; Boufassa, Faroudy; Brockmeyer, Norbert; Calmy, Alexandra; Dabis, François; Jarrin, Inma; Dorrucci, Maria; Duque, Vitor; Fätkenheuer, Gerd; Zangerle, Robert; Ferrer, Elena; Porter, Kholoud; Judd, Ali; Sipsas, Nikolaos V; Lambotte, Olivier; Shepherd, Leah; Leport, Catherine; Morrison, Charles; Mussini, Cristina; Obel, Niels; Ruelle, Jean; Schwarze-Zander, Carolyne; Sonnerborg, Anders; Teira, Ramon; Torti, Carlo; Valadas, Emilia; Colin, Celine; Friis-Møller, Nina; Costagliola, Dominique; Thiebaut, Rodolphe; Chene, Geneviève; Matheron, Sophie

2017-10-01

CD4 cell recovery following first-line combination ART (cART) is poorer in HIV-2+ than in HIV-1+ patients. Only large comparisons may allow adjustments for demographic and pretreatment plasma viral load (pVL). ART-naive HIV+ adults from two European multicohort collaborations, COHERE (HIV-1 alone) and ACHIeV2e (HIV-2 alone), were included, if they started first-line cART (without NNRTIs or fusion inhibitors) between 1997 and 2011. Patients without at least one CD4 cell count before start of cART, without a pretreatment pVL and with missing a priori-defined covariables were excluded. Evolution of CD4 cell count was studied using adjusted linear mixed models. We included 185 HIV-2+ and 30321 HIV-1+ patients with median age of 46 years (IQR 36-52) and 37 years (IQR 31-44), respectively. Median observed pretreatment CD4 cell counts/mm3 were 203 (95% CI 100-290) in HIV-2+ patients and 223 (95% CI 100-353) in HIV-1+ patients. Mean observed CD4 cell count changes from start of cART to 12 months were +105 (95% CI 77-134) in HIV-2+ patients and +202 (95% CI 199-205) in HIV-1+ patients, an observed difference of 97 cells/mm3 in 1 year. In adjusted analysis, the mean CD4 cell increase was overall 25 CD4 cells/mm3/year lower (95% CI 5-44; P = 0.0127) in HIV-2+ patients compared with HIV-1+ patients. A poorer CD4 cell increase during first-line cART was observed in HIV-2+ patients, even after adjusting for pretreatment pVL and other potential confounders. Our results underline the need to identify more potent therapeutic regimens or strategies against HIV-2. © The Author 2017. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Inflammation and glandular duct dilatation of the tongue from patients with chronic Chagas disease.

PubMed

de Lima Pereira, Sanívia Aparecida; Rodrigues, Denise Bertulucci Rocha; da Fonseca Ferraz, Mara Lúcia; da Cunha Castro, Eumenia Costa; dos Reis, Marlene Antonia; de Paula Antunes Teixeira, Vicente

2006-01-01

The purpose of this study was to evaluate morphologically the tongue of individuals with chronic Chagas disease (CD) in comparison to the non-chagasic ones. Twenty-four protocol cases of autopsies were selected. They were subdivided into CD patients (10 cases) and non-chagasic ones (14 cases). The morphometric analysis was accomplished for the tongue muscle and salivary glands duct lumen area. In three CD patients, perineuritis was found, and two of them showed megaesophagus and megacolon. The intensity of the inflammation in the von Ebner's glands, the tongue muscles, and the salivary glands duct lumen area was significantly higher in the CD patients. We concluded that the CD patients show salivary glands duct dilatation, which probably would have a relation with alterations in the autonomic nervous system. The inflammation found in CD patients is in accordance with that described in comparative studies on the digestive tract and heart. These morphological findings suggest that the histopathological analysis of the tongue associated with other organs, or even in an isolated manner, can add in the diagnosis and pathogenesis of the CD chronic phase.

Monocyte profile in peripheral blood of gestational diabetes mellitus patients.

PubMed

Angelo, Ana G S; Neves, Carla T C; Lobo, Thalita F; Godoy, Ramon V C; Ono, Érika; Mattar, Rosiane; Daher, Silvia

2018-07-01

Gestational diabetes Mellitus has been considered an inflammatory disease involving different cells and mediators in its development. The role of innate immune cells in GDM physiopathology remains unclear, therefore this study was conducted to assess monocyte profile in GDM patients. This was a case-control study including 20 glucose-tolerant pregnant women (controls) and 18 GDM patients. Flow cytometry was used to assess peripheral blood monocytes subsets (classical, intermediate, non-classical), the expression of TLR4 and CCR2 chemokine receptor (CD192) and cytokines (TNFA, IL6, IL10) secretion by monocytes subsets. In addition, sCD14 serum levels were evaluated by ELISA. We observed increased percentage of CD14 + cells, decreased frequency of intermediate monocytes (CD14 + CD16 + ), and lower percentage of circulating monocytes (classical, intermediate and non-classical) that express TLR4 in the diabetic group compared to controls. Soluble CD14 + serum levels were higher in GDM patients compared to controls. There were no differences in the expression of the CCR2 chemokine receptor and cytokines (TNFA, IL6 and IL10) secretion between the studied groups. Our results demonstrated that GDM patients present impaired monocyte profile in the peripheral blood, suggesting that these cells are involved in GDM physiopathology. Copyright © 2017 Elsevier Ltd. All rights reserved.

Head and neck cancer relapse after chemoradiotherapy correlates with CD163+ macrophages in primary tumour and CD11b+ myeloid cells in recurrences.

PubMed

Balermpas, P; Rödel, F; Liberz, R; Oppermann, J; Wagenblast, J; Ghanaati, S; Harter, P N; Mittelbronn, M; Weiss, C; Rödel, C; Fokas, E

2014-10-14

We investigated the prognostic role of tumour-associated macrophages (TAMs) in patients with head and neck squamous cell carcinoma (HNSCC) treated with definitive chemoradiotherapy (CRT). The expression of CD68+, CD163+ and CD11b+ cells was assessed using immunohistochemistry in n=106 pre-treatment tumour biopsy samples and was correlated with clinicopathological characteristics, including T-stage, N-stage, grading, tumour localisation, age and sex as well as local failure-free survival (LFFS), distant metastases-free survival (DMFS), progression-free (PFS), and overall survival (OS). Finally, TAMs expression and vessel density (CD31) were examined in n=12 available early local recurrence samples and compared with their matched primary tumours . The diagnostic images and radiotherapy plans of these 12 patients were also analysed. All local recurrences occurred in the high radiation dose region (⩾70 Gy). With a median follow-up of 40 months, OS at 2 years was 60.5%. High CD163 expression in primary tumours was associated with decreased OS (P=0.010), PFS (P=0.033), LFFS (P=0.036) and DMFS (P=0.038) in multivariate analysis. CD163 demonstrated a strong prognostic value only in human papillomavirus (p16(INK4))-negative patients. Early local recurrence specimens demonstrated a significantly increased infiltration of CD11b+ myeloid cells (P=0.0097) but decreased CD31-positive vessel density (P=0.0004) compared with their matched primary samples. Altogether, baseline CD163 expression predicts for an unfavourable clinical outcome in HNSCC after definitive CRT. Early local recurrences showed increased infiltration by CD11b+ cells. These data provide important insight on the role of TAMs in mediating response to CRT in patients with HNSCC.

Cancer stem cell markers in patterning differentiation and in prognosis of oral squamous cell carcinoma.

PubMed

Mohanta, Simple; Siddappa, Gangotri; Valiyaveedan, Sindhu Govindan; Dodda Thimmasandra Ramanjanappa, Ravindra; Das, Debashish; Pandian, Ramanan; Khora, Samanta Sekhar; Kuriakose, Moni Abraham; Suresh, Amritha

2017-06-01

Differentiation is a major histological parameter determining tumor aggressiveness and prognosis of the patient; cancer stem cells with their slow dividing and undifferentiated nature might be one of the factors determining the same. This study aims to correlate cancer stem cell markers (CD44 and CD147) with tumor differentiation and evaluate their subsequent effect on prognosis. Immunohistochemical analysis in treatment naïve oral cancer patients (n = 53) indicated that the expression of CD147 was associated with poorly differentiated squamous cell carcinoma and moderately differentiated squamous cell carcinoma (p < 0.01). Furthermore, co-expression analysis showed that 45% each of moderately differentiated squamous cell carcinoma and poorly differentiated squamous cell carcinoma patients were CD44 high /CD147 high as compared to only 10% of patients with well-differentiated squamous cell carcinoma. A three-way analysis indicated that differentiation correlated with recurrence and survival (p < 0.05) in only the patients with CD44 high /CD147 high cohort. Subsequently, relevance of these cancer stem cell markers in patterning the differentiation characteristics was evaluated in oral squamous cell carcinoma cell lines originating from different grades of oral cancer. Flowcytometry-based analysis indicated an increase in CD44 + /CD147 + cells in cell lines of poorly differentiated squamous cell carcinoma (94.35 ± 1.14%, p < 0.001) and moderately differentiated squamous cell carcinoma origin (93.49 ± 0.47%, p < 0.001) as compared to cell line of well-differentiated squamous cell carcinoma origin (23.12% ± 0.49%). Expression profiling indicated higher expression of cancer stem cell and epithelial-mesenchymal transition markers in SCC029B (poorly differentiated squamous cell carcinoma originated; p ≤ 0.001), which was further translated into increased spheroid formation, migration, and invasion (p < 0.001) as compared to cell line of well-differentiated squamous cell carcinoma origin. This study suggests that CD44 and CD147 together improve the prognostic efficacy of tumor differentiation; in vitro results further point out that these markers might be determinant of differentiation characteristics, imparting properties of increased self-renewal, migration, and invasion.

Effects of modified FOLFOX-6 chemotherapy on cellular immune function in patients with gastric cancer

PubMed Central

Wang, Liang; Zhou, Donger; Ren, Haitao; Chen, Yan

2018-01-01

Tumor immunosuppression serves an important role in the occurrence and development of gastric cancer. However, the effect of chemotherapy on the immune function of patients remains unclear. The present study aimed to investigate changes in cellular immune function and regulatory T cells (Tregs) in patients with gastric cancer prior to and following chemotherapy. In the peripheral blood of patients with gastric cancer, the percentage of CD4+ T cells was substantially decreased compared with that of healthy controls (11.39±5.91 vs. 22.34±3.37%, respectively; P<0.05). High frequencies of CD8+ T cells and Tregs were also observed in the peripheral blood of patients. Although the number of T cells decreased following chemotherapy (the proportions of CD4+ and CD8+ cells were 8.99±7.31 and 16.00±4.51%, respectively), the ratio of CD4+/CD8+ T cells increased (0.31±0.17 vs. 0.56±0.22; P<0.05). Furthermore, the level of C-C motif chemokine ligand 20 (CCL20) was increased in patients prior to chemotherapy compared with healthy controls. As the sole receptor for CCL20, a high level of expression of C-C motif chemokine receptor 6 on circulating Tregs was also identified in the patients, which decreased following chemotherapy. These results suggest that chemotherapy may efficiently promote cellular immune function and inhibit immunosuppression in patients with gastric cancer.

Osteocalcin expression by circulating endothelial progenitor cells in patients with coronary atherosclerosis.

PubMed

Gössl, Mario; Mödder, Ulrike I; Atkinson, Elizabeth J; Lerman, Amir; Khosla, Sundeep

2008-10-14

This study was designed to test whether patients with coronary atherosclerosis have increases in circulating endothelial progenitor cells (EPCs) expressing an osteogenic phenotype. Increasing evidence indicates a link between bone and the vasculature, and bone marrow and circulating osteogenic cells have been identified by staining for the osteoblastic marker, osteocalcin (OCN). Endothelial progenitor cells contribute to vascular repair, but repair of vascular injury may result in calcification. Using cell surface markers (CD34, CD133, kinase insert domain receptor [KDR]) to identify EPCs, we examined whether patients with coronary atherosclerosis had increases in the percentage of EPCs expressing OCN. We studied 72 patients undergoing invasive coronary assessment: control patients (normal coronary arteries and no endothelial dysfunction, n = 21) versus 2 groups with coronary atherosclerosis-early coronary atherosclerosis (normal coronary arteries but with endothelial dysfunction, n = 22) and late coronary atherosclerosis (severe, multivessel coronary artery disease, n = 29). Peripheral blood mononuclear cells were analyzed using flow cytometry. Compared with control patients, patients with early or late coronary atherosclerosis had significant increases (approximately 2-fold) in the percentage of CD34+/KDR+ and CD34+/CD133+/KDR+ cells costaining for OCN. Even larger increases were noted in the early and late coronary atherosclerosis patients in the percentage of CD34+/CD133-/KDR+ cells costaining for OCN (5- and 2-fold, p < 0.001 and 0.05, respectively). A higher percentage of EPCs express OCN in patients with coronary atherosclerosis compared with subjects with normal endothelial function and no structural coronary artery disease. These findings have potential implications for the mechanisms of vascular calcification and for the development of novel markers for coronary atherosclerosis.

Office-Based Point of Care Testing (IgA/IgG-Deamidated Gliadin Peptide) for Celiac Disease.

PubMed

Lau, Michelle S; Mooney, Peter D; White, William L; Rees, Michael A; Wong, Simon H; Hadjivassiliou, Marios; Green, Peter H R; Lebwohl, Benjamin; Sanders, David S

2018-06-19

Celiac disease (CD) is common yet under-detected. A point of care test (POCT) may improve CD detection. We aimed to assess the diagnostic performance of an IgA/IgG-deamidated gliadin peptide (DGP)-based POCT for CD detection, patient acceptability, and inter-observer variability of the POCT results. From 2013-2017, we prospectively recruited patients referred to secondary care with gastrointestinal symptoms, anemia and/or weight loss (group 1); and patients with self-reported gluten sensitivity with unknown CD status (group 2). All patients had concurrent POCT, IgA-tissue transglutaminase (IgA-TTG), IgA-endomysial antibodies (IgA-EMA), total IgA levels, and duodenal biopsies. Five hundred patients completed acceptability questionnaires, and inter-observer variability of the POCT results was compared among five clinical staff for 400 cases. Group 1: 1000 patients, 58.5% female, age 16-91, median age 57. Forty-one patients (4.1%) were diagnosed with CD. The sensitivities of the POCT, IgA-TTG, and IgA-EMA were 82.9, 78.1, and 70.7%; the specificities were 85.4, 96.3, and 99.8%. Group 2: 61 patients, 83% female; age 17-73, median age 35. The POCT had 100% sensitivity and negative predictive value in detecting CD in group 2. Most patients preferred the POCT to venepuncture (90.4% vs. 2.8%). There was good inter-observer agreement on the POCT results with a Fleiss Kappa coefficient of 0.895. The POCT had comparable sensitivities to serology, and correctly identified all CD cases in a gluten sensitive cohort. However, its low specificity may increase unnecessary investigations. Despite its advantage of convenience and rapid results, it may not add significant value to case finding in an office-based setting.

Association of neutrophil-lymphocyte ratio and T lymphocytes with the pathogenesis and progression of HBV-associated primary liver cancer

PubMed Central

Han, Junyan; Wang, Lijia; Li, Mengge; Jiang, Yuyong; Wang, Xianbo; Yang, Zhiyun

2017-01-01

Background The neutrophil–lymphocyte ratio (NLR) is a new prognostic predictor for patients with liver cancer. The association of NLR and T lymphocytes with the pathogenesis and progression of liver cancer is poorly understood. Methods Seventy-three patients with hepatitis B virus (HBV)-associated primary liver cancer (HBV-PLC), 50 patients with HBV-associated liver cirrhosis (HBV-LC) and 37 patients with chronic HBV infection (CHB) were prospectively enrolled from July 1, 2013 to February 28, 2014 in Beijing Ditan Hospital, Capital Medical University (Beijing, China). The NLR, proportions and concentrations of neutrophils and lymphocytes, concentration of subpopulations of lymphocytes, and the expression of CD31 (index for recent thymic output) and HLA-DR (index for activation of T lymphocytes) of T cells in the peripheral blood samples of the patients were assessed and statistically compared between different groups. Results The NLR was significantly increased from patients with CHB, those with HBV-LC to those with HBV-PLC (P<0.05), along with significant increase of neutrophils and decrease of lymphocytes in the same way (P<0.05). The concentrations of T lymphocytes, natural killer cells, B cells, CD4+ T cells and CD8+ T cells were decreased from patients with CHB, those with HBV-LC to those with HBV-PLC, and were significantly reduced in patients with HBV-PLC compared with those in patients with CHB (P<0.05). The CD31 and HLA-DR expression of naive CD4+ and CD8+ T cells was significantly decreased and increased, respectively in patients with HBV-PLC compared with that in patients with CHB. Conclusions Elevated NLR, resulted from the increase of neutrophils and decrease of lymphocytes, is positively associated with the pathogenesis and progression of HBV-PLC. The reduced thymic output and hyperactivation of T lymphocytes may contribute to the decrease of T lymphocytes, which could be also related to the pathogenesis of HBV-PLC. PMID:28231294

Regulatory B cells (CD19(+)CD38(hi)CD24(hi)) in alloimmunized and non-alloimmunized children with β-thalassemia major.

PubMed

Zahran, Asmaa M; Elsayh, Khalid I; Saad, Khaled; Embaby, Mostafa; Ali, Ahmed M

2016-03-01

β-Thalassemia major (BTM) is considered the most common hemoglobinopathy in Egypt and is one of the major health problems in our locality. We investigated the frequency of B-regulatory cells (CD19(+)CD38(hi)CD24(hi)); (Bregs) among polytransfused alloimmunized and non-alloimmunized children with BTM. The study included 110 polytransfused pediatric patients with β-thalassemia major. Clinical and transfusion records of all studied patients were reviewed. Indirect antiglobulin test was performed to detect the presence of alloantibodies. We used flow cytometry for detection of CD19(+)CD38(hi)CD24(hi) regulatory B cells. Alloimmunization was detected in 35.5% of thalassemic patients (39/110). The analysis of our data showed a significantly higher frequency of Bregs (CD19(+)CD38(hi)CD24(hi)) in the peripheral blood of both alloimmunized and non-alloimmunized patients as compared to healthy controls. Our data showed that the frequencies of CD19(+)CD24(hi)CD38(hi) Bregs cells were significantly increased in children with BTM. Our data suggested that Bregs cells could play a role in the clinical course of BTM. The relationship of Bregs to immune disorders in BTM children remains to be determined. Further longitudinal study with a larger sample size is warranted to explore the mechanisms of Breg cells in the disease process in BTM patients. Copyright © 2016 Elsevier Inc. All rights reserved.

Characterization of clinical and immunological features in patients coinfected with dengue virus and HIV.

PubMed

Torrentes-Carvalho, Amanda; Hottz, Eugênio Damaceno; Marinho, Cintia Ferreira; da Silva, Jéssica Badolato-Corrêa; Pinto, Luzia Maria de Oliveira; Fialho, Luciana Gomes; Bozza, Fernando Augusto; Cunha, Rivaldo Venâncio; Damasco, Paulo Vieira; Kubelka, Claire Fernandes; de Azeredo, Elzinandes Leal

2016-03-01

The pathogenesis of dengue in subjects coinfected with HIV remains largely unknown. We investigate clinical and immunological parameters in coinfected DENV/HIV patients. According to the new dengue classification, most coinfected DENV/HIV patients presented mild clinical manifestations of dengue infection. Herein, we show that DENV/HIV coinfected patients had higher CD8 T cells percentages reflected as a lower CD4/CD8 ratio. Furthermore, CCR5 expression on CD4 T cells and CD107a expression on both T subsets were significantly higher in coinfected patients when compared with monoinfected DENV and HIV individuals respectively. Increased inflammatory response was observed in treated HAART coinfected patients despite undetectable HIV load. These data indicate that DENV infection may influence the clinical profile and immune response in individuals concomitantly infected with HIV. Copyright © 2016 Elsevier Inc. All rights reserved.

Exercise capacity in pediatric patients with inflammatory bowel disease.

PubMed

Ploeger, Hilde E; Takken, Tim; Wilk, Boguslaw; Issenman, Robert M; Sears, Ryan; Suri, Soni; Timmons, Brian W

2011-05-01

To examine exercise capacity in youth with Crohn's disease (CD) and ulcerative colitis (UC). Eleven males and eight females with CD and six males and four females with UC participated. Patients performed standard exercise tests to assess peak power (PP) and mean power (MP) and peak aerobic mechanical power (W(peak)) and peak oxygen uptake (VO(2peak)). Fitness variables were compared with reference data and also correlated with relevant clinical outcomes. Pediatric patients with inflammatory bowel disease had lower PP (∼90% of predicted), MP (∼88% of predicted), W(peak) (∼91% of predicted), and VO(2peak) (∼75% of predicted) compared with reference values. When patients with CD or UC were compared separately to reference values, W(peak) was significantly lower only in the CD group. No statistically significant correlations were found between any exercise variables and disease duration (r = 0.01 to 0.14, P = .47 to .95) or disease activity (r = -0.19 to -0.31, P = .11 to .38), measured by pediatric CD activity index or pediatric ulcerative colitis activity index. After controlling for chronological age, recent hemoglobin levels were significantly correlated with PP (r = 0.45, P = .049), MP (r = 0.63, P = .003), VO(2peak) (r = 0.62, P = .004), and W(peak) (r = 0.70, P = .001). Pediatric patients with inflammatory bowel disease exhibit impaired aerobic and anaerobic exercise capacity compared with reference values. Copyright © 2011 Mosby, Inc. All rights reserved.

Expansion of highly activated invariant natural killer T cells with altered phenotype in acute dengue infection

PubMed Central

Kamaladasa, A.; Wickramasinghe, N.; Adikari, T. N.; Gomes, L.; Shyamali, N. L. A.; Salio, M.; Cerundolo, V.; Ogg, G. S.

2016-01-01

Summary Invariant natural killer T (iNKT) cells are capable of rapid activation and production of cytokines upon recognition of antigenic lipids presented by CD1d molecules. They have been shown to play a significant role in many viral infections and were observed to be highly activated in patients with acute dengue infection. In order to characterize further their role in dengue infection, we investigated the proportion of iNKT cells and their phenotype in adult patients with acute dengue infection. The functionality of iNKT cells in patients was investigated by both interferon (IFN)‐γ and interleukin (IL)−4 ex‐vivo enzyme‐linked immunospot (ELISPOT) assays following stimulation with alpha‐galactosyl‐ceramide (αGalCer). We found that circulating iNKT cell proportions were significantly higher (P = 0·03) in patients with acute dengue when compared to healthy individuals and were predominantly of the CD4+ subset. iNKT cells of patients with acute dengue had reduced proportions expressing CD8α and CD161 when compared to healthy individuals. The iNKT cells of patients were highly activated and iNKT activation correlated significantly with dengue virus‐specific immunoglobulin (Ig)G antibody levels. iNKT cells expressing Bcl‐6 (P = 0·0003) and both Bcl‐6 and inducible T cell co‐stimulator (ICOS) (P = 0·006) were increased significantly in patients when compared to healthy individuals. Therefore, our data suggest that in acute dengue infection there is an expansion of highly activated CD4+ iNKT cells, with reduced expression of CD161 markers. PMID:26874822

Resilience linked to personality dimensions, alexithymia and affective symptoms in motor functional neurological disorders.

PubMed

Jalilianhasanpour, Rozita; Williams, Benjamin; Gilman, Isabelle; Burke, Matthew J; Glass, Sean; Fricchione, Gregory L; Keshavan, Matcheri S; LaFrance, W Curt; Perez, David L

2018-04-01

Reduced resilience, a construct associated with maladaptive stress coping and a predisposing vulnerability for Functional Neurological Disorders (FND), has been under-studied compared to other neuropsychiatric factors in FND. This prospective case-control study investigated self-reported resilience in patients with FND compared to controls and examined relationships between resilience and affective symptoms, personality traits, alexithymia, health status and adverse life event burden. 50 individuals with motor FND and 47 healthy controls participated. A univariate test followed by a logistic regression analysis investigated group-level differences in Connor-Davidson Resilience Scale (CD-RISC) scores. For within-group analyses performed separately in patients with FND and controls, univariate screening tests followed by multivariate linear regression analyses examined factors associated with self-reported resilience. Adjusting for age, gender, education status, ethnicity and lifetime adverse event burden, patients with FND reported reduced resilience compared to controls. Within-group analyses in patients with FND showed that individual-differences in mental health, extraversion, conscientiousness, and openness positively correlated with CD-RISC scores; post-traumatic stress disorder symptom severity, depression, anxiety, alexithymia and neuroticism scores negatively correlated with CD-RISC scores. Extraversion independently predicted resilience scores in patients with FND. In control subjects, univariate associations were appreciated between CD-RISC scores and gender, personality traits, anxiety, alexithymia and physical health; conscientiousness independently predicted resilience in controls. Patients with FND reported reduced resilience, and CD-RISC scores covaried with other important predisposing vulnerabilities for the development of FND. Future research should investigate if the CD-RISC is predictive of clinical outcomes in patients with FND. Copyright © 2018 Elsevier Inc. All rights reserved.

Disease progression in recurrent glioblastoma patients treated with the VEGFR inhibitor axitinib is associated with increased regulatory T cell numbers and T cell exhaustion.

PubMed

Du Four, Stephanie; Maenhout, Sarah K; Benteyn, Daphné; De Keersmaecker, Brenda; Duerinck, Johnny; Thielemans, Kris; Neyns, Bart; Aerts, Joeri L

2016-06-01

Recurrent glioblastoma is associated with a poor overall survival. Antiangiogenic therapy results in a high tumor response rate but has limited impact on survival. Immunotherapy has emerged as an efficient treatment modality for some cancers, and preclinical evidence indicates that anti-VEGF(R) therapy can counterbalance the immunosuppressive tumor microenvironment. We collected peripheral blood mononuclear cells (PBMC) of patients with recurrent glioblastoma treated in a randomized phase II clinical trial comparing the effect of axitinib with axitinib plus lomustine and analyzed the immunophenotype of PBMC, the production of cytokines and expression of inhibitory molecules by circulating T cells. PBMC of 18 patients were collected at baseline and at 6 weeks after initiation of study treatment. Axitinib increased the number of naïve CD8(+) T cells and central memory CD4(+) and CD8(+) T cells and reduced the TIM3 expression on CD4(+) and CD8(+) T cells. Patients diagnosed with progressive disease on axitinib had a significantly increased number of regulatory T cells and an increased level of PD-1 expression on CD4(+) and CD8(+) T cells. In addition, reduced numbers of cytokine-producing T cells were found in progressive patients as compared to patients responding to treatment. Our results suggest that axitinib treatment in patients with recurrent glioblastoma has a favorable impact on immune function. At the time of acquired resistance to axitinib, we documented further enhancement of a preexisting immunosuppression. Further investigations on the role of axitinib as potential combination partner with immunotherapy are necessary.

Monocyte-derived macrophages from Crohn's disease patients are impaired in the ability to control intracellular adherent-invasive Escherichia coli and exhibit disordered cytokine secretion profile.

PubMed

Vazeille, Emilie; Buisson, Anthony; Bringer, Marie-Agnès; Goutte, Marion; Ouchchane, Lemlih; Hugot, Jean-Pierre; de Vallée, Amélie; Barnich, Nicolas; Bommelaer, Gilles; Darfeuille-Michaud, Arlette

2015-05-01

Ileal lesions of Crohn's disease [CD] patients are colonised by adherent-invasive Escherichia coli [AIEC] able to survive in macrophage cell lines. We analysed the ability of monocyte-derived macrophages [MDM] from CD patients to control AIEC intracellular replication and the pro-inflammatory cytokine response of the infected-MDM. Peripheral blood MDM were obtained from 24 CD genotyped for NOD2 and ATG16L1 mutations, 5 ulcerative colitis [UC] patients and 12 healthy controls [HC]. The numbers of intracellular bacteria were determined using gentamicin assay. Cytokine secretion was quantified by ELISA assay. We observed that higher levels of bacteria were internalised within MDM from CD patients than MDM from HC or UC patients. MDM from CD patients were unable to restrict AIEC intracellular replication. Infection of MDM from CD patients with AIEC resulted in significantly increased secretion of IL-6 and tumour necrosis factor alpha [TNF α] than did infection with non-pathogenic E. coli. AIEC-infected MDM from CD patients exhibited a disordered cytokines secretion compared with MDM from UC patients and HC. AIEC-infected MDM from patients with quiescent CD released significantly higher amounts of IL-6 and TNF-alpha than those with active disease or those from HC. The level of secreted TNF-alpha was correlated to the number of intracellular AIEC in MDM from CD patients. Treatment of MDM with infliximab did not change the MDM behaviour. MDM from CD patients are unable to restrict intracellular AIEC replication, leading to disordered inflammatory response influenced by disease activity. Copyright © 2015 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Bronchoalveolar Lavage Fluid Characteristics of Patients With Sarcoidosis and Nonsarcoidosis Interstitial Lung Diseases: Ten-Year Experience of a Single Center in Turkey

PubMed Central

Tanriverdi, Hakan; Erboy, Fatma; Altinsoy, Bulent; Uygur, Firat; Arasli, Mehmet; Ozel Tekin, Ishak; Tor, Muge Meltem; Atalay, Figen

2015-01-01

Background: Bronchoalveolar lavage (BAL) is a noninvasive and useful technique for evaluating interstitial lung diseases (ILDs). Flow cytometric analysis of BAL fluid reveals specific diagnostic information in some unusual ILDs, and helps to narrow down the possible causes of interstitial diseases in most patients with more common disorders. A high BAL CD4/CD8 ratio is highly specific for sarcoidosis but can also be seen in other ILDs. Objectives: In this retrospective, descriptive, cross-sectional study, we compared BAL fluid characteristics and clinical variables in patients with sarcoidosis and non-sarcoidosis ILDs in a large cohort. Patients and Methods: The study was conducted in a tertiary university hospital in Zonguldak, the biggest city of the western Black Sea region of Turkey. Between 2004 and 2014, all patients who underwent both fiberoptic bronchoscopy and BAL with a suspicion of ILD were included in the study, retrospectively. Patients were divided into two main groups: sarcoidosis and non-sarcoidosis ILDs. Non-sarcoidosis ILDs were further divided into subgroups: pneumoconiosis, tuberculosis (TB), collagen vascular diseases, idiopathic interstitial pneumonias, malignancies, and unclassified ILDs. The clinical data of patients, including age, gender, smoking status, pulmonary function tests, and BAL flow cytometric analysis results, were compared among groups. Results: In total, 261 patients (119 sarcoidosis and 142 non-sarcoidosis ILDs) were enrolled. The median (interquartile range) BAL CD4/CD8 ratio and lymphocyte fraction were significantly higher in sarcoidosis than in non-sarcoidosis ILDs: 3.88 (3.76) versus 0.88 (1.01), respectively, and 20.6 (28.3) versus 6.0 (13.7), respectively. T cell receptor γ delta, CD16+56+, CD103+, CD8+103+, and CD3+16+56+ cells were significantly lower in sarcoidosis than in non-sarcoidosis ILDs. The median BAL CD4/CD8 ratios were significantly higher in patients with TB (1.87, P = 0.01) and malignancies (1.69, P = 0.03) than in other non-sarcoidosis ILDs. Conclusions: Among BAL fluid flow cytometric parameters, CD4/CD8 and lymphocyte fraction may be helpful for distinguishing sarcoidosis from other ILDs, but they are neither specific nor diagnostic for any lung disease. Thus, a multidisciplinary diagnostic discussion is required to differentiate various ILDs. PMID:26566455

Characterisation of an epigenetically altered CD4+ CD28+ Kir+ T cell subset in autoimmune rheumatic diseases by multiparameter flow cytometry

PubMed Central

Strickland, Faith M; Patel, Dipak; Somers, Emily; Robida, Aaron M; Pihalja, Michael; Swartz, Richard; Marder, Wendy; Richardson, Bruce

2016-01-01

Objectives Antigen-specific CD4+ T cells epigenetically modified with DNA methylation inhibitors overexpress genes normally suppressed by this mechanism, including CD11a, CD70, CD40L and the KIR gene family. The altered cells become autoreactive, losing restriction for nominal antigen and responding to self-class II major histocompatibility complex (MHC) molecules without added antigen, and are sufficient to cause a lupus-like disease in syngeneic mice. T cells overexpressing the same genes are found in patients with active lupus. Whether these genes are co-overexpressed on the same or different cells is unknown. The goal of this study was to determine whether these genes are overexpressed on the same or different T cells and whether this subset of CD4+ T cells is also present in patients with lupus and other rheumatic diseases. Methods Multicolour flow cytometry was used to compare CD11a, CD70, CD40L and KIR expression on CD3+CD4+CD28+ T cells to their expression on experimentally demethylated CD3+CD4+CD28+ T cells and CD3+CD4+CD28+ T cells from patients with active lupus and other autoimmune diseases. Results Experimentally demethylated CD4+ T cells and T cells from patients with active lupus have a CD3+CD4+CD28+CD11ahiCD70+CD40LhiKIR+ subset, and the subset size is proportional to lupus flare severity. A similar subset is found in patients with other rheumatic diseases including rheumatoid arthritis, systemic sclerosis and Sjögren's syndrome but not retroperitoneal fibrosis. Conclusions Patients with active autoimmune rheumatic diseases have a previously undescribed CD3+CD4+CD28+CD11ahiCD70+CD40LhiKIR+ T cell subset. This subset may play an important role in flares of lupus and related autoimmune rheumatic diseases, provide a biomarker for disease activity and serve as a novel therapeutic target for the treatment of lupus flares. PMID:27099767

Prognostic value of CD44 expression in penile squamous cell carcinoma: a pilot study.

PubMed

Minardi, Daniele; Lucarini, Guendalina; Filosa, Alessandra; Zizzi, Antonio; Simonetti, Oriana; Offidani, Anna Maria; d'Anzeo, Gianluca; Di Primio, Roberto; Montironi, Rodolfo; Muzzonigro, Giovanni

2012-10-01

Several studies have reported on the prognostic value of molecular markers for metastasis risk and survival in penile squamous cell carcinoma (SCC) patients. The usefulness of CD44 expression as such a marker has been studied in different tumors, but not in penile SCC. Our aim was to determine whether CD44 expression may serve as a prognostic marker for lymph node metastasis and survival in penile SCC patients. CD44 immunoistochemical expression was investigated in tissue specimens from 39 patients with penile SCC. CD44 cell positivity, staining intensity and distribution were analyzed and correlated with tumor stage, grade, lymph node status and disease-specific survival. CD44 expression was detected in epithelial cells of both intratumoral and normal tissues with different intensities and staining distributions. In normal tissues CD44 protein was mainly detected in cell membranes, whereas in the tumor compartments it was found in both the cell membranes and the cytoplasm. The intensities and percentages of CD44 expressing cells did not correlate with tumor stage and/or grade. Seventy-three percent of the patients with lymph node metastasis showed high intensities of CD44 staining, as compared to 44% of the patients without lymph node metastasis (P = 0.03). Lymph node-positive patients showed both cytoplasmic and membranous CD44 expression. High CD44 expression was found to be significantly correlated with a decreased 5 year overall survival (P = 0.01). CD44 levels and patterns of expression can be considered as markers for penile SCC aggressiveness and, in addition, may serve as predictive markers for lymph node metastasis, also in patients with clinically negative lymph nodes. CD44 expression may provide prognostic information for penile SCC patients, next to classical clinical-pathological factors.

Systemic Sclerosis Patients Present Alterations in the Expression of Molecules Involved in B-Cell Regulation

PubMed Central

Soto, Lilian; Ferrier, Ashley; Aravena, Octavio; Fonseca, Elianet; Berendsen, Jorge; Biere, Andrea; Bueno, Daniel; Ramos, Verónica; Aguillón, Juan Carlos; Catalán, Diego

2015-01-01

The activation threshold of B cells is tightly regulated by an array of inhibitory and activator receptors in such a way that disturbances in their expression can lead to the appearance of autoimmunity. The aim of this study was to evaluate the expression of activating and inhibitory molecules involved in the modulation of B cell functions in transitional, naive, and memory B-cell subpopulations from systemic sclerosis patients. To achieve this, blood samples were drawn from 31 systemic sclerosis patients and 53 healthy individuals. Surface expression of CD86, MHC II, CD19, CD21, CD40, CD22, Siglec 10, CD35, and FcγRIIB was determined by flow cytometry. IL-10 production was evaluated by intracellular flow cytometry from isolated B cells. Soluble IL-6 and IL-10 levels were measured by ELISA from supernatants of stimulated B cells. Systemic sclerosis patients exhibit an increased frequency of transitional and naive B cells related to memory B cells compared with healthy controls. Transitional and naive B cells from patients express higher levels of CD86 and FcγRIIB than healthy donors. Also, B cells from patients show high expression of CD19 and CD40, whereas memory cells from systemic sclerosis patients show reduced expression of CD35. CD19 and CD35 expression levels associate with different autoantibody profiles. IL-10+ B cells and secreted levels of IL-10 were markedly reduced in patients. In conclusion, systemic sclerosis patients show alterations in the expression of molecules involved in B-cell regulation. These abnormalities may be determinant in the B-cell hyperactivation observed in systemic sclerosis. PMID:26483788

Stress and brain functional changes in patients with Crohn's disease: A functional magnetic resonance imaging study.

PubMed

Agostini, A; Ballotta, D; Righi, S; Moretti, M; Bertani, A; Scarcelli, A; Sartini, A; Ercolani, M; Nichelli, P; Campieri, M; Benuzzi, F

2017-10-01

In Crohn's disease (CD) patients, stress is believed to influence symptoms generation. Stress may act via central nervous system pathways to affect visceral sensitivity and motility thus exacerbating gastrointestinal symptoms. The neural substrate underpinning these mechanisms needs to be investigated in CD. We conducted an explorative functional magnetic resonance imaging (fMRI) study in order to investigate potential differences in the brain stress response in CD patients compared to controls. 17 CD patients and 17 healthy controls underwent a fMRI scan while performing a stressful task consisting in a Stroop color-word interference task designed to induce mental stress in the fMRI environment. Compared to controls, in CD patients the stress task elicited greater blood oxygen level dependent (BOLD) signals in the midcingulate cortex (MCC). The MCC integrate "high" emotional processes with afferent sensory information ascending from the gut. In light of these integrative functions, the stress-evoked MCC hyperactivity in CD patients might represent a plausible neural substrate for the association between stress and symptomatic disease. The MCC dysfunction might be involved in mechanisms of central disinhibition of nociceptive inputs leading to amplify the visceral sensitivity. Finally, the stress-evoked MCC hyperactivity might affect the regulation of intestinal motility resulting in exacerbation of disease symptoms and the autonomic and neuroendocrine regulation of inflammation resulting in enhanced inflammatory activity. © 2017 John Wiley & Sons Ltd.

The potential association of CMV-specific CD8+ T lymphocyte reconstitution with the risk of CMV reactivation and persistency in post allogeneic stem cell transplant patients.

PubMed

Shams El-Din, Ahmed Ali; El-Desoukey, Nermeen Ahmed; Amin Tawadrous, Dalia Gamil; Fouad, Neveen Mohammed Baha El-Din; Abdel-Mooti, Mohammed; Hotar, Said Fathy

2018-01-09

development of cytomegalovirus (CMV)-specific CD8+ T cell response is crucial in preventing symptomatic CMV infection specially, in stem cell transplant (SCT) patients. The aim of this study was to evaluate CMV-specific CD8+ T cell reconstitution in allogeneic SCT recipients and to study the possible association between CMV-specific CD8+ T cell recovery with protection from CMV reactivation and persistency. Human leuKocyte antigen (HLA)-tetramers were used for CMV-specific CD8+ cell quantitation by Flow cytometry in twenty post-allogeneic SCT patients. Nine patients (45%) developed rapid recovery of CMV-specific CD8+ cells, among them; 7 patients (78%) had no CMV reactivation in the first 95 days post-transplant. Five patients had developed persistent CMV viremia; all of them had not developed CMV-specific CD8+ recovery till day 95 post-transplant. Patients with persistent CMV viremia had a statistically significant lower means of CMV-specific CD8+ percent and absolute count compared to those without persistent viremia (p = .001, .015), respectively. The incidence of CMV reactivation and persistency was higher among patients with delayed CMV-specific CD8+ reconstitution in the first 95 days post-transplant. CMV-specific CD8+ cells can help in categorizing patients into risk groups: (early recovery/low risk) and (delayed recovery/increased risk), this tool may guide clinicians in the selection of patients who may profit from prophylactic antiviral therapy and frequent viral monitoring.

Immune response to Mycobacterium tuberculosis infection in the parietal pleura of patients with tuberculous pleurisy.

PubMed

Caramori, Gaetano; Lasagna, Lisa; Casalini, Angelo G; Adcock, Ian M; Casolari, Paolo; Contoli, Marco; Tafuro, Federica; Padovani, Anna; Chung, Kian Fan; Barnes, Peter J; Papi, Alberto; Rindi, Guido; Bertorelli, Giuseppina

2011-01-01

The T lymphocyte-mediated immune response to Mycobacterium tuberculosis infection in the parietal pleura of patients with tuberculous pleurisy is unknown. The aim of this study was to investigate the immune response in the parietal pleura of tuberculous pleurisy compared with nonspecific pleuritis. We have measured the numbers of inflammatory cells particularly T-cell subsets (Th1/Th2/Th17/Treg cells) in biopsies of parietal pleura obtained from 14 subjects with proven tuberculous pleurisy compared with a control group of 12 subjects with nonspecific pleuritis. The number of CD3+, CD4+ and CCR4+ cells and the expression of RORC2 mRNA were significantly increased in the tuberculous pleurisy patients compared with the nonspecific pleuritis subjects. The number of toluidine blue+ cells, tryptase+ cells and GATA-3+ cells was significantly decreased in the parietal pleura of patients with tuberculous pleurisy compared with the control group of nonspecific pleuritis subjects. Logistic regression with receiver operator characteristic (ROC) analysis for the three single markers was performed and showed a better performance for GATA-3 with a sensitivity of 75%, a specificity of 100% and an AUC of 0.88. There was no significant difference between the two groups of subjects in the number of CD8, CD68, neutrophil elastase, interferon (IFN)-γ, STAT4, T-bet, CCR5, CXCR3, CRTH2, STAT6 and FOXP3 positive cells. Elevated CD3, CD4, CCR4 and Th17 cells and decreased mast cells and GATA-3+ cells in the parietal pleura distinguish patients with untreated tuberculous pleurisy from those with nonspecific pleuritis.

Over-expression of CD8+ T-cell activation is associated with decreased CD4+ cells in patients seeking treatment of Alcohol Use Disorder.

PubMed

Zuluaga, Paola; Sanvisens, Arantza; Martínez-Cáceres, Eva; Teniente, Aina; Tor, Jordi; Muga, Robert

2017-11-01

Harmful alcohol consumption may have an impact on the adaptive immune system through an imbalance in T cell subpopulations and changes in cell activation. We aimed to analyze profiles of CD4 and CD8T cell activation in patients with alcohol use disorder (AUD). We used a cross-sectional study with patients seeking treatment of the disorder. Blood samples for immunophenotyping were obtained at admission. Profiles of T cell activation were defined: (I) CD38 + /HLA-DR + , (II) CD38 + /HLA-DR - , (III) CD38 - /HLA-DR + , (IV) CD38 - /HLA-DR - and compared with healthy controls. We calculated a CD8 + T cell activation indicator (AI) that was defined as the quotient of non-activated cells (CD38 - /HLA-DR - ) and activated cells (CD38 + /HLA-DR + ). 60 patients were eligible (83%M); median age was 49 years [IQR: 44-54] and alcohol consumption was 145g/day [IQR: 90-205]. Mean±SD of CD38 + /HLA-DR - was 50.3±50.6 cells/μL in patients and 33.5±24.5 cells/μL in controls (p=0.03), for the CD38 - /HLA-DR + it was 61±62.2 cells/μL in patients and 21.2±17.3 cells/μL in controls (p<0.001) and for the CD38 + /HLA-DR + it was 20.2±15.6 cells/μL in patients and 10.8±10.3 cells/μL in controls (p<0.001). In patients, an inverse correlation was observed between absolute number and percentage of CD4 + T cells, and the percentage of CD38 + /HLA-DR + CD8 + T cells (r=0.37, p=0.003; r=0.2, p=0.086, respectively). Patients with AUD have an increased expression of immune activation with respect to healthy individuals. This excess of activated CD8 + T cells correlates with the absolute CD4 + T cells. Copyright © 2017 Elsevier B.V. All rights reserved.

Phenotyping of peripheral blood mononuclear cells during acute dengue illness demonstrates infection and increased activation of monocytes in severe cases compared to classic dengue fever

PubMed Central

Durbin, Anna P.; Vargas, Maria José; Wanionek, Kimberli; Hammond, Samantha N.; Gordon, Aubree; Rocha, Crisanta; Balmaseda, Angel; Harris, Eva

2008-01-01

In vitro studies have attempted to identify dengue virus (DEN) target cells in peripheral blood; however, extensive phenotyping of peripheral blood mononuclear cells (PBMCs) from dengue patients has not been reported. PBMCs collected from hospitalized children suspected of acute dengue were analyzed for DEN prM, CD32, CD86, CD14, CD11c, CD16, CD209, CCR7, CD4, and CD8 by flow cytometry to detect DEN antigen in PBMCs and to phenotype DEN-positive cells. DEN prM was detected primarily in activated monocytes (CD14+, CD32+, CD86+, CD11c+). A subset of samples analyzed for DEN nonstructural protein 3 (NS3) confirmed that approximately half of DEN antigen-positive cells contained replicating virus. A higher percentage of PBMCs from DHF patients expressed prM, CD86, CD32, and CD11c than did those from DF patients. Increased activation of monocytes and greater numbers of DEN-infected cells were associated with more severe dengue, implicating a role for monocyte activation in dengue immunopathogenesis. PMID:18452966

Comparison of basophil activation tests using CD63 or CD203c expression in patients with insect venom allergy.

PubMed

Eberlein-König, B; Varga, R; Mempel, M; Darsow, U; Behrendt, H; Ring, J

2006-09-01

Flow cytometric basophil activation tests have been developed as cellular tests for in vitro diagnosis of IgE-mediated reactions. Different activation markers (CD63 or CD203c) with distinct ways of regulation have been used after stimulation with various allergens. It was the aim of the present study to compare basophil activation tests by measuring both CD63 and CD203c upregulation in patients with insect venom allergy. 43 patients with a history of insect venom anaphylaxis were examined. A careful allergy history was taken, and skin tests and determination of specific IgE-antibodies were performed. Basophil activation tests (BAT) using CD63 or CD203c expression were done after stimulation with different concentrations of bee and wasp venom extracts. 25 healthy subjects with negative history of insect venom allergy were studied as controls. The CD203c protocol showed a slightly higher sensitivity than the CD63 protocol (97% vs. 89%) with regard to patients' history. The magnitude of basophil response was higher with CD203c in comparison to CD63 for both insect venoms. Specificity was 100% for the CD63 protocol and 89% for the CD203c protocol with regard to controls with negative history and negative RAST. These results support the reliability of basophil activation tests using either CD63 or CD203c as cellular tests in the in vitro diagnosis of patients with bee or wasp venom allergy with a slightly higher sensitivity for the CD203c protocol.

Soluble CD40L Is a Useful Marker to Predict Future Strokes in Patients With Minor Stroke and Transient Ischemic Attack.

PubMed

Li, Jiejie; Wang, Yilong; Lin, Jinxi; Wang, David; Wang, Anxin; Zhao, Xingquan; Liu, Liping; Wang, Chunxue; Wang, Yongjun

2015-07-01

Elevated soluble CD40 ligand (sCD40L) was shown to be related to cardiovascular events, but the role of sCD40L in predicting recurrent stroke remains unclear. Baseline sCD40L levels were measured in 3044 consecutive patients with acute minor stroke and transient ischemic attack, who had previously been enrolled in the Clopidogrel in High-Risk Patients With Acute Nondisabling Cerebrovascular Events (CHANCE) trial. Cox proportional-hazards model was used to assess the association of sCD40L with recurrent stroke. Patients in the top tertile of sCD40L levels had increased risk of recurrent stroke comparing with those in the bottom tertile, after adjusted for conventional confounding factors (hazard ratio, 1.49; 95% confidence interval, 1.11-2.00; P=0.008). The patients with elevated levels of both sCD40L and high-sensitive C-reactive protein also had increased risk of recurrent stroke (hazard ratio, 1.81; 95% confidence interval, 1.23-2.68; P=0.003). Elevated sCD40L levels independently predict recurrent stroke in patients with minor stroke and transient ischemic attack. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00979589. © 2015 American Heart Association, Inc.

CD25 expression status improves prognostic risk classification in AML independent of established biomarkers: ECOG phase 3 trial, E1900

PubMed Central

Gönen, Mithat; Sun, Zhuoxin; Figueroa, Maria E.; Patel, Jay P.; Abdel-Wahab, Omar; Racevskis, Janis; Ketterling, Rhett P.; Fernandez, Hugo; Rowe, Jacob M.; Tallman, Martin S.; Melnick, Ari; Levine, Ross L.

2012-01-01

We determined the prognostic relevance of CD25 (IL-2 receptor-α) expression in 657 patients (≤ 60 years) with de novo acute myeloid leukemia (AML) treated in the Eastern Cooperative Oncology Group trial, E1900. We identified CD25POS myeloblasts in 87 patients (13%), of whom 92% had intermediate-risk cytogenetics. CD25 expression correlated with expression of stem cell antigen CD123. In multivariate analysis, controlled for prognostic baseline characteristics and daunorubicin dose, CD25POS patients had inferior complete remission rates (P = .0005) and overall survival (P < .0001) compared with CD25NEG cases. In a subset of 396 patients, we integrated CD25 expression with somatic mutation status to determine whether CD25 impacted outcome independent of prognostic mutations. CD25 was positively correlated with internal tandem duplications in FLT3 (FLT3-ITD), DNMT3A, and NPM1 mutations. The adverse prognostic impact of FLT3-ITDPOS AML was restricted to CD25POS patients. CD25 expression improved AML prognostication independent of integrated, cytogenetic and mutational data, such that it reallocated 11% of patients with intermediate-risk disease to the unfavorable-risk group. Gene expression analysis revealed that CD25POS status correlated with the expression of previously reported leukemia stem cell signatures. We conclude that CD25POS status provides prognostic relevance in AML independent of known biomarkers and is correlated with stem cell gene-expression signatures associated with adverse outcome in AML. PMID:22855599

HIV-TB coinfection impairs CD8(+) T-cell differentiation and function while dehydroepiandrosterone improves cytotoxic antitubercular immune responses.

PubMed

Suarez, Guadalupe V; Angerami, Matías T; Vecchione, María B; Laufer, Natalia; Turk, Gabriela; Ruiz, Maria J; Mesch, Viviana; Fabre, Bibiana; Maidana, Patricia; Ameri, Diego; Cahn, Pedro; Sued, Omar; Salomón, Horacio; Bottasso, Oscar A; Quiroga, María F

2015-09-01

Tuberculosis (TB) is the leading cause of death among HIV-positive patients. The decreasing frequencies of terminal effector (TTE ) CD8(+) T cells may increase reactivation risk in persons latently infected with Mycobacterium tuberculosis (Mtb). We have previously shown that dehydroepiandrosterone (DHEA) increases the protective antitubercular immune responses in HIV-TB patients. Here, we aimed to study Mtb-specific cytotoxicity, IFN-γ secretion, memory status of CD8(+) T cells, and their modulation by DHEA during HIV-TB coinfection. CD8(+) T cells from HIV-TB patients showed a more differentiated phenotype with diminished naïve and higher effector memory and TTE T-cell frequencies compared to healthy donors both in total and Mtb-specific CD8(+) T cells. Notably, CD8(+) T cells from HIV-TB patients displayed higher Terminal Effector (TTE ) CD45RA(dim) proportions with lower CD45RA expression levels, suggesting a not fully differentiated phenotype. Also, PD-1 expression levels on CD8(+) T cells from HIV-TB patients increased although restricted to the CD27(+) population. Interestingly, DHEA plasma levels positively correlated with TTE in CD8(+) T cells and in vitro DHEA treatment enhanced Mtb-specific cytotoxic responses and terminal differentiation in CD8(+) T cells from HIV-TB patients. Our data suggest that HIV-TB coinfection promotes a deficient CD8(+) T-cell differentiation, whereas DHEA may contribute to improving antitubercular immunity by enhancing CD8(+) T-cell functions during HIV-TB coinfection. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Altered CD19/CD22 balance in Egyptian children and adolescents with systemic lupus erythematosus.

PubMed

El-Sayed, Zeinab A; Ragab, Seham M; Khalifa, Khaled A; El Ashmawy, Ramy A

2009-01-01

B cells from systemic lupus erythematosus (SLE) patients display signalling defects that may underlie disease pathogenesis activity.CD19 and CD22 play a major role as regulators of B-cell response. The aim of this study was to clarify the relationship between B cell surface markers namely CD19, CD20 and CD22 expression and clinical and laboratory indices of SLE activity. The study included 33 SLE patients and 20 healthy children and adolescents as controls. Flowcytometric assay of dual markers, CD19/CD20, and CD20/CD22 was done. SLE disease activity was assessed by SLEDAI score. CD22% was significantly higher while CD20% was significantly lower in the study compared to the control group. No significant difference was observed in both groups with respect to CD19% or CD19/CD22% ratio. The level of CD22 expression was significantly lower in high and very high active cases than in mild and moderate cases and negatively correlated with SLDEAI score and ESR. Results obtained showed that, B cell surface receptors CD20 and CD22 are significantly affected in patients with SLE, pointing to their possible involvement in the aetiopathogenesis of the disease and in the regulatory mechanisms in response to the immune disturbance.

Effect of liniment levamisole on cellular immune functions of patients with chronic hepatitis B.

PubMed

Wang, Ke-Xia; Zhang, Li-Hua; Peng, Jiang-Long; Liang, Yong; Wang, Xue-Feng; Zhi, Hui; Wang, Xiang-Xia; Geng, Huan-Xiong

2005-12-07

To explore the effects of liniment levamisole on cellular immune functions of patients with chronic hepatitis B. The levels of T lymphocyte subsets and mIL-2R in peripheral blood mononuclear cells (PBMCs) were measured by biotin-streptavidin (BSA) technique in patients with chronic hepatitis B before and after the treatment with liniment levamisole. After one course of treatment with liniment levamisole, the levels of CD3(+), CD4(+), and the ratio of CD4(+)/CD8(+) increased as compared to those before the treatment but the level of CD8(+) decreased. The total expression level of mIL-2R in PBMCs increased before and after the treatment with liniment levamisole. Liniment levamisole may reinforce cellular immune functions of patients with chronic hepatitis B.

Immune cell infiltration in head and neck squamous cell carcinoma and patient outcome: a retrospective study.

PubMed

Schneider, Karolin; Marbaix, Etienne; Bouzin, Caroline; Hamoir, Marc; Mahy, Pierre; Bol, Vanesa; Grégoire, Vincent

2018-03-01

Human papillomavirus (HPV) prevalence in oropharynx squamous cell carcinoma (OPSCC) is on the rise. HPV-linked OPSCCs represent a distinct clinical entity with a better treatment response and patient survival compared to tumors not linked to HPV. An emerging role in treatment response has been attributed to immune cell infiltration in human tumors. In this study, we investigated immune cell infiltration in human SCC of the head and neck region and its relation to overall survival after treatment with surgery (with or without radiotherapy) or concomitant chemo (or cetuximab)-radiotherapy. Paraffin-embedded tumor samples of 136 patients with SCC of the larynx, hypopharynx, oral cavity and oropharynx were processed for immunohistochemical detection of CD3 + T-cells, CD8 + cytotoxic T-cells, CD20 + B-cells and CD163 + M2 macrophages within the tumor infiltrated area. Clinico-pathological data were analyzed as a function of tumor location and p16-status. Immune cell infiltration was represented as stained area on the whole tumor infiltrated area, compared for the different tumor locations and correlated to patient survival. Patients with oropharynx tumors expressing significant p16 levels (p16-sg) had a 5-year overall survival of 85% compared to 43% for patients with no significant p16 (p16-ns) expression (HR: 0.3 - 95% CI: 0.1-0.6). Median immune cell infiltration (T- and B-lymphocytes) was significantly elevated in p16-sg oropharyngeal tumors, compared to p16-ns oropharyngeal tumors and to all other head and neck tumor locations. No difference in CD163 + macrophage infiltration was observed across the different patient groups. In the whole population, a high infiltration by CD3 + T-lymphocytes was associated to a significantly (p = .03; HR: 0.6, 95% CI: 0.4-0.97) better overall survival. Oropharynx cancer with significant p16 expression showed an increased overall survival and elevated T- and B-lymphocyte infiltration, which suggests a prognostic relevance of immune cell infiltration.

Protective Cytomegalovirus (CMV)-Specific T-Cell Immunity Is Frequent in Kidney Transplant Patients without Serum Anti-CMV Antibodies.

PubMed

Litjens, Nicolle H R; Huang, Ling; Dedeoglu, Burç; Meijers, Ruud W J; Kwekkeboom, Jaap; Betjes, Michiel G H

2017-01-01

The absence of anti-cytomegalovirus (CMV) immunoglobulin G (IgG) is used to classify pretransplant patients as naïve for CMV infection (CMV neg patients). This study assessed whether pretransplant CMV-specific T-cell immunity exists in CMV neg patients and whether it protects against CMV infection after kidney transplantation. The results show that CMV-specific CD137 + IFNγ + CD4 + and CD137 + IFNγ + CD8 + memory T cells were present in 46 and 39% of CMV neg patients ( n  = 28) although at much lower frequencies compared to CMV pos patients (median 0.01 versus 0.58% for CD4 + and 0.05 versus 0.64% for CD8 + T cells) with a less differentiated CD28-expressing phenotype. In line with these data, CMV-specific proliferative CD4 + and CD8 + T cells were observed in CMV neg patients, which significantly correlated with the frequency of CMV-specific T cells. CMV-specific IgG antibody-secreting cells (ASC) could be detected at low frequency in 36% of CMV neg patients (1 versus 45 ASC/10 5 cells in CMV pos patients). CMV neg patients with pretransplant CMV-specific CD137 + IFNγ + CD4 + T cells had a lower risk to develop CMV viremia after transplantation with a CMV pos donor kidney (relative risk: 0.43, P  = 0.03). In conclusion, a solitary CMV-specific T-cell response without detectable anti-CMV antibodies is frequent and clinically relevant as it is associated with protection to CMV infection following transplantation with a kidney from a CMV pos donor.

Reduction of regulatory T cells in skin lesions but not in peripheral blood of patients with systemic scleroderma.

PubMed

Klein, S; Kretz, C C; Ruland, V; Stumpf, C; Haust, M; Hartschuh, W; Hartmann, M; Enk, A; Suri-Payer, E; Oberle, N; Krammer, P H; Kuhn, A

2011-08-01

To determine the frequency and suppressive capacity of regulatory T cells (T(reg)) and their association with clinical parameters in patients with systemic scleroderma (SSc). Peripheral blood from 25 patients with SSc, 15 patients with localised scleroderma (LS) and 29 healthy controls (HC) was studied. Analysis of CD4(+) forkhead box P3 (Foxp3)(+) and CD4(+)CD25(++)Foxp3(+) T(reg) subpopulations was carried out by flow cytometry and cell proliferation was quantified by (3)H-thymidine incorporation. Quantitative analysis of T(reg) was further performed in skin biopsies from 17 patients with SSc and 21 patients with LS using anti-CD4 and anti-Foxp3 monoclonal antibodies for immunohistochemistry. The frequency of CD4(+)Foxp3(+) and CD4(+)CD25(++)Foxp3(+) T(reg) in peripheral blood from patients with SSc was not significantly different from that of patients with LS or HC. The suppressive capacity of CD4(+)CD25(++) T(reg) in SSc was also found to be similar to that of HC. Phenotypic and functional data revealed no significant difference between the limited or diffuse form of SSc. Moreover, therapy with bosentan showed no significant effect on the frequency of T(reg) during the course of the disease. However, the frequency of T(reg) in skin lesions from patients with SSc or LS, determined as the percentage of CD4(+) cells expressing Foxp3 in the inflammatory infiltrate, was significantly reduced compared with other inflammatory skin diseases. These results indicate that although the authors found no defect in the frequency or function of peripheral T(reg) subpopulations, the reduction of CD4(+)Foxp3(+) T(reg) in the skin of patients with SSc may be important in the pathogenesis of the disease.

Vitamin D increases programmed death receptor-1 expression in Crohn’s disease

PubMed Central

Bendix, Mia; Greisen, Stinne; Dige, Anders; Hvas, Christian L.; Bak, Nina; Jørgensen, Søren P.; Dahlerup, Jens F.; Deleuran, Bent; Agnholt, Jørgen

2017-01-01

Background: Vitamin D modulates inflammation in Crohns disease (CD). Programmed death (PD)-1 receptor contributes to the maintenance of immune tolerance. Vitamin D might modulate PD-1 signalling in CD. Aim: To investigate PD-1 expression on T cell subsets in CD patients treated with vitamin D or placebo. Methods: We included 40 CD patients who received 1200 IU vitamin D3 for 26 weeks or placebo and eight healthy controls. Peripheral blood mononuclear cells (PBMCs) and plasma were isolated at baseline and week 26. The expressions of PD-1, PD-L1, and surface activation markers were analysed by flow cytometry. Soluble PD-1 plasma levels were measured by ELISA. Results: PD-1 expression upon T cell stimulation was increased in CD4+CD25+int T cells in vitamin D treated CD patients from 19% (range 10 39%) to 29% (11 79%)(p = 0.03) compared with placebo-treated patients. Vitamin D treatment, but not placebo, decreased the expression of the T cell activation marker CD69 from 42% (31 62%) to 33% (19 - 54%)(p = 0.01). Soluble PD-1 levels were not influenced by vitamin D treatment. Conclusions: Vitamin D treatment increases CD4+CD25+int T cells ability to up-regulate PD-1 in response to activation and reduces the CD69 expression in CD patients. PMID:28412753

Activity of Bruton's tyrosine-kinase inhibitor ibrutinib in patients with CD117-positive acute myeloid leukaemia: a mechanistic study using patient-derived blast cells.

PubMed

Rushworth, Stuart A; Pillinger, Genevra; Abdul-Aziz, Amina; Piddock, Rachel; Shafat, Manar S; Murray, Megan Y; Zaitseva, Lyubov; Lawes, Matthew J; MacEwan, David J; Bowles, Kristian M

2015-05-01

Roughly 80% of patients with acute myeloid leukaemia have high activity of Bruton's tyrosine-kinase (BTK) in their blast cells compared with normal haemopoietic cells, rendering the cells sensitive to the oral BTK inhibitor ibrutinib in vitro. We aimed to develop the biological understanding of the BTK pathway in acute myeloid leukaemia to identify clinically relevant diagnostic information that might define a subset of patients that should respond to ibrutinib treatment. We obtained acute myeloid leukaemia blast cells from unselected patients attending our UK hospital between Feb 19, 2010, and Jan 20, 2014. We isolated primary acute myeloid leukaemia blast cells from heparinised blood and human peripheral blood mononuclear cells to establish the activity of BTK in response to CD117 activation. Furthermore, we investigated the effects of ibrutinib on CD117-induced BTK activation, downstream signalling, adhesion to primary bone-marrow mesenchymal stromal cells, and proliferation of primary acute myeloid leukaemia blast cells. We used the Mann-Whitney U test to compare results between groups. We obtained acute myeloid leukaemia blast cells from 29 patients. Ibrutinib significantly inhibited CD117-mediated proliferation of primary acute myeloid leukaemia blast cells (p=0·028). CD117 activation increased BTK activity by inducing phosphorylated BTK in patients with CD117-positive acute myeloid leukaemia. Furthermore, ibrutinib inhibited CD117-induced activity of BTK and downstream kinases at a concentration of 100 nM or more. CD117-mediated adhesion of CD117-expressing blast cells to bone-marrow stromal cells was significantly inhibited by Ibrutinib at 500 nM (p=0·028) INTERPRETATION: As first-in-man clinical trials of ibrutinib in patients with acute myeloid leukaemia commence, the data suggest not all patients will respond. Our findings show that BTK has specific pro-tumoural biological actions downstream of surface CD117 activation, which are inhibited by ibrutinib. Accordingly, we propose that patients with acute myeloid leukaemia whose blast cells express CD117 should be considered for forthcoming clinical trials of ibrutinib. Worldwide Cancer Research, The Big C, UK National Institutes for Health Research, the Humane Research Trust, the Department of Higher Education and Research of the Libyan Government, and Norwich Research Park. Copyright © 2015 Elsevier Ltd. All rights reserved.

Kidney Stones as an Underrecognized Clinical Sign in Pediatric Cushing Disease.

PubMed

Rahman, Sara H; Papadakis, Georgios Z; Keil, Margaret F; Faucz, Fabio R; Lodish, Maya B; Stratakis, Constantine A

2016-03-01

To investigate the prevalence of kidney stones in a population of children with Cushing disease (CD) and to compare it with the prevalence of kidney stones in healthy children. Clinical and biochemical data from 139 pediatric patients with CD (68 females, 71 males) were analyzed retrospectively. Computed tomography scans were reviewed for kidney stones. Among 139 patients, 27 with CD (19.4%) had either radiographic evidence and/or a history of kidney stones. Those with kidney stones had higher urine free cortisol (P = .008) and transsphenoidal surgery at an older age (P = .007). The average urinary calcium/creatinine ratio was elevated in patients with CD (0.22 ± 0.11). The prevalence of kidney stones was higher in children with CD than in normal children (19.42% vs 1.0%; P < .001). Our results illustrate that kidney stones are an underestimated complication of pediatric CD, especially when compared with the prevalence of nephrolithiasis in the general pediatric population. Long-term consequences for kidney function are not known and need to be studied. Published by Elsevier Inc.

The CD47 “don’t eat me signal” is highly expressed in human ovarian cancer

PubMed Central

Brightwell, RM; Grzankowski, KS; Lele, S; Eng, K; Arshad, M; Chen, H; Odunsi, K

2016-01-01

Objectives The CD47 “don’t eat me” signal allows tumor immune evasion. We tested the association of CD47 expression with outcomes in EOC. Methods CD47 expression was examined within the TCGA database for ovarian carcinoma. For validation, IHC was performed on a TMA consisting of specimens from 265 patients with EOC. The medical records of the patients were also retrospectively reviewed to correlate demographic and survival data. Results CD47 was amplified in 15/316 (5%) ovarian serous cancers in TCGA. In the validation cohort, the majority of patients had stage III/IV disease (208/265, 78.4%). CD47 expression was seen in 210/265 (79.2%). Patients were categorized into CD47hi (129/265; 48.7%) versus CD47lo (136/265; 51.3%). Patients with CD47lo tumors were more likely to have a complete response to adjuvant therapy than CD47hi (65% vs 50%, p= 0.026). Although there was a trend towards an increase in median OS (37.64 vs 45.26 mos, p=0.92) in the CD47lo group compared with CD47hi, the difference was not significant. Conclusions CD47 is expressed at high frequency in EOC. Patients with CD47lo EOC had a better treatment response to standard therapy, and trended towards improved OS. This demonstrates that while CD47 may be an immunologic shield that may be considered for targeted therapies, it is likely that it operates in concert with other mechanisms of immune evasion. Future studies to evaluate CD47 expression with other known mechanisms of immune escape in the tumor microenvironment may help further define its role. PMID:27569584

Immunohistochemical study of intestinal eosinophils in inflammatory bowel disease.

PubMed

Carvalho, Ana Teresa Pugas; Elia, Celeste Carvalho Siqueira; de Souza, Heitor Siffert Pereira; Elias, Paulo Roberto Pinheiro; Pontes, Eduardo Lopes; Lukashok, Hannah Pitanga; de Freitas, Fernanda Cristina Dias; Lapa e Silva, José Roberto

2003-02-01

Eosinophil accumulation and activation are characteristic features of inflammation in allergic diseases and in host defense against parasites. To investigate the involvement of eosinophils in inflamed and noninflamed mucosa of patients with inflammatory bowel disease (IBD). Specimens of inflamed colonic mucosa from 15 patients with ulcerative colitis (UC) and inflamed and noninflamed colonic mucosa from 15 patients with Crohn's disease (CD) were submitted to histologic and immunohistochemical studies. Twelve patients with irritable bowel syndrome were studied as controls. Sirius red was used to label eosinophils in tissue. EG1, EG2, and anti-hIL-5 were used as primary antibodies in an indirect alkaline phosphatase-labeled immunostaining protocol. Both positive and negative lamina propria cells were assessed by a quantitative grading system and the results expressed as cell numbers per mm. Increased proportions of eosinophils stained with Sirius red, EG1, EG2, and anti-hIL-5+ cells were found in the colon of patients with UC and in inflamed and noninflamed colon of CD patients as compared with controls. Crohn's disease patients showed increased proportions of EG1+ and EG2+ cells as compared with those with UC. Increased proportions of IL-5+ cells were detected in UC patients as compared with those with CD. Quantitative eosinophil alterations and IL-5+ cells may indicate enhanced cellular activation with degranulation, which is implicated in the pathogenesis of IBD. Increase in IL-5+ cells may reflect a predominant local Th2 response in UC as compared with CD.

Identification of the Ki-1 antigen (CD30) as a novel therapeutic target in systemic mastocytosis

PubMed Central

Blatt, Katharina; Cerny-Reiterer, Sabine; Schwaab, Juliana; Sotlar, Karl; Eisenwort, Gregor; Stefanzl, Gabriele; Hoermann, Gregor; Mayerhofer, Matthias; Schneeweiss, Mathias; Knapp, Sylvia; Rülicke, Thomas; Hadzijusufovic, Emir; Bauer, Karin; Smiljkovic, Dubravka; Willmann, Michael; Reiter, Andreas; Horny, Hans-Peter

2015-01-01

The Ki-1 antigen (CD30) is an established therapeutic target in patients with Hodgkin lymphoma and anaplastic large-cell lymphoma. We have recently shown that CD30 is expressed abundantly in the cytoplasm of neoplastic mast cells (MCs) in patients with advanced systemic mastocytosis (SM). In the current study, we asked whether CD30 is expressed on the surface of neoplastic MCs in advanced SM, and whether this surface structure may serve as therapeutic target in SM. As assessed by flow cytometry, CD30 was found to be expressed on the surface of neoplastic MCs in 3 of 25 patients (12%) with indolent SM, 4 of 7 patients (57%) with aggressive SM, and 4 of 7 patients (57%) with MC leukemia. The immature RAS-transformed human MC line MCPV-1.1 also expressed cell surface CD30, whereas the KIT-transformed MC line HMC-1.2 expressed no detectable CD30. The CD30-targeting antibody-conjugate brentuximab-vedotin inhibited proliferation in neoplastic MCs, with lower IC50 values obtained in CD30+ MCPV-1.1 cells (10 µg/mL) compared with CD30− HMC-1.2 cells (>50 µg/mL). In addition, brentuximab-vedotin suppressed the engraftment of MCPV-1.1 cells in NSG mice. Moreover, brentuximab-vedotin produced apoptosis in all CD30+ MC lines tested as well as in primary neoplastic MCs in patients with CD30+ SM, but did not induce apoptosis in neoplastic MCs in patients with CD30− SM. Furthermore, brentuximab-vedotin was found to downregulate anti-IgE–induced histamine release in CD30+ MCs. Finally, brentuximab-vedotin and the KIT D816V-targeting drug PKC412 produced synergistic growth-inhibitory effects in MCPV-1.1 cells. Together, CD30 is a promising new drug target for patients with CD30+ advanced SM. PMID:26486787

Heme oxygenase-1 restores impaired GARPCD4⁺CD25⁺ regulatory T cells from patients with acute coronary syndrome by upregulating LAP and GARP expression on activated T lymphocytes.

PubMed

Liu, Yuzhou; Zhao, Xiaoqi; Zhong, Yucheng; Meng, Kai; Yu, Kunwu; Shi, Huairui; Wu, Bangwei; Tony, Hasahya; Zhu, Jianghao; Zhu, Ruirui; Peng, Yudong; Mao, Yi; Cheng, Peng; Mao, Xiaobo; Zeng, Qiutang

2015-01-01

Accumulating evidence shows that the pathological autoreactive immune response is responsible for plaque rupture and the subsequent onset of acute coronary syndrome (ACS). Naturally occurring CD4(+)CD25(+)regulatory T cells (nTregs) are indispensable in suppressing the pathological autoreactive immune response and maintaining immune homeostasis. However, the number and the suppressive function of glycoprotein-A repetitions predominant (GARP) (+) CD4(+) CD25(+) activated nTregs were impaired in patients with ACS. Recent evidence suggests that heme oxygenase-1 (HO-1) can regulate the adaptive immune response by promoting the expression of Foxp3. We therefore hypothesized that HO-1 may enhance the function of GARP(+) CD4(+) CD25(+)Tregs in patients with ACS and thus regulate immune imbalance. T lymphocytes were isolated from healthy volunteers (control, n=30) and patients with stable angina (SA, n=40) or ACS (n=51). Half of these cells were treated with an HO-1 inducer (hemin) for 48 h, and the other half were incubated with complete RPMI-1640 medium. The frequencies of T-helper 1 (Th1), Th2, Th17 and latency-associated peptide (LAP) (+)CD4(+) T cells and the expression of Foxp3 and GARP by CD4(+)CD25(+)T cells were then assessed by measuring flow cytometry after stimulation in vitro. The suppressive function of activated Tregs was measured by thymidine uptake. The levels of transforming growth factor-1 (TGF-β1) in the plasma were measured using enzyme-linked immunosorbent assay (ELISA). The expression levels of the genes encoding these proteins were analyzed by real-time polymerase chain reaction. Patients with ACS exhibited an impaired number and suppressive function of GARP(+) CD4(+) CD25(+)Tregs and a mixed Th1/Th17-dominant T cell response when compared with the SA and control groups. The expression of LAP in T cells was also lower in patients with ACS compared to patients with SA and the control individuals. Treatment with an HO-1 inducer enhanced the biological activity of GARP(+) CD4(+) CD25(+)Tregs and resulted in increased expression of LAP and GARP by activated T cells. The reduced number and impaired suppressive function of GARP(+) CD4(+) CD25(+)Tregs result in excess effector T cell proliferation, leading to plaque instability and the onset of ACS. HO-1 can effectively restore impaired GARP(+) CD4(+) CD25(+)Tregs from patients with ACS by promoting LAP and GARP expression on activated T cells. © 2015 S. Karger AG, Basel.

Chemotherapy alters the increased numbers of myeloid-derived suppressor and regulatory T cells in children with acute lymphoblastic leukemia.

PubMed

Salem, Mohamed Labib; El-Shanshory, Mohamed R; Abdou, Said H; Attia, Mohamed S; Sobhy, Shymaa M; Zidan, Mona F; Zidan, Abdel-Aziz A

2018-04-01

Acute lymphoblastic leukemia (ALL) is the most common cancer diagnosed in children. The precise mechanism behind the relapse in this disease is not clearly known. One possible mechanism could be the accumulation of immunosuppressive cells, including myeloid-derived suppressor cells (MDSCs) and T regulatory cells (T regs ) which we and others have reported to mediate suppression of anti-tumor immune responses. In this study, we aimed to analyze the numbers of these cells in a population of B-ALL pediatric patients. Peripheral blood samples withdrawn from B-ALL pediatric patients (n = 45 before, during and after the induction phase of chemotherapy. Using multi parametric flow cytometric analysis. MDSCs were identified as Lin - HLA-DR - CD33 + CD11b + ; and T reg cells were defined as CD4 + CD25 + CD127 -/low . Early diagnosed B-ALL patients showed significant increases in the numbers of MDSCs and T regs as compared to healthy volunteers. During induction of chemotherapy, however, the patients showed higher and lower numbers of MDSCs and T reg cells, respectively as compared to early diagnosed patients (i.e., before chemotherapy). After induction of chemotherapy, the numbers of MDSCs and T reg cells showed higher increases and decreases, respectively as compared to the numbers in patients during chemotherapy. Our results indicate that B-ALL patients harbor high numbers of both MDSCs and T regs cells. This pilot study opens a new avenue to investigate the mechanism mediating the emergence of these cells on larger number of B-ALL patients at different treatment stages.

Essential trace elements and antioxidant status in relation to severity of HIV in Nigerian patients.

PubMed

Olaniyi, J A; Arinola, O G

2007-01-01

This study was designed to determine the plasma levels of some antioxidants and trace elements in three severity groups of HIV patients compared with non-HIV-infected controls. The plasma levels of antioxidants (total antioxidant, albumin, bilirubin and uric acid) and trace elements (Mg, Fe, Zn, Mn, Cu, Cr, Cd and Se) were estimated spectrophotometrically in controls and patients with CD4 counts of <200; 200-499 and > or =500 cells/microl. Uric acid and Zn were significantly higher, while vitamin E and all the trace elements (except Zn) were significantly lower in HIV-infected patients compared to healthy controls. The highest level of uric acid was observed in those with CD4 counts of <200 cells/microl. All the trace elements (except Zn) were higher in HIV subjects with a CD4 count of 200-499 cells/microl compared to >500 cells/microl. Only uric acid and Zn showed significant correlation with CD4 count. Based on the results of this study, we recommend routine assessment and appropriate supplementation of antioxidants/trace elements in HIV subjects. This supplementation is hoped to strengthen the immune system and reduce the adverse consequences of HIV- related oxidative stress. Copyright 2007 S. Karger AG, Basel.

Quantifying Muscle Asymmetries in Cervical Dystonia with Electrical Impedance: A Preliminary Assessment

PubMed Central

Lungu, Codrin; Tarulli, Andrew W; Tarsy, Daniel; Mongiovi, Phillip; Vanderhorst, Veronique G; Rutkove, Seward B

2010-01-01

Objective Cervical Dystonia (CD) lacks an objective quantitative measure. Electrical impedance myography (EIM) is a non-invasive assessment method sensitive to changes in muscle structure and physiology. We evaluate the potential role of EIM in quantifying CD, hypothesizing that patients would demonstrate differences in the symmetry of muscle electrical resistance compared to controls, and that this asymmetry would decrease after botulinum neurotoxin (BoNT) treatment. Methods EIM was performed on the sternocleidomastoid (SCM) and cervical paraspinal (PS) muscles of CD patients and age-matched controls. 50kHz Resistance was analyzed, comparing side-to-side asymmetry in patients and controls, and, in patients, before and after BoNT treatment. Results 16 patients and 10 controls were included. Resistance asymmetry was on average 3-5 times higher in patients than controls. Receiver operating characteristic analysis demonstrated 91% accuracy of discriminating CD from normal. From pre-treatment to maximum BoNT effect, asymmetry decreased from 20.8 (13.9-26.1)% to 6.2 (3.1-9.9)% (SCM), and from 16.0(14.3-16.0)% to 8.4(7.0-9.2)% (PS), p<0.05 (median, interquartile range). Conclusions EIM effectively differentiates normal subjects from CD patients by revealing asymmetries in resistance values and detects improvement in muscle symmetry after treatment. Significance These results suggest that EIM, a painless, non-invasive measure, can provide a useful quantitative metric in CD evaluation and deserves further study. PMID:20943436

Quantifying muscle asymmetries in cervical dystonia with electrical impedance: a preliminary assessment.

PubMed

Lungu, Codrin; Tarulli, Andrew W; Tarsy, Daniel; Mongiovi, Phillip; Vanderhorst, Veronique G; Rutkove, Seward B

2011-05-01

Cervical dystonia (CD) lacks an objective quantitative measure. Electrical impedance myography (EIM) is a non-invasive assessment method sensitive to changes in muscle structure and physiology. We evaluate the potential role of EIM in quantifying CD, hypothesizing that patients would demonstrate differences in the symmetry of muscle electrical resistance compared to controls, and that this asymmetry would decrease after botulinum neurotoxin (BoNT) treatment. EIM was performed on the sternocleidomastoid (SCM) and cervical paraspinal (PS) muscles of CD patients and age-matched controls. 50 kHz resistance was analyzed, comparing side-to-side asymmetry in patients and controls, and, in patients, before and after BoNT treatment. Sixteen patients and 10 controls were included. Resistance asymmetry was on average 3-5 times higher in patients than controls. Receiver operating characteristic analysis demonstrated 91% accuracy of discriminating CD from normal. From pre-treatment to maximum BoNT effect, asymmetry decreased from 20.8(13.9-26.1)% to 6.2(3.1-9.9)% (SCM), and from 16.0(14.3-16.0)% to 8.4(7.0-9.2)% (PS), p<0.05 (median, interquartile range). EIM effectively differentiates normal subjects from CD patients by revealing asymmetries in resistance values and detects improvement in muscle symmetry after treatment. These results suggest that EIM, a painless, non-invasive measure, can provide a useful quantitative metric in CD evaluation and deserves further study. Published by Elsevier Ireland Ltd.

Immunological role of CD4+CD28null T lymphocytes, natural killer cells, and interferon-gamma in pediatric patients with sickle cell disease: relation to disease severity and response to therapy.

PubMed

ElAlfy, Mohsen Saleh; Adly, Amira Abdel Moneam; Ebeid, Fatma Soliman ElSayed; Eissa, Deena Samir; Ismail, Eman Abdel Rahman; Mohammed, Yasser Hassan; Ahmed, Manar Elsayed; Saad, Aya Sayed

2018-06-20

Sickle cell disease (SCD) is associated with alterations in immune phenotypes. CD4 + CD28 null T lymphocytes have pro-inflammatory functions and are linked to vascular diseases. To assess the percentage of CD4 + CD28 null T lymphocytes, natural killer cells (NK), and IFN-gamma levels, we compared 40 children and adolescents with SCD with 40 healthy controls and evaluated their relation to disease severity and response to therapy. Patients with SCD steady state were studied, focusing on history of frequent vaso-occlusive crisis, hydroxyurea therapy, and IFN-gamma levels. Analysis of CD4 + CD28 null T lymphocytes and NK cells was done by flow cytometry. Liver and cardiac iron overload were assessed. CD4 + CD28 null T lymphocytes, NK cells, and IFN-gamma levels were significantly higher in patients than controls. Patients with history of frequent vaso-occlusive crisis and those with vascular complications had higher percentage of CD4 + CD28 null T lymphocytes and IFN-gamma while levels were significantly lower among hydroxyurea-treated patients. CD4 + CD28 null T lymphocytes were positively correlated to transfusional iron input while these cells and IFN-gamma were negatively correlated to cardiac T2* and duration of hydroxyurea therapy. NK cells were correlated to HbS and indirect bilirubin. Increased expression of CD4 + CD28 null T lymphocytes highlights their role in immune dysfunction and pathophysiology of SCD complications.

Full-length soluble CD147 promotes MMP-2 expression and is a potential serological marker in detection of hepatocellular carcinoma

PubMed Central

2014-01-01

Background As a surface glycoprotein, CD147 is capable of stimulating the production of matrix metalloproteinases (MMPs) from neighboring fibroblasts. The aim of the present study is to explore the role of soluble CD147 on MMPs secretion from hepatocellular carcinoma (HCC) cells, and to investigate the diagnostic value of serum soluble CD147 in the HCC detection. Methods We identified the form of soluble CD147 in cell culture supernate of HCC cells and serum of patients with HCC, and explored the role of soluble CD147 on MMPs secretion. Serum CD147 levels were detected by the enzyme-linked immunosorbent assay, and the value of soluble CD147 as a marker in HCC detection was analyzed. Results Full length soluble CD147 was presented in the culture medium of HCC cells and serum of patients with HCC. The extracellular domain of soluble CD147 promoted the expression of CD147 and MMP-2 from HCC cells. Knockdown of CD147 markedly diminished the up-regulation of CD147 and MMP-2 which induced by soluble CD147. Soluble CD147 activated ERK, FAK, and PI3K/Akt pathways, leading to the up-regulation of MMP-2. The level of soluble CD147 in serum of patients with HCC was significantly elevated compared with healthy individuals (P < 0.001). Soluble CD147 levels were found to be associated with HCC tumor size (P = 0.007) and Child-Pugh grade (P = 0.007). Moreover, soluble CD147 showed a better performance in distinguishing HCC compared with alpha-fetoprotein. Conclusions The extracellular domain of soluble CD147 enhances the secretion of MMP-2 from HCC cells, requiring the cooperation of membrane CD147 and activation of ERK, FAK, and PI3K/Akt signaling. The measurement of soluble CD147 may offer a useful approach in diagnosis of HCC. PMID:24996644

Full-length soluble CD147 promotes MMP-2 expression and is a potential serological marker in detection of hepatocellular carcinoma.

PubMed

Wu, Jiao; Hao, Zhi-Wei; Zhao, You-Xu; Yang, Xiang-Min; Tang, Hao; Zhang, Xin; Song, Fei; Sun, Xiu-Xuan; Wang, Bin; Nan, Gang; Chen, Zhi-Nan; Bian, Huijie

2014-07-04

As a surface glycoprotein, CD147 is capable of stimulating the production of matrix metalloproteinases (MMPs) from neighboring fibroblasts. The aim of the present study is to explore the role of soluble CD147 on MMPs secretion from hepatocellular carcinoma (HCC) cells, and to investigate the diagnostic value of serum soluble CD147 in the HCC detection. We identified the form of soluble CD147 in cell culture supernate of HCC cells and serum of patients with HCC, and explored the role of soluble CD147 on MMPs secretion. Serum CD147 levels were detected by the enzyme-linked immunosorbent assay, and the value of soluble CD147 as a marker in HCC detection was analyzed. Full length soluble CD147 was presented in the culture medium of HCC cells and serum of patients with HCC. The extracellular domain of soluble CD147 promoted the expression of CD147 and MMP-2 from HCC cells. Knockdown of CD147 markedly diminished the up-regulation of CD147 and MMP-2 which induced by soluble CD147. Soluble CD147 activated ERK, FAK, and PI3K/Akt pathways, leading to the up-regulation of MMP-2. The level of soluble CD147 in serum of patients with HCC was significantly elevated compared with healthy individuals (P < 0.001). Soluble CD147 levels were found to be associated with HCC tumor size (P = 0.007) and Child-Pugh grade (P = 0.007). Moreover, soluble CD147 showed a better performance in distinguishing HCC compared with alpha-fetoprotein. The extracellular domain of soluble CD147 enhances the secretion of MMP-2 from HCC cells, requiring the cooperation of membrane CD147 and activation of ERK, FAK, and PI3K/Akt signaling. The measurement of soluble CD147 may offer a useful approach in diagnosis of HCC.

A decrease of regulatory T cells and altered expression of NK receptors are observed in subacute sclerosing panencephalitis.

PubMed

Yentur, Sibel P; Gurses, Candan; Demirbilek, Veysi; Adin-Cinar, Suzan; Kuru, Umit; Uysal, Serap; Yapici, Zuhal; Yilmaz, Gülden; Cokar, Ozlem; Onal, Emel; Gökyigit, Aysen; Saruhan-Direskeneli, Güher

2014-12-01

Subacute sclerosing panencephalitis (SSPE) is caused by a persistent measles virus infection. Regulatory mechanisms can be responsible for a failure of immunosurveillance in children with SSPE. In this study, peripheral blood cells of 71 patients with SSPE and 57 children with other diseases were compared phenotypically. The proportions of CD4(+), CD8(+) T, and NK cells were homogenous, whereas total CD3(+) T and Treg (CD4(+)CD25(+)CD152(+)) cells were decreased in patients with SSPE. The proportion of CD8(+) T cells expressing the inhibitory NKG2A(+) receptor was also decreased (1.7% ± 1.7% vs. 2.6% ± 1.9%, p = 0.007) in patients with SSPE, whereas the proportion of NK cells expressing activating NKG2C was increased compared with the control group (30.0% ± 17.3% vs. 22.2% ± 17.0%, p = 0.039). The decrease in the number of cells with regulatory phenotype, the lower presence of the inhibitory NK receptors on CD8(+) cells, and higher activating NK receptors on NK cells in SSPE indicate an upregulation of these cell types that favors their response. This state of active immune response may be caused by chronic stimulation of viral antigens leading to altered regulatory pathways.

Granulocyte colony-stimulating factor mobilizes functional endothelial progenitor cells in patients with coronary artery disease.

PubMed

Powell, Tiffany M; Paul, Jonathan D; Hill, Jonathan M; Thompson, Michael; Benjamin, Moshe; Rodrigo, Maria; McCoy, J Philip; Read, Elizabeth J; Khuu, Hanh M; Leitman, Susan F; Finkel, Toren; Cannon, Richard O

2005-02-01

Endothelial progenitor cells (EPCs) that may repair vascular injury are reduced in patients with coronary artery disease (CAD). We reasoned that EPC number and function may be increased by granulocyte colony-stimulating factor (G-CSF) used to mobilize hematopoietic progenitor cells in healthy donors. Sixteen CAD patients had reduced CD34(+)/CD133(+) (0.0224+/-0.0063% versus 0.121+/-0.038% mononuclear cells [MNCs], P<0.01) and CD133(+)/VEGFR-2(+) cells, consistent with EPC phenotype (0.00033+/-0.00015% versus 0.0017+/-0.0006% MNCs, P<0.01), compared with 7 healthy controls. Patients also had fewer clusters of cells in culture, with out-growth consistent with mature endothelial phenotype (2+/-1/well) compared with 16 healthy subjects at high risk (13+/-4/well, P<0.05) or 14 at low risk (22+/-3/well, P<0.001) for CAD. G-CSF 10 microg/kg per day for 5 days increased CD34(+)/CD133(+) cells from 0.5+/-0.2/microL to 59.5+/-10.6/microL and CD133(+)/ VEGFR-2(+) cells from 0.007+/-0.004/microL to 1.9+/-0.6/microL (both P<0.001). Also increased were CD133(+) cells that coexpressed the homing receptor CXCR4 (30.4+/-8.3/microL, P<0.05). Endothelial cell-forming clusters in 10 patients increased to 27+/-9/well after treatment (P<0.05), with a decline to 9+/-4/well at 2 weeks (P=0.06). Despite reduced EPCs compared with healthy controls, patients with CAD respond to G-CSF with increases in EPC number and homing receptor expression in the circulation and endothelial out-growth in culture. Endothelial progenitor cells (EPCs) are reduced in coronary artery disease. Granulocyte colony-stimulating factor (CSF) administered to patients increased: (1) CD133+/VEGFR-2+ cells consistent with EPC phenotype; (2) CD133+ cells coexpressing the chemokine receptor CXCR4, important for homing of EPCs to ischemic tissue; and (3) endothelial cell-forming clusters in culture. Whether EPCs mobilized into the circulation will be useful for the purpose of initiating vascular growth and myocyte repair in coronary artery disease patients must be tested in clinical trials.

The Prognostic Role of Cancer Stem Cell Markers for Long-term Outcome After Resection of Colonic Liver Metastases.

PubMed

Spelt, Lidewij; Sasor, Agata; Ansari, Daniel; Hilmersson, Katarzyna Said; Andersson, Roland

2018-01-01

To assess the expression of cancer stem cell (CSC) markers CD44, CD133 and CD24 in colon cancer liver metastases and analyse their predictive value for overall survival (OS) and disease-free survival (DFS) after liver resection. Patients operated on for colon cancer liver metastases were included. CSC marker expression was determined through immunohistochemistry analysis. OS and DFS were compared between marker-positive and marker-negative patients. Multivariate analysis was performed to select predictive variables for OS and DFS. CD133-positive patients had a worse DFS than CD133-negative patients, with a median DFS of 12 and 25 months (p=0.051). Multivariate analysis selected CD133 expression as a significant predictor for DFS. CD44 and CD24 were not found to predict OS or DFS. CD133 expression in colonic liver metastases is a negative prognostic factor for DFS after liver resection. In the future, CD133 could be used as a biomarker for risk stratification, and possibly for developing novel targeted therapy. Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

Expansion of CD14+CD16+ monocytes producing TNF-α in complication-free diabetes type 1 juvenile onset patients.

PubMed

Myśliwska, Jolanta; Smardzewski, Marcin; Marek-Trzonkowska, Natalia; Myśliwiec, Małgorzata; Raczyńska, Krystyna

2012-10-01

We concentrated on the complication-free phase of juvenile onset type 1 diabetes mellitus (T1DM) searching for associations between concentration of inflammatory factors TNF-α, CRP and VEGF and two monocyte subsets the CD14(++)CD16(-) and CD14(+)CD16(+). We analysed a randomly selected group of 150 patients without complications (disease duration 2.74 ± 2.51 years) at the start of the project and 5 years later. They were compared with 24 patients with retinopathy (6.53 ± 3.39 years of disease) and 30 healthy volunteers. Our results indicate that in the complication-free period the concentration of TNF-α significantly increased and continued to increase after retinopathy was established. After 5 years the percentage and absolute number of CD14(+)CD16(+) monocytes doubled in complication-free patients. Our study indicates that the size of CD14(+)CD16(+) monocyte subset may be used alternatively to CRP values as an indicator of inflammation grade. Our results imply the necessity of trials using anti-TNF-α therapy in the complication-free phase of the disease. Copyright © 2012 Elsevier Ltd. All rights reserved.

Narcolepsy Type 1 Is Associated with a Systemic Increase and Activation of Regulatory T Cells and with a Systemic Activation of Global T Cells.

PubMed

Lecendreux, Michel; Churlaud, Guillaume; Pitoiset, Fabien; Regnault, Armelle; Tran, Tu Anh; Liblau, Roland; Klatzmann, David; Rosenzwajg, Michelle

2017-01-01

Narcolepsy is a rare neurologic disorder characterized by excessive daytime sleepiness, cataplexy and disturbed nocturnal sleep patterns. Narcolepsy type 1 (NT1) has been shown to result from a selective loss of hypothalamic hypocretin-secreting neurons with patients typically showing low CSF-hypocretin levels (<110 pg/ml). This specific loss of hypocretin and the strong association with the HLA-DQB1*06:02 allele led to the hypothesis that NT1 could be an immune-mediated pathology. Moreover, susceptibility to NT1 has recently been associated with several pathogens, particularly with influenza A H1N1 virus either through infection or vaccination. The goal of this study was to compare peripheral blood immune cell populations in recent onset pediatric NT1 subjects (post or non-post 2009-influenza A H1N1 vaccination) to healthy donors. We demonstrated an increased number of central memory CD4+ T cells (CD62L+ CD45RA-) associated to an activated phenotype (increase in CD69 and CD25 expression) in NT1 patients. Percentage and absolute count of regulatory T cells (Tregs) in NT1 patients were increased associated with an activated phenotype (increase in GITR and LAP expression), and of activated memory phenotype. Cytokine production by CD4+ and CD8+ T cells after activation was not modified in NT1 patients. In H1N1 vaccinated NT1 patients, absolute counts of CD3+, CD8+ T cells, and B cells were increased compared to non-vaccinated NT1 patients. These results support a global T cell activation in NT1 patients and thus support a T cell-mediated autoimmune origin of NT1, but do not demonstrate the pathological role of H1N1 prophylactic vaccination. They should prompt further studies of T cells, particularly of Tregs (such as suppression and proliferation antigen specific assays, and also T-cell receptor sequencing), in NT1.

[Hepatitis-associated aplastic anaemia: clinical characteristics and immunosuppressive therapy outcomes].

PubMed

Yang, W R; Jing, L P; Zhou, K; Peng, G X; Li, Y; Ye, L; Li, Y; Li, J P; Fan, H H; Song, L; Zhao, X; Yang, Y; Zhang, F K; Zhang, L

2016-05-14

To analyze the clinical characteristics and to evaluate immunosuppressive therapy (IST) response and survival in hepatitis-associated aplastic anemia (HAAA). We retrospectively analyzed clinical characteristics, IST response, long-term survival and clonal evolution in 41 HAAA patients, and compared those with age and bone marrow failure matched idiopathic aplastic anemia (IAA) patients. The prevalence of HAAA among cases of SAA was 4.34% (41/944). The proportion of VSAA in HAAA cases was significantly higher than IAA (65.9% vs 39.4%, P=0.001). There was no significant difference in the prevalence of hemorrhage and infections between HAAA and IAA patients, but the duration of infection persistence in HAAA group was much longer than IAA group [21 (4-100) d vs 13 (3-139) d, P=0.048]. The absolute counts of CD3(+) T-cell, CD3(+)CD4(+)T-cell, CD3(+)CD8(+)T-cell and ratio of CD4(+) T-cell/CD8(+) T-cell in HAAA were significant lower than that in IAA patients. However, the percentage of CD3(+)CD8(+)T-cell in HAAA was significant higher than that in IAA (P <0.05). The total response in HAAA and IAA patients treated with IST were 34.1% vs 34.1% (P=1.000), 56.1% vs 53.7% (P=0.787), and 73.2% vs 68.3% (P=0.558) at 3, 6, 12 months after IST, respectively. There were no significant difference in 5-year overall survival and event-free survival between HAAA and IAA patients (90% vs 87.1%, P=0.700; 71.9% vs 62.4%, P=0.450). HAAA was a rare distinct variant of aplastic anemia with more severe bone marrow failure and more severe imbalance of the T cell immune system than IAA. Treatment outcomes were comparable in patients with HAAA and IAA.

Prevalence of celiac disease in patients with severe food allergy.

PubMed

Pillon, R; Ziberna, F; Badina, L; Ventura, A; Longo, G; Quaglia, S; De Leo, L; Vatta, S; Martelossi, S; Patano, G; Not, T; Berti, I

2015-10-01

The association between food allergy and celiac disease (CD) is still to be clarified. We screened for CD 319 patients with severe food allergy (IgE > 85 kU/l against food proteins and a history of severe allergic reactions) who underwent specific food oral immunotherapy (OIT), together with 128 children with mild allergy who recovered without OIT, and compared the prevalence data with our historical data regarding healthy schoolchildren. Sixteen patients (5%) with severe allergy and one (0.8%) with mild allergy tested positive for both genetic and serological CD markers, while the prevalence among the schoolchildren was 1%. Intestinal biopsies were obtained in 13/16 patients with severe allergy and in the one with mild allergy, confirming the diagnosis of CD. Sufferers from severe food allergy seem to be at a fivefold increased risk of CD. Our findings suggest that routine screening for CD should be recommended in patients with severe food allergy. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Intestinal Microbiota and Celiac Disease: Cause, Consequence or Co-Evolution?

PubMed

Cenit, María Carmen; Olivares, Marta; Codoñer-Franch, Pilar; Sanz, Yolanda

2015-08-17

It is widely recognized that the intestinal microbiota plays a role in the initiation and perpetuation of intestinal inflammation in numerous chronic conditions. Most studies report intestinal dysbiosis in celiac disease (CD) patients, untreated and treated with a gluten-free diet (GFD), compared to healthy controls. CD patients with gastrointestinal symptoms are also known to have a different microbiota compared to patients with dermatitis herpetiformis and controls, suggesting that the microbiota is involved in disease manifestation. Furthermore, a dysbiotic microbiota seems to be associated with persistent gastrointestinal symptoms in treated CD patients, suggesting its pathogenic implication in these particular cases. GFD per se influences gut microbiota composition, and thus constitutes an inevitable confounding factor in studies conducted in CD patients. To improve our understanding of whether intestinal dysbiosis is the cause or consequence of disease, prospective studies in healthy infants at family risk of CD are underway. These studies have revealed that the CD host genotype selects for the early colonizers of the infant's gut, which together with environmental factors (e.g., breast-feeding, antibiotics, etc.) could influence the development of oral tolerance to gluten. Indeed, some CD genes and/or their altered expression play a role in bacterial colonization and sensing. In turn, intestinal dysbiosis could promote an abnormal response to gluten or other environmental CD-promoting factors (e.g., infections) in predisposed individuals. Here, we review the current knowledge of host-microbe interactions and how host genetics/epigenetics and environmental factors shape gut microbiota and may influence disease risk. We also summarize the current knowledge about the potential mechanisms of action of the intestinal microbiota and specific components that affect CD pathogenesis.

In Vitro Fertilization in Women With Inflammatory Bowel Disease Is as Successful as in Women From the General Infertility Population

PubMed Central

Oza, Sveta Shah; Pabby, Vikas; Dodge, Laura E.; Moragianni, Vasiliki A.; Hacker, Michele R.; Fox, Janis H.; Correia, Katharine; Missmer, Stacey A.; Ibrahim, Yetunde; Penzias, Alan S.; Burakoff, Robert; Friedman, Sonia; Cheifetz, Adam S.

2015-01-01

BACKGROUND & AIMS Inflammatory bowel disease (IBD) affects women of reproductive age, so there are concerns about its effects on fertility. We investigated the success of in vitro fertilization (IVF) in patients with IBD compared with the general (non-IBD) IVF population. METHODS We conducted a matched retrospective cohort study of female patients with IBD who under-went IVF from 1998 through 2011 at 2 tertiary care centers. Patients were matched 4:1 to those without IBD (controls). The primary outcome was the cumulative rate of live births after up to 6 cycles of IVF. Secondary outcomes included the proportion of patients who became pregnant and the rate of live births for each cycle. RESULTS Forty-nine patients with Crohn’s disease (CD), 71 patients with ulcerative colitis (UC), 1 patient with IBD-unclassified, and 470 controls underwent IVF during the study period. The cumulative rate of live births was 53% for controls, 69% for patients with UC (P = .08 compared with controls), and 57% for patients with CD (P = .87 compared with controls). The incidence of pregnancy after the first cycle of IVF was similar among controls (40.9%), patients with UC (49.3%; P = .18), and patients with CD (42.9%; P = .79). Similarly, the incidence of live births after the first cycle of IVF was similar among controls (30.2%), patients with UC (33.8%; P = .54), and patients with CD (30.6%; P = .95). CONCLUSIONS Based on a matched cohort study, infertile women with IBD achieve rates of live births after IVF that are comparable with those of infertile women without IBD. PMID:25818081

Altered status of CD4(+)CD25(+) regulatory T cells in patients with acute coronary syndromes.

PubMed

Mor, Adi; Luboshits, Galia; Planer, David; Keren, Gad; George, Jacob

2006-11-01

Considerable evidence supports the role of innate and adaptive immunity in the progression and destabilization of the atheromatous plaque. Naturally occurring CD4(+)CD25(+) regulatory T cells (Tregs) are a subpopulation of lymphocytes that are capable of suppressing the progression of experimental autoimmune disorders. We have hypothesized that peripheral numbers and function of Tregs would be deranged in patients with acute coronary syndromes (ACS). Peripheral numbers of Tregs were evaluated by FACS employing labelled antibodies to CD4 and CD25. Functional suppressive properties of Tregs were assayed by establishing a triple-cell culture in which purified Tregs were incubated with irradiated antigen-presenting cells and anti-CD3-activated responder T cells. Proliferation in the presence or absence of oxidized LDL (oxLDL) was evaluated by thymidine incorporation. mRNA and protein content of foxp3, a master transcriptional regulator of Tregs, were determined for all subjects. Patients with ACS exhibited significantly reduced numbers of peripheral Tregs as compared with patients with stable angina and normal coronary artery subjects. Moreover, oxLDL induced a more profound reduction in Treg numbers in patients with ACS. Tregs in ACS patients were significantly compromised as their ability to suppress responder CD4(+)CD25(-) T-cell proliferation was attenuated. mRNA and protein content of foxp3 were significantly reduced in purified Tregs obtained from patients with ACS. In patients with ACS, naturally occurring CD4(+)CD25(+) Treg numbers are reduced and their functional properties compromised. These findings may aid in understanding the mechanisms leading to culprit plaque associated T-cell activation in patients with ACS.

Temporal lobe volumes in patients with hippocampal sclerosis with or without cortical dysplasia.

PubMed

Diehl, B; Najm, I; LaPresto, E; Prayson, R; Ruggieri, P; Mohamed, A; Ying, Z; Lieber, M; Babb, T; Bingaman, W; Lüders, H O

2004-05-25

Recent MRI-based volume reconstruction studies in intractable temporal lobe epilepsy (TLE) due to hippocampal sclerosis (HS) suggested atrophy that extends to the adjacent neocortical areas. To study the extent of temporal lobe volume (TLV) abnormalities in patients with pathologically confirmed HS (with or without cortical dysplasia [CD]) who underwent anterior temporal lobectomy for the treatment of drug-resistant TLE. Fifty patients (right TLE: n = 24; left TLE: n = 26) were found to have HS (hippocampal cell loss of >30%). Associated neocortical CD was seen in 20 patients (43%). MRI-based TLVs and hippocampal and hemispheric volume reconstructions in all patients were compared between pathologic groups and with volumes acquired from 10 age-matched control subjects. TLVs ipsilateral to the epileptogenic zone in patients with TLE were smaller than TLVs in control subjects (p < 0.01). In patients with left TLE, TLVs ipsilateral to the epileptogenic zone were smaller than contralateral TLVs (left: 66.6 +/- 8.3 cm3, right: 74.9 +/- 10.0 cm3; p < 0.001). In patients with right TLE, there were no significant asymmetries. The contralateral TLVs (regardless of the side of surgery) were smaller in the HS + CD group than the HS group (HS + CD group: 74.9 +/- 8.6 cm3, HS group: 79.7 +/- 6.6 cm3; p < 0.05). Patients with HS + CD had a tendency to have less hippocampal atrophy and slightly smaller TLVs ipsilateral to the epileptogenic zone, accounting for significantly smaller TLV/hippocampal volume ratios compared with patients with HS alone. Drug-resistant TLE due to HS is associated with extrahippocampal temporal lobe atrophy. The presence of bilateral temporal lobe atrophy is suggestive of a more widespread (bilateral) temporal lobe involvement in patients with HS and CD.

CD8 apoptosis may be a predictor of T cell number normalization after immune reconstitution in HIV

PubMed Central

Lewis, Dorothy E; Gross, Kimber L; Diez, Martine M; Martinez, Maria L; Lukefahr, Helen N; Kozinetz, Claudia A; Arduino, Roberto C

2007-01-01

Background As part of the Houston Vanguard study, a subset of 10 patients randomized to receive IL-2 therapy were compared to 4 patients randomized to not receive IL-2, for markers of T cell activation and death during the first three cycles of IL-2. All patients were treated with combination antiretroviral therapy (ART) and were virally suppressed. The purpose of the study was to examine the role of CD8+ T cell death in responses to ART and IL-2 therapy. Methods Lymphocytes were examined at Day 0, 5 and 30 days during three cycles of IL-2 therapy. CD25, CD38, HLA-DR expression and annexin (cell death) were examined on CD4 and CD8 subpopulations. Follow up studies examined CD4 levels and CD4:CD8 reconstitution after 6 years using both univariant and multivariate analyses. Results Human lymphocytes responded to IL-2 therapy by upregulation of CD25 on CD4+ T cells, leading to an increase in CD4 cell counts. CD8+ T cells did not increase CD25 expression, but upregulated activation antigens (CD38 and DR) and had increased death. At baseline, 7 of the 14 patients had high CD8+ T cell apoptosis (mean 17.0% ± 6.0). We did an exploratory analysis of immune status after six years, and found that baseline CD8+ T cell apoptosis was correlated with CD4 cell count gain beginning two years post enrollment. Patients with low levels of CD8+ T cell apoptosis at baseline (mean 2.2% ± 2.1) had significantly higher CD4 cell counts and more normalized CD4:CD8 ratios than patients with high CD8+ T cell apoptosis (mean CD4 cell counts 1,209 ± 164 vs 754 ± 320 cells/mm3; CD4:CD8 ratios 1.55 vs. 0.70, respectively). Conclusion We postulate that CD8+ T cell apoptosis may reflect inherent activation status, which continues in some patients even though viral replication is suppressed which influences the ability of CD4+ T cells to rebound. Levels of CD8+ T cell apoptosis may therefore be an independent predictor of immune status, which should be shown in a prospective study. PMID:17263884

CD8 apoptosis may be a predictor of T cell number normalization after immune reconstitution in HIV.

PubMed

Lewis, Dorothy E; Gross, Kimber L; Diez, Martine M; Martinez, Maria L; Lukefahr, Helen N; Kozinetz, Claudia A; Arduino, Roberto C

2007-01-30

As part of the Houston Vanguard study, a subset of 10 patients randomized to receive IL-2 therapy were compared to 4 patients randomized to not receive IL-2, for markers of T cell activation and death during the first three cycles of IL-2. All patients were treated with combination antiretroviral therapy (ART) and were virally suppressed. The purpose of the study was to examine the role of CD8(+) T cell death in responses to ART and IL-2 therapy. Lymphocytes were examined at Day 0, 5 and 30 days during three cycles of IL-2 therapy. CD25, CD38, HLA-DR expression and annexin (cell death) were examined on CD4 and CD8 subpopulations. Follow up studies examined CD4 levels and CD4:CD8 reconstitution after 6 years using both univariant and multivariate analyses. Human lymphocytes responded to IL-2 therapy by upregulation of CD25 on CD4(+) T cells, leading to an increase in CD4 cell counts. CD8(+) T cells did not increase CD25 expression, but upregulated activation antigens (CD38 and DR) and had increased death. At baseline, 7 of the 14 patients had high CD8+ T cell apoptosis (mean 17.0% +/- 6.0). We did an exploratory analysis of immune status after six years, and found that baseline CD8+ T cell apoptosis was correlated with CD4 cell count gain beginning two years post enrollment. Patients with low levels of CD8(+) T cell apoptosis at baseline (mean 2.2% +/- 2.1) had significantly higher CD4 cell counts and more normalized CD4:CD8 ratios than patients with high CD8(+) T cell apoptosis (mean CD4 cell counts 1,209 +/- 164 vs 754 +/- 320 cells/mm(3); CD4:CD8 ratios 1.55 vs. 0.70, respectively). We postulate that CD8(+) T cell apoptosis may reflect inherent activation status, which continues in some patients even though viral replication is suppressed which influences the ability of CD4(+) T cells to rebound. Levels of CD8(+) T cell apoptosis may therefore be an independent predictor of immune status, which should be shown in a prospective study.

Thiopurine treatment in patients with Crohn's disease leads to a selective reduction of an effector cytotoxic gene expression signature revealed by whole-genome expression profiling.

PubMed

Bouma, G; Baggen, J M; van Bodegraven, A A; Mulder, C J J; Kraal, G; Zwiers, A; Horrevoets, A J; van der Pouw Kraan, C T M

2013-07-01

Crohn's disease (CD) is characterized by chronic inflammation of the gastrointestinal tract, as a result of aberrant activation of the innate immune system through TLR stimulation by bacterial products. The conventional immunosuppressive thiopurine derivatives (azathioprine and mercaptopurine) are used to treat CD. The effects of thiopurines on circulating immune cells and TLR responsiveness are unknown. To obtain a global view of affected gene expression of the immune system in CD patients and the treatment effect of thiopurine derivatives, we performed genome-wide transcriptome analysis on whole blood samples from 20 CD patients in remission, of which 10 patients received thiopurine treatment, compared to 16 healthy controls, before and after TLR4 stimulation with LPS. Several immune abnormalities were observed, including increased baseline interferon activity, while baseline expression of ribosomal genes was reduced. After LPS stimulation, CD patients showed reduced cytokine and chemokine expression. None of these effects were related to treatment. Strikingly, only one highly correlated set of 69 genes was affected by treatment, not influenced by LPS stimulation and consisted of genes reminiscent of effector cytotoxic NK cells. The most reduced cytotoxicity-related gene in CD was the cell surface marker CD160. Concordantly, we could demonstrate an in vivo reduction of circulating CD160(+)CD3(-)CD8(-) cells in CD patients after treatment with thiopurine derivatives in an independent cohort. In conclusion, using genome-wide profiling, we identified a disturbed immune activation status in peripheral blood cells from CD patients and a clear treatment effect of thiopurine derivatives selectively affecting effector cytotoxic CD160-positive cells. Copyright © 2013 Elsevier Ltd. All rights reserved.

Trogocytosis of multiple B-cell surface markers by CD22 targeting with epratuzumab.

PubMed

Rossi, Edmund A; Goldenberg, David M; Michel, Rosana; Rossi, Diane L; Wallace, Daniel J; Chang, Chien-Hsing

2013-10-24

Epratuzumab, a humanized anti-CD22 antibody, is currently in clinical trials of B-cell lymphomas and autoimmune diseases, demonstrating therapeutic activity in non-Hodgkin lymphoma (NHL) and systemic lupus erythematosus (SLE). Thus, epratuzumab offers a promising option for CD22-targeted immunotherapy, yet its mechanism of action remains poorly understood. Here we report for the first time that epratuzumab promptly induces a marked decrease of CD22 (>80%), CD19 (>50%), CD21 (>50%), and CD79b (>30%) on the surface of B cells in peripheral blood mononuclear cells (PBMCs) obtained from normal donors or SLE patients, and of NHL cells (Daudi and Raji) spiked into normal PBMCs. Although some Fc-independent loss of CD22 is expected from internalization by epratuzumab, the concurrent and prominent reduction of CD19, CD21, and CD79b is Fc dependent and results from their transfer from epratuzumab-opsonized B cells to FcγR-expressing monocytes, natural killer cells, and granulocytes via trogocytosis. The findings of reduced levels of CD19 are implicative for the efficacy of epratuzumab in autoimmune diseases because elevated CD19 has been correlated with susceptibility to SLE in animal models as well as in patients. This was confirmed herein by the finding that SLE patients receiving epratuzumab immunotherapy had significantly reduced CD19 compared with treatment-naïve patients.

The CD4+/CD8+ Ratio in Pulmonary Tuberculosis: Systematic and Meta-Analysis Article.

PubMed

Yin, Yongmei; Qin, Jie; Dai, Yaping; Zeng, Fanwei; Pei, Hao; Wang, Jun

2015-02-01

The ratio of CD4+/CD8+ has been used as a clinically index to evaluate patients' immunity. Numerous researchers have studied CD4+/CD8+ ratio in pulmonary tuberculosis (PTB) patients. However, the change of CD4+/CD8+ ratio remains controversial. We present a meta-analysis of 15 case-control studies to identify the change of CD4+/CD8+ ratio in PTB patients. We assessed heterogeneity of effect estimates within each group using I(2) test. Subgroup analysis was performed to explore the potential source of heterogeneity. To investigate further the potential publication bias, we visually examined the funnel plots. For robustness of results, we performed sensitivity analysis by removing studies. Data entry and analyses were carried out with RevMan 5.2 (The Nordic Cochrane Centre). Twelve peripheral blood studies were categorized into two subgroups. Eight studies presented a significant decrease of CD4+/CD8+ ratio in PTB cases compared to healthy subjects (SMD: -0.45; 95% CI -0.65--0.25; I(2) = 7%). Other four studies researched on the newly diagnosed patients presented a more seriously and significantly decrease (SMD: -2.17; 95% CI -2.61--1.74; I(2) = 37%). The pooled analysis of bronchoalveolar lavage fluid (BALF) studies showed a significant increase of CD4+/CD8+ ratio using Flow Cytometry (FCM) (SMD: 4.75; 95% CI 3.44-6.05; I(2) =0%). The present meta-analysis indicated that there was a synthetic evidence for the reduced CD4+/CD8+ ratio in peripheral blood of PTB patients, especially newly diagnosed cases. However, the CD4+/CD8+ ratio in BALF was increased using method of FCM.

CD83 is a new potential biomarker and therapeutic target for Hodgkin lymphoma.

PubMed

Li, Ziduo; Ju, Xinsheng; Lee, Kenneth; Clarke, Candice; Hsu, Jennifer L; Abadir, Edward; Bryant, Christian E; Pears, Suzanne; Sunderland, Neroli; Heffernan, Scott; Hennessy, Annemarie; Lo, Tsun-Ho; Pietersz, Geoffrey A; Kupresanin, Fiona; Fromm, Phillip D; Silveira, Pablo A; Tsonis, Con; Cooper, Wendy A; Cunningham, Ilona; Brown, Christina; Clark, Georgina J; Hart, Derek N J

2018-04-01

Chemotherapy and hematopoietic stem cell transplantation are effective treatments for most Hodgkin lymphoma patients, however there remains a need for better tumor-specific target therapy in Hodgkin lymphoma patients with refractory or relapsed disease. Herein, we demonstrate that membrane CD83 is a diagnostic and therapeutic target, highly expressed in Hodgkin lymphoma cell lines and Hodgkin and Reed-Sternberg cells in 29/35 (82.9%) Hodgkin lymphoma patient lymph node biopsies. CD83 from Hodgkin lymphoma tumor cells was able to trogocytose to surrounding T cells and, interestingly, the trogocytosing CD83 + T cells expressed significantly more programmed death-1 compared to CD83 - T cells. Hodgkin lymphoma tumor cells secreted soluble CD83 that inhibited T-cell proliferation, and anti-CD83 antibody partially reversed the inhibitory effect. High levels of soluble CD83 were detected in Hodgkin lymphoma patient sera, which returned to normal in patients who had good clinical responses to chemotherapy confirmed by positron emission tomography scans. We generated a human anti-human CD83 antibody, 3C12C, and its toxin monomethyl auristatin E conjugate, that killed CD83 positive Hodgkin lymphoma cells but not CD83 negative cells. The 3C12C antibody was tested in dose escalation studies in non-human primates. No toxicity was observed, but there was evidence of CD83 positive target cell depletion. These data establish CD83 as a potential biomarker and therapeutic target in Hodgkin lymphoma. Copyright© 2018 Ferrata Storti Foundation.

Isolation and characterization of circulating tumor cells from human gastric cancer patients.

PubMed

Yuan, Dandan; Chen, Liang; Li, Mingxing; Xia, Hongwei; Zhang, Yuchen; Chen, Tie; Xia, Rui; Tang, Qiulin; Gao, Fabao; Mo, Xianming; Liu, Ming; Bi, Feng

2015-04-01

Circulating tumor cells (CTCs) have been proved to be responsible for tumor metastasis and resistant to anticancer therapies. This study aims to isolate and characterize circulating tumor cells from human gastric cancer patients, and investigate characteristic differences between gastric CTCs and gastric cancer cell lines. We analyzed 31 cases of gastric cancer patients using anti-CD45 antibody-conjugated magnetic microbeads negative separation, combined with fluorescence activated cell sorter CD44 positive screening. Abilities of tumor formation, metastasis, invasion, migration, irradiation and drug sensitivity of CTCs and gastric cancer cell lines were detected and compared. Of all the 31 patients, CD44(+)/CD45(-)CTCs were isolated in 14 patients, of which 3 cases were stage IIA, 2 cases stage IIB, 2 cases stage IIIC and 7 cases stage IV. The malignant behavior was demonstrated by both clonogenetic assay and tumor xenograft in nude mice. Compared with human gastric cancer cell lines, the migration and invasion abilities of CTCs increased to 3.21-12.6-fold and 2.3-6.7-fold, respectively (all p values <0.05). In addition, the metastatic potential of CTCs is much higher in vivo than that of the control. Furthermore, CTCs were found to be relatively sensitive to FU, cisplatin and paclitaxel, but relatively resistant to irradiation, oxaliplatin, cetuximab and trastuzumab. CD44(+)/CD45(-) gastric CTCs were isolated and found to exhibit stronger malignant behavior when compared with human gastric cancer cell lines. Furthermore, CTCs cultured in vitro have potential implications in drug sensitivity screening for the future anticancer treatments.

Intraepithelial lymphocyte eotaxin-2 expression and perineural mast cell degranulation differentiate allergic/eosinophilic colitis from classic IBD.

PubMed

Torrente, Franco; Barabino, Arrigo; Bellini, Tommaso; Murch, Simon H

2014-09-01

Allergic colitis shows overlap with classic inflammatory bowel disease (IBD). Clinically, allergic colitis is associated with dysmotility and abdominal pain, and mucosal eosinophilia is characteristic. We thus aimed to characterise mucosal changes in children with allergic colitis compared with normal tissue and classic IBD, focusing on potential interaction between eosinophils and mast cells with enteric neurones. A total of 15 children with allergic colitis, 10 with Crohn disease (CD), 10 with ulcerative colitis (UC), and 10 histologically normal controls were studied. Mucosal biopsies were stained for CD3 T cells, Ki-67, eotaxin-1, and eotaxin-2. Eotaxin-2, IgE, and tryptase were localised compared with mucosal nerves, using neuronal markers neurofilament protein, neuron-specific enolase, and nerve growth factor receptor. Overall inflammation was greater in patients with CD and UC than in patients with allergic colitis. CD3 T-cell density was increased in patients with allergic colitis, similar to that in patients with CD but lower than in patients with UC, whereas eosinophil density was higher than in all other groups. Eotaxin-1 and -2 were localised to basolateral crypt epithelium in all specimens, with eotaxin-1+ lamina propria cells found in all of the colitis groups. Eotaxin-2+ intraepithelial lymphocyte (IEL) density was significantly higher in allergic colitis specimens than in all other groups. Mast cell degranulation was strikingly increased in patients with allergic colitis (12/15) compared with that in patients with UC (1/10) and CD (0/1). Tryptase and IgE colocalised on enteric neurons in patients with allergic colitis but rarely in patients with IBD. Eotaxin-2+ IELs may contribute to the periepithelial eosinophil accumulation characteristic of allergic colitis. The colocalisation of IgE and tryptase with mucosal enteric nerves is likely to promote the dysmotility and visceral hyperalgesia classically seen in allergic gastrointestinal inflammation.

Atrial Electromechanical Properties in Coeliac Disease.

PubMed

Efe, Tolga Han; Ertem, Ahmet Goktug; Coskun, Yusuf; Bilgin, Murat; Algul, Engin; Beton, Osman; Asarcikli, Lale Dinc; Erat, Mehmet; Ayturk, Mehmet; Yuksel, Ilhami; Yeter, Ekrem

2016-02-01

Coeliac disease (CD) is an autoimmune and inflammatory disorder of the small intestine. There is reasonable evidence linking inflammation to the initiation and continuation of atrial fibrillation (AF) in inflammatory conditions. Atrial electro-mechanic delay (EMD) was suggested as an early marker of AF in previous studies. The objectives of this study were to evaluate atrial electromechanical properties measured by tissue Doppler imaging and simultaneous electrocardiography (ECG) tracing in patients with CD. Thirty-nine patients with coeliac disease (CD), and 26 healthy volunteers, matched for age and sex, were enrolled in the study. Atrial electromechanical properties were measured by using transthoracic echocardiography and surface ECG. Interatrial electro-mechanic delay (EMD), left intraatrial EMD, right intratrial EMD were calculated. There was no difference between CD patients and healthy volunteers in terms of basal characteristics. Patients with CD had significantly prolonged left and right intraatrial EMDs, and interatrial EMD compared to healthy controls (p= 0.03, p= 0.02, p<0.0001, respectively). Interatrial EMD was positively correlated with age, disease duration, anti-gliadin IgG, anti-endomysium and disease status. In multiple linear regression, interatrial EMD was independently associated with disease duration, anti-endomysium and disease status after adjusting for age and sex. In the present study, atrial EMDs were found significantly higher in patients with CD compared with healthy individuals. Measurement of atrial EMD parameters might be used to predict the risk of development of AF in patients with CD. Copyright © 2015 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier B.V. All rights reserved.

Detection of CD34/CXCR4+ stem cells in peripheral blood of patients following acute myocardial infarction.

PubMed

Abdallah, Khaled Omar; Saleh, Rasha Mamdouh; Al-Shawarby, Laila Abd Al-Aala; Amer, Hanaa Ahmed; Mostafa, Sara

2014-01-01

Bone marrow harbors a population of tissue-committed stem cells that are CD34+/CXCR4+. These potential cardiac progenitors which express cardiac and endothelial markers may contribute to cardiac regeneration. The ability of injured myocardium to recruit extracardiac stem cells after injury would be beneficial to aid in myocardial repair and regeneration. The aim of this study was to answer the question whether acute myocardial infarction (AMI) related stress may trigger the increase of CD34/CXCR4+ stem cells number in peripheral blood in response to myocardial ischemic injury which might be accompanied with increased release of this population of stem cells in peripheral blood as well as to correlate this phenomenon with other clinical and laboratory parameters such as diabetes, chest pain, smoking, streptokinase administration and elevated cardiac enzymes. The study was conducted on 25 newly diagnosed AMI patients who attended the emergency department of National Heart Institute. They were compared to a control group of 25 apparently healthy sex and age matched individuals. The percentage of CD34+ cells as well as percentage of cells coexpressing CD34/CXCR4+ and their expression intensity were assessed by Flowcytometery. These parameters were correlated to other laboratory and clinical data. The absolute CD34+ as well as the CD34/CXCR4+ cell counts were significantly higher in patients upon admission in comparison to control group (P < 0.01). While CD34 expression was significantly higher in patients compared to control group, CXCR4 expression on CD34+ cells was significantly lower in patients than control group (P < 0.05). Diabetes, duration of chest pain and streptokinase administration had no significant effect on CD34/CXCR4+ number or the expression intensity of both markers (p > 0.05). Otherwise, CXCR4 intensity was lower in non-smoker than smoker patients (P < 0.05). Patients admitted with normal cardiac enzymes, including Creatine Kinase (CK) and Creatine Kinase MB fraction (CK-MB) activity, showed no significant difference in CD34/CXCR4+ number or the expression intensity of CD34 marker in comparison to those admitted with high levels of enzymes (P > 0.05). However, the expression intensity of CXCR4 was significantly low in patients admitted with elevated cardiac enzymes (P < 0.05). In conclusion, there is a pool of CD34/CXCR4+ stem cells circulating in large number in peripheral blood of AMI patients post infarction together with low CXCR4 expression on these cells which are likely to contribute to myocardial repair following the acute ischemic injury.

Synergistic immunosuppression by candida in HIV infection: a cytokine based analysis.

PubMed

Bajaj, J S; Singh, A; Aggarwal, S K; Chattopadhya, D; Baveja, U K

2000-03-01

Candida is a common opportunistic pathogen in HIV infection and is regarded a signal infection for progression to AIDS. Cytokine imbalances between Th1/Th2 groups have been described in both candida and HIV infections. A study was undertaken to assess the role of candida in furthering immunosuppression in HIV infection based on cytokine levels and CD4 cell counts. 30 Indian subjects were enrolled; 10 HIV positive patients with and 10 without mucosal candidiasis and 10 age matched controls. Th1 cytokines; interleukin (IL) 2, IL 12 and interferon (IFN) gamma, Th2 cytokines; IL 4, IL 6, IL 10 and tumor necrosis factor (TNF) alpha with CD 4 cell counts were estimated using ELISA in all subjects. CD4 cell counts were reduced in both patient groups as compared to controls; significantly more in patients with both HIV and candida infections. There was a decrease in Th1 cytokine levels in all patients; lower levels of Th1 cytokines were seen in patients with both infections. Among the Th2 cytokines, there was a significant increase in the levels of IL 6, IL 10 and TNF alpha in both patient groups; IL 10 and TNF alpha values were significantly raised in patients with dual HIV and candida infections as compared to the other patients. There was no difference in IL 4 values across the subject groups. A positive correlation between CD4 cell counts and Th1 cytokine levels and a negative correlation with Th2 cytokines were noted; these were stronger in patients with both HIV and candidiasis. Thus, there was a Th1/Th2 cytokine imbalance with CD4 cell count reduction in all HIV infected patients, which was more pronounced in patients with both infections. It can be concluded that, owing to the depressed CD4 cell count and Th1 response and increased Th2 cytokines in patients with both candidiasis and HIV as compared to patients with only HIV candidiasis may have a synergistic immunosuppressive effect with HIV in patients with dual infections.

Impact of benznidazole treatment on the functional response of Trypanosoma cruzi antigen-specific CD4+CD8+ T cells in chronic Chagas disease patients.

PubMed

Pérez-Antón, Elena; Egui, Adriana; Thomas, M Carmen; Puerta, Concepción J; González, John Mario; Cuéllar, Adriana; Segovia, Manuel; López, Manuel Carlos

2018-05-11

Chagas disease is caused by Trypanosoma cruzi. The persistence of the parasite is associated with the disease chronicity and the impairment of the cellular immune response. It has been reported that the CD4+CD8+ T cell population expands in chronic Chagas disease patients. Few studies have focused on this subset of cells, and very little is known about the impact of antiparasitic treatment on this population. Thirty-eight chronic Chagas disease patients (20 asymptomatic and 18 symptomatic) and twelve healthy controls were enrolled in this study. Peripheral blood mononuclear cells were stimulated with soluble T. cruzi antigens to analyze the production of cytokines and cytotoxic molecules by CD4+CD8+ T cells before and after benznidazole treatment. Additionally, expression and co-expression of five inhibitory receptors in these patients after treatment were studied using a multiparameter flow cytometry technique. The frequency of CD4+CD8+ T cells was higher in chronic Chagas disease patients compared with healthy donors. Furthermore, a higher ratio of CD4+CD8low/CD4+CD8high subpopulations was observed in chronic Chagas disease patients than in healthy donors. Additionally, CD4+CD8+ T cells from these patients expressed and co-expressed higher levels of inhibitory receptors in direct proportion to the severity of the pathology. Benznidazole treatment reduced the frequency of CD4+CD8+ T cells and decreased the ratio of CD4+CD8low/CD4+CD8high subpopulations. The co-expression level of the inhibitory receptor was reduced after treatment simultaneously with the enhancement of the multifunctional capacity of CD4+CD8+ T cells. After treatment, an increase in the frequency of T. cruzi antigen-specific CD4+CD8+ T cells expressing IL-2 and TNF-α was also observed. CD4+CD8+ T cells could play an important role in the control of T. cruzi infection since they were able to produce effector molecules for parasite control. Benznidazole treatment partially reversed the exhaustion process caused by T. cruzi infection in these cells with an improvement in the functional response of the T. cruzi antigen-specific CD4+CD8+ T cells.

Impact of benznidazole treatment on the functional response of Trypanosoma cruzi antigen-specific CD4+CD8+ T cells in chronic Chagas disease patients

PubMed Central

Pérez-Antón, Elena; Egui, Adriana; Thomas, M. Carmen; Puerta, Concepción J.; González, John Mario; Cuéllar, Adriana; Segovia, Manuel

2018-01-01

Background Chagas disease is caused by Trypanosoma cruzi. The persistence of the parasite is associated with the disease chronicity and the impairment of the cellular immune response. It has been reported that the CD4+CD8+ T cell population expands in chronic Chagas disease patients. Few studies have focused on this subset of cells, and very little is known about the impact of antiparasitic treatment on this population. Methodology Thirty-eight chronic Chagas disease patients (20 asymptomatic and 18 symptomatic) and twelve healthy controls were enrolled in this study. Peripheral blood mononuclear cells were stimulated with soluble T. cruzi antigens to analyze the production of cytokines and cytotoxic molecules by CD4+CD8+ T cells before and after benznidazole treatment. Additionally, expression and co-expression of five inhibitory receptors in these patients after treatment were studied using a multiparameter flow cytometry technique. Principal findings The frequency of CD4+CD8+ T cells was higher in chronic Chagas disease patients compared with healthy donors. Furthermore, a higher ratio of CD4+CD8low/CD4+CD8high subpopulations was observed in chronic Chagas disease patients than in healthy donors. Additionally, CD4+CD8+ T cells from these patients expressed and co-expressed higher levels of inhibitory receptors in direct proportion to the severity of the pathology. Benznidazole treatment reduced the frequency of CD4+CD8+ T cells and decreased the ratio of CD4+CD8low/CD4+CD8high subpopulations. The co-expression level of the inhibitory receptor was reduced after treatment simultaneously with the enhancement of the multifunctional capacity of CD4+CD8+ T cells. After treatment, an increase in the frequency of T. cruzi antigen-specific CD4+CD8+ T cells expressing IL-2 and TNF-α was also observed. Conclusions CD4+CD8+ T cells could play an important role in the control of T. cruzi infection since they were able to produce effector molecules for parasite control. Benznidazole treatment partially reversed the exhaustion process caused by T. cruzi infection in these cells with an improvement in the functional response of the T. cruzi antigen-specific CD4+CD8+ T cells. PMID:29750791

Does preoperative enteral or parenteral nutrition reduce postoperative complications in Crohn's disease patients: a meta-analysis.

PubMed

Brennan, Gregory T; Ha, Iris; Hogan, Christopher; Nguyen, Emily; Jamal, M M; Bechtold, Matthew L; Nguyen, Douglas L

2018-05-07

Crohn's disease (CD) patients frequently develop complications that require surgery for management. The high prevalence of malnutrition in CD patients presents a challenge because poor preoperative nutritional status has been shown to increase postoperative complications. In this study, we assessed whether preoperative enteral nutrition (EN) or total parenteral nutrition (TPN) decreases postoperative complications in CD patients. A three-point systematic and comprehensive literature search was carried out on multiple databases followed by a meta-analysis with results presented as odds ratio (OR) using two models, the Mantel-Haenszel model and the DerSimonian and Laird model. The I measure of inconsistency was utilized to assess heterogeneity. If statistically significant heterogeneity was identified, the results underwent a separate sensitivity analysis. Five studies met inclusion criteria totaling 1111 CD patients. The rate of postoperative complications in the group receiving preoperative nutrition (EN or TPN) support was 20.0% compared with 61.3% in the group who had standard care without nutrition support [OR=0.26, 95% confidence interval (CI): 0.07-0.99, P<0.001]. Postoperative complications occurred in 15.0% of patients in the group who received preoperative TPN compared with 24.4% in the group who did not (OR=0.65, 95% CI: 0.23-1.88, P=0.43). Postoperative complications occurred in 21.9% in the group who received preoperative EN compared with 73.2% in the group that did not received preoperative EN (OR=0.09, 95% CI: 0.06-0.13, P<0.001). Preoperative nutrition supplementation reduces postoperative complications in CD patients. In particular, EN in CD patients before undergoing surgery is superior to standard of care without nutrition support with a number needed to treat of 2. There is a trend toward TPN being superior to standard of care without nutrition support, but this trend did not reach statistical significance. Further studies are necessary to evaluate specific components in EN or TPN that may be most beneficial for CD patients requiring surgical intervention.

Increased Protease-Activated Receptor-2 (PAR-2) Expression on CD14++CD16+ Peripheral Blood Monocytes of Patients with Severe Asthma

PubMed Central

Shrestha Palikhe, Nami; Nahirney, Drew; Laratta, Cheryl; Gandhi, Vivek Dipak; Vethanayagam, Dilini; Bhutani, Mohit; Mayers, Irvin

2015-01-01

Background Protease-Activated Receptor-2 (PAR-2), a G protein coupled receptor activated by serine proteases, is widely expressed in humans and is involved in inflammation. PAR-2 activation in the airways plays an important role in the development of allergic airway inflammation. PAR-2 expression is known to be upregulated in the epithelium of asthmatic subjects, but its expression on immune and inflammatory cells in patients with asthma has not been studied. Methods We recruited 12 severe and 24 mild/moderate asthmatics from the University of Alberta Hospital Asthma Clinics and collected baseline demographic information, medication use and parameters of asthma severity. PAR-2 expression on blood inflammatory cells was analyzed by flow cytometry. Results Subjects with severe asthma had higher PAR-2 expression on CD14++CD16+ monocytes (intermediate monocytes) and also higher percentage of CD14++CD16+PAR-2+ monocytes (intermediate monocytes expressing PAR-2) in blood compared to subjects with mild/moderate asthma. Receiver operating characteristics (ROC) curve analysis showed that the percent of CD14++CD16+PAR-2+ in peripheral blood was able to discriminate between patients with severe and those with mild/moderate asthma with high sensitivity and specificity. In addition, among the whole populations, subjects with a history of asthma exacerbations over the last year had higher percent of CD14++CD16+ PAR-2+ cells in peripheral blood compared to subjects without exacerbations. Conclusions PAR-2 expression is increased on CD14++CD16+ monocytes in the peripheral blood of subjects with severe asthma and may be a biomarker of asthma severity. Our data suggest that PAR-2 -mediated activation of CD14++CD16+ monocytes may play a role in the pathogenesis of severe asthma. PMID:26658828

Increased Protease-Activated Receptor-2 (PAR-2) Expression on CD14++CD16+ Peripheral Blood Monocytes of Patients with Severe Asthma.

PubMed

Shrestha Palikhe, Nami; Nahirney, Drew; Laratta, Cheryl; Gandhi, Vivek Dipak; Vethanayagam, Dilini; Bhutani, Mohit; Mayers, Irvin; Cameron, Lisa; Vliagoftis, Harissios

2015-01-01

Protease-Activated Receptor-2 (PAR-2), a G protein coupled receptor activated by serine proteases, is widely expressed in humans and is involved in inflammation. PAR-2 activation in the airways plays an important role in the development of allergic airway inflammation. PAR-2 expression is known to be upregulated in the epithelium of asthmatic subjects, but its expression on immune and inflammatory cells in patients with asthma has not been studied. We recruited 12 severe and 24 mild/moderate asthmatics from the University of Alberta Hospital Asthma Clinics and collected baseline demographic information, medication use and parameters of asthma severity. PAR-2 expression on blood inflammatory cells was analyzed by flow cytometry. Subjects with severe asthma had higher PAR-2 expression on CD14++CD16+ monocytes (intermediate monocytes) and also higher percentage of CD14++CD16+PAR-2+ monocytes (intermediate monocytes expressing PAR-2) in blood compared to subjects with mild/moderate asthma. Receiver operating characteristics (ROC) curve analysis showed that the percent of CD14++CD16+PAR-2+ in peripheral blood was able to discriminate between patients with severe and those with mild/moderate asthma with high sensitivity and specificity. In addition, among the whole populations, subjects with a history of asthma exacerbations over the last year had higher percent of CD14++CD16+ PAR-2+ cells in peripheral blood compared to subjects without exacerbations. PAR-2 expression is increased on CD14++CD16+ monocytes in the peripheral blood of subjects with severe asthma and may be a biomarker of asthma severity. Our data suggest that PAR-2 -mediated activation of CD14++CD16+ monocytes may play a role in the pathogenesis of severe asthma.

Evaluation of serum levels of tumour necrosis factor-alpha (TNF-alpha) and soluble IL-2 receptor (sIL-2R) and CD4, CD8 and natural killer (NK) populations during infrared pulsed laser device (IPLD) treatment.

PubMed Central

Santana-Blank, L A; Castes, M; Rojas, M E; Vargas, F; Scott-Algara, D

1992-01-01

The purpose of this study was to evaluate serum levels of TNF-alpha, sIL-2R and distribution of peripheral leucocyte subsets in patients with advanced neoplastic disease undergoing IPLD treatment. Fifteen cancer patients with evidence of persistent disease were further divided in two groups according to outcome at the end of the period of clinical evaluation: group 1 patients were still alive and group 2 patients had died. Our results show: (i) an increase in the initial level of TNF-alpha in both groups; (ii) a decrease in TNF-alpha levels during the follow up of group 1 patients; (iii) a significant increase in serum levels of sIL-2R in patients in group 2 compared with those in group 1; (iv) a progressive and constant increase in TNF-alpha levels in group 2; (v) a decrease in CD4+CD45RA+ subpopulation in both groups; (vi) an increase in CD25+ cells; (vii) an increase in CD4+, CD4+CD45RA+ and CD25+ cells during the follow up of group 2 patients. The data generated here form the basis for further investigations on the use of IPLD as a single agent and in combination with other biological response modifiers in cancer patients. PMID:1395099

CD16-positive circulating monocytes and fibrotic manifestations of systemic sclerosis.

PubMed

Lescoat, Alain; Lecureur, Valérie; Roussel, Mikael; Sunnaram, Béatrice Ly; Ballerie, Alice; Coiffier, Guillaume; Jouneau, Stéphane; Fardel, Olivier; Fest, Thierry; Jégo, Patrick

2017-07-01

The objective of this study is to assess the association of clinical manifestations of systemic sclerosis (SSc) with the absolute count of circulating blood monocyte subpopulations according to their membrane expression of CD16. Forty-eight consecutive patients fulfilling the 2013 ACR/EULAR classification criteria for SSc were included in this cross-sectional study. CD16+ monocyte absolute count was defined by flow cytometry and confronted to the clinical characteristics of SSc patients. Twenty-three healthy donors (HD) were randomly selected for comparison. SSc patients had an increased number of total circulating blood monocytes compared to HD (p < 0.001). The CD16- subpopulation absolute count was increased in SSc patients compared to HD (p < 0.001) but was similar in limited SSc (lSSc) and diffuse SSc (dSSc). On the contrary, the CD16+ population absolute count was increased in dSSc compared to both HD and lSSc patients (dSSc 0.071 Giga/L (±0.034) vs HD 0.039 Giga/L (±0.030), p < 0.01, and dSSc 0.071 Giga/L (±0.034) vs lSSc 0.048 Giga/L (±0.024), p < 0.05). The CD16+ monocyte subpopulation absolute count was significantly correlated with the severity of skin fibrosis evaluated by the modified Rodnan skin score (p < 0.001). The CD16+ monocyte subpopulation was also associated with pulmonary fibrosis (p < 0.05), with the severity of the restrictive ventilatory defect evaluated by total lung capacity (p < 0.05) and with the pulmonary function impairment reflected by diffusing capacity of the lungs for carbon monoxyde measures (p < 0.01). These results suggest that CD16+ monocytes are associated with the main fibrotic manifestations of SSc and their role in the pathogenesis of fibrosis in this autoimmune disorder should therefore be further considered.

Increased prevalence of psychopathology and maladaptive personality traits after long-term cure of Cushing's disease.

PubMed

Tiemensma, Jitske; Biermasz, Nienke R; Middelkoop, Huub A M; van der Mast, Roos C; Romijn, Johannes A; Pereira, Alberto M

2010-10-01

Psychopathology and maladaptive personality traits are often observed during the active phase of Cushing's disease (CD). We hypothesized that patients with long-term cure of CD show persistent psychopathology and maladaptive personality traits. Four questionnaires on frequently occurring psychopathology in somatic illnesses were used, including the Apathy Scale, Irritability Scale, Hospital Anxiety and Depression Scale, and Mood and Anxiety Symptoms Questionnaire short-form. Personality was assessed using the Dimensional Assessment of Personality Pathology short-form (DAPPs). We included 51 patients cured of CD (16% men, 53 ± 13 yr) and 51 matched controls. In addition, we included 55 patients treated for nonfunctioning pituitary macroadenomas (55% men, 62 ± 10 yr), and 55 matched controls. Mean duration of remission was 11 yr (range 1-32 yr). Compared with matched controls, patients cured from CD scored significantly worse on virtually all questionnaires. Compared with nonfunctioning pituitary macroadenoma patients, patients treated for CD scored worse on apathy (P < 0.001), irritability (P < 0.001), anxiety (P < 0.001), negative affect and lack of positive affect (P < 0.001 on both scales), somatic arousal (P < 0.001), and 11 of 18 subscales of the Dimensional Assessment of Personality Pathology short-form (P < 0.05). Patients with long-term cured CD show an increased prevalence of psychopathology and maladaptive personality traits. These observations suggest irreversible effects of previous glucocorticoid excess on the central nervous system rather than an effect of pituitary tumors and/or their treatment in general. This may also be of relevance for patients treated with high doses of exogenous glucocorticoids.

The Clinical Correlation of Regulatory T Cells and Cyclic Adenosine Monophosphate in Enterovirus 71 Infection

PubMed Central

Wang, Shih-Min; Chen, I-Chun; Liao, Yu-Ting; Liu, Ching-Chuan

2014-01-01

Background Brainstem encephalitis (BE) and pulmonary edema (PE) are notable complications of enterovirus 71 (EV71) infection. Objective This study investigated the immunoregulatory characterizations of EV71 neurological complications by disease severity and milrinone treatment. Study Design Patients <18 years with virologically confirmed EV71 infections were enrolled and divided into 2 groups: the hand, foot, and mouth disease (HFMD) or BE group, and the autonomic nervous system (ANS) dysregulation or PE group. Cytokine and cyclic adenosine monophosphate (cAMP) levels, and the regulatory T cell (Tregs) profiles of the patients were determined. Results Patients with ANS dysregulation or PE exhibited significantly low frequency of CD4+CD25+Foxp3+ and CD4+Foxp3+ T cells compared with patients with HFMD or BE. The expression frequency of CD4−CD8− was also significantly decreased in patients with ANS dysregulation or PE. Among patients with ANS dysregulation or PE, the expression frequency of CD4+Foxp3+ increased markedly after milrinone treatment, and was associated with reduction of plasma levels IL-6, IL-8 and IL-10. Plasma concentrations of cAMP were significantly decreased in patients with ANS dysregulation or PE compared with patients with HFMD or BE; however, cAMP levels increased after milrinone treatment. Conclusions These findings suggested decreased different regulatory T populations and cAMP expression correlate with increased EV71 disease severity. Improved outcome after milrinone treatment may associate with increased regulatory T populations, cAMP expression and modulation of cytokines levels. PMID:25010330

Evaluation of depression, quality of life and body image in patients with Cushing's disease.

PubMed

Alcalar, Nilufer; Ozkan, Sedat; Kadioglu, Pinar; Celik, Ozlem; Cagatay, Penbe; Kucukyuruk, Baris; Gazioglu, Nurperi

2013-09-01

The aim of this study was to evaluate patients with Cushing's disease (CD) who had undergone transsphenoidal surgery in terms of depression, quality of life (QoL), and perception of body image in comparison to healthy controls. Forty patients with CD and 40 healthy controls matched for demographic characteristics were included in the study. The subjects were evaluated with the Beck depression inventory (BDI), the health survey-short form (SF-36) and the multidimensional body-self relations questionnaire (MBSRQ). Subgroups of the patients with CD were formed on the basis of remission status and BDI scores. In this study, QoL in the general health category and body image were lower in the patients with CD than in the healthy subjects. However, no differences in depression scores were found between the two groups. When the CD group was evaluated according to remission rate, the mean BDI score was significantly higher in the CD patients without remission than in both the CD patients with remission and the healthy subjects (p = 0.04). However, the physical functioning, bodily pain and general health scores of the CD patients without remission on the SF-36 questionnaire were lower than in the CD patients in remission and the healthy subjects (p = 0.002, p = 0.04, p = 0.002, respectively). Fitness evaluation, health evaluation and body areas satisfaction scores of the MBSRQ were significantly different in the three groups (p = 0.003, p = 0.009 and p = 0.001, respectively). In this study, patients with CD were found to have lower QoL, lower body image perception and higher levels of depression compared to healthy controls, particularly if the disease is persistant despite surgery.

Diagnostic and prognostic value of sCD14-ST--presepsin for patients admitted to hospital intensive care unit (ICU).

PubMed

Godnic, Matej; Stubljar, David; Stubjar, David; Skvarc, Miha; Jukic, Tomislav

2015-07-01

Sepsis is a serious problem in intensive care units all over the world. Biomarkers could be useful to identify patients at risk. We focused especially on the performance of presepsin (sCD14-ST), compared to C-reactive protein (CRP), procalcitonin (PCT) and CD64, to determine its diagnostic and prognostic indications. The study was conducted on 47 hospitalized patients after procedures, who were divided into three groups; systemic inflammatory response (SIRS), sepsis and septic shock. Expression of CD64 on neutrophils presented as CD64 index, sCD14-ST, CRP and PCT were measured in whole blood or plasma samples. All patients had standard samples like urine, respiratory tract samples etc. taken for culturing. Blood cultures were drawn to confirm bloodstream infection. Forty (85 %) patients had SIRS with bacterial infection and seven (15 %) patients had SIRS with no infection. All infections were confirmed with blood cultures. Biomarkers were evaluated in all patients. In patients with confirmed infection the values were high. The patients with bacterial infection showed statistical significance with CD64 index (p = 0.003), CRP (p = 0.049) and sCD14-ST (p = 0.026), but not with PCT (p = 1.000). The severity of diagnosed SIRS was significant only with PCT (p < 0.001). CD64 index, CRP and sCD14-ST served as good parameters to determine possible infection in patients that needed intensive care after major procedures. Values of PCT were the only ones to predict SIRS severity and could distinguish between sepsis and severe sepsis or septic shock.

Increase in TGF-β Secreting CD4+CD25+ FOXP3+ T Regulatory Cells in Anergic Lepromatous Leprosy Patients

PubMed Central

Saini, Chaman; Ramesh, Venkatesh; Nath, Indira

2014-01-01

Background Lepromatous leprosy caused by Mycobacterium leprae is associated with antigen specific T cell unresponsiveness/anergy whose underlying mechanisms are not fully defined. We investigated the role of CD25+FOXP3+ regulatory T cells in both skin lesions and M.leprae stimulated PBMC cultures of 28 each of freshly diagnosed patients with borderline tuberculoid (BT) and lepromatous leprosy (LL) as well as 7 healthy household contacts of leprosy patients and 4 normal skin samples. Methodology/Principle Findings Quantitative reverse transcribed PCR (qPCR), immuno-histochemistry/flowcytometry and ELISA were used respectively for gene expression, phenotype characterization and cytokine levels in PBMC culture supernatants. Both skin lesions as well as in vitro antigen stimulated PBMC showed increased percentage/mean fluorescence intensity of cells and higher gene expression for FOXP3+, TGF-β in lepromatous (p<0.01) as compared to tuberculoid leprosy patients. CD4+CD25+FOXP3+ T cells (Tregs) were increased in unstimulated basal cultures (p<0.0003) and showed further increase in in vitro antigen but not mitogen (phytohemaglutinin) stimulated PBMC (iTreg) in lepromatous as compared to tuberculoid leprosy patients (p<0.002). iTregs of lepromatous patients showed intracellular TGF-β which was further confirmed by increase in TGF-β in culture supernatants (p<0.003). Furthermore, TGF-β in iTreg cells was associated with phosphorylation of STAT5A. TGF-β was seen in CD25+ cells of the CD4+ but not that of CD8+ T cell lineage in leprosy patients. iTregs did not show intracellular IFN-γ or IL-17 in lepromatous leprosy patients. Conclusions/Significance Our results indicate that FOXP3+ iTregs with TGF-β may down regulate T cell responses leading to the antigen specific anergy associated with lepromatous leprosy. PMID:24454972

CD81 expression on CD19+ peripheral blood lymphocytes is associated with chronic HCV disease and increased risk for HCV infection: a putative role for inflammatory cytokines.

PubMed

D'Agosto, G; Trento, E; Nosotti, L; Bordignon, V; Battista, M; Prignano, G; Pimpinelli, F; Biolcati, G; Macrì, A; Palamara, G; Miglioresi, L; Morrone, A; Di Carlo, A; Cordiali-Fei, P; Ensoli, F

2009-01-01

The level of CD81 cell surface expression, a cellular co-receptor for hepatitis C virus (HCV), is critical for productive HCV infection of host cells. In addition, the cross-linking of HCV-E2 protein to CD81 can alter the function of T and B lymphocytes as well as that of NK cells by interfering with the activation signalling pathway. The down-regulation of CD81 expression on peripheral blood lymphocytes (PBL) has been associated to effective therapy of HCV infection. The aim of the present study is to quantitatively assess the levels of CD81 expression in PBL from HCV-infected patients compared to subjects at high risk for HCV infection such as HIV-infected individuals or patients with Porphyria Cutanea Tarda (PCT). The expression of CD81 was quantified by flow-cytometry using Phycoerythrin-labelled standard beads. Determination of CD81 was performed on CD3+ and CD19+ lymphocytes from 34 healthy controls, 51 patients with HCV infection and different clinical outcomes [these included HCV-RNA-negative subjects (8), patients with chronic active hepatitis (16), recipients of liver transplantation under immunosuppressive therapy (12), a subgroup with concomitant HIV infection (9) or concomitant PCT (6)]. In addition, 60 HIV-infected subjects and 4 patients with PCT were studied. The putative role of inflammatory cytokines in modulating CD81 was explored in vitro by assessing the effect of IL-6 or IFN-gamma on cultured human hepatocytes. A significant increase of the CD81 expression was found on CD19+ lymphocytes in association with either HIV or HCV infection, as compared to the control group. Immunosuppressive therapy with FK506, subsequent to liver transplantation, restored CD81 expression at normal levels. Data gathered in vitro using the WRL 68 hepatocytic cell line confirmed that inflammatory cytokines can up-regulate CD81 expression in liver cell inclusion. Our data suggest that CD81 up-regulation can increase the risk of HCV infection, particularly in HIV-infected subjects. In addition, the results strongly suggest that the cytokines released by activated lymphocytes at sites of inflammation may play a part in up-regulating CD81 expression.

CD19(+)CD21(low) B cells and patients at risk for NIH-defined chronic graft-versus-host disease with bronchiolitis obliterans syndrome.

PubMed

Kuzmina, Zoya; Krenn, Katharina; Petkov, Ventzislav; Körmöczi, Ulrike; Weigl, Roman; Rottal, Arno; Kalhs, Peter; Mitterbauer, Margit; Ponhold, Lothar; Dekan, Gerhard; Greinix, Hildegard T; Pickl, Winfried F

2013-03-07

Bronchiolitis obliterans syndrome (BOS), pathognomonic for chronic graft-versus-host disease (cGVHD) of the lung, is a progressive and often fatal complication after allogeneic hematopoietic cell transplantation (HCT). Biomarkers for the prediction and diagnosis of BOS are urgently needed to improve patients' prognosis. We prospectively evaluated B-cell subpopulations and B-cell activating factor (BAFF) in 136 patients (46 BOS, 41 no cGVHD, 49 cutaneous cGVHD) to define novel biomarkers for early diagnosis of National Institutes of Health-defined BOS diagnosed a median of 11 mo after HCT. Patients with newly diagnosed BOS had significantly higher percentages of CD19(+)CD21(low) B cells (25.5 versus 6.6%, P < .0001), BAFF (7.3 versus 3.5 ng/mL, P = .02), and BAFF/CD19(+) ratio (0.18 versus 0.02 ng/10(3) CD19(+) B cells, P 5 .007) compared with patients without cGVHD. The area under the receiver operating curve for CD19(+)CD21(low) B cells was 0.97 (95% confidence interval, 0.94-0.99) and a cutoff point >9% was optimal for diagnosing BOS in patients with first drop of pulmonary function tests with a sensitivity of 96% and a negative predictive value of 94%. Thus, elevated levels of CD19(+)CD21(low) B cells are a potential novel biomarker for HCT patients at risk for developing BOS at an early stage and could allow improvement of patient outcome.

Distinctive CD8+ T cell and MHC class I signatures in polycythemia vera patients.

PubMed

Cardoso, Elsa M; Esgalhado, André J; Patrão, Luís; Santos, Mónica; Neves, Vasco Pinto; Martinez, Jorge; Patto, Maria Assunção Vaz; Silva, Helena; Arosa, Fernando A

2018-05-22

Polycythemia vera (PV) is a myeloproliferative neoplasm characterized by overproduction of red blood cells. We have performed a comprehensive characterization of blood immune cells for expression of naïve and memory receptors as well as β 2 m-associated and β 2 m-free MHC class I heavy chains, also known as closed and open conformers, respectively, in PV patients and age-matched controls (CTR). We show that the peripheral CD3 + CD8 + T cell pool in PV patients is clearly divided into two discrete populations, a more granular CD3 + CD8 high T cell population enriched in effector-memory CD45RA + T cells (CD8 + TEMRA) when compared to CTR (P < 0.001), and a less granular CD3 + CD8 int T cell population that is completely absent in the CTR group (78 vs. 0%, P < 0.001) and is a mixture of naïve (CD8 + T N ) and CD8 + TEMRA cells expressing intermediate levels of CD28, i.e., CD3 + CD8 int CD28 int . While the percentage of CD3 + CD8 int TN cells correlated positively with the number of erythrocytes, the percentage of CD3 + CD8 int TEMRA correlated negatively with the number of platelets. Finally, we report that PV patients' lymphocytes and monocytes display lower levels of closed (W6/32 + ) MHC-I conformers at the cell surface while exhibiting increased amounts of open (HC-10 + ) MHC-I conformers. The implications of this distinctive immune signature are discussed.

Effect of liniment levamisole on cellular immune functions of patients with chronic hepatitis B

PubMed Central

Wang, Ke-Xia; Zhang, Li-Hua; Peng, Jiang-Long; Liang, Yong; Wang, Xue-Feng; Zhi, Hui; Wang, Xiang-Xia; Geng, Huan-Xiong

2005-01-01

AIM: To explore the effects of liniment levamisole on cellular immune functions of patients with chronic hepatitis B. METHODS: The levels of T lymphocyte subsets and mIL-2R in peripheral blood mononuclear cells (PBMCs) were measured by biotin-streptavidin (BSA) technique in patients with chronic hepatitis B before and after the treatment with liniment levamisole. RESULTS: After one course of treatment with liniment levamisole, the levels of CD3+, CD4+, and the ratio of CD4+/CD8+ increased as compared to those before the treatment but the level of CD8+ decreased. The total expression level of mIL-2R in PBMCs increased before and after the treatment with liniment levamisole. CONCLUSION: Liniment levamisole may reinforce cellular immune functions of patients with chronic hepatitis B. PMID:16437674

Increased percentages of PD-1 on CD4+ T cells is associated with higher INF-γ production and altered IL-17 production in patients with systemic lupus erythematosus.

PubMed

Dolff, S; Quandt, D; Feldkamp, T; Jun, C; Mitchell, A; Hua, F; Specker, C; Kribben, A; Witzke, O; Wilde, B

2014-01-01

Programmed death (PD)-1 is a cell death receptor that, upon stimulation, leads to apoptosis. Previous studies have shown alteration of PD-1 expression on T cells and PD-1 genes in patients with systemic lupus erythematosus (SLE). The aim of this study was to assess the expression of this receptor on effector T cells in patients with SLE. In this study we enrolled 32 SLE patients and 31 healthy controls. T cells from peripheral blood were analysed by flow cytometry for the expression of PD-1. Interferon (IFN)-γ and interleukin (IL)-17-producing cells were investigated for the expression of this co-stimulatory marker. Percentages of CD4(+) T cells expressing PD-1 were significantly increased in patients with SLE compared to healthy controls. The percentage of PD-1 expression was correlated with the production of INF-γ (r = 0.83, p < 0.0001). We also investigated the production of IL-17 by PD-1(+) CD3(+) T cells. Inactive patients (3.2 ± 1.2% vs. 5.9 ± 3.5%, p = 0.002) and patients without lupus nephritis (LN) (3.2 ± 1.5% vs. 5.9 ± 3.5%, p = 0.005) showed lower levels of IL-17 compared to healthy controls. We have demonstrated increased expression of PD-1 on CD4(+) T cells in SLE patients and an association between PD-1 expression on CD4(+) T cells and IFN-γ expression on CD3(+) T cells. We have also shown that there is an altered subset of PD-1(+) T cells in inactive patients and patients without LN producing lower amounts of IL-17.

Bifidobacterium infantis NLS Super Strain Reduces the Expression of α-Defensin-5, a Marker of Innate Immunity, in the Mucosa of Active Celiac Disease Patients.

PubMed

Pinto-Sánchez, Maria I; Smecuol, Edgardo C; Temprano, Maria P; Sugai, Emilia; González, Andrea; Moreno, María L; Huang, Xianxi; Bercik, Premysl; Cabanne, Ana; Vázquez, Horacio; Niveloni, Sonia; Mazure, Roberto; Mauriño, Eduardo; Verdú, Elena F; Bai, Julio C

2017-10-01

We have previously shown a reduction of gastrointestinal symptoms after the oral administration of Bifidobacterium infantis Natren Life Start super strain (NLS-SS) in untreated celiac disease (CD) patients. The symptomatic improvement was not associated with changes in intestinal permeability or serum levels of cytokines, chemokines, or growth factors. Therefore, we hypothesized that the beneficial symptomatic effect observed previously in patients with CD treated with B. infantis may be related to the modulation of innate immunity. To investigate the potential mechanisms of a probiotic B. infantis Natren Life Start super strain on the mucosal expression of innate immune markers in adult patients with active untreated CD compared with those treated with B. infantis×6 weeks and after 1 year of gluten-free diet (GFD). Numbers of macrophages and Paneth cells and α-defensin-5 expression were assessed by immunohistochemistry in duodenal biopsies. We showed that GFD decreases duodenal macrophage counts in CD patients more effectively than B. infantis. In contrast, B. infantis decreases Paneth cell counts and expression of α-defensin-5 in CD (P<0.001). The results identify differential innate immune effects of treatment with B. infantis compared with 1 year of GFD. Further studies are needed to investigate synergistic effects of GFD and B. infantis supplementation in CD.

NOTCH1 Is Aberrantly Activated in Chronic Lymphocytic Leukemia Hematopoietic Stem Cells.

PubMed

Di Ianni, Mauro; Baldoni, Stefano; Del Papa, Beatrice; Aureli, Patrizia; Dorillo, Erica; De Falco, Filomena; Albi, Elisa; Varasano, Emanuela; Di Tommaso, Ambra; Giancola, Raffaella; Accorsi, Patrizia; Rotta, Gianluca; Rompietti, Chiara; Silva Barcelos, Estevão Carlos; Campese, Antonio Francesco; Di Bartolomeo, Paolo; Screpanti, Isabella; Rosati, Emanuela; Falzetti, Franca; Sportoletti, Paolo

2018-01-01

To investigate chronic lymphocytic leukemia (CLL)-initiating cells, we assessed NOTCH1 mutation/expression in hematopoietic stem cells (HSCs). In NOTCH1- mutated CLL, we detected subclonal mutations in 57% CD34+/CD38- HSCs. NOTCH1 mutation was present in 66% CD34+/CD38+ progenitor cells displaying an increased mutational burden compared to HSCs. Flow cytometric analysis revealed significantly higher NOTCH1 activation in CD34+/CD38- and CD34+/CD38+ cells from CLL patients, regardless NOTCH1 mutation compared to healthy donors. Activated NOTCH1 resulted in overexpression of the NOTCH1 target c-MYC. We conclude that activated NOTCH1 is an early event in CLL that may contribute to aberrant HSCs in this disease.

Clinical significance of Tim3-positive T cell subsets in patients with multiple sclerosis.

PubMed

Feng, Xuemei; Feng, Juan

2016-12-01

The present study evaluated associations between the percentages of T cell immunoglobulin and mucin domain 3 (Tim3)-positive T cells and related cytokines and multiple sclerosis (MS). We collected peripheral blood samples from 30 MS patients and 30 healthy controls. Flow cytometry was used to determine the proportions of CD3 + Tim3 + , CD4 + Tim3 + , and CD4 + CD25 + Tim3 + in peripheral blood mononuclear cells (PBMCs) and related cell subsets. The serum concentrations of galectin-9, IL-17, and IFN-γ also were determined using enzyme-linked immunosorbent assays (ELISA). The percentages of Tim3-positive T cells in CD4 + and CD4 + CD25 + T cell subsets were significantly lower among MS patients than among controls. This difference was particularly evident in the CD4 + CD25(high) T cell subset. The proportions of CD4 + Tim3 + and CD4 + CD25 + Tim3 + cells in PBMCs were significantly lower in the MS group than in the control group, whereas no significant differences were detected regarding the percentages of CD3 + Tim3 + in PBMCs and T cell subsets. The serum concentrations of galectin-9, IL-17, and IFN-γ all were increased in MS patients compared with healthy controls. Our results support that Tim3 and related cytokines may be involved in the onset of MS. Copyright © 2016 Elsevier Ltd. All rights reserved.

The effects of using a human patient simulator compared to a CD-ROM in teaching critical thinking and performance.

PubMed

Johnson, Don; Johnson, Sabine

2014-01-01

Military healthcare personnel, including nurse anesthetists, must have the knowledge and skills to care for the extensive, severe injuries incurred on the battlefield. No studies have compared the 2 teaching strategies of using the human patient simulator (HPS) and a CD-ROM in caring for combat injuries relative to critical thinking and performance using nurse anesthesia participants. A prospective, pretest-posttest experimental, mixed design (within and between) was used to determine if there were statistically significant differences in HPS and CD-ROM educational strategies relative to caring for patients who have trauma. Two instruments were used: critical thinking, which consisted of multiple-choice questions; and a combat performance instrument that measured ability to care for patients. A repeated analysis of variance and a least significant difference post-hoc test were used to analyze the data. The HPS group performed better than the CD-ROM and control groups relative to performance (P=.000) but not on critical thinking (P=.239). There was no difference between the CD-ROM and control group (P=.171) on the combat performance instrument. In this study, the HPS method of instruction was a more effective method of teaching than the CD-ROM approach.

Gastro-oesophageal reflux symptoms and coeliac disease: no role for routine duodenal biopsy.

PubMed

Mooney, Peter D; Evans, Kate E; Kurien, Matthew; Hopper, Andrew D; Sanders, David S

2015-06-01

Coeliac disease (CD) has been linked to gastro-oesophageal reflux disease (GORD). Previous studies have demonstrated an increased prevalence of reflux in patients with CD. However data on the risk for CD in patients presenting with reflux are conflicting. The aim of this study was to establish the prevalence of CD in patients with GORD and to elucidate the mechanisms for reflux symptoms in newly diagnosed CD patients. Group A: patients who had undergone routine duodenal biopsy were prospectively recruited between 2004 and 2014. Diagnostic yield was compared with that of a screening cohort. Group B: 32 patients with newly diagnosed CD who had undergone oesophageal manometry and 24-h pH studies were prospectively recruited. Group A: 3368 patients (58.7% female, mean age 53.4 years) underwent routine duodenal biopsy. Of these patients, 850 (25.2%) presented with GORD. The prevalence of CD among GORD patients was 1.3% (0.7-2.4%), which was not significantly higher than that in the general population (P=0.53). Within the context of routine duodenal biopsy at endoscopy (when corrected for concurrent symptoms, age and sex), reflux was found to be negatively associated with CD [adjusted odds ratio 0.12 (0.07-0.23), P<0.0001]. In group B, 34% of patients complained of reflux. On manometry, 9% had a hypotensive lower oesophageal sphincter and 40.6% had oesophageal motor abnormalities, with 25% significantly hypocontractile. On pH studies, 33% demonstrated reflux episodes. The prevalence of undiagnosed CD among GORD patients is similar to that in the general population, and routine duodenal biopsy cannot be recommended. A significant number of patients with newly diagnosed CD were found to have reflux and/or oesophageal dysmotility on pH/manometry studies; this may explain the high prevalence of reflux symptoms in CD.

CD4 count-based failure criteria combined with viral load monitoring may trigger worse switch decisions than viral load monitoring alone.

PubMed

Hoffmann, Christopher J; Maritz, Jean; van Zyl, Gert U

2016-02-01

CD4 count decline often triggers antiretroviral regimen switches in resource-limited settings, even when viral load testing is available. We therefore compared CD4 failure and CD4 trends in patients with viraemia with or without antiretroviral resistance. Retrospective cohort study investigating the association of HIV drug resistance with CD4 failure or CD4 trends in patients on first-line antiretroviral regimens during viraemia. Patients with viraemia (HIV RNA >1000 copies/ml) from two HIV treatment programmes in South Africa (n = 350) were included. We investigated the association of M184V and NNRTI resistance with WHO immunological failure criteria and CD4 count trends, using chi-square tests and linear mixed models. Fewer patients with the M184V mutation reached immunologic failure criteria than those without: 51 of 151(34%) vs. 90 of 199 (45%) (P = 0.03). Similarly, 79 of 220 (36%) patients, who had major NNRTI resistance, had immunological failure, whereas 62 of 130 (48%) without (chi-square P = 0.03) did. The CD4 count decline among patients with the M184V mutation was 2.5 cells/mm(3) /year, whereas in those without M184V it was 14 cells/mm(3) /year (P = 0.1), but the difference in CD4 count decline with and without NNRTI resistance was marginal. Our data suggest that CD4 count monitoring may lead to inappropriate delayed therapy switches for patients with HIV drug resistance. Conversely, patients with viraemia but no drug resistance are more likely to have a CD4 count decline and thus may be more likely to be switched to a second-line regimen. © 2015 John Wiley & Sons Ltd.

Combined influence of adjuvant therapy and interval after surgery on peripheral CD4+ T lymphocytes in patients with esophageal squamous cell carcinoma

PubMed Central

LING, YANG; FAN, LIEYING; DONG, CHUNLEI; ZHU, JING; LIU, YONGPING; NI, YAN; ZHU, CHANGTAI; ZHANG, CHANGSONG

2010-01-01

The aim of this study was to investigate possible differences in cellular immunity between chemo- and/or radiotherapy groups during a long interval after surgery in esophageal squamous cell carcinoma (ESCC) patients. Cellular immunity was assessed as peripheral lymphocyte subsets in response to chemotherapy (CT), radiotherapy (RT) and CT+RT by flow cytometric analysis. There were 139 blood samples obtained at different time points relative to surgery from 73 patients with ESCC. The changes in the absolute and relative proportions of lymphocyte phenotypes were significant among the adjuvant therapy groups. There were significant differences in the absolute counts of CD4+ and CD8+ T cells among the interval groups, and a lower CD4/CD8 ratio was found in patients following a prolonged interval. RT alone had a profound effect on the absolute counts of CD3+, CD4+ and CD8+ T cells compared with the other groups. CD4+ T cells exhibited a decreasing trend during a long interval, leading to a prolonged T-cell imbalance after surgery. Univariate analysis revealed that the interaction of the type of adjuvant therapy and the interval after surgery was correlated only with the percentage of CD4+ T cells. The percentage of CD4+ T cells can be used as an indicator of the cellular immunity after surgery in ESCC patients. However, natural killer cells consistently remained suppressed in ESCC patients following adjuvant therapy after surgery. These findings confirm an interaction between adjuvant therapy and the interval after surgery on peripheral CD4+ T cells, and implies that adjuvant therapy may have selective influence on the cellular immunity of ESCC patients after surgery. PMID:23136603

Cardiac Magnetic Resonance-Verified Myocardial Fibrosis in Chagas Disease: Clinical Correlates and Risk Stratification

PubMed Central

Uellendahl, Marly; de Siqueira, Maria Eduarda Menezes; Calado, Eveline Barros; Kalil-Filho, Roberto; Sobral, Dário; Ribeiro, Clébia; Oliveira, Wilson; Martins, Silvia; Narula, Jagat; Rochitte, Carlos Eduardo

2016-01-01

Background Chagas disease (CD) is an important cause of heart failure and mortality, mainly in Latin America. This study evaluated the morphological and functional characteristics of the heart as well the extent of myocardial fibrosis (MF) in patients with CD by cardiac magnetic resonance (CMR). The prognostic value of MF evaluated by myocardial-delayed enhancement (MDE) was compared with that via Rassi score. Methods This study assessed 39 patients divided into 2 groups: 28 asymptomatic patients as indeterminate form group (IND); and symptomatic patients as Chagas Heart Disease (CHD) group. All patients underwent CMR using the techniques of cine-MRI and MDE, and the amount of MF was compared with the Rassi score. Results Regarding the morphological and functional analysis, significant differences were observed between both groups (p < 0.001). Furthermore, there was a strong correlation between the extent of MF and the Rassi score (r = 0.76). Conclusions CMR is an important technique for evaluating patients with CD, stressing morphological and functional differences in all clinical presentations. The strong correlation with the Rassi score and the extent of MF detected by CMR emphasizes its role in the prognostic stratification of patients with CD. PMID:27982271

Modulation of B cell regulatory molecules CD22 and CD72 in myasthenia gravis and multiple sclerosis.

PubMed

Lu, Jiayin; Li, Jing; Zhu, Tai-qing; Zhang, Longbo; Wang, Yuzhong; Tian, Fa-fa; Yang, Huan

2013-06-01

B cell activation mediated by cluster of differentiation (CD) molecules plays an important role in B cell-related autoimmune diseases. CD22 and CD72 have been demonstrated to act as B cell inhibitory receptors in many autoimmune diseases. Activated B cells are involved in the pathogenesis of myasthenia gravis (MG) by secretion of anti-acetylcholine receptor (AchR) antibodies. However, the roles of CD22 and CD72 on B cells of MG are unknown. In this study, we detected the expression of CD22 and CD72 on B cells of MG, compared to multiple sclerosis (MS) patient controls and healthy controls by flow cytometry and quantitative real-time polymerase transcription chain reaction. Our data demonstrated that aberrant expression of CD72 exists on B cells of MG and MS patients and expression level of CD72 molecule has a significantly negative correlation with anti-AchR antibody levels in MG, which suggests that CD72 may be involved in the pathogenesis of MG and MS. There were no significant differences between study patients (MG, ocular MG, generalized MG, and MS) and healthy controls.

Elevated pretransplantation soluble CD30 is associated with decreased early allograft function after human lung transplantation.

PubMed

Shah, Ashish S; Leffell, M Sue; Lucas, Donna; Zachary, Andrea A

2009-02-01

Early allograft function after lung transplantation is variable. Clinical criteria have limited predictive value for early graft function. Recipient immunologic state before LTx may affect early lung function. We investigated the association between pretransplantation soluble CD30 (sCD30), a marker of Th2-type T-cell activation, and early clinical parameters of allograft function. Between September 2002 and January 2007, a total of 80 transplantations were performed at Johns Hopkins Hospital. Of the patients, 43 had a pretransplantation sCD30 level determined. Pre- and postoperative patient variables were collected, and patients were stratified into two groups: sCD30 <20 (low sCD30) and >20 (high sCD30). High sCD30 (n = 26) and low sCD30 (n = 17) groups were similar in age, gender, and ischemia time. In the high sCD30 group, a higher percentage of patients had pulmonary fibrosis and a lower percentage had emphysema. Oxygenation at 48 hours was significantly worse in the high sCD30 group as compared with the low sCD30 (p = 0.003). Moreover, prolonged intubation and 90-day mortality were greater in the high sCD30 group. This represents the first report of the use of sCD30 as a marker for early allograft function in human lung transplanation. Increased pretransplantation recipient sCD30 appears to be associated with decreased early post-transplantation gas exchange, prolonged intubation, and early mortality.

Impaired circulating CD4+ LAP+ regulatory T cells in patients with acute coronary syndrome and its mechanistic study.

PubMed

Zhu, Zheng-Feng; Meng, Kai; Zhong, Yu-Cheng; Qi, Liang; Mao, Xiao-Bo; Yu, Kun-Wu; Zhang, Wei; Zhu, Peng-Fei; Ren, Ze-Peng; Wu, Bang-Wei; Ji, Qin-Wei; Wang, Xiang; Zeng, Qiu-Tang

2014-01-01

CD4(+) latency-associated peptide (LAP)(+) regulatory T cells (Tregs) are a newly discovered T cell subset in humans and the role of these cells in patients with acute coronary syndrome (ACS) has not been explored. We designed to investigate whether circulating frequency and function of CD4(+)LAP(+) Tregs are defective in ACS. One hundred eleven ACS patients (acute myocardial infarction and unstable angina) and 117 control patients were enrolled in the study. The control patients consisted of chronic stable angina (CSA) and chest pain syndrome (CPS). The frequencies of circulating CD4(+)LAP(+) Tregs and the expression of the transmembrane protein glycoprotein-A repetitions predominant (GARP) on CD4(+) T cells were determined by flow cytometry. The function of CD4(+)LAP(+) Tregs was detected using thymidine uptake. Serum interleukin-10 (IL-10) and transforming growth factor-β protein (TGF-β) levels were detected using ELISA and expression of GARP mRNA in peripheral blood mononuclear cells (PBMCs) was measured by real time-polymerase chain reaction. We found ACS patients had a significantly lower frequency of circulating CD4(+)LAP(+) Tregs, and the function of these cells was reduced compared to controls. The expression of GARP in CD4(+) T cells and the serum levels of TGF-β in ACS patients were lower than those of control patients. The serum levels of IL-10 were similar between the two cohorts. A novel regulatory T cell subset, defined as CD4(+)LAP(+) T cells is defective in ACS patients.

Association between serum soluble CD40 ligand levels and mortality in patients with severe sepsis.

PubMed

Lorente, Leonardo; Martín, María M; Varo, Nerea; Borreguero-León, Juan María; Solé-Violán, Jordi; Blanquer, José; Labarta, Lorenzo; Díaz, César; Jiménez, Alejandro; Pastor, Eduardo; Belmonte, Felipe; Orbe, Josune; Rodríguez, José A; Gómez-Melini, Eduardo; Ferrer-Agüero, José M; Ferreres, José; Llimiñana, María C; Páramo, José A

2011-03-15

CD40 Ligand (CD40L) and its soluble counterpart (sCD40L) are proteins that exhibit prothrombotic and proinflammatory properties on binding to their cell surface receptor CD40. The results of small clinical studies suggest that sCD40L levels could play a role in sepsis; however, there are no data on the association between sCD40L levels and mortality of septic patients. Thus, the aim of this study was to determine whether circulating sCD40L levels could be a marker of adverse outcome in a large cohort of patients with severe sepsis. This was a multicenter, observational and prospective study carried out in six Spanish intensive care units. Serum levels of sCD40L, tumour necrosis factor-alpha and interleukin-10, and plasma levels of tissue factor were measured in 186 patients with severe sepsis at the time of diagnosis. Serum sCD40L was also measured in 50 age- and sex-matched controls. Survival at 30 days was used as the endpoint. Circulating sCD40L levels were significantly higher in septic patients than in controls (P = 0.01), and in non-survivors (n = 62) compared to survivors (n = 124) (P = 0.04). However, the levels of CD40L were not different regarding sepsis severity. Logistic regression analysis showed that sCD40L levels >3.5 ng/mL were associated with higher mortality at 30 days (odds ratio = 2.89; 95% confidence interval = 1.37 to 6.07; P = 0.005). The area under the curve of sCD40L levels >3.5 ng/mL as predictor of mortality at 30 days was 0.58 (95% CI = 0.51 to 0.65; P = 0.03). In conclusion, circulating sCD40L levels are increased in septic patients and are independently associated with mortality in these patients; thus, its modulation could represent an attractive therapeutic target.

Celiac disease: Serologic prevalence in patients with irritable bowel syndrome.

PubMed

Mehdi, Zobeiri; Sakineh, Ebrahimi; Mohammad, Farahvash; Mansour, Rezaei; Alireza, Abdollahi

2012-09-01

The prevalence of irritable bowel syndrome (IBS) in the community is 10%-20% and have symptom based diagnostic criteria. Many symptoms of celiac disease (CD) with 1% prevalence in some communities can mimic IBS. Sensitive and specific serologic tests of CD can detect asymptomatic cases. The purpose of this study was to compare the level of anti-tissue-transglutaminase (tTG) IgA in IBS patients and controls group. This case-control study was performed at a University hospital in which 107 patients with IBS who met the Rome II criteria for their diagnosis were compared with 126 healthy age and sex-matched controls. Both groups were investigated for CD by analysis of their serum tTG IgA antibody with human recombinant antigen. Titers were positive containing over 10u/ml and borderline if they were between 4 and 10 u/ml. 86 percent of IBS patients were female. The mean antibody level was 0.837 u/ml in IBS group and 0.933 u/ml in control group without any significant difference. Results of this study may intensify disagreement on the situation of CD in IBS patients.

Platelets Toll-like receptor-4 in Crohns disease.

PubMed

Schmid, Werner; Novacek, Gottfried; Vogelsang, Harald; Papay, Pavol; Primas, Christian; Eser, Alexander; Panzer, Simon

2017-02-01

Platelets are activated in Crohn's disease (CD) and interplay with leukocytes. Engagement of Toll-like receptor-4 (TLR-4), which is expressed in human platelets, may be involved in crosstalks between platelets and leukocytes leading to their mutual activation for host defense. Human neutrophil peptides (HNPs), lipoprotein binding peptides, and sCD14 were determined by enzyme-linked immunosorbent assays in 42 patients with active CD, in 43 patients with CD in remission, and in 30 healthy individuals. Neutrophil-platelet aggregates and binding of the TLR-4 monoclonal antibody to platelets were determined by flow cytometry. Levels of HNPs were higher in patients with CD than in controls (P = 0.0003 vs. active CD and P = 0.01 vs. CD in remission). Likewise, neutrophils with adhering platelets were higher in patients with active CD than in controls (P = 0.004). Binding of the TLR-4 antibody in patients with active CD was similar to that in controls, while patients in remission had significantly higher binding capacities (P = 0.59 and P = 0.003). Incubation of plasma from patients with active disease or patients in remission with platelets from healthy controls confirmed lower binding of the TLR-4 antibody in the presence of plasma from active diseased patients compared to controls (P = 0.039), possibly due to high levels of lipopolysaccharides, as suggested by high levels of sCD14 and lipoprotein binding protein. Our study indicates involvement of platelet TLR-4 in enhancing the secretion of antimicrobial peptides from neutrophils. While platelet aggregation can be due to a variety of mechanisms in inflammatory disease, the mutual activation of platelets and neutrophils may augment host defense. © 2016 Stichting European Society for Clinical Investigation Journal Foundation.

Reduced sTWEAK and Increased sCD163 Levels in HIV-Infected Patients: Modulation by Antiretroviral Treatment, HIV Replication and HCV Co-Infection

PubMed Central

Beltrán, Luis M.; García Morillo, José S.; Egido, Jesús; Noval, Manuel Leal; Ferrando-Martinez, Sara; Blanco-Colio, Luis M.; Genebat, Miguel; Villar, José R.; Moreno-Luna, Rafael; Moreno, Juan Antonio

2014-01-01

Background Patients infected with the human immunodeficiency virus (HIV) have an increased risk of cardiovascular disease due to increased inflammation and persistent immune activation. CD163 is a macrophage scavenger receptor that is involved in monocyte-macrophage activation in HIV-infected patients. CD163 interacts with TWEAK, a member of the TNF superfamily. Circulating levels of sTWEAK and sCD163 have been previously associated with cardiovascular disease, but no previous studies have fully analyzed their association with HIV. Objective The aim of this study was to analyze circulating levels of sTWEAK and sCD163 as well as other known markers of inflammation (hsCRP, IL-6 and sTNFRII) and endothelial dysfunction (sVCAM-1 and ADMA) in 26 patients with HIV before and after 48 weeks of antiretroviral treatment (ART) and 23 healthy subjects. Results Patients with HIV had reduced sTWEAK levels and increased sCD163, sVCAM-1, ADMA, hsCRP, IL-6 and sTNFRII plasma concentrations, as well as increased sCD163/sTWEAK ratio, compared with healthy subjects. Antiretroviral treatment significantly reduced the concentrations of sCD163, sVCAM-1, hsCRP and sTNFRII, although they remained elevated when compared with healthy subjects. Antiretroviral treatment had no effect on the concentrations of ADMA and sTWEAK, biomarkers associated with endothelial function. The use of protease inhibitors as part of antiretroviral therapy and the presence of HCV-HIV co-infection and/or active HIV replication attenuated the ART-mediated decrease in sCD163 plasma concentrations. Conclusion HIV-infected patients showed a proatherogenic profile characterized by increased inflammatory, immune-activation and endothelial-dysfunction biomarkers that partially improved after ART. HCV-HIV co-infection and/or active HIV replication enhanced immune activation despite ART. PMID:24594990

Fibroblast growth factor-2 (FGF2) and syndecan-1 (SDC1) are potential biomarkers for putative circulating CD15+/CD30+ cells in poor outcome Hodgkin lymphoma patients

PubMed Central

2013-01-01

Background High risk, unfavorable classical Hodgkin lymphoma (cHL) includes those patients with primary refractory or early relapse, and progressive disease. To improve the availability of biomarkers for this group of patients, we investigated both tumor biopsies and peripheral blood leukocytes (PBL) of untreated (chemo-naïve, CN) Nodular Sclerosis Classic Hodgkin Lymphoma (NS-cHL) patients for consistent biomarkers that can predict the outcome prior to frontline treatment. Methods and materials Bioinformatics data mining was used to generate 151 candidate biomarkers, which were screened against a library of 10 HL cell lines. Expression of FGF2 and SDC1 by CD30+ cells from HL patient samples representing good and poor outcomes were analyzed by qRT-PCR, immunohistochemical (IHC), and immunofluorescence analyses. Results To identify predictive HL-specific biomarkers, potential marker genes selected using bioinformatics approaches were screened against HL cell lines and HL patient samples. Fibroblast Growth Factor-2 (FGF2) and Syndecan-1 (SDC1) were overexpressed in all HL cell lines, and the overexpression was HL-specific when compared to 116 non-Hodgkin lymphoma tissues. In the analysis of stratified NS-cHL patient samples, expression of FGF2 and SDC1 were 245 fold and 91 fold higher, respectively, in the poor outcome (PO) group than in the good outcome (GO) group. The PO group exhibited higher expression of the HL marker CD30, the macrophage marker CD68, and metastatic markers TGFβ1 and MMP9 compared to the GO group. This expression signature was confirmed by qualitative immunohistochemical and immunofluorescent data. A Kaplan-Meier analysis indicated that samples in which the CD30+ cells carried an FGF2+/SDC1+ immunophenotype showed shortened survival. Analysis of chemo-naive HL blood samples suggested that in the PO group a subset of CD30+ HL cells had entered the circulation. These cells significantly overexpressed FGF2 and SDC1 compared to the GO group. The PO group showed significant down-regulation of markers for monocytes, T-cells, and B-cells. These expression signatures were eliminated in heavily pretreated patients. Conclusion The results suggest that small subsets of circulating CD30+/CD15+ cells expressing FGF2 and SDC1 represent biomarkers that identify NS-cHL patients who will experience a poor outcome (primary refractory and early relapsing). PMID:23988031

Effects of high CD4 cell counts on death and attrition among HIV patients receiving antiretroviral treatment: an observational cohort study.

PubMed

Tang, Zhenzhu; Pan, Stephen W; Ruan, Yuhua; Liu, Xuanhua; Su, Jinming; Zhu, Qiuying; Shen, Zhiyong; Zhang, Heng; Chen, Yi; Lan, Guanghua; Xing, Hui; Liao, Lingjie; Feng, Yi; Shao, Yiming

2017-06-09

Current WHO guidelines recommend initiating ART regardless of CD4+ cell count. In response, we conducted an observational cohort study to assess the effects of pre-ART CD4+ cell count levels on death, attrition, and death or attrition in HIV treated patients. This large HIV treatment cohort study (n = 49,155) from 2010 to 2015 was conducted in Guangxi, China. We used a Cox regression model to analyze associations between pre-ART CD4+ cell counts and death, attrition, and death or attrition. The average mortality and ART attrition rates among all treated patients were 2.63 deaths and 5.32 attritions per 100 person-years, respectively. Compared to HIV patients with <350 CD4+ cells/mm 3 at ART initiation, HIV patients with >500 CD4+ cells/mm 3 at ART initiation had a significantly lower mortality rate (Adjusted hazard ratio: 0.56, 95% CI: 0.40-0.79), but significantly higher ART attrition rate (AHR: 1.17, 95% CI: 1.03-1.33). Results from this study suggest that HIV patients with high CD4+ cell counts at the time of ART initiation may be at greater risk of treatment attrition. To further reduce ART attrition, it is imperative that patient education and healthcare provider training on ART adherence be enhanced and account for CD4 levels at ART initiation.

Implementation and Operational Research: CD4 Count Monitoring Frequency and Risk of CD4 Count Dropping Below 200 Cells Per Cubic Millimeter Among Stable HIV-Infected Patients in New York City, 2007-2013.

PubMed

Myers, Julie E; Xia, Qiang; Torian, Lucia V; Irvine, Mary; Harriman, Graham; Sepkowitz, Kent A; Shepard, Colin W

2016-03-01

The evidence has begun to mount for diminishing the frequency of CD4 count testing. To determine whether these observations were applicable to an urban US population, we used New York City (NYC) surveillance data to explore CD4 testing among stable patients in NYC, 2007-2013. We constructed a population-based retrospective open cohort analysis of NYC HIV surveillance data. HIV+ patients aged ≥ 13 years with stable viral suppression (≥ 1 viral load the previous year; all <400 copies per milliliter) and immune status (≥ 1 CD4 the previous year; all ≥ 200 cells per cubic millimeter) entered the cohort the following year beginning January 1, 2007. Each subsequent year, eligible patients not previously included entered the cohort on January 1. Outcomes were annual frequency of CD4 monitoring and probability of maintaining CD4 ≥ 200 cells per cubic millimeter. A multivariable Cox model identified factors associated with maintaining CD4 ≥ 200 cells per cubic millimeter. During 1.9 years of observation (median), 62,039 patients entered the cohort. The mean annual number of CD4 measurements among stable patients was 2.8 and varied little by year or characteristic. Two years after entering, 93.4% and 97.8% of those with initial CD4 350-499 and CD4 ≥ 500 cells per cubic millimeter, respectively, maintained CD4 ≥ 200 cells per cubic millimeter. Compared to those with initial CD4 ≥ 500 cells per cubic millimeter, those with CD4 200-349 cells per cubic millimeter and CD4 350-499 cells per cubic millimeter were more likely to have a CD4 <200 cells per cubic millimeter, controlling for sex, race, age, HIV risk group, and diagnosis year. In a population-based US cohort with well-controlled HIV, the probability of maintaining CD4 ≥ 200 cells per cubic millimeter for ≥ 2 years was >90% among those with initial CD4 ≥ 350 cells per cubic millimeter, suggesting that limited CD4 monitoring in these patients is appropriate.

T-Cell-Mediated Immune Responses in Patients with Cutaneous or Mucosal Leishmaniasis: Long-Term Evaluation after Therapy

PubMed Central

Da-Cruz, Alda Maria; Bittar, Rita; Mattos, Marise; Oliveira-Neto, Manuel P.; Nogueira, Ricardo; Pinho-Ribeiro, Vanessa; Azeredo-Coutinho, Rilza Beatriz; Coutinho, Sergio G.

2002-01-01

T-cell immune responses in patients with cutaneous leishmaniasis (CL) and mucosal leishmaniasis (ML) were studied during the active disease, at the end of therapy, and 1 to 17 years posttherapy (long-term follow-up). Lymphocyte proliferative responses, phenotypic characterization of CD4+ and CD8+ Leishmania-reactive T cells, and cytokine production were assayed. Patients with active ML and CL showed higher proportions of CD4+ than CD8+ T cells. In CL, the healing process was associated with a decrease of CD4+ and an increase of CD8+, leading to similar CD4+ and CD8+ proportions. This pattern was only seen in ML after long-term therapy. Long-term follow-up of patients with CL showed a positive CD4+/CD8+ ratio as observed during the active disease, although the percentages of these T cell subsets were significantly lower. Patients with CL did not show significant differences between gamma interferon (IFN-γ) and interleukin-5 (IL-5) production during the period of study. Patients with active ML presented higher IFN-γ and IL-5 levels compared to patients with active CL. IL-4 was only detected during active disease. Patients long term after cure from ML showed increasing production of IFN-γ, significant decrease of IL-5, and no IL-4 production. Two apparently beneficial immunological parameters were detected in tegumentary leishmaniasis: (i) decreasing proportions of CD4+ Leishmania-reactive T cells in the absence of IL-4 production associated with cure of CL and ML and (ii) decreasing levels of IL-5 long after cure, better detected in patients with ML. The observed T-cell responses maintained for a long period in healed patients could be relevant for immunoprotection against reinfection and used as a parameter for determining the prognosis of patients and selecting future vaccine preparations. PMID:11874860

Differences in Expansion Potential of Naive Chimeric Antigen Receptor T Cells from Healthy Donors and Untreated Chronic Lymphocytic Leukemia Patients.

PubMed

Hoffmann, Jean-Marc; Schubert, Maria-Luisa; Wang, Lei; Hückelhoven, Angela; Sellner, Leopold; Stock, Sophia; Schmitt, Anita; Kleist, Christian; Gern, Ulrike; Loskog, Angelica; Wuchter, Patrick; Hofmann, Susanne; Ho, Anthony D; Müller-Tidow, Carsten; Dreger, Peter; Schmitt, Michael

2017-01-01

Therapy with chimeric antigen receptor T (CART) cells for hematological malignancies has shown promising results. Effectiveness of CART cells may depend on the ratio of naive (T N ) vs. effector (T E ) T cells, T N cells being responsible for an enduring antitumor activity through maturation. Therefore, we investigated factors influencing the T N /T E ratio of CART cells. CART cells were generated upon transduction of peripheral blood mononuclear cells with a CD19.CAR-CD28-CD137zeta third generation retroviral vector under two different stimulating culture conditions: anti-CD3/anti-CD28 antibodies adding either interleukin (IL)-7/IL-15 or IL-2. CART cells were maintained in culture for 20 days. We evaluated 24 healthy donors (HDs) and 11 patients with chronic lymphocytic leukemia (CLL) for the composition of cell subsets and produced CART cells. Phenotype and functionality were tested using flow cytometry and chromium release assays. IL-7/IL-15 preferentially induced differentiation into T N , stem cell memory (T SCM : naive CD27+ CD95+), CD4+ and CXCR3+ CART cells, while IL-2 increased effector memory (T EM ), CD56+ and CD4+ T regulatory (T Reg ) CART cells. The net amplification of different CART subpopulations derived from HDs and untreated CLL patients was compared. Particularly the expansion of CD4+ CART N cells differed significantly between the two groups. For HDs, this subtype expanded >60-fold, whereas CD4+ CART N cells of untreated CLL patients expanded less than 10-fold. Expression of exhaustion marker programmed cell death 1 on CART N cells on day 10 of culture was significantly higher in patient samples compared to HD samples. As the percentage of malignant B cells was expectedly higher within patient samples, an excessive amount of B cells during culture could account for the reduced expansion potential of CART N cells in untreated CLL patients. Final T N /T E ratio stayed <0.3 despite stimulation condition for patients, whereas this ratio was >2 in samples from HDs stimulated with IL-7/IL-15, thus demonstrating efficient CART N expansion. Untreated CLL patients might constitute a challenge for long-lasting CART effects in vivo since only a low number of T N among the CART product could be generated. Depletion of malignant B cells before starting CART production might be considered to increase the T N /T E ratio within the CART product.

Very high levels of soluble CD30 recognize the patients with classical Hodgkin's lymphoma retaining a very poor prognosis.

PubMed

Visco, Carlo; Nadali, Gianpaolo; Vassilakopoulos, Theodoros P; Bonfante, Valeria; Viviani, Simonetta; Gianni, Alessandro M; Federico, Massimo; Luminari, Stefano; Peethambaram, Prema; Witzig, Thomas E; Pangalis, Gerassimos; Cabanillas, Fernando; Medeiros, L Jeffrey; Sarris, Andreas H; Pizzolo, Giovanni

2006-11-01

To evaluate the prognostic role of pretreatment serum levels of soluble CD30 (sCD30) in patients with advanced stage classical Hodgkin's lymphoma (cHL) treated with adriamycin, bleomycin, vinblastine, and dacarbazine or equivalent regimens. We identified 321 previously untreated patients with cHL who presented to the participating centers between 1985 and 2002, and had serum samples available for the determination of sCD30 levels. With a median follow-up of 72 months, the actuarial 5-year overall survival was 82%, and failure-free survival (FFS) was 71%. The median serum level of sCD30 was 65 U/mL (range: 1-2230), and was significantly higher (P < 0.0001) when compared with a group of 113 healthy controls (4 U/mL, range: 0-20). Increasing level of sCD30 was associated with a continuous worsening of FFS and OS, and patients with sCD30 >or=200 U/mL had a 5-year FFS of 39%. With multivariate analysis, sCD30, Ann Arbor stage, and lactic acid dehydrogenase were significant independent factors in terms of FFS. The association of the above-mentioned three independent prognostic variables could discriminate 22% of patients with 5-year FFS of 40%. Our data confirm the independent prognostic role of sCD30 in identifying the patients with high risk of treatment failure, and show that its association with other variables can recognize patients with FFS considerably lower than 50%.

Role of effector cells (CCR7(-)CD27(-)) and effector-memory cells (CCR7(-)CD27(+)) in drug-induced maculopapular exanthema.

PubMed

Fernandez, T D; Torres, M J; Lopez, S; Antunez, C; Gomez, E; Del Prado, M F; Canto, G; Blanca, M; Mayorga, C

2010-01-01

Maculopapular exanthema (MPE) induced by drugs is a T-cell mediated reaction and effector cells may play an important role in its development. We assessed the effector and cutaneous homing phenotype in peripheral blood cells from allergic patients after drug stimulation. This study included 10 patients and 10 controls. The effector phenotype (CCR7(-)CD27(+/-)), chemokine receptors (CCR4 and CCR10), and activation (CD25(low)) and regulatory markers (CD25(high)) were measured by flow cytometry in both peripheral blood mononuclear cells (PBMCs) and CD4-T-lymphocytes. Proliferation was determined by 5-(-6)-carboxyfluorescein diacetate succinimidyl ester (CFSE) assay and the migratory capacity by a chemotaxis assay using CCL17 and CCL27. Compared to controls, CCR7(-)CD27(-) cells were increased in patients without (p=0.003) and with drug stimulation (p less than 0.001) and had significantly higher proliferation (p=0.010). CCR10 expression was increased in patients after drug stimulation in total and memory CD27(+) T-cells. Lymphocyte migration with CCL27 was higher in patients with drug stimulation (p=0.048), with a decrease in CCR7(-)CD27(-) (p less than 0.0001) and an increase in CCR7(-)CD27(+) (p=0.017). In patients, CD4-T-lymphocytes were significantly activated after drug stimulation (p less than 0.001). In conclusion, we show that effector memory CD4(+) T-cells (CCR7(-)CD27(+)) respond specifically to the drug responsible for MPE and confirm previous data about the involvement of CCR10 in cell trafficking to the skin.

A Regional Outbreak of Clostridium difficile PCR-Ribotype 027 Infections in Southeastern France from a Single Long-Term Care Facility.

PubMed

Cassir, Nadim; Delarozière, Jean-Christophe; Dubourg, Gregory; Delord, Marion; Lagier, Jean-Christophe; Brouqui, Phillipe; Fenollar, Florence; Raoult, Didier; Fournier, Pierre Edouard

2016-11-01

OBJECTIVE To describe and analyze a large outbreak of Clostridium difficile 027 (CD-027) infections. METHODS Confirmed CD-027 cases were defined as CD infection plus real-time polymerase chain reaction assay (PCR) positive for CD-027. Clinical and microbiological data on patients with CD-027 infection were collected from January 2013 to December 2015 in the Provence-Alpes-Côte-d'Azur region (southeastern France). RESULTS In total, 19 healthcare facilities reported 144 CD-027 infections (112 confirmed and 32 probable CD-027 infections) during a 22-month period outbreak. Although the incidence rate per 10,000 bed days was lower in long-term care facilities (LTCFs) than in acute care facilities (0.05 vs 0.14; P<.001), cases occurred mainly in LTCFs, one of which was the probable source of this outbreak. After centralization of CD testing, the rate of confirmed CD-027 cases from LTCFs or residential-care homes increased significantly (69% vs 92%; P<.001). Regarding confirmed CD-027 patients, the sex ratio and the median age were 0.53 and 84.2 years, respectively. The 30-day crude mortality rate was 31%. Most patients (96%) had received antibiotics within 3 months prior to the CD colitis diagnosis. During the study period, the rate of patients with CD-027 (compared with all patients tested in the point-of-care laboratories) decreased significantly (P=.03). CONCLUSIONS A large CD-027 outbreak occurred in southeastern France as a consequence of an initial cluster of cases in a single LTCF. Successful interventions included rapid isolation and testing of residents with potentially infectious diarrhea and cohorting of case patients in a specialized infectious diseases ward to optimize management. Infect Control Hosp Epidemiol 2016;1-5.

Aberrant expression of cancer stem cell markers (CD44, CD90, and CD133) contributes to disease progression and reduced survival in hepatoblastoma patients: 4-year survival data.

PubMed

Bahnassy, Abeer A; Fawzy, Mohamed; El-Wakil, Mohamed; Zekri, Abdel-Rahman N; Abdel-Sayed, Ahmed; Sheta, Marwa

2015-03-01

Hepatoblastoma (HB) is an embryonal tumor of the liver in children. Prognosis and response to treatment in HB are highly variable. Cancer stem cells (CSCs) constitute a population of cells, which contribute to the development and progression of many tumors. However, their role in HB is not well defined yet. We assessed the prognostic and predictive values of some CSC markers in HB patients. Protein and messenger RNA expressions of the CSC markers CD133, CD90, and CD44 were assessed in 43 HB patients and 20 normal hepatic tissues using immunohistochemistry and quantitative real-time polymerase chain reaction. The expression levels of these markers were correlated to standard prognostic factors, patients' response to treatment, overall survival (OS), and disease-free survival (DFS). CD44, CD90, and CD133 proteins were detected in 48.8%, 32.6%, and 48.8% compared with 46.5%, 41.7%, and 58.1% RNA, respectively (concordance, 77.8%-96%). None of the normal tissue samples was positive for any of the markers. Significant correlations were reported between α-fetoprotein and both CD44 and CD133 (P = 0.02) as well as between tumor types CD90 and CD133 (P = 0.009). Reduced OS correlated with CD44, CD90, and CD133 expressions (P < 0.001), advanced stage (P < 0.001), response to treatment (P < 0.001), and total excision of the tumor. Reduced DFS correlated with CD44 and CD133 expressions (P < 0.001) only. In conclusion, CD133, CD44, and CD90 could be used as prognostic and predictive markers in HB. High expression of these markers is significantly associated with poor response to treatment and reduced survival. Moreover, complete surgical resection and systemic chemotherapy are essential to achieve good response and prolonged survival, especially in early stage patients. Copyright © 2015 Elsevier Inc. All rights reserved.

Risk of Idiopathic Dilated Cardiomyopathy in 29 000 Patients With Celiac Disease

PubMed Central

Emilsson, Louise; Andersson, Bert; Elfström, Peter; Green, Peter H.R.; Ludvigsson, Jonas F.

2012-01-01

Background Dilated cardiomyopathy (DCM) is a rare disease of largely unknown origin. Previous studies have suggested an increased prevalence of celiac disease (CD) in patients with DCM. These studies, however, were based on a maximum of 5 patients with both CD and DCM. In the present large Swedish population-based cohort study, we examined the risk of idiopathic DCM in patients with CD determined by small-intestinal histopathology. Methods and Results From 2006 to 2008, we collected duodenal/jejunal biopsy data on CD (equal to villous atrophy, Marsh stage 3, n=29 071 unique individuals) from (all) 28 pathology departments in Sweden. These individuals were compared with 144 429 reference individuals matched for age, sex, calendar year, and county. Data on DCM were obtained through the National Patient Register and confirmed by patient charts and echocardiography data. During follow-up, 17 patients with CD and 52 reference individuals developed idiopathic DCM. Thus, patients with CD were at an increased risk of idiopathic DCM (hazard ratio, 1.73; 95% confidence interval, 1.00 to 3.00), although the risk estimate failed to attain statistical significance (P=0.052). Conclusion This nationwide study found a moderately but not statistically significantly increased risk of idiopathic DCM in patients with biopsy-verified CD. (J Am Heart Assoc. 2012;1:e001594 doi: 10.1161/JAHA.112.001594.) PMID:23130142

Morphological and molecular features of oral fluid-derived exosomes: oral cancer patients versus healthy individuals.

PubMed

Zlotogorski-Hurvitz, Ayelet; Dayan, Dan; Chaushu, Gavriel; Salo, Tuula; Vered, Marilena

2016-01-01

Oral cancer (OC) patients are at high risk to develop recurrent disease or secondary primary cancers with no available biomarkers to detect these events until a visible lesion is readily present and diagnosed by biopsy. Exosomes secreted by cancer cells are involved in tumor growth, invasion and metastasis. We aimed to determine morphological and molecular differences between oral fluid (OF)-derived exosomes of OC patients and those isolated from healthy individuals (HI). OF from OC patients (n = 36) and HI (n = 25) was initially assessed by nanoparticle tracking analysis (NTA). Following ultracentrifugation, exosomal pellets of OC patients and HI were morphologically examined by transmission electron microscopy and atomic force microscopy (AFM). Enzyme-linked immunosorbent assay (ELISA) and western blotting (WB) were used to analyze the expression of exosomal markers--CD9, CD81 and CD63. NTA showed that OC samples of OF had a significantly higher concentration of nanoparticles/ml (p = 0.01) and modal nanoparticle size (p = 0.002) compared to HI. The difference in size was structurally highlighted by AFM three-dimensional images applied on exosomal pellets. ELISA and WB showed differential expression of exosomal markers in OC exosomes compared to HI: lower expression of CD81 and CD9 in contrast to a higher expression of CD63 (~53 kDa). OF-derived exosomes from OC patients differ both morphologically and molecularly from exosomes present in HI. This study is a baseline that provides a starting point for finding exosomal biomarkers for early detection of malignant changes in high-risk patients without overt clinical signs/lesions.

Characteristics and Outcome of Patients Diagnosed With HIV at Older Age.

PubMed

Asher, Ilan; Guri, Keren Mahlab; Elbirt, Daniel; Bezalel, Shira Rosenberg; Maldarelli, Frank; Mor, Orna; Grossman, Zehava; Sthoeger, Zev M

2016-01-01

To characterize the clinical, virological, and immunological status at presentation as well as the outcome of patients diagnosed with HIV above the age of 50. A retrospective study of 418 patients newly diagnosed with HIV in 1 Israeli center, between the years 2004 and 2013. Patients with new HIV diagnosis ≥ 50 years of age defined as "older' and < 50 defined as "younger.' Patients were evaluated every 1 to 3 months (mean follow-up 53 ± 33 months). Patients with < 2 CD4/viral-load measurements or with < 1 year of follow-up were excluded. Time of HIV infection was estimated by HIV sequence ambiguity assay. Ambiguity index ≤ 0.43 indicated recent (≤ 1 year) HIV infection. Eighty nine (21%) patients were diagnosed with HIV at an older age. Those older patients presented with significant lower CD4 cell counts and higher viral-load compared with the younger patients. At the end of the study, the older patients had higher mortality rate (21% vs 3.5%; P < 0.001) and lower CD4 cell counts (381 ± 228 vs 483 ± 26 cells/μL; P < 0.001) compared with the younger patients. This difference was also observed between older and younger patients with similar CD4 cell counts and viral load at the time of HIV diagnosis and among patients with a recent (≤ 1 year) HIV infection. One-fifth of HIV patients are diagnosed at older age (≥ 50 years). Those older patients have less favorable outcome compared with the younger patients. This point to the need of educational and screening programs within older populations and for a closer follow-up of older HIV patients.

Characteristics and Outcome of Patients Diagnosed With HIV at Older Age

PubMed Central

Asher, Ilan; Guri, Keren Mahlab; Elbirt, Daniel; Bezalel, Shira Rosenberg; Maldarelli, Frank; Mor, Orna; Grossman, Zehava; Sthoeger, Zev M.

2016-01-01

Abstract To characterize the clinical, virological, and immunological status at presentation as well as the outcome of patients diagnosed with HIV above the age of 50. A retrospective study of 418 patients newly diagnosed with HIV in 1 Israeli center, between the years 2004 and 2013. Patients with new HIV diagnosis ≥50 years of age defined as “older" and <50 defined as “younger." Patients were evaluated every 1 to 3 months (mean follow-up 53 ± 33 months). Patients with <2 CD4/viral-load measurements or with <1 year of follow-up were excluded. Time of HIV infection was estimated by HIV sequence ambiguity assay. Ambiguity index ≤0.43 indicated recent (≤1 year) HIV infection. Eighty nine (21%) patients were diagnosed with HIV at an older age. Those older patients presented with significant lower CD4 cell counts and higher viral-load compared with the younger patients. At the end of the study, the older patients had higher mortality rate (21% vs 3.5%; P < 0.001) and lower CD4 cell counts (381 ± 228 vs 483 ± 261cells/μL; P < 0.001) compared with the younger patients. This difference was also observed between older and younger patients with similar CD4 cell counts and viral load at the time of HIV diagnosis and among patients with a recent (≤1 year) HIV infection. One-fifth of HIV patients are diagnosed at older age (≥50 years). Those older patients have less favorable outcome compared with the younger patients. This point to the need of educational and screening programs within older populations and for a closer follow-up of older HIV patients. PMID:26735534

[Influence of Leukodeplated Blood Transfusion on Cellular Immunity of Acute Leukemia Patients].

PubMed

Lu, Ya-Lan; Zhang, Xin; Wang, Yu-Fang; Ke, Shan-Dong; Ke, Jin-Yong; Liu, Geng-Fu; Chen, Shi-Ming

2016-08-01

To study the influence of leukodeplated blood transfusion on cellular immunity of patients with acute leuemia, so as to provide support for application of leuko-deplated blood transfusion in clinic. A total of 100 AL patients from January 2012 to December 2015 were chosen, and were divided into 2 groups: leukodeplated blood transfusion group(50 cases) and routine blood transfusion group(RBT) as control (50 cases). The effective rate, side effects, peripheral blood T cells and expression level of TLR2 and TLR4 were compared between 2 groups. The expression levels CD3(+), CD4(+), CD8(+), CD4(+)/CD8(+) of TLR2 and TLR4 in control group were (52.18±2.14)%, （27.28±1.19）%,（24.21±1.65）%,1.22±0.18,0.62±0.04 and 0.57±0.05, respectively, after treatment; while these indicators in LdBT group were （52.18±2.14）%,（30.97±2.01）%,（27.08±1.55）%,1.39±0.24,0.91±0.06 and 0.87±0.07, respectively, and above-mentioned indicators in LdBT group were significantly higher than those in control group（P<0.05）. Compared with these indicators before treatment, CD3(+), CD4(+), CD8(+) and CD4(+)/CD8(+) in the patients increased significantly（P<0.05）. The efficiency was 92.00% (46/50) in LdBT group, and 84.00% (42/50) in control group, without statistically significant difference（P>0.05）. The rate of side effects in study group was 6% (3/50), 18% (9/50) in control group, with statistically significance difference （P<0.05）. Leukodeplated blood transfusion can improve the cellular immunity of AL patients, and reduce the rate of side effects.

Expression of natural killer cell activity with CD107a on ectopic endometrium in woman with endometriosis compared with non-endometriosis

NASA Astrophysics Data System (ADS)

Lubis, H. P.; Aldiansyah, D.; Siregar, H. S.; Rivany, R.; Hariadi, T. S.

2018-03-01

Some factors have an important role in endometriosis pathogenesis; there is an immune cell that plays an important role in endometrial cells that have reflux. Woman with endometriosis experienced the cellular immune disorder. It is suspected that decrease of NK cell in the peritoneal fluid caused by its qualitative defect with CD107a expression as the best marker. The aim of this study was to compare expression of NK Cell activity with CD107a between awoman with endometriosis and non-endometriosis. A case-control study from March until July 2015 in Haji Adam Malik General Hospital. The case group was ectopic endometrial tissue block paraffin and control group was normal endometrial tissue block paraffin. This study included 23 patients in endometriosis group and control group respectively. A majority proportion of CD107a expression in endometriosis group was +1 (16 patients (69.6%)), while the control group was +3 (9 patients (39.1%)). Expression of NK cell activity with CD107a in patients with endometriosis was lower than the control group (p<0.05). It suggested that cellular immune factors may play a role in the pathogenesis of endometriosis.

Corneal Endothelial Alterations in Chronic Renal Failure.

PubMed

Sati, Alok; Jha, Ashok; Moulick, P S; Shankar, Sandeep; Gupta, Sandeep; Khan, M A; Dogra, Manu; Sangwan, Virender S

2016-10-01

To evaluate the corneal endothelial changes in patients with chronic renal failure. A total of 128 corneas of 128 subjects were studied, and 3 groups were formed. The first, the dialyzed group, composed of 32 corneas of 32 patients; the second, the nondialyzed group, composed of 34 corneas of 34 patients; and the third, the age-matched control group, composed of 64 corneas of 64 healthy subjects were examined by a specular microscope and the endothelial parameters were compared. The dialyzed group (enhanced level of toxins in the blood) was further analyzed to assess the influence of blood urea, serum creatinine, serum calcium, and serum phosphorus including the duration of dialysis on corneal endothelium. On comparing the 3 groups using analysis of variance and posthoc tests, a significant difference was found in the central corneal thickness (CCT) and endothelial cell density (CD) between the control (CCT: 506 ± 29 μm, CD: 2760 ± 304 cells/mm) and dialyzed groups (CCT: 549 ± 30 μm, CD: 2337 ± 324 cells/mm) [P < 0.001 (CCT); P < 0.001 (CD)]; control and nondialyzed groups (CCT: 524 ± 27 μm, CD: 2574 ± 260 cells/mm) [P = 0.023 (CCT); P = 0.016 (CD)]; and dialyzed and nondialyzed groups [P = 0.002 (CCT); P = 0.007 (CD)]. Using the linear generalized model, a significant correlation was found between the endothelial parameters and blood urea only [P = 0.006 (CCT), 0.002 (coefficient of variation), 0.022 (CD), and 0.026 (percentage of hexagonality)], although the correlation was poorly positive for CCT but poorly negative for the remaining endothelial parameters. Corneal endothelial alteration is present in patients with chronic renal failure, more marked in patients undergoing hemodialysis and with raised blood urea level.

Activated Pancreatic Stellate Cells Sequester CD8+ T-Cells to Reduce Their Infiltration of the Juxtatumoral Compartment of Pancreatic Ductal Adenocarcinoma

PubMed Central

Ene-Obong, Abasi; Clear, Andrew J.; Watt, Jennifer; Wang, Jun; Fatah, Rewas; Riches, John C.; Marshall, John F.; Chin-Aleong, Joanne; Chelala, Claude; Gribben, John G.; Ramsay, Alan G.; Kocher, Hemant M.

2013-01-01

Background & Aims Pancreatic ductal adenocarcinoma (PDAC) is characterized by a prominent desmoplastic microenvironment that contains many different immune cells. Activated pancreatic stellate cells (PSCs) contribute to the desmoplasia. We investigated whether distinct stromal compartments are differentially infiltrated by different types of immune cells. Method We used tissue microarray analysis to compare immune cell infiltration of different pancreatico-biliary diseased tissues (PDAC, ampullary carcinoma, cholangiocarcinoma, mucinous cystic neoplasm, chronic inflammation, and chronic pancreatitis), and juxtatumoral stromal (<100 μm from tumor) and panstromal compartments. We investigated the association between immune infiltrate and patient survival times. We analyzed T-cell migration and tumor infiltration in LSL-KrasG12D/+; LSL-Trp53R172H/+; Pdx-1-Cre (KPC) mice, and the effects of all-trans retinoic acid (ATRA) on these processes. Results Juxtatumoral compartments in PDAC samples from 2 independent groups of patients contained increased numbers of myeloperoxidase+ and CD68+ cells, compared with panstromal compartments. However, juxtatumoral compartments of PDACs contained fewer CD8+, FoxP3+, CD56+, or CD20+ cells than panstromal compartments, a distinction absent in ampullary carcinomas and cholangiocarcinomas. Patients with PDACs that had high densities of CD8+ T-cells in the juxtatumoral compartment had longer survival times than patients with lower densities. In KPC mice, administration of ATRA, which renders PSCs quiescent, increased numbers of CD8+ T-cells in juxtatumoral compartments. We found that activated PSCs express cytokines, chemokines, and adhesion molecules that regulate T-cell migration. In vitro migration assays showed that CD8+ T-cells from PDAC patients had increased chemotaxis towards activated PSCs, which secrete CXCL12, compared with quiescent PSC or tumor cells. These effects could be reversed by knockdown of CXCL12 or treatment of PSCs with ATRA. Conclusion Based on studies of human PDAC samples and KPC mice, activated PSCs appear to reduce migration of CD8+ T-cells to juxtatumoral stromal compartments, preventing their access to cancer cells. Deregulated signaling by activated PSCs could prevent an effective anti-tumor immune response. PMID:23891972

Increased risk of esophageal eosinophilia and eosinophilic esophagitis in patients with active celiac disease on biopsy

PubMed Central

Jensen, Elizabeth T.; Eluri, Swathi; Lebwohl, Benjamin; Genta, Robert M.; Dellon, Evan S.

2015-01-01

Background and Aims The possible association between eosinophilic esophagitis (EoE) and celiac disease (CD) is controversial as prior results have been contradictory. We aimed to determine the relationship between EoE and CD among patients with concomitant esophageal and duodenal biopsies. Methods We conducted a cross-sectional study in a U.S. national pathology database, using data from January 2009 and June 2012. Our primary case definition was defined by the presence of esophageal eosinophilia with ≥ 15 eosinophils per high-power field. The crude and adjusted (for age and sex) odds of esophageal eosinophilia for patients with active CD were compared to those without CD. Sensitivity analyses were performed using more stringent case definitions and by estimating the associations between CD and reflux esophagitis, and CD and Barrett's esophagus (BE). Results Of 292,621 patients in the source population, 88,517 with both esophageal and duodenal biopsies were studied. 4,101 (4.6%) met criteria for EoE and 1,203 (1.4%) met criteria for CD. Odds of EoE were 26% higher in patients with CD than patients without CD (aOR: 1.26, 95% confidence interval [CI]: 0.98 – 1.60). The magnitude of association varied according to EoE case definition (Table 3), but all definitions showed a weak, positive association between the two conditions. There was no association between CD and reflux esophagitis (aOR 0.95, 95% CI: 0.85 – 1.07) or BE (aOR 0.89, 95% CI: 0.69 – 1.14) and CD. Conclusions There is a weak increase in EoE in patients with CD. This association strengthened with increasingly stringent definitions of EoE, and was not observed for other esophageal conditions. In patients with CD, concomitant EoE should be considered in the correct clinical setting. PMID:25724709

Platelet-, monocyte-derived and tissue factor-carrying circulating microparticles are related to acute myocardial infarction severity.

PubMed

Chiva-Blanch, Gemma; Laake, Kristian; Myhre, Peder; Bratseth, Vibeke; Arnesen, Harald; Solheim, Svein; Badimon, Lina; Seljeflot, Ingebjørg

2017-01-01

Circulating microparticles (cMPs) are phospholipid-rich vesicles released from cells when activated or injured, and contribute to the formation of intracoronary thrombi. Tissue factor (TF, CD142) is the main trigger of fibrin formation and TF-carrying cMPs are considered one of the most procoagulant cMPs. Similar types of atherosclerotic lesions may lead to different types of AMI, although the mechanisms behind are unresolved. Therefore, we aimed to investigate the phenotype of cMPs found in plasma of ACS patients and its relation to AMI severity and thrombotic burden. In a cross-sectional study, two hundred patients aged 75±4 years were included in the study 2-8 weeks after suffering an AMI. Annexin V positive (AV+)-cMPs derived from blood and vascular cells were measured by flow cytometry. Plasma procoagulant activity (TF-PCA) was measured through a chromogenic assay. STEMI patients (n = 75) showed higher levels of platelet-derived cMPs [CD61+/AV+, CD31+/AV+, CD42b+/AV+ and CD31+/CD42b+/AV+, P = 0.048, 0.038, 0.009 and 0.006, respectively], compared to NSTEMI patients (n = 125). Patients who suffered a heart failure during AMI (n = 17) had increased levels of platelet (CD61+)-and monocyte (CD14+)-derived cMPs carrying TF (CD142+) (P<0.0001 and 0.004, respectively). Additionally, NYHA class III (n = 23) patients showed higher levels of CD142+/AV+, CD14+/AV+ and CD14+/CD142+/AV+ cMPs than those in class I/II (P = 0.001, 0.015 and 0.014, respectively). The levels of these cMPs positively correlated with TF-PCA (r≥0.166, P≤0.027, all). Platelets and monocytes remain activated in AMI patients treated as per guidelines and release cMPs that discriminate AMI severity. Therefore, TF-MPs, and platelet- and monocyte-MPs may reflect thrombotic burden in AMI patients.

DC type 2 polarization depends on both the allergic status of the individual and protease activity of Per a 10.

PubMed

Goel, Chhavi; Gaur, S N; Bhati, Gaurav; Arora, Naveen

2015-10-01

Cockroach proteases are important risk factors for asthma development in predisposed individuals. In the present study, effect of allergic status of patients on DCs polarization in response to protease allergen Per a 10 was investigated. Cockroach-allergic, other-allergic patients and healthy individuals were selected following the guidelines of ATS/ARIA. Monocyte-derived dendritic cells (DCs) were generated from the selected individuals and stimulated with Per a 10. Flow cytometric analysis showed a significantly high expression of CD80 and CD86 on DCs from cockroach-allergic patients after Per a 10 stimulation as compared to healthy individuals or other-allergic patients (P<0.05). Per a 10 induced comparable level of CD83 expression on DCs from all the 3 groups, showing it was irrespective of the allergic status. CD40 expression was significantly low (P<0.05) on the DCs from cockroach-allergic patients as compared to healthy individuals or other-allergic patients. Further, proteolytically active Per a 10 induced lower CD40 expression on DCs than the heat-inactivated Per a 10 (P<0.05) indicating role of protease activity in the generation of an immune response. The sCD40 level in active Per a 10 stimulated DC cultures was significantly higher than in heat-inactivated Per a 10 (P<0.05). There was two-fold decrease (P<0.05) in IL-12 production by active Per a 10-stimulated DCs than heat-inactivated Per a 10-stimulated DCs. Per a 10-stimulated DCs from cockroach-allergic patients secreted high levels of IL-5, IL-6, TNF-α than that from healthy individuals or other-allergic patients (P<0.05). Furthermore, Per a 10-stimulated DCs from cockroach-allergic patients induced increased secretions of IL-4, IL-5, IL-6, TNF-α and low IL-12 by T cells as compared to those from other groups (P<0.05). Thus, in presence of Per a 10 allergen, polarization of DCs shifts toward type 2 in cockroach-allergic patients but not in the healthy individuals or other-allergic patients. In conclusion, both allergic status of the individual and protease activity of Per a 10 are important parameters that participate in DCs polarization. Copyright © 2015 Elsevier GmbH. All rights reserved.

Relationship between vagal tone, cortisol, TNF-alpha, epinephrine and negative affects in Crohn's disease and irritable bowel syndrome.

PubMed

Pellissier, Sonia; Dantzer, Cécile; Mondillon, Laurie; Trocme, Candice; Gauchez, Anne-Sophie; Ducros, Véronique; Mathieu, Nicolas; Toussaint, Bertrand; Fournier, Alicia; Canini, Frédéric; Bonaz, Bruno

2014-01-01

Crohn's disease (CD) and irritable bowel syndrome (IBS) involve brain-gut dysfunctions where vagus nerve is an important component. The aim of this work was to study the association between vagal tone and markers of stress and inflammation in patients with CD or IBS compared to healthy subjects (controls). The study was performed in 73 subjects (26 controls, 21 CD in remission and 26 IBS patients). The day prior to the experiment, salivary cortisol was measured at 8:00 AM and 10:00 PM. The day of the experiment, subjects completed questionnaires for anxiety (STAI) and depressive symptoms (CES-D). After 30 min of rest, ECG was recorded for heart rate variability (HRV) analysis. Plasma cortisol, epinephrine, norepinephrine, TNF-alpha and IL-6 were measured in blood samples taken at the end of ECG recording. Compared with controls, CD and IBS patients had higher scores of state-anxiety and depressive symptomatology. A subgroup classification based on HRV-normalized high frequency band (HFnu) as a marker of vagal tone, showed that control subjects with high vagal tone had significantly lower evening salivary cortisol levels than subjects with low vagal tone. Such an effect was not observed in CD and IBS patients. Moreover, an inverse association (r =  -0.48; p<0.05) was observed between the vagal tone and TNF-alpha level in CD patients exclusively. In contrast, in IBS patients, vagal tone was inversely correlated with plasma epinephrine (r =  -0.39; p<0.05). No relationship was observed between vagal tone and IL-6, norepinephrine or negative affects (anxiety and depressive symptomatology) in any group. In conclusion, these data argue for an imbalance between the hypothalamus-pituitary-adrenal axis and the vagal tone in CD and IBS patients. Furthermore, they highlight the specific homeostatic link between vagal tone and TNF-alpha in CD and epinephrine in IBS and argue for the relevance of vagus nerve reinforcement interventions in those diseases.

Influence of CD94 and NKG2A variants on susceptibility to rheumatoid arthritis and efficacy of anti-TNF treatment.

PubMed

Iwaszko, Milena; Świerkot, Jerzy; Kolossa, Katarzyna; Jeka, Sławomir; Wiland, Piotr; Bogunia-Kubik, Katarzyna

2016-01-01

The present study aimed to investigate relationships between the CD94 and NKG2A gene polymorphisms and the risk of rheumatoid arthritis (RA) development as well as their association with the response to anti-TNF therapy. A total of 284 patients with RA receiving anti-TNF therapy and 124 healthy subjects were enrolled to the study. Genotypings for CD94 (rs2302489) and NKG2A (rs7301582, rs2734440, rs2734414) polymorphisms were performed using a polymerase chain reaction (PCR) amplification employing LightSNiP assays (TIB-MolBiol, Berlin, Germany). Clinical response was evaluated at 12th and 24th week after initiation of the therapy according to the EULAR response criteria. The frequency of the CD94 AA genotype was significantly decreased in RA patients compared to controls (OR=0.44; P=0.016). The CD94 AA homozygotes were also more common among patients negative to anti-cyclic citrullinated peptide (anti-CCP) antibodies (OR=11.28; P=0.001) as compared to anti-CCP-positive patients and the presence of the CD94 allele A was associated with lack of anti-CCP antibodies (OR=5.00; P=0.0005). The CD94 rs2302489 TT genotype was over-represented in patients exhibiting worse EULAR response at 12th week (OR=3.33; P=0.017). Furthermore, the lack of response after 12 weeks was more frequent among patients carrying the NKG2A rs7301582C allele (OR=3.68; P=0.019) or the CC genotype (OR=3.58; P=0.035) in comparison to allele T or CT/TT genotypes, respectively. These results indicate that CD94 and NKG2A polymorphisms may contribute to genetic susceptibility to RA or affect the response to anti-TNF therapy in patients of Caucasian origin. Copyright © 2015 Société française de rhumatologie. Published by Elsevier SAS. All rights reserved.

CD4+ T-cell recovery with suppressive ART-induced rapid sequence evolution in hepatitis C virus envelope but not NS3.

PubMed

Liu, Lin; Nardo, David; Li, Eric; Wang, Gary P

2016-03-13

CD4 T-cell depletion from HIV infection leads to a global decline in anti-hepatitis C virus (HCV) envelope neutralizing antibody (nAb) response, which may play a role in accelerating liver fibrosis. An increase in anti-HCV nAb titers has been reported during antiretroviral therapy (ART) but its impact on HCV remains poorly understood. The objective of this study is to determine the effects of ART on long-term HCV evolution. We examined HCV quasispecies structure and long-term evolution in HIV/HCV coinfected patients with ART-induced CD4 T-cell recovery, and compared with patients with CD4 T-cell depletion from delayed ART. We applied a single-variant sequencing (SVS) method to construct authentic viral quasispecies and compared sequence evolution in HCV envelope, the primary target for humoral immune responses, and NS3, a target for cellular immunity, between the two cohorts. The SVS method corrected biases known to skew the proportions of viral variants, revealing authentic HCV quasispeices structures. We observed higher rates of HCV envelope sequence evolution in patients with ART-induced CD4 T-cell recovery, compared with patients with CD4 T-cell depletion from delayed ART (P = 0.03). Evolutionary rates for NS3 were considerably lower than the rates for envelope (P < 0.01), with no significant difference observed between the two groups. ART-induced CD4 T-cell recovery results in rapid sequence evolution in HCV envelope, but not in NS3. These results suggest that suppressive ART disproportionally enhances HCV-specific humoral responses more than cellular responses, resulting in rapid sequence evolution in HCV envelope but not NS3.

Reduced frequency of CD56 dim CD16 pos natural killer cells in pediatric systemic inflammatory response syndrome/sepsis patients.

PubMed

Halstead, E Scott; Carcillo, Joseph A; Schilling, Bastian; Greiner, Robert J; Whiteside, Theresa L

2013-10-01

Sepsis continues to be a leading cause of death in infants and children. Natural killer (NK) cells serve as a bridge between innate and adaptive immunity, yet their role in pediatric sepsis has not been well characterized. We tested the hypothesis that decreased NK cell cytotoxicity is a common feature of pediatric systemic inflammatory response syndrome (SIRS)/sepsis patients by measuring, using flow cytometry, NK cell cytotoxicity and cell surface phenotype in the peripheral blood of 38 pediatric intensive care patients who demonstrated signs and symptoms of SIRS and/or sepsis. NK cell cytotoxicity was significantly reduced in peripheral blood mononuclear cells (PBMCs) of pediatric SIRS/sepsis patients as compared with healthy controls, and the percentage of CD56(dim) CD16(+) cytotoxic NK cells in PBMCs was lower in patients with SIRS/sepsis than in normal donors. However, on a per cell basis, CD56(dim) CD16(+) NK cells in patients mediated cytotoxicity as well as those in normal donors. The NK cell dysfunction in pediatric SIRS/sepsis patients reflects a quantitative rather than a qualitative difference from healthy controls.

Descriptive information about Crohn disease: content analysis of patient education brochures.

PubMed

Tanaka, Makoto; Kawakami, Aki; Iwao, Yasushi

2010-01-01

Although providing necessary information to patients with Crohn disease (CD) can influence their quality of life, there has been no study regarding the information provided by healthcare providers to CD patients. The aim of our study was to describe the contents of brochures given to CD patients in Japanese hospitals. These brochures were compared with ones used in the United States, Canada, and the United Kingdom. Forty-nine members of the research group on inflammatory bowel disease in Japan were asked to answer a questionnaire regarding educational brochures for CD patients. We obtained 15 Japanese and three foreign brochures and conducted content analyses for seven global brochures. We received 34 replies. Only 15 (44%) of 34 hospitals gave the brochures to all newly diagnosed CD patients. In the Japanese brochures, a lot of content was devoted to nutrition therapy and self-management in terms of diet. On the contrary, foreign brochures devoted more content to symptoms and drug therapy. The existing approaches for providing information in Japanese hospitals were unsatisfactory. Furthermore, Japanese educational brochures for CD patients emphasized nutritional therapy and dietary restriction. This reflected the differences in treatment strategies among countries.

Prevalence and clinicopathologic features of CD30-positive de novo diffuse large B-cell lymphoma in Chinese patients: a retrospective study of 232 cases

PubMed Central

Gong, Qi-Xing; Lu, Ting-Xun; Liu, Chong; Wang, Zhen; Liang, Jin-Hua; Xu, Wei; Li, Jian-Yong; Zhang, Zhi-Hong; Chen, Qi

2015-01-01

Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease that great efforts had been made in to build up molecular and immunophenotypic subgroups that could relatively accurate indicate prognosis and give clue to therapy. Recently, CD30 was reported as a useful predictor with favorable clinical outcome. However, CD30 expression patterns and the clinicopathologic features of CD30 positive DLBCL are not well described thus far, especially in Asian patients. Here, we studied 232 cases of de novo DLBCL in East China to investigate the prevalence and clinicopathological features of CD30-positive DLBCL using a panel of immunohistochemical markers. Applying a >0% threshold, CD30 was expressed in approximately 12% patients with Epstein-Barr virus (EBV) negative DLBCL, affecting younger people and showing a lower frequency of BCL2 expression and MYC/BCL2 co-expression. Patients with CD30-positive DLBCLs showed better progression-free survival and overall survival compared with patients with CD30-negative DLBCLs, although the superior outcome of CD30 positivity had minimal effects on BCL2+ DLBCL or DLBCL with MYC/BCL2 co-expression. Moreover, CD30 could express in CD5+ DLBCL. We concluded that CD30 may be useful as a prognostic marker in rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) treated DLBCLs, indicating favorable outcomes in a Chinese population. Further studies with larger samples should be performed to investigate the function of CD30 expression in BCL2+ DLBCLs, DLBCLs with MYC/BCL2 co-expression, and CD5+ DLBCLs, and to evaluate the feasibility of anti-CD30 targeted treatment in DLBCL therapy. PMID:26884853

Intraportal Infusion of Bone Marrow Mononuclear or CD133+ Cells in Patients With Decompensated Cirrhosis: A Double-Blind Randomized Controlled Trial

PubMed Central

Mohamadnejad, Mehdi; Vosough, Massoud; Moossavi, Shirin; Nikfam, Sepideh; Mardpour, Soura; Akhlaghpoor, Shahram; Ashrafi, Mandana; Azimian, Vajiheh; Jarughi, Neda; Hosseini, Seyedeh-Esmat; Moeininia, Fatemeh; Bagheri, Mohamad; Sharafkhah, Maryam; Aghdami, Nasser

2016-01-01

The present study assessed the effects of intraportal infusions of autologous bone marrow-derived mononuclear cells (MNCs) and/or CD133+ cells on liver function in patients with decompensated cirrhosis. We randomly assigned 27 eligible patients to a placebo, MNCs, and/or CD133+ cells. Cell infusions were performed at baseline and month 3. We considered the absolute changes in the Model for End-Stage Liver Disease (MELD) scores at months 3 and 6 after infusion as the primary outcome. The participants and those who assessed the outcomes were unaware of the treatment intervention assignments. After 6 months, 9 patients were excluded because of liver transplantation (n = 3), hepatocellular carcinoma (n = 1), loss to follow-up (n = 3), and death (n = 2). The final analysis included 4 patients from the CD133+ group, 8 from the MNC group, and 6 from the placebo group. No improvement was seen in the MELD score at month 6 using either CD133+ cells or MNC infusions compared with placebo. However, at month 3 after infusion, a trend was seen toward a higher mean absolute change in the MELD score in patients who had received CD133+ cells compared with placebo (−2.00 ± 1.87 vs. −0.13 ± 1.46; p = .08). No significant adverse events occurred in the present study. A transient improvement in the MELD score was observed in subjects treated with CD133+ cells but not in the MNC or placebo group. Although the study was not powered to make definitive conclusions, the data justify further study of CD133+ therapy in cirrhotic patients. Significance Cell therapy is a new approach in liver disease. Several clinical experiments have been reported on the safety of bone marrow-derived stem cells to treat liver disorders. However, the effectiveness of these approaches in the long-term follow-ups of patients initiated controversial discussions among the scientific community. A double-blind randomized controlled trial was designed to address this concern scientifically. A transient improvement in the patients’ signs occurred; however, for a sustainable result, more work is needed. The results of multiple administrations of cells reported in the present study can be compared with the results from other single-injection studies. PMID:26659833

Compliance with the gluten-free diet: the role of locus of control in celiac disease.

PubMed

Bellini, Anna; Zanchi, Chiara; Martelossi, Stefano; Di Leo, Grazia; Not, Tarcisio; Ventura, Alessandro

2011-03-01

To verify whether subjects with celiac disease (CD) have a different locus of control (LoC) compared with healthy subjects, and to evaluate the relationship between LoC and compliance with a prescribed gluten-free diet (GFD) and quality of life (QoL). We studied 156 subjects on a GFD (mean age, 10 years) and 353 healthy controls (mean age, 12 years). All subjects completed tests on the Nowicki-Strickland Locus of Control Scale; the subjects with CD also completed a questionnaire to measure compliance with dietary treatment and the disease's impact on QoL. There was no difference in LoC values between patients with CD and controls. Subjects with CD with good dietary compliance had a more internal LoC compared with those who were not compliant (P = .01). Patients who reported a satisfactory QoL had a more internal LoC compared with those who reported negative affects on QoL due to CD (P = .01). Our study confirms the usefulness of the LoC concept for identifying those patients who might be at risk for dietary transgression. Given the enhanced, psychological, and social well being that can result from adherence to a GFD, educational and psychological support can help internalize the LoC in those patients at risk for dietary transgression. Copyright © 2011 Mosby, Inc. All rights reserved.

CD4+/CD25(high)/FoxP3+/CD127- regulatory T cells in bronchoalveolar lavage fluid of lung cancer patients.

PubMed

Osińska, Iwona; Stelmaszczyk-Emmel, Anna; Polubiec-Kownacka, Małgorzata; Dziedzic, Dariusz; Domagała-Kulawik, Joanna

2016-10-01

The aim of the study was to compare the presence of regulatory T cells (Tregs) in the local lung cancer environment versus systemic immune response based on the examination of bronchoalveolar lavage fluid (BALf) and peripheral blood (PB) from the same patient. 35 patients with lung cancer were investigated. Flow cytometry method with panel of antibodies: anti CD4/CD25/FoxP3/CD127 for Tregs identification was used. We observed significantly higher proportion of Tregs in the BALF than in PB (median 9.4 vs. 5.4%, p<0.05). The increased proportion of Tregs in patients with advanced disease and in adenocarcinoma was found. This study confirmed the usefulness of BALF analysis in evaluation of immune response in lung cancer. Detection of Tregs in the local tumour environment may have therapeutic relevance in individual indication for anti-cancer immune-therapies. Copyright © 2016 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.

Correlation of Biomarker Expression in Colonic Mucosa with Disease Phenotype in Crohn's Disease and Ulcerative Colitis.

PubMed

Bruno, Maria E C; Rogier, Eric W; Arsenescu, Razvan I; Flomenhoft, Deborah R; Kurkjian, Cathryn J; Ellis, Gavin I; Kaetzel, Charlotte S

2015-10-01

Inflammatory bowel diseases (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), are characterized by chronic intestinal inflammation due to immunological, microbial, and environmental factors in genetically predisposed individuals. Advances in the diagnosis, prognosis, and treatment of IBD require the identification of robust biomarkers that can be used for molecular classification of diverse disease presentations. We previously identified five genes, RELA, TNFAIP3 (A20), PIGR, TNF, and IL8, whose mRNA levels in colonic mucosal biopsies could be used in a multivariate analysis to classify patients with CD based on disease behavior and responses to therapy. We compared expression of these five biomarkers in IBD patients classified as having CD or UC, and in healthy controls. Patients with CD were characterized as having decreased median expression of TNFAIP3, PIGR, and TNF in non-inflamed colonic mucosa as compared to healthy controls. By contrast, UC patients exhibited decreased expression of PIGR and elevated expression of IL8 in colonic mucosa compared to healthy controls. A multivariate analysis combining mRNA levels for all five genes resulted in segregation of individuals based on disease presentation (CD vs. UC) as well as severity, i.e., patients in remission versus those with acute colitis at the time of biopsy. We propose that this approach could be used as a model for molecular classification of IBD patients, which could further be enhanced by the inclusion of additional genes that are identified by functional studies, global gene expression analyses, and genome-wide association studies.

Angiogenic T cell expansion correlates with severity of peripheral vascular damage in systemic sclerosis.

PubMed

Manetti, Mirko; Pratesi, Sara; Romano, Eloisa; Bellando-Randone, Silvia; Rosa, Irene; Guiducci, Serena; Fioretto, Bianca Saveria; Ibba-Manneschi, Lidia; Maggi, Enrico; Matucci-Cerinic, Marco

2017-01-01

The mechanisms underlying endothelial cell injury and defective vascular repair in systemic sclerosis (SSc) remain unclear. Since the recently discovered angiogenic T cells (Tang) may have an important role in the repair of damaged endothelium, this study aimed to analyze the Tang population in relation to disease-related peripheral vascular features in SSc patients. Tang (CD3+CD31+CXCR4+) were quantified by flow cytometry in peripheral blood samples from 39 SSc patients and 18 healthy controls (HC). Circulating levels of the CXCR4 ligand stromal cell-derived factor (SDF)-1α and proangiogenic factors were assessed in paired serum samples by immunoassay. Serial skin sections from SSc patients and HC were subjected to CD3/CD31 and CD3/CXCR4 double immunofluorescence. Circulating Tang were significantly increased in SSc patients with digital ulcers (DU) compared either with SSc patients without DU or with HC. Tang levels were significantly higher in SSc patients with late nailfold videocapillaroscopy (NVC) pattern than in those with early/active NVC patterns and in HC. No difference in circulating Tang was found when comparing either SSc patients without DU or patients with early/active NVC patterns and HC. In SSc peripheral blood, Tang percentage was inversely correlated to levels of SDF-1α and CD34+CD133+VEGFR-2+ endothelial progenitor cells (EPC), and positively correlated to levels of vascular endothelial growth factor and matrix metalloproteinase-9. Tang were frequently detected in SSc dermal perivascular inflammatory infiltrates. In summary, our findings demonstrate for the first time that Tang cells are selectively expanded in the circulation of SSc patients displaying severe peripheral vascular complications like DU. In SSc, Tang may represent a potentially useful biomarker reflecting peripheral vascular damage severity. Tang expansion may be an ineffective attempt to compensate the need for increased angiogenesis and EPC function. Further studies are required to clarify the function of Tang cells and investigate the mechanisms responsible for their change in SSc.

Internet-orientated Assessment of QOL and Actual Treatment Status in Japanese Patients with Inflammatory Bowel Disease: The 3I survey.

PubMed

Matsumoto, Takayuki; Yanai, Shunichi; Toya, Yosuke; Ueno, Masato; Nakamura, Shotaro

2015-06-01

This survey aimed to compare actual lifestyle factors and QOL between Japanese IBD patients and healthy Japanese controls, by questionnaire using an internet-web system. Through the internet-web system, we asked 464 patients with Crohn's disease [CD], 360 patients with ulcerative colitis [UC], and 4100 healthy controls to answer a questionnaire including an eight-item short-form health survey [SF-8]. The survey was conducted until data had been accumulated from the predetermined numbers of patients [120 patients each with CD and UC] and healthy controls [240 subjects]. QOL assessment by SF-8 revealed scores for six of the eight subscale items and the summary score for the mental component to be significantly lower in the CD and UC groups than in controls. There was a significant negative correlation between each SF-8 score and the degree of CD and UC symptoms. The marriage rate in adult patients was significantly lower in the CD than in the UC group or the controls. The mean annual income and the employment rate were significantly lower in the CD than in the UC group or the controls. CD patients receiving biologicals were more frequently satisfied with the efficacy of treatment than UC patients were with their treatment regimens [56% vs 29%]. Actual lifestyle factors and QOL appear to be impaired in Japanese patients with IBD, especially those with CD. The subjective efficacy of biologicals might be greater in CD than in UC. Copyright © 2015 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.

TRAIL Death Receptor-4, Decoy Receptor-1 and Decoy Receptor-2 Expression on CD8+ T Cells Correlate with the Disease Severity in Patients with Rheumatoid Arthritis

PubMed Central

2010-01-01

Background Rheumatoid Arthritis (RA) is a chronic autoimmune inflammatory disorder. Although the pathogenesis of disease is unclear, it is well known that T cells play a major role in both development and perpetuation of RA through activating macrophages and B cells. Since the lack of TNF-Related Apoptosis Inducing Ligand (TRAIL) expression resulted in defective thymocyte apoptosis leading to an autoimmune disease, we explored evidence for alterations in TRAIL/TRAIL receptor expression on peripheral T lymphocytes in the molecular mechanism of RA development. Methods The expression of TRAIL/TRAIL receptors on T cells in 20 RA patients and 12 control individuals were analyzed using flow cytometry. The correlation of TRAIL and its receptor expression profile was compared with clinical RA parameters (RA activity scored as per DAS28) using Spearman Rho Analysis. Results While no change was detected in the ratio of CD4+ to CD8+ T cells between controls and RA patient groups, upregulation of TRAIL and its receptors (both death and decoy) was detected on both CD4+ and CD8+ T cells in RA patients compared to control individuals. Death Receptor-4 (DR4) and the decoy receptors DcR1 and DcR2 on CD8+ T cells, but not on CD4+ T cells, were positively correlated with patients' DAS scores. Conclusions Our data suggest that TRAIL/TRAIL receptor expression profiles on T cells might be important in revelation of RA pathogenesis. PMID:20799941

[Effects of Early Enteral Immunonutrition on Postoperative Immune Function and Rehabilitation of Patients with Gastric Cancer and Nutritional Risk].

PubMed

Peng, Chang-Bing; Li, Wen-Zhong; Xu, Rui; Zhuang, Wen

2017-05-01

To investigate the effects of early enteral immunonutrition on postoperative immune function and rehabilitation of gastric cancer patients with nutritional risk. New hospitalized patients with gastric cancer were evaluated the nutrient status based on NRS 2002. The patients who scored between 3 to 5 points were randomized into two groups(30 cases for each group), and those in experimental group were given 7-d early postoperative enteral immune nutrition, those in control group were given normal nutrition. The immune indexes (CD3 + , CD4 + , CD8 + and CD4 + /CD8 + ) and nutritional indexes(transferrin, pre-albumin, albumin) were measured before operation and at the 3 rd and 7 th day postoperatively. In addition, the first flatus time, gastrointestinal adverse reactions and complications, length of hospital stays were compared between the two groups. The level of CD4 + /CD8 + and transferrin, pre-albumin, albumin in experimental group were significantly higher than those in control group at the third and seventh day postoperatively ( P <0.05).Compared with the control group, the experimental group had shorter first flatus time after surgery, which were (63.5±7.3) h vs. (72.8±8.6 ) h respectively ( P <0.05).There were no statistically difference on pneumonia, anastomosis leakage, severe abdominal distension, inflammatory bowel obstruction and total postoperative hospitalization time between the two groups ( P >0.05). Early enteral immunonutrition can effectively promote the recovery of nutritional status and immune function in gastric cancer patients with nutrition risk.

Immunologic and psychosocial status in chronic fatigue syndrome.

PubMed

Nas, K; Cevik, R; Batum, S; Sarac, A J; Acar, S; Kalkanli, S

2011-01-01

The aim of the study was to investigate the immunologic functions and psychosocial status in patients with chronic fatigue syndrome (CFS). Twenty-five patients with CFS diagnosed by the international CFS definition criteria and 20 age- and gender-matched healthy controls were recruited. Depression was assessed by Beck Depression Inventory (BDI) and health status was assessed by Nottingham Health Profile (NHP). Monoclonal antibodies (MAbs) were measured to identify the following NK cell subsets: CD3, CD4, CD8 and CD56 and cytokine measurements were performed for IL2r, IL6 and IL8 in both patients and control subjects. The BDI and NHP scores of CFS group were found to be significantly higher than in the control group. The absolute numbers of CD56 cell were also significantly decreased in the patients with CFS compared with the healthy controls. There were no other significant differences of NK cell activity (CD3, CD4 and CD8) and there were significant differences in IL6 and IL2r levels between patients and controls. There were significant correlations between serum IL-6 level and sleep, social isolation and physical ability NHP subscores, and betweenCD56 NK cell activity and emotional reaction NHP sub score in CFS patients. Significantly higher ratios of psychological and physical disturbances were found in patients with CFS. Decreased CD56 NK cell activity and increased IL2r levels seem to be important immunopathologic changes in CFS. IL-6 and CD 56 NK cell activity may play an important role in sleep, physical, social, and physicological manifestations of CFS (Tab. 3, Fig. 1, Ref. 36). Full Text in free PDF www.bmj.sk.

Soluble CD30 and Hepatocyte growth factor as predictive markers of antibody-mediated rejection of the kidney allograft.

PubMed

Pavlova, Yelena; Viklicky, Ondrej; Slatinska, Janka; Bürgelova, Marcela; Süsal, Caner; Skibova, Jelena; Honsová, Eva; Striz, Ilja; Kolesar, Libor; Slavcev, Antonij

2011-07-01

Our retrospective study was aimed to assess the relevance of pre- and post-transplant measurements of serum concentrations of the soluble CD30 molecule (soluble CD30, sCD30) and the cytokine Hepatocyte growth factor (HGF) for prediction of the risk for development of antibody-mediated rejection (AMR) in kidney transplant patients. Evaluation of sCD30, HGF levels and the presence of HLA-specific antibodies in a cohort of 205 patients was performed before, 2weeks and 6months after transplantation. Patients were followed up for kidney graft function and survival for two years. We found a tendency of higher incidence of AMR in retransplanted patients with elevated pre-transplant sCD30 (≥100U/ml) (p=0.051), however no such correlation was observed in first-transplant patients. Kidney recipients with simultaneously high sCD30 and HLA-specific antibodies (sCD30+/Ab+) before transplantation had significantly lower AMR-free survival compared to the other patient groups (p<0.001). HGF concentrations were not associated with the incidence of AMR at any time point of measurement, nevertheless, the combined analysis HGF and sCD30 showed increased incidence of AMR in recipients with elevated pretransplant sCD30 and low HGF levels. the predictive value of pretransplant sCD30 for the development of antibody-mediated rejection after transplantation is significantly potentiated by the co-presence of HLA specific antibodies. The role of HGF as a rejection-protective factor in patients with high pretransplant HGF levels would need further investigation. Copyright © 2011 Elsevier B.V. All rights reserved.

Role of LAP+CD4+ T cells in the tumor microenvironment of colorectal cancer.

PubMed

Zhong, Wu; Jiang, Zhi-Yuan; Zhang, Lei; Huang, Jia-Hao; Wang, Shi-Jun; Liao, Cun; Cai, Bin; Chen, Li-Sheng; Zhang, Sen; Guo, Yun; Cao, Yun-Fei; Gao, Feng

2017-01-21

To investigate the abundance and potential functions of LAP + CD4 + T cells in colorectal cancer (CRC). Proportions of LAP + CD4 + T cells were examined in peripheral blood and tumor/paratumor tissues of CRC patients and healthy controls using flow cytometry. Expression of phenotypic markers such as forkhead box (Fox)p3, cytotoxic T-lymphocyte-associated protein (CTLA)-4, chemokine CC receptor (CCR)4 and CCR5 was measured using flow cytometry. LAP - CD4 + and LAP + CD4 + T cells were isolated using a magnetic cell-sorting system and cell purity was analyzed by flow cytometry. Real-time quantitative polymerase chain reaction was used to measure expression of cytokines interleukin (IL)-10 and transforming growth factor (TGF)-β. The proportion of LAP + CD4 + T cells was significantly higher in peripheral blood from patients (9.44% ± 3.18%) than healthy controls (1.49% ± 1.00%, P < 0.001). Among patients, the proportion of LAP + CD4 + T cells was significantly higher in tumor tissues (11.76% ± 3.74%) compared with paratumor tissues (3.87% ± 1.64%, P < 0.001). We also observed positive correlations between the proportion of LAP + CD4 + T cells and TNM stage ( P < 0.001), distant metastasis ( P < 0.001) and serum level of carcinoembryonic antigen ( P < 0.05). Magnetic-activated cell sorting gave an overall enrichment of LAP + CD4 + T cells (95.02% ± 2.87%), which was similar for LAP - CD4 + T cells (94.75% ± 2.76%). In contrast to LAP - CD4 + T cells, LAP + CD4 + T cells showed lower Foxp3 expression but significantly higher levels of CTLA-4, CCR4 and CCR5 ( P < 0.01). LAP + CD4 + T cells expressed significantly larger amounts of IL-10 and TGF-β but lower levels of IL-2, IL-4, IL-17 and interferon-γ, compared with LAP - CD4 + T cells. LAP + CD4 + T cells accumulated in the tumor microenvironment of CRC patients and were involved in immune evasion mediated by IL-10 and TGF-β.

CD4 responses in the setting or suboptimal virological responses to antiretroviral therapy: features, outcomes, and associated factors.

PubMed

Collazos, Julio; Asensi, Víctor; Cartón, José Antonio

2009-07-01

The factors associated with discordant viroimmunological responses following antiretroviral therapy are unclear. We studied 1380 patients who initiated a protease inhibitor (PI)-based antiretroviral regimen and who fulfilled the criteria for inclusion. Of them, 255 (18.5%) had CD4 increases > or =100 cells/microl after 1 year of therapy despite detectable viral load (immunological responders); they were compared with 669 patients (48.5%) who had CD4 increases <100 cells/microl regardless of their final viral load (immunological nonresponders). Immunological responders had higher rates of sexual acquisition of HIV (p = 0.03), lower rates of clinical progression (p = 0.02), higher probabilities of being naive to antiretroviral therapy (p = 0.006) or to PI if antiretroviral experienced (p = 0.03), higher rates of receiving only nucleoside reverse transcriptase inhibitors in addition to the PI (p = 0.04), and lower baseline CD4 counts (p = 0.007) and higher viral loads (p = 0.009), as compared with nonresponders. Multivariate analysis revealed that sexual transmission of HIV (homosexual p = 0.004, heterosexual p = 0.03), no prior PI experience (p = 0.005), absence of clinical progression (p = 0.02), and lower baseline CD4 counts (p = 0.03) were independently associated with immunological response. However, these factors differed according to the patients' prior antiretroviral status, as higher baseline viral load was also associated with immunological response in antiretroviral-experienced patients (p = 0.02), whereas baseline CD4 count (p = 0.007) was the only predictive parameter in antiretroviral-naive patients. We conclude that immunological responses despite suboptimal viral suppression are common. Prior PI experience, HIV transmission category, baseline CD4 counts, and clinical progression were independently predictive of this condition, although the associated factors were different depending on the patient's prior antiretroviral history.

CD30 downregulation, MMAE resistance, and MDR1 upregulation are all associated with resistance to brentuximab vedotin

PubMed Central

Chen, Robert; Hou, Jessie; Newman, Edward; Kim, Young; Donohue, Cecile; Liu, Xueli; Thomas, Sandra H.; Forman, Stephen J.; Kane, Susan E.

2015-01-01

Brentuximab vedotin (BV) is an antibody-drug conjugate that specifically delivers the potent cytotoxic drug MMAE to CD30-positive cells. BV is FDA-approved for treatment of relapsed/refractory Hodgkin lymphoma (HL) and anaplastic large cell lymphoma (ALCL); however, many patients do not achieve complete remission and develop BV resistant disease. We selected for BV-resistant HL (L428) and ALCL (Karpas-299) cell lines using either constant (ALCL) or pulsatile (HL) exposure to BV. We confirmed drug resistance by MTS assay, and analyzed CD30 expression in resistant cells by flow cytometry, qRT-PCR, and Western blotting. We also measured drug exporter expression, MMAE resistance, and intracellular MMAE concentrations in BV-resistant cells. Additionally, tissue biopsy samples from 10 HL and 5 ALCL patients who had relapsed or progressed after BV treatment were analyzed by immunohistocytochemistry for CD30 expression. The resistant ALCL cell line, but not the HL cell line, demonstrated downregulated CD30 expression compared to the parental cell line. In contrast, the HL cell line, but not the ALCL cell line, exhibited MMAE resistance and increased expression of the MDR1 drug exporter compared to the parental line. For both HL and ALCL, samples from patients relapsed/resistant on BV persistently expressed CD30 by immunohistocytochemistry. One HL patient sample expressed MDR1 by immunohistocytochemistry. Although loss of CD30 expression is a possible mode of BV resistance in ALCL in vitro models, this has not been confirmed in patients. MMAE resistance and MDR1 expression are possible modes of BV resistance for HL both in vitro and in patients. PMID:25840583

Central memory CD4 T cells are associated with incomplete restoration of the CD4 T cell pool after treatment-induced long-term undetectable HIV viraemia.

PubMed

Rallón, Norma; Sempere-Ortells, José M; Soriano, Vincent; Benito, José M

2013-11-01

It is unclear to what extent T cell reconstitution may be possible in HIV-1-infected individuals on continuous successful highly active antiretroviral therapy (HAART). Herein, we analysed distinct phenotypic markers of immune recovery in patients with undetectable viraemia for 8 years, taking as reference untreated patients and healthy controls. Seventy-two subjects were examined: 28 HIV-1+ patients on successful long-term HAART, 24 HIV-1+ untreated viraemic patients and 20 age-matched healthy controls. Analysis of naive and memory CD4 and CD8 T cells was combined with measurements of activation status (expression of CD38) and with thymic function (expression of CD31). Statistical significance was determined by non-parametric tests. After long-term HAART, the majority of parameters were normalized compared with age-matched control values, including T cell activation and thymic function. However, absolute counts of naive and central memory CD4 T cells remained below normal levels. The only parameters significantly associated with CD4 counts at the end of follow-up were the pre-HAART CD4 count ( β ± SD = 0.54 ± 0.16, P = 0.003) and the level of CD4 central memory cells at the end of follow-up (β ± SD = 1.18 ± 0.23, P < 0.0001). Only patients starting HAART with CD4 counts >350 cells/mm(3) reached a complete normalization of CD4 counts. Even after long-term successful HAART, complete CD4 restoration may be attainable only in patients starting therapy with moderately high CD4 counts, prompting early initiation of antiretroviral therapy. Incomplete CD4 restoration may be associated with a defective restoration of central memory CD4 T cells, a cell subset with a pivotal role in T cell homeostasis.

Phenotype and function of T cells infiltrating visceral metastases from gastrointestinal cancers and melanoma: implications for adoptive cell transfer therapy.

PubMed

Turcotte, Simon; Gros, Alena; Hogan, Katherine; Tran, Eric; Hinrichs, Christian S; Wunderlich, John R; Dudley, Mark E; Rosenberg, Steven A

2013-09-01

Adoptive cell transfer of tumor-infiltrating lymphocytes (TILs) can mediate cancer regression in patients with metastatic melanoma, but whether this approach can be applied to common epithelial malignancies remains unclear. In this study, we compared the phenotype and function of TILs derived from liver and lung metastases from patients with gastrointestinal (GI) cancers (n = 14) or melanoma (n = 42). Fewer CD3(+) T cells were found to infiltrate GI compared with melanoma metastases, but the proportions of CD8(+) cells, T cell differentiation stage, and expression of costimulatory molecules were similar for both tumor types. Clinical-scale expansion up to ~50 × 10(9) T cells on average was obtained for all patients with GI cancer and melanoma. From GI tumors, however, TIL outgrowth in high-dose IL-2 yielded 22 ± 1.4% CD3(+)CD8(+) cells compared with 63 ± 2.4% from melanoma (p < 0.001). IFN-γ ELISA demonstrated MHC class I-mediated reactivity of TIL against autologous tumor in 5 of 7 GI cancer patients tested (9% of 188 distinct TIL cultures) and in 9 of 10 melanoma patients (43% of 246 distinct TIL cultures). In these assays, MHC class I-mediated up-regulation of CD137 (4-1BB) expression on CD8(+) cells suggested that 0-3% of TILs expanded from GI cancer metastases were tumor-reactive. This study implies that the main challenge to the development of TIL adoptive cell transfer for metastatic GI cancers may not be the in vitro expansion of bulk TILs, but the ability to select and enrich for tumor-reactive T cells.

Phenotype and Function of T Cells Infiltrating Visceral Metastases from Gastrointestinal Cancers and Melanoma: Implications for Adoptive Cell Transfer Therapy

PubMed Central

Turcotte, Simon; Gros, Alena; Hogan, Katherine; Tran, Eric; Hinrichs, Christian S.; Wunderlich, John R.; Dudley, Mark E.

2013-01-01

Adoptive cell transfer of tumor-infiltrating lymphocytes (TILs) can mediate cancer regression in patients with metastatic melanoma, but whether this approach can be applied to common epithelial malignancies remains unclear. In this study, we compared the phenotype and function of TILs derived from liver and lung metastases from patients with gastrointestinal (GI) cancers (n = 14) or melanoma (n = 42). Fewer CD3+ T cells were found to infiltrate GI compared with melanoma metastases, but the proportions of CD8+ cells, T cell differentiation stage, and expression of costimulatory molecules were similar for both tumor types. Clinical-scale expansion up to ∼50 × 109 T cells on average was obtained for all patients with GI cancer and melanoma. From GI tumors, however, TIL outgrowth in high-dose IL-2 yielded 22 ± 1.4% CD3+CD8+ cells compared with 63 ± 2.4% from melanoma (p < 0.001). IFN-γ ELISA demonstrated MHC class I–mediated reactivity of TIL against autologous tumor in 5 of 7 GI cancer patients tested (9% of 188 distinct TIL cultures) and in 9 of 10 melanoma patients (43% of 246 distinct TIL cultures). In these assays, MHC class I–mediated up-regulation of CD137 (4-1BB) expression on CD8+ cells suggested that 0–3% of TILs expanded from GI cancer metastases were tumor-reactive. This study implies that the main challenge to the development of TIL adoptive cell transfer for metastatic GI cancers may not be the in vitro expansion of bulk TILs, but the ability to select and enrich for tumor-reactive T cells. PMID:23904171

The Redax® Coaxial Drain in pulmonary lobectomy: a study of efficacy

PubMed Central

Parini, Sara; Papalia, Esther; Massera, Fabio; Turello, Davide; Baietto, Guido; Casadio, Caterina

2017-01-01

Background Pleural drainage is required after pulmonary lobectomy to evacuate air-leak and fluid. We compared the performance of the new Redax® Coaxial Drain (CD) (Redax, Mirandola, Italy) with a standard chest tube (CT) in terms of fluid and air-leak evacuation. Methods Fifty-two patients receiving a 24-F CD under water-seal after pulmonary lobectomy through open surgery or video-assisted thoracic surgery (VATS) were matched according to demographic, clinical and pathological variables with 104 patients receiving a 24-F CT. Fluid evacuation and post-operative day 0 (POD0) fluid evacuation rate, air-leak rate, tension pneumothorax or increasing subcutaneous emphysema, tube occlusion at removal, visual analog scale (VAS) score at rest and during cough, chest drain duration, pleural fluid accumulation or residual pleural cavity after tube removal, post-operative morbidity and mortality rate were recorded and compared between the two groups. Results No differences were recorded in post-operative morbidity and mortality rates. Fluid drainage rates on POD0 were significantly higher in CD group (73% vs. 48%; P=0.004); air-leak occurrence was similar in both groups and no differences were recorded in terms of tension pneumothorax or increasing subcutaneous emphysema rates; VAS score was lower for CD when compared with CT and it reached significant difference in the subgroups of patients operated on by VATS; no cases of occlusion at removal were recorded in CD patient. Conclusions Redax® CD is safe and efficient in air-leak and fluid evacuation; due to its design and constituting material it is superior to standard CTs in terms of fluid evacuation rate and patient post-operative comfort. PMID:29221298

Social phobia in coeliac disease.

PubMed

Addolorato, Giovanni; Mirijello, Antonio; D'Angelo, Cristina; Leggio, Lorenzo; Ferrulli, Anna; Vonghia, Luisa; Cardone, Silvia; Leso, Veruscka; Miceli, Antonio; Gasbarrini, Giovanni

2008-01-01

A high prevalence of anxiety and depression has been reported in coeliac disease (CD). Although social phobia is included among the anxiety disorders, its presence in CD has never been investigated. The aim of the present study was to evaluate social phobia in CD patients. A total of 40 CD patients were consecutively enrolled in the study. Fifty healthy subjects were studied as controls. Social phobia was assessed by the Liebowitz Social Anxiety Scale (LSAS) and current depression by the modified version of the Zung Self-rating Depression Scale (M-SDS). The percentage of subjects with social phobia was significantly higher in CD patients than in controls (70% versus 16%; p<0.0001), and also when the more severe generalized form was considered (15.0% versus 0%; p=0.006). The percentage of subjects with social phobia was not statistically different between newly diagnosed subjects and patients on a gluten free diet (73.3% versus 68%; p: NS), nor considering its generalized form (7.0% versus 20%; p: NS). Current depression was present in a significantly higher percentage of CD patients in comparison with controls (52.5% versus 8%; p<0.0001). A direct correlation between social phobia and current depression was found in CD patients (r=0.582; p<0.0001). Despite the limited number of cases evaluated, the present study showed a significantly higher prevalence of social phobia in CD patients compared with in healthy subjects. Future studies are needed to clarify the possible social phobia-induced risks such as school and/or work failure in CD patients.

The clinical characteristics and the features of immunophenotype of peripheral lymphocytes of adult onset chronic active Epstein-Barr virus disease at a Tertiary Care Hospital in Beijing.

PubMed

Luo, Ling; Wang, Huanling; Fan, Hongwei; Xie, Jing; Qiu, Zhifeng; Li, Taisheng

2018-03-01

Chronic active Epstein-Barr virus (CAEBV) infection is a rare disease with high mortality. Most of CAEBV patients have been reported from Japan and are pediatric cases.The goal was to describe the clinical characteristics and the immunophenotypic features of peripheral lymphocytes in adult onset CAEBV patients.We retrospectively reviewed and analyzed all adult onset CAEBV cases admitted to Peking Union Medical College Hospital (PUMCH) between 2012 and 2016. Demographic, clinical, laboratory data, and the immunophentyping data of peripheral lymphocytes were collected.There were 28 adult onset CAEBV patients. The median age was 45 (range, 20-81). Most of the patients presented with fever; splenomegaly; lymphadenopathy and hepatitis. Unlike pediatric cases reported, the manifestations of cardiovascular diseases in our patients were pulmonary arterial hypertension, decreased cardiac function and aorta vasculitis. Prevalence of interstitial pneumonitis in our patients were comparatively higher and prevalence of hypersensitivity to mosquito bites were comparatively lower than that reported by Japan. In this study, CAEBV patients had decreased B cell, NK cell, CD4 cell and CD8 cell counts. The prevalence of low level of B cells, NK cells, CD4 cells was relatively higher than reported ever.Chinese adult onset CAEBV patients have different clinical characteristics and are featured by an immunosuppression status as demonstrated by decreased B cell, NK cell, CD4 cell and CD8 cell.

Red flags in children with chronic abdominal pain and Crohn's disease-a single center experience.

PubMed

El-Chammas, Khalil; Majeskie, Angela; Simpson, Pippa; Sood, Manu; Miranda, Adrian

2013-04-01

To compare history and symptoms at initial presentation of patients with chronic abdominal pain (CAP) and Crohn's disease (CD). Red flags are used to help determine which patients with CAP are likely to have an underlying disease such as CD. However, red flags have not been validated and pediatric studies are lacking. Patients seen in the outpatient Pediatric Gastroenterology Clinic at Children's Hospital of Wisconsin between 2005 and 2008 prospectively completed a demographic, history, and symptom questionnaire. Patients with abdominal pain for at least 1 month and no evidence of organic disease were compared with patients diagnosed with CD confirmed by mucosal biopsies. Data were collected on 606 patients (128 with CD and 478 with functional gastrointestinal disorders). Patients with functional gastrointestinal disorders had more stressors (P < .001), were more likely to have a positive family history of irritable bowel syndrome, reflux, or constipation (P < .05), were more likely to have vomiting but less likely to have hematochezia, weight loss, and problems gaining weight (P < .05); wake from sleep and joint pain were no different between groups. Anemia, hematochezia, and weight loss were most predictive of CD (cumulative sensitivity of 94%). The presence of anemia, hematochezia, and weight loss help identify patients with CAP who require further work-up and referral to a pediatric gastroenterologist. Furthermore, waking from sleep or joint pain occurred similarly between groups and should not be considered as "red flags." Copyright © 2013. Published by Mosby, Inc.

The clinical characteristics and the features of immunophenotype of peripheral lymphocytes of adult onset chronic active Epstein-Barr virus disease at a Tertiary Care Hospital in Beijing

PubMed Central

Luo, Ling; Wang, Huanling; Fan, Hongwei; Xie, Jing; Qiu, Zhifeng; Li, Taisheng

2018-01-01

Abstract Chronic active Epstein-Barr virus (CAEBV) infection is a rare disease with high mortality. Most of CAEBV patients have been reported from Japan and are pediatric cases. The goal was to describe the clinical characteristics and the immunophenotypic features of peripheral lymphocytes in adult onset CAEBV patients. We retrospectively reviewed and analyzed all adult onset CAEBV cases admitted to Peking Union Medical College Hospital (PUMCH) between 2012 and 2016. Demographic, clinical, laboratory data, and the immunophentyping data of peripheral lymphocytes were collected. There were 28 adult onset CAEBV patients. The median age was 45 (range, 20–81). Most of the patients presented with fever; splenomegaly; lymphadenopathy and hepatitis. Unlike pediatric cases reported, the manifestations of cardiovascular diseases in our patients were pulmonary arterial hypertension, decreased cardiac function and aorta vasculitis. Prevalence of interstitial pneumonitis in our patients were comparatively higher and prevalence of hypersensitivity to mosquito bites were comparatively lower than that reported by Japan. In this study, CAEBV patients had decreased B cell, NK cell, CD4 cell and CD8 cell counts. The prevalence of low level of B cells, NK cells, CD4 cells was relatively higher than reported ever. Chinese adult onset CAEBV patients have different clinical characteristics and are featured by an immunosuppression status as demonstrated by decreased B cell, NK cell, CD4 cell and CD8 cell. PMID:29489682

The Selective Centrifugation Ensures a Better In Vitro Isolation of ASCs and Restores a Soft Tissue Regeneration In Vivo.

PubMed

De Francesco, Francesco; Guastafierro, Antonio; Nicoletti, Gianfranco; Razzano, Sergio; Riccio, Michele; Ferraro, Giuseppe A

2017-05-12

Autologous fat grafting procedures in plastic surgery have been extensively used to reinforce soft tissue in congenital or acquired tissue impairments. With this background, the aim of this study is firstly to examine the impact of a selective centrifugation on existing adipose stem cells (ASCs) in terms of stemness profile maintenance and, secondly, to investigate the effect of restoring volume in reconstruction on patients affected by soft tissue damage. After centrifugation, the fat graft products were separated into two layers and subsequently examined in vitro for the expression of CD34, CD90, CD117, CD105, CD29, CD31, CD44, CD73, CD133, CD14 and CD45 markers by flow cytometry and gene expression analyses were performed for Sox2, WNT3A, END, CD44, FUT4, COLL1, CTNNB1, hbEGF, KRTLG, MMP2 and VIM genes. The results showed that in the middle-high density (MHD) layer there was a peak concentration of ASCs, compared to another layer obtained after centrifugation. Research carried out on patients under treatment for soft tissue regeneration using cells obtained from MHD layer selection will be fundamental in comparative analysis. These studies will lead to an adequate standardization of outcomes, provided that treatment is performed through cell selection. Therefore, a unique procedure in tissue reconstruction and regeneration through fat grafting is presented here.

Immunological changes in peripheral blood and in lymphoid tissue after treatment of HIV-infected subjects with highly active anti-retroviral therapy (HAART) or HAART + IL-2

PubMed Central

Zanussi, S; Simonelli, C; Bortolin, M T; D'Andrea, M; Crepaldi, C; Vaccher, E; Nasti, G; Politi, D; Barzan, L; Tirelli, U; De Paoli, P

1999-01-01

This study presents the immunophenotypic and functional analysis of lymphocyte subsets obtained from peripheral blood and lymphoid tissue from HIV+ individuals treated with highly active anti-retroviral therapy (HAART) alone or in combination with 6 million units international (MUI) s.c. IL-2. Before treatment, the HIV+ patients had reduced CD4 and increased CD8 values in the peripheral blood and lymphoid tissue and impaired cytokine production by peripheral blood mononuclear cells (PBMC). After 24 weeks of treatment, all the HIV+ patients demonstrated increased CD4 values in peripheral blood and lymphoid tissue. The use of IL-2 did not promote an additional CD4 expansion compared with HAART alone; increased ‘naive’ and CD26+ CD4 cells and reduced CD8 cells were found in the peripheral blood and lymphoid tissue of the IL-2-treated, but not of the HAART-treated patients. Both types of treatment induced a significant reduction of the CD8/CD38+ cells. While HAART alone had negligible effects on cytokine production by PBMC, the combined use of HAART + IL-2 was unable to increase the endogenous production of IL-2, but caused an increase of IL-4, IL-13 and interferon-gamma (IFN-γ) and a reduction of monocyte chemoattractant protein-1 (MCP-1) production. These data suggest that, although in this schedule IL-2 has minimal efficacy on CD4 recovery when compared with HAART alone, it produces an increase of ‘naive’ and CD26+CD4 cells and a partial restoration of cytokine production. These data may be used to better define clinical trials aiming to improve the IL-2-dependent immunological reconstitution of HIV-infected subjects. PMID:10361239

The association between semaphorin 3A levels and gluten-free diet in patients with celiac disease.

PubMed

Kessel, Aharon; Lin, Chen; Vadasz, Zahava; Peri, Regina; Eiza, Nasren; Berkowitz, Drora

2017-11-01

Celiac disease (CD) is an inflammatory disease affecting the small intestine. We aim to assess serum level and expression of semaphorin 3A (Sema3A) on T regulatory (Treg) cells in CD patients. Twenty-six newly diagnosed celiac patients, 13 celiac patients on a gluten-free diet and 16 healthy controls included in the study. Sema3A protein level in the serum of celiac patients was significantly higher compared to healthy group (7.17±1.8ng/ml vs. 5.67±1.5ng/ml, p=0.012). Sema3A expression on Treg cells was statistically lower in celiac patients compared to healthy subjects (p=0.009) and significantly lower in celiac patients compared to celiac patients on gluten free diet (p=0.04). Negative correlation was found between Sema3A on Teg cells and the level of IgA anti-tTG antibodies (r=-0.346, p<0.01) and anti-DGP (r=-0.448, p<0.01). This study suggests involvement of the Sema3A in the pathogenesis of CD. Copyright © 2017 Elsevier Inc. All rights reserved.

Antigen-Presenting Intratumoral B Cells Affect CD4+ TIL Phenotypes in Non-Small Cell Lung Cancer Patients.

PubMed

Bruno, Tullia C; Ebner, Peggy J; Moore, Brandon L; Squalls, Olivia G; Waugh, Katherine A; Eruslanov, Evgeniy B; Singhal, Sunil; Mitchell, John D; Franklin, Wilbur A; Merrick, Daniel T; McCarter, Martin D; Palmer, Brent E; Kern, Jeffrey A; Slansky, Jill E

2017-10-01

Effective immunotherapy options for patients with non-small cell lung cancer (NSCLC) are becoming increasingly available. The immunotherapy focus has been on tumor-infiltrating T cells (TILs); however, tumor-infiltrating B cells (TIL-Bs) have also been reported to correlate with NSCLC patient survival. The function of TIL-Bs in human cancer has been understudied, with little focus on their role as antigen-presenting cells and their influence on CD4 + TILs. Compared with other immune subsets detected in freshly isolated primary tumors from NSCLC patients, we observed increased numbers of intratumoral B cells relative to B cells from tumor-adjacent tissues. Furthermore, we demonstrated that TIL-Bs can efficiently present antigen to CD4 + TILs and alter the CD4 + TIL phenotype using an in vitro antigen-presentation assay. Specifically, we identified three CD4 + TIL responses to TIL-Bs, which we categorized as activated, antigen-associated, and nonresponsive. Within the activated and antigen-associated CD4 + TIL population, activated TIL-Bs (CD19 + CD20 + CD69 + CD27 + CD21 + ) were associated with an effector T-cell response (IFNγ + CD4 + TILs). Alternatively, exhausted TIL-Bs (CD19 + CD20 + CD69 + CD27 - CD21 - ) were associated with a regulatory T-cell phenotype (FoxP3 + CD4 + TILs). Our results demonstrate a new role for TIL-Bs in NSCLC tumors in their interplay with CD4 + TILs in the tumor microenvironment, establishing them as a potential therapeutic target in NSCLC immunotherapy. Cancer Immunol Res; 5(10); 898-907. ©2017 AACR . ©2017 American Association for Cancer Research.

CD 10 expression intensity in various grades and stages of urothelial carcinoma of urinary bladder.

PubMed

Atique, Muhammad; Abbasi, Muhammad Sajjad; Jamal, Shahid; Khadim, Muhammad Tahir; Akhtar, Farhan; Jamal, Nighat

2014-05-01

To evaluate CD10 expression in urothelial carcinoma of the urinary bladder and the association of immunohistochemical (IHC) CD10 expression intensity with grade and stage. Descriptive cross-sectional analytical study. Armed Forces Institute of Pathology, Rawalpindi, from January to December 2011. Fifty consecutive cases of urothelial bladder carcinomas, obtained through transurethral resections, were included in this study. Hematoxylin-eosin (HE) stained sections from each case were re-evaluated histopathologically according to WHO 2004 grading system. The TNM system was used for pathologic staging. On selected slides IHC CD10 marker was applied and a semiquantitative scoring for its expression based on the percentage of positive cells and intensity was performed. Data was entered and analysed on SPSS version 17. Fisher's exact test was used to compare grades, stages of urothelial carcinoma with CD 10 expression and age groups. P < 0.05 was taken as level of significance. Urothelial carcinoma was more common in males. The male to female ratio was 9:1. The older patients > 50 years had higher grade and stage as compared to the younger patients. All cases of high grade urothelial carcinoma showed higher positivity for CD 10. Twenty cases (86.95%) of high grade urothelial carcinoma were positive with +2 immunostaining while 3 cases (13.04 %) were positive with +1 staining. None of the tumors of stage pTa was positive for CD 10 expression. Of all patients with stage pT 1 tumor, 1 case (5.3%) was CD 10 negative and 17 cases (89.9%) were CD 10 positive having +1 staining with 5 - 50% staining and 1 case (5.3%) had +2 staining with more then 50% expression. Out of all patients with stage pT 2, no tumor was CD 10 negative, 3 (13.6%) patients were CD 10 positive with +1 staining and 19 (86.4%) with stage pT 2 tumor had stained positive with +2 staining. CD 10 expression was greater in high grade and invasive urothelial carcinomas; it may be associated with tumor progression in bladder cancer pathogenesis.

Emotion-motion interactions in conversion disorder: an FMRI study.

PubMed

Aybek, Selma; Nicholson, Timothy R; O'Daly, Owen; Zelaya, Fernando; Kanaan, Richard A; David, Anthony S

2015-01-01

To evaluate the neural correlates of implicit processing of negative emotions in motor conversion disorder (CD) patients. An event related fMRI task was completed by 12 motor CD patients and 14 matched healthy controls using standardised stimuli of faces with fearful and sad emotional expressions in comparison to faces with neutral expressions. Temporal changes in the sensitivity to stimuli were also modelled and tested in the two groups. We found increased amygdala activation to negative emotions in CD compared to healthy controls in region of interest analyses, which persisted over time consistent with previous findings using emotional paradigms. Furthermore during whole brain analyses we found significantly increased activation in CD patients in areas involved in the 'freeze response' to fear (periaqueductal grey matter), and areas involved in self-awareness and motor control (cingulate gyrus and supplementary motor area). In contrast to healthy controls, CD patients exhibited increased response amplitude to fearful stimuli over time, suggesting abnormal emotional regulation (failure of habituation / sensitization). Patients with CD also activated midbrain and frontal structures that could reflect an abnormal behavioral-motor response to negative including threatening stimuli. This suggests a mechanism linking emotions to motor dysfunction in CD.

Asymmetric pallidal neuronal activity in patients with cervical dystonia

PubMed Central

Moll, Christian K. E.; Galindo-Leon, Edgar; Sharott, Andrew; Gulberti, Alessandro; Buhmann, Carsten; Koeppen, Johannes A.; Biermann, Maxine; Bäumer, Tobias; Zittel, Simone; Westphal, Manfred; Gerloff, Christian; Hamel, Wolfgang; Münchau, Alexander; Engel, Andreas K.

2014-01-01

The origin of asymmetric clinical manifestation of symptoms in patients suffering from cervical dystonia (CD) is hitherto poorly understood. Dysregulated neuronal activity in the basal ganglia has been suggested to have a role in the pathophysiology of CD. Here, we re-assessed the question to what extent relative changes occur in the direct vs. indirect basal ganglia pathway in CD, whether these circuit changes are lateralized, and how these alterations relate to CD symptoms. To this end, we recorded ongoing single cell and local field potential (LFP) activity from the external (GPe) and internal pallidal segment (GPi) of 13 CD patients undergoing microelectrode-guided stereotactic surgery for deep brain stimulation in the GPi. We compared pallidal recordings from CD patients operated under local anaesthesia (LA) with those obtained in CD patients operated under general anaesthesia (GA). In awake patients, mean GPe discharge rate (52 Hz) was lower than that of GPi (72 Hz). Mean GPi discharge ipsilateral to the side of head turning was higher than contralateral and correlated with torticollis symptom severity. Lateralized differences were absent at the level of the GPe and in recordings from patients operated under GA. Furthermore, in the GPi of CD patients there was a subpopulation of theta-oscillatory cells with unique bursting characteristics. Power and coherence of GPe– and GPi–LFPs were dominated by a theta peak and also exhibited band-specific interhemispheric differences. Strong cross-frequency coupling of low-gamma amplitude to theta phase was a feature of pallidal LFPs recorded under LA, but not GA. These results indicate that CD is associated with an asymmetric pallidal outflow. Based on the finding of symmetric neuronal discharges in the GPe, we propose that an imbalanced interhemispheric direct pathway gain may be involved in CD pathophysiology. PMID:24574981

Coeliac disease screening is suboptimal in a tertiary gastroenterology setting.

PubMed

Iskandar, Heba; Gray, Darrell M; Vu, Hongha; Mirza, Faiz; Rude, Mary Katherine; Regan, Kara; Abdalla, Adil; Gaddam, Srinivas; Almaskeen, Sami; Mello, Michael; Marquez, Evelyn; Meyer, Claire; Bolkhir, Ahmed; Kanuri, Navya; Sayuk, Gregory; Gyawali, C Prakash

2017-08-01

Coeliac disease (CD) is widely prevalent in North America, but case-finding techniques currently used may not be adequate for patient identification. We aimed to determine the adequacy of CD screening in an academic gastroenterology (GI) practice. Consecutive initial visits to a tertiary academic GI practice were surveyed over a 3-month period as a fellow-initiated quality improvement project. All electronic records were reviewed to look for indications for CD screening according to published guidelines. The timing of screening was noted (before or after referral), as well as the screening method (serology or biopsy). Data were analysed to compare CD screening practices across subspecialty clinics. 616 consecutive patients (49±0.6 years, range 16-87 years, 58.5% females, 94% Caucasian) fulfilled inclusion criteria. CD testing was indicated in 336 (54.5%), but performed in only 145 (43.2%). The need for CD screening was highest in luminal GI and inflammatory bowel disease clinics, followed by biliary and hepatology clinics (p<0.0001); CD screening rate was highest in the luminal GI clinic (p=0.002). Of 145 patients screened, 4 patients (2.4%) had serology consistent with CD, of which 2 were proven by duodenal biopsy. Using this proportion, an additional 5 patients might have been diagnosed in 191 untested patients with indications for CD screening. More than 50% of patients in a tertiary GI clinic have indications for CD screening, but <50% of indicated cases are screened. Case-finding techniques therefore are suboptimal, constituting a gap in patient care and an important target for future quality improvement initiatives. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

CD147/basigin reflects renal dysfunction in patients with acute kidney injury.

PubMed

Nagaya, Hiroshi; Kosugi, Tomoki; Maeda-Hori, Mayuko; Maeda, Kayaho; Sato, Yuka; Kojima, Hiroshi; Hayashi, Hiroki; Kato, Noritoshi; Ishimoto, Takuji; Sato, Waichi; Yuzawa, Yukio; Matsuo, Seiichi; Kadomatsu, Kenji; Maruyama, Shoichi

2014-10-01

Acute tubular necrosis (ATN) describes a form of intrinsic acute kidney injury (AKI) that results from persistent hypoperfusion and subsequent activation of the immune system. A glycosylated transmembrane protein, CD147/basigin, is involved in the pathogenesis of renal ischemia and fibrosis. The present study investigated whether CD147 can reflect pathological features and renal dysfunction in patients with AKI. Plasma and spot urine samples were collected from 24 patients (12 controls and 12 with ATN) who underwent renal biopsy between 2008 and 2012. In another study, patients undergoing open surgery to treat abdominal aortic aneurysms (AAAs) were enrolled in 2004. We collected urine and plasma samples from seven patients with AKI and 33 patients without AKI, respectively. In these experiments, plasma and urinary CD147, and urinary L-fatty acid-binding protein (L-FABP) levels were measured, and the former expression in kidneys was examined by immunostaining. In biopsy tissues of ATN with severe histological features, CD147 induction was strikingly present in inflammatory cells such as macrophages and lymphocytes in the injured interstitium, but not in damaged tubules representing atrophy. Both plasma and urinary CD147 levels were strikingly increased in ATN patients; both values showed greater correlations with renal dysfunction compared to urinary L-FABP. In patients who had undergone open AAA surgery, urinary and plasma CD147 values in AKI patients were significantly higher than in non-AKI patients at post-operative day 1, similar to the profile of urinary L-FABP. CD147 was prominent in its ability to detect AKI and may allow the start of preemptive medication.

Immune Reconstitution After Allogeneic Hematopoietic Stem Cell Transplantation and Association With Occurrence and Outcome of Invasive Aspergillosis.

PubMed

Stuehler, Claudia; Kuenzli, Esther; Jaeger, Veronika K; Baettig, Veronika; Ferracin, Fabrizia; Rajacic, Zarko; Kaiser, Deborah; Bernardini, Claudia; Forrer, Pascal; Weisser, Maja; Elzi, Luigia; Battegay, Manuel; Halter, Joerg; Passweg, Jakob; Khanna, Nina

2015-09-15

Invasive aspergillosis (IA) remains a leading cause of morbidity and mortality in patients receiving allogeneic hematopoietic stem cell transplantation (HSCT). To date, no reliable immunological biomarkers for management and outcome of IA exist. Here, we investigated reconstitution of antifungal immunity in patients during the first 12 months after HSCT and correlated it with IA. Fifty-one patients were included, 9 with probable/proven IA. We determined quantitative and qualitative reconstitution of polymorphonuclear (PMN), CD4, CD8, and natural killer (NK) cells against Aspergillus fumigatus over 5 time points and compared the values to healthy donors. Absolute CD4 and CD8 cell counts, antigen-specific T-cell responses, and killing capacity of PMN against A. fumigatus were significantly decreased in all patients over 12 months. In patients with probable/proven IA, reactive oxygen species (ROS) production tended to be lower compared to patients without IA, and absolute NK-cell counts remained below 200 cells/µL. Patients with well-controlled IA showed significantly higher ROS production and NK-cell counts compared to patients with poor outcome. This study highlights the importance of functional PMN, T-cell, and NK-cell immunity for the outcome of IA. Larger multicenter studies should address the potential use of NK-cell counts for the management of antifungal therapy. © The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Exhausted Cytotoxic Control of Epstein-Barr Virus in Human Lupus

PubMed Central

Larsen, Martin; Sauce, Delphine; Deback, Claire; Arnaud, Laurent; Mathian, Alexis; Miyara, Makoto; Boutolleau, David; Parizot, Christophe; Dorgham, Karim; Papagno, Laura; Appay, Victor; Amoura, Zahir; Gorochov, Guy

2011-01-01

Systemic Lupus Erythematosus (SLE) pathology has long been associated with an increased Epstein-Barr Virus (EBV) seropositivity, viremia and cross-reactive serum antibodies specific for both virus and self. It has therefore been postulated that EBV triggers SLE immunopathology, although the mechanism remains elusive. Here, we investigate whether frequent peaks of EBV viral load in SLE patients are a consequence of dysfunctional anti-EBV CD8+ T cell responses. Both inactive and active SLE patients (n = 76 and 42, respectively), have significantly elevated EBV viral loads (P = 0.003 and 0.002, respectively) compared to age- and sex-matched healthy controls (n = 29). Interestingly, less EBV-specific CD8+ T cells are able to secrete multiple cytokines (IFN-γ, TNF-α, IL-2 and MIP-1β) in inactive and active SLE patients compared to controls (P = 0.0003 and 0.0084, respectively). Moreover, EBV-specific CD8+ T cells are also less cytotoxic in SLE patients than in controls (CD107a expression: P = 0.0009, Granzyme B release: P = 0.0001). Importantly, cytomegalovirus (CMV)-specific responses were not found significantly altered in SLE patients. Furthermore, we demonstrate that EBV-specific CD8+ T cell impairment is a consequence of their Programmed Death 1 (PD-1) receptor up-regulation, as blocking this pathway reverses the dysfunctional phenotype. Finally, prospective monitoring of lupus patients revealed that disease flares precede EBV reactivation. In conclusion, EBV-specific CD8+ T cell responses in SLE patients are functionally impaired, but EBV reactivation appears to be an aggravating consequence rather than a cause of SLE immunopathology. We therefore propose that autoimmune B cell activation during flares drives frequent EBV reactivation, which contributes in a vicious circle to the perpetuation of immune activation in SLE patients. PMID:22028659

Exhausted cytotoxic control of Epstein-Barr virus in human lupus.

PubMed

Larsen, Martin; Sauce, Delphine; Deback, Claire; Arnaud, Laurent; Mathian, Alexis; Miyara, Makoto; Boutolleau, David; Parizot, Christophe; Dorgham, Karim; Papagno, Laura; Appay, Victor; Amoura, Zahir; Gorochov, Guy

2011-10-01

Systemic Lupus Erythematosus (SLE) pathology has long been associated with an increased Epstein-Barr Virus (EBV) seropositivity, viremia and cross-reactive serum antibodies specific for both virus and self. It has therefore been postulated that EBV triggers SLE immunopathology, although the mechanism remains elusive. Here, we investigate whether frequent peaks of EBV viral load in SLE patients are a consequence of dysfunctional anti-EBV CD8+ T cell responses. Both inactive and active SLE patients (n = 76 and 42, respectively), have significantly elevated EBV viral loads (P = 0.003 and 0.002, respectively) compared to age- and sex-matched healthy controls (n = 29). Interestingly, less EBV-specific CD8+ T cells are able to secrete multiple cytokines (IFN-γ, TNF-α, IL-2 and MIP-1β) in inactive and active SLE patients compared to controls (P = 0.0003 and 0.0084, respectively). Moreover, EBV-specific CD8+ T cells are also less cytotoxic in SLE patients than in controls (CD107a expression: P = 0.0009, Granzyme B release: P = 0.0001). Importantly, cytomegalovirus (CMV)-specific responses were not found significantly altered in SLE patients. Furthermore, we demonstrate that EBV-specific CD8+ T cell impairment is a consequence of their Programmed Death 1 (PD-1) receptor up-regulation, as blocking this pathway reverses the dysfunctional phenotype. Finally, prospective monitoring of lupus patients revealed that disease flares precede EBV reactivation. In conclusion, EBV-specific CD8+ T cell responses in SLE patients are functionally impaired, but EBV reactivation appears to be an aggravating consequence rather than a cause of SLE immunopathology. We therefore propose that autoimmune B cell activation during flares drives frequent EBV reactivation, which contributes in a vicious circle to the perpetuation of immune activation in SLE patients.

Differential influence of vemurafenib and dabrafenib on patients’ lymphocytes despite similar clinical efficacy in melanoma

PubMed Central

Schilling, B.; Sondermann, W.; Zhao, F.; Griewank, K. G.; Livingstone, E.; Sucker, A.; Zelba, H.; Weide, B.; Trefzer, U.; Wilhelm, T.; Loquai, C.; Berking, C.; Hassel, J.; Kähler, K. C.; Utikal, J.; Al Ghazal, P.; Gutzmer, R.; Goldinger, S. M.; Zimmer, L.; Paschen, A.; Hillen, U.; Schadendorf, D.

2014-01-01

Background Since the majority of melanomas eventually become resistant and progress, combining selective BRAF inhibitors (BRAFi) with immunotherapies has been proposed to achieve more durable treatment responses. Here, we explored the impact of selective BRAFi on the hosts' immune system. Patients and methods Clinical data, whole blood counts (WBC) and serum lactate dehydrogenase (LDH) of 277 vemurafenib- and 65 dabrafenib-treated melanoma patients were evaluated. The frequency and phenotype of lymphocyte subpopulations were determined by flow cytometry while T cell cytokine secretion was measured by multiplex assays. Results Progression-free survival (PFS) as well as overall survival (OS) were similar in patients treated with either BRAFi. High pretreatment LDH was associated with shorter PFS and OS in both groups. During therapy, peripheral lymphocytes decreased by 24.3% (median, P < 0.0001) in vemurafenib-treated patients but remained unchanged in dabrafenib-treated patients (+1.2%, P = 0.717). Differentiation of peripheral lymphocytes of vemurafenib-treated patients showed a significant decrease in CD4+ T cells (P < 0.05). Within CD4+ T cells obtained during treatment, an increase in CCR7+CD45RA+ (naïve) and a decrease in CCR7+CD45RA− (central memory) populations were found (P < 0.01 for both). Furthermore, secretion of interferon-γ and interleukin-9 by CD4+ T cells was significantly lower in samples obtained during vemurafenib treatment compared with baseline samples. Conclusion While both compounds have comparable clinical efficacy, vemurafenib but not dabrafenib decreases patients peripheral lymphocyte counts and alters CD4+ T cell phenotype and function. Thus, selective BRAFi can significantly affect patients' peripheral lymphocyte populations. Fully understanding these effects could be critical for successfully implementing combinatorial therapies of BRAFi with immunomodulatory agents. PMID:24504444

Impaired CD4-cell immune reconstitution upon HIV therapy in patients with toxoplasmic encephalitis compared to patients with pneumocystis pneumonia as AIDS indicating disease

PubMed Central

2009-01-01

Objectives There is only little data on immune reconstitution in antiretroviral naïve AIDS-patients with toxoplasmosis. The observation of several cases with reduced increase of CD4-cells upon start of antiretroviral treatment (ART) prompted us to investigate the topic using the ClinSurv cohort. Methods 17 German HIV treatment centers contribute to ClinSurv, a multicentre observational cohort under the auspices of the Robert Koch Institute. We retrospectively selected all antiretroviral-naïve patients with toxoplasmic encephalitis (TE) and -as comparator group -with pneumocystosis (PCP) between January 1999 and December 2005. Results A total of 257 patients were included in the analysis, 61 with TE and 196 with PCP. Demographic baseline data showed differences with regard to gender, transmission group, and baseline CD4+ counts (60.9 vs. 44.7/μl, p = 0.022). After ART-initiation the increase in CD4+ lymphocytes was lower in the TE-versus the PCP-group in the first, second and fourth three-month-period (74.4 vs. 120.3/μl, p = 0.006; 96.6 vs. 136.2/μl, p = 0.021; 156.5 vs. 211.5/μl, p = 0.013). Viral load (VL) was higher in the PCP-group at baseline (4.46 log10cop/ml vs. 5.00 log10cop/ml, p = 0.008), while virological success of ART was equal. Conclusions Our data show for the first time that the average CD4+ T-cell increase of patients with toxoplasmosis is impaired compared to PCP-patients. Most clinicians would not be prepared to discontinue follow-up TE-therapy unless CD4+ counts of 200/μl are reached. Explanation for our finding might be the myelosuppressive side effect of pyrimethamine, possible interactions of toxoplasmosis therapy with ART, or an unknown direct biological influence of toxoplasmosis on immune restoration. PMID:19541584

Impaired CD4-cell immune reconstitution upon HIV therapy in patients with toxoplasmic encephalitis compared to patients with pneumocystis pneumonia as AIDS indicating disease.

PubMed

Kastenbauer, U; Wolf, E; Kollan, C; Hamouda, O; Bogner, J R

2009-06-18

There is only little data on immune reconstitution in antiretroviral naive AIDS-patients with toxoplasmosis. The observation of several cases with reduced increase of CD4-cells upon start of antiretroviral treatment (ART) prompted us to investigate the topic using the ClinSurv cohort. 17 German HIV treatment centers contribute to ClinSurv, a multicentre observational cohort under the auspices of the Robert Koch Institute. We retrospectively selected all antiretroviral-naive patients with toxoplasmic encephalitis (TE) and - as comparator group - with pneumocystosis (PCP) between January 1999 and December 2005. A total of 257 patients were included in the analysis, 61 with TE and 196 with PCP. Demographic baseline data showed differences with regard to gender, transmission group, and baseline CD4 superset+ counts (60.9 vs. 44.7/microl, p = 0.022). After ART-initiation the increase in CD4 superset+ lymphocytes was lower in the TE- versus the PCP-group in the first, second and fourth three-month-period (74.4 vs. 120.3/microl, p = 0.006; 96.6 vs. 136.2/microl, p = 0.021; 156.5 vs. 211.5/microl, p = 0.013). Viral load (VL) was higher in the PCP-group at baseline (4.46 log subset10cop/ml vs. 5.00 log subset10cop/ml, p = 0.008), while virological success of ART was equal. Our data show for the first time that the average CD4 superset+ T-cell increase of patients with toxoplasmosis is impaired compared to PCP-patients. Most clinicians would not be prepared to discontinue follow-up TE-therapy unless CD4 superset+ counts of 200/microl are reached. Explanation for our finding might be the myelosuppressive side effect of pyrimethamine, possible interactions of toxoplasmosis therapy with ART, or an unknown direct biological influence of toxoplasmosis on immune restoration.

Involvement of Macrophages in the Pathogenesis of Familial Amyloid Polyneuropathy and Efficacy of Human iPS Cell-Derived Macrophages in Its Treatment

PubMed Central

Komohara, Yoshihiro; Takamatsu, Koutaro; Kakuma, Tatsuyuki; Tasaki, Masayoshi; Misumi, Yohei; Ueda, Mitsuharu; Ito, Takaaki; Senju, Satoru; Ando, Yukio

2016-01-01

We hypothesized that tissue-resident macrophages in familial amyloid polyneuropathy (FAP) patients will exhibit qualitative or quantitative abnormalities, that may accelerate transthyretin (TTR)-derived amyloid deposition. To evaluate this, we examined the number and subset of tissue-resident macrophages in heart tissue from amyloid-deposited FAP and control patients. In both FAP and control patients, tissue-resident macrophages in heart tissue were all Iba+/CD163+/CD206+ macrophages. However, the number of macrophages was significantly decreased in FAP patients compared with control patients. Furthermore, the proportion of intracellular TTR in CD14+ monocytes was reduced in peripheral blood compared with healthy donors. Based on these results, we next examined degradation and endocytosis of TTR in human induced pluripotent stem (iPS) cell-derived myeloid lineage cells (MLs), which function like macrophages. iPS-MLs express CD163 and CD206, and belong to the inhibitory macrophage category. In addition, iPS-MLs degrade both native and aggregated TTR in a cell-dependent manner in vitro. Further, iPS-MLs endocytose aggregated, and especially polymerized, TTR. These results suggest that decreased tissue-localized macrophages disrupt clearance of TTR-derived amyloid deposits, leading to progression of a pathological condition in FAP patients. To improve this situation, clinical application of pluripotent stem cell-derived MLs may be useful as an approach for FAP therapy. PMID:27695122

The effects of a human patient simulator vs. a CD-ROM on performance.

PubMed

Johnson, Don; Corrigan, Theresa; Gulickson, Gary; Holshouser, Elizabeth; Johnson, Sabine

2012-10-01

Military health care personnel need to have skills relative to caring for patients on the battlefield. No studies have compared the two teaching strategies of using the human patient simulator (HPS) and a CD-ROM in caring for combat injuries. The objective of this study was to determine if there were statistically significant differences in HPS and CD-ROM educational strategies relative to caring for patients who have trauma. A pretest/post-test prospective experimental design was used. Anesthesia students were randomly assigned to one of three groups: HPS, CD-ROM, or a control group. A valid and reliable instrument, Combat Performance, was used to evaluate the participant's ability to give care to trauma patients. A repeated analysis of variance and a least significant difference post hoc test were used to analyze the data. The HPS group performed better than the CD-ROM and control groups relative to performance (p = 0.001). There was no difference between the CD-ROM and control group (p = 0.171). We speculate that the HPS group performed better than the CD-ROM group because of the realism. In this study, the HPS method of instruction was a more effective method of teaching than the CD-ROM approach.

Apoptosis of circulating lymphocytes during pediatric cardiac surgery

NASA Astrophysics Data System (ADS)

Bocsi, J.; Pipek, M.; Hambsch, J.; Schneider, P.; Tárnok, A.

2006-02-01

There is a constant need for clinical diagnostic systems that enable to predict disease course for preventative medicine. Apoptosis, programmed cell death, is the end point of the cell's response to different induction and leads to changes in the cell morphology that can be rapidly detected by optical systems. We tested whether apoptosis of T-cells in the peripheral blood is useful as predictor and compared different preparation and analytical techniques. Surgical trauma is associated with elevated apoptosis of circulating leukocytes. Increased apoptosis leads to partial removal of immune competent cells and could therefore in part be responsible for reduced immune defence. Cardiovascular surgery with but not without cardiopulmonary bypass (CPB) induces transient immunosuppression. Its effect on T-cell apoptosis has not been shown yet. Flow-cytometric data of blood samples from 107 children (age 3-16 yr.) who underwent cardiac surgery with (78) or without (29) CPB were analysed. Apoptotic T-lymphocytes were detected based on light scatter and surface antigen (CD45/CD3) expression (ClinExpImmunol2000;120:454). Results were compared to staining with CD3 antibodies alone and in the absence of antibodies. T-cell apoptosis rate was comparable when detected with CD45/CD3 or CD3 alone, however not in the absence of CD3. Patients with but not without CPB surgery had elevated lymphocyte apoptosis. T-cell apoptosis increased from 0.47% (baseline) to 0.97% (1 day postoperatively). In CPB patients with complication 1.10% significantly higher (ANOVA p=0.01) comparing to CPB patients without complications. Quantitation of circulating apoptotic cells based on light scatter seems an interesting new parameter for diagnosis. Increased apoptosis of circulating lymphocytes and neutrophils further contributes to the immune suppressive response to surgery with CPB. (Support: MP, Deutsche Herzstiftung, Frankfurt, Germany)

Death rates in HIV-positive antiretroviral-naive patients with CD4 count greater than 350 cells per microL in Europe and North America: a pooled cohort observational study

PubMed Central

2011-01-01

Background It is unclear whether antiretroviral (ART) naive HIV-positive individuals with high CD4 counts have a raised mortality risk compared with the general population, but this is relevant for considering earlier initiation of antiretroviral therapy. Methods Pooling data from 23 European and North American cohorts, we calculated country-, age-, sex-, and year-standardised mortality ratios (SMRs), stratifying by risk group. Included patients had at least one pre-ART CD4 count above 350 cells/mm3. The association between CD4 count and death rate was evaluated using Poisson regression methods. Findings Of 40,830 patients contributing 80,682 person-years of follow up with CD4 count above 350 cells/mm3, 419 (1.0%) died. The SMRs (95% confidence interval) were 1.30 (1.06-1.58) in homosexual men, and 2.94 (2.28-3.73) and 9.37 (8.13-10.75) in the heterosexual and IDU risk groups respectively. CD4 count above 500 cells/mm3 was associated with a lower death rate than 350-499 cells/mm3: adjusted rate ratios (95% confidence intervals) for 500-699 cells/mm3 and above 700 cells/mm3 were 0.77 (0.61-0.95) and 0.66 (0.52-0.85) respectively. Interpretation In HIV-infected ART-naive patients with high CD4 counts, death rates were raised compared with the general population. In homosexual men this was modest, suggesting that a proportion of the increased risk in other groups is due to confounding by other factors. Even in this high CD4 count range, lower CD4 count was associated with raised mortality. PMID:20638118

Fuzhengpaidu granule regulates immune activation molecules CD38 and human leukocyte antigen-D related on CD4+ and CD8+ T cells in patients with acquired immunodeficiency syndrome/human immunodeficiency virus.

PubMed

Jiang, Feng; Zhang, Rongxin; Gu, Zhenfang; Zhang, Huailing; Guo, Huijun; Deng, Xin; Liang, Jian

2013-08-01

To evaluate the effect of Fuzhengpaidu granule (FZPDG) on immune activation molecules CD38 and human leukocyte antigen-D related (HLA-DR) on CD4+ and CD8+ cells in HIV/AIDS patients, and to explore the underlying mechanism of this therapy. Plasma changes in CD3+, CD4+, CD8+, CD3 + CD4 + CD38 +, CD3 + CD4 + HLA-DR+, CD3 + CD8+CD38+, and CD3+CD8+HLA-DR+ levels in HIV/ AIDS patients treated with FZPDG for six months were examined by flow cytometry and compared with levels in healthy controls. The clinical trial included 34 outpatients with HIV/AIDS. Before treatment, plasma levels of CD38+ and HLA-DR+ on CD4/CD8 cells were higher than those in 28 health controls (P < 0.05). There were no significant changes in serum levels of CD3+, CD4+, and CD8+ T cells between pretreatment baseline versus after treatment, which were 82.85% +/- 5.41%, 14.57% +/- 10.31% and 54.55% +/- 11.43% before treatment and 79.15% +/- 8.21%, 19.96% +/- 9.58% and 56.36% +/- 11.67% after treatment, respectively (P > 0.05). Plasma levels of CD3+ CD4+CD38+ and CD3+CD4+HLA-DR+ were 2.3% +/-2.2% and 7.8% +/- 5.5% before treatment and 1.2% +/-0.8% and 2.6% +/- 1.0% after treatment, respectively. Plasma levels of CD3+CD8+CD38+ and CD3+CD8+ HLA-DR+ were 41.4% +/- 13.4% and 17.8% +/- 11.3% before treatment, which changed to 27.1% +/- 10.2% and 3.8% +/- 2.4% after treatment, respectively (P < 0.05). HIV/AIDS patients exhibited an immune activation profile following FZPDG treatment. A potential mechanism of action for FZPDG appears to lie in its ability to up-regulate CD38 and HLA-DR levels on CD4+ T cells, and down-regulate them on CD8+ cells, thereby modulating immune activation of CD4+and CD8+T cells.

Isolation of circulating plasma cells from blood of patients diagnosed with clonal plasma cell disorders using cell selection microfluidics.

PubMed

Kamande, Joyce W; Lindell, Maria A M; Witek, Małgorzata A; Voorhees, Peter M; Soper, Steven A

2018-02-19

Blood samples from patients with plasma cell disorders were analysed for the presence of circulating plasma cells (CPCs) using a microfluidic device modified with monoclonal anti-CD138 antibodies. CPCs were immuno-phenotyped using a CD38/CD56/CD45 panel and identified in 78% of patients with monoclonal gammopathy of undetermined significance (MGUS), all patients with smouldering and symptomatic multiple myeloma (MM), and none in the controls. The burden of CPCs was higher in patients with symptomatic MM compared with MGUS and smouldering MM (p < 0.05). FISH analysis revealed the presence of chromosome 13 deletions in CPCs that correlated with bone marrow results. Point mutations in KRAS were identified, including different mutations from sub-clones derived from the same patient. The microfluidic assay represents a highly sensitive method for enumerating CPCs and allows for the cytogenetic and molecular characterization of CPCs.

Favorable long-term outcomes of bilateral adrenalectomy in Cushing's disease.

PubMed

Oßwald, Andrea; Plomer, Eva; Dimopoulou, Christina; Milian, Monika; Blaser, Rainer; Ritzel, Katrin; Mickisch, Anne; Knerr, Ferengis; Stanojevic, Milan; Hallfeldt, Klaus; Schopohl, Jochen; Kuhn, Klaus A; Stalla, Günter; Beuschlein, Felix; Reincke, Martin

2014-08-01

Bilateral adrenalectomy (BADX) is an important treatment option for patients with Cushing's syndrome (CS). Our aim is to analyze the long-term outcomes, surgical, biochemical, and clinical as well as morbidity and mortality, of patients who underwent BADX. A total of 50 patients who underwent BADX since 1990 in two German centers were identified. Of them, 34 patients had Cushing's disease (CD), nine ectopic CS (ECS), and seven ACTH-independent bilateral adrenal hyperplasia (BAH). Standardized follow-up examination was performed in 36 patients with a minimum follow-up time of 6 months after BADX and a median follow-up time of 11 years. Surgical morbidity and mortality were 6 and 4% respectively. All patients were found to be in remission after BADX. Almost all Cushing's-specific comorbidities except for psychiatric diseases improved significantly. Health-related quality of life remained impaired in 45.0% of female and 16.7% of male patients compared with a healthy population. The median number of adrenal crises per 100 patient-years was four. Nelson tumor occurred in 24% of CD patients after a median time span of 51 months. Long-term mortality after 10 years was high in ECS (44%) compared with CD (3%) and BAH (14%). BADX is an effective and relatively safe treatment option especially in patients with CD. The majority of patients experience considerable improvement of Cushing's symptoms. © 2014 European Society of Endocrinology.

Retrospective Evaluation of Hairy Cell Leukemia Patients Treated with Three Different First-Line Treatment Modalities in the Last Two Decades: A Single-Center Experience.

PubMed

Öngören, Şeniz; Eşkazan, Ahmet Emre; Berk, Selin; Elverdi, Tuğrul; Salihoğlu, Ayşe; Ar, Muhlis Cem; Başlar, Zafer; Aydın, Yıldız; Tüzüner, Nükhet; Soysal, Teoman

2017-12-01

In this study, we retrospectively analyzed the clinical outcome, treatment responses, infectious complications, and survival rates of 71 hairy cell leukemia (HCL) cases. Sixty-seven patients received a first-line treatment and 2-chlorodeoxyadenosine (cladribine-2-CdA) was administered in 31 cases, 19 patients received interferon-alpha (INF-α), splenectomy was performed in 16 cases, and rituximab was used in one. Although the highest overall response rate (ORR) was observed in patients receiving 2-CdA upfront, ORRs were comparable in the 2-CdA, INF-α, and splenectomy subgroups. Relapse rates were significantly lower in patients who received first-line 2-CdA. The progression-free survival (PFS) rate with 2-CdA was significantly higher than in patients with INF-α and splenectomy, but we found similar overall survival rates with all three upfront treatment modalities. Infections including tuberculosis were a major problem. Although purine analogues have improved the ORRs and PFS, there is still much progress to make with regard to overall survival and relapsed/refractory disease in patients with HCL.

Effects of Hydroxychloroquine on Immune Activation and Disease Progression Among HIV-Infected Patients Not Receiving Antiretroviral Therapy A Randomized Controlled Trial

PubMed Central

Paton, Nicholas I.; Goodall, Ruth L.; Dunn, David T.; Franzen, Samuel; Collaco-Moraes, Yolanda; Gazzard, Brian G.; Williams, Ian G.; Fisher, Martin J.; Winston, Alan; Fox, Julie; Orkin, Chloe; Herieka, Elbushra A.; Ainsworth, Jonathan G.; Post, Frank A.; Wansbrough-Jones, Mark; Kelleher, Peter

2013-01-01

Context Therapies to decrease immune activation might be of benefit in slowing HIV disease progression. Objective To determine whether hydroxychloroquine decreases immune activation and slows CD4 cell decline. Design, Setting, and Patients Randomized, double-blind, placebo-controlled trial performed at 10 HIV outpatient clinics in the United Kingdom between June 2008 and February 2011. The 83 patients enrolled had asymptomatic HIV infection, were not taking antiretroviral therapy, and had CD4 cell counts greater than 400 cells/μL. Intervention Hydroxychloroquine, 400 mg, or matching placebo once daily for 48 weeks. Main Outcome Measures The primary outcome measure was change in the proportion of activated CD8 cells (measured by the expression of CD38 and HLA-DR surface markers), with CD4 cell count and HIV viral load as secondary outcomes. Analysis was by intention to treat using mixed linear models. Results There was no significant difference in CD8 cell activation between the 2 groups (−4.8% and −4.2% in the hydroxychloroquine and placebo groups, respectively, at week 48; difference, −0.6%; 95% CI, −4.8% to 3.6%; P=.80). Decline in CD4 cell count was greater in the hydroxychloroquine than placebo group (−85 cells/μL vs −23 cells/μL at week 48; difference, −62 cells/μL; 95% CI, −115 to −8; P=.03). Viral load increased in the hydroxychloroquine group compared with placebo (0.61 log10 copies/mL vs 0.23 log10 copies/mL at week 48; difference, 0.38 log10 copies/mL; 95% CI, 0.13 to 0.63; P=.003). Antiretroviral therapy was started in 9 patients in the hydroxychloroquine group and 1 in the placebo group. Trial medication was well tolerated, but more patients reported influenza-like illness in the hydroxychloroquine group compared with the placebo group (29% vs 10%; P=.03). Conclusion Among HIV-infected patients not taking antiretroviral therapy, the use of hydroxychloroquine compared with placebo did not reduce CD8 cell activation but did result in a greater decline in CD4 cell count and increased viral replication. Trial Registration isrctn.org Identifier: ISRCTN30019040 PMID:22820788

CD44 is a direct target of miR-199a-3p and contributes to aggressive progression in osteosarcoma

PubMed Central

Gao, Yan; Feng, Yong; Shen, Jacson K.; Lin, Min; Choy, Edwin; Cote, Gregory M.; Harmon, David C.; Mankin, Henry J.; Hornicek, Francis J.; Duan, Zhenfeng

2015-01-01

Osteosarcoma is the most common primary bone malignancy in children and adolescents. Herein, we investigated the role of cluster of differentiation 44 (CD44), a cell-surface glycoprotein involved in cell-cell interactions, cell adhesion, and migration in osteosarcoma. We constructed a human osteosarcoma tissue microarray with 114 patient tumor specimens, including tumor tissues from primary, metastatic, and recurrent stages, and determined the expression of CD44 by immunohistochemistry. Results showed that CD44 was overexpressed in metastatic and recurrent osteosarcoma as compared with primary tumors. Higher expression of CD44 was found in both patients with shorter survival and patients who exhibited unfavorable response to chemotherapy before surgical resection. Additionally, the 3′-untranslated region of CD44 mRNA was the direct target of microRNA-199a-3p (miR-199a-3p). Overexpression of miR-199a-3p significantly inhibited CD44 expression in osteosarcoma cells. miR-199a-3p is one of the most dramatically decreased miRs in osteosarcoma cells and tumor tissues as compared with normal osteoblast cells. Transfection of miR-199a-3p significantly increased the drug sensitivity through down-regulation of CD44 in osteosarcoma cells. Taken together, these results suggest that the CD44-miR-199a-3p axis plays an important role in the development of metastasis, recurrence, and drug resistance of osteosarcoma. Developing strategies to target CD44 may improve the clinical outcome of osteosarcoma. PMID:26079799

Characterization of lymphocyte populations in nonspecific interstitial pneumonia*

PubMed Central

Keogh, Karina A; Limper, Andrew H

2005-01-01

Study objectives Nonspecific interstitial pneumonia (NSIP) has been identified as a distinct entity with a more favorable prognosis and better response to immunosuppressive therapies than usual interstitial pneumonia (UIP). However the inflammatory profile of NSIP has not been characterized. Design Using immunohistochemistry techniques on open lung biopsy specimens, the infiltrate in NSIP was characterized in terms of T and B cells, and macrophages, and the T cell population further identified as either CD4 (helper) or CD8 (suppressor-cytotoxic) T cells. The extent of Th1 and Th2 cytokine producing cells was determined and compared to specimens from patients with UIP. Results In ten NSIP tissue samples 41.4 ± 4% of mononuclear cells expressed CD3, 24.7 ± 1.8% CD4, 19.1 ± 2% CD8, 27.4 ± 3.9% CD20, and 14.3 ± 1.6% had CD68 expression. Mononuclear cells expressed INFγ 21.9 ± 1.9% of the time and IL-4 in 3.0 ± 1%. In contrast, biopsies from eight patients with UIP demonstrated substantially less cellular staining for either cytokine (INFγ; 4.6 ± 1.7% and IL-4; 0.6 ± 0.3%). Significant populations of CD20 positive B-cells were also identified. Conclusion The lymphocytic infiltrate in NSIP is characterized by an elevated CD4/CD8 T-cell ratio, and is predominantly of Th1 type, with additional populations rich in B-cells. Such features are consistent with the favorable clinical course observed in patients with NSIP compared to UIP. PMID:16287509

Elevated Expression of Immunoreceptor Tyrosine-Based Inhibitory Motif (TIGIT) on T Lymphocytes is Correlated with Disease Activity in Rheumatoid Arthritis.

PubMed

Luo, Qing; Deng, Zhen; Xu, Chuxin; Zeng, Lulu; Ye, Jianqing; Li, Xue; Guo, Yang; Huang, Zikun; Li, Junming

2017-03-10

BACKGROUND It is well known that lymphocytes play an important role in rheumatoid arthritis (RA). T cell immunoreceptors with immunoglobulin (Ig) and immunoreceptor tyrosine-based inhibitory motif (TIGIT) have immunosuppressive co-stimulatory molecules that mediate inhibitory effects, but their roles in RA are poorly understood. MATERIAL AND METHODS Were recruited 76 patients with RA and 33 healthy controls (HC). Clinical manifestations, laboratory measurements, physical examination, and medical history of RA patients were recorded. The expression of TIGIT on CD3+ T lymphocytes, B lymphocytes, monocytes, neutrophils, CD3+CD4+ T lymphocytes, and CD3+CD8+ T lymphocytes was determined using flow cytometry. The expression of TIGIT on T lymphocytes in patients with RA was further analyzed to investigate its correlations with markers of autoimmune response, inflammation, and disease activity in RA. RESULTS Compared with HC, the expression levels of TIGIT on CD3+CD4+ T lymphocytes and CD3+CD8+ T lymphocytes were significantly increased in patients with RA (P < 0.01). The frequency of TIGIT-expressing CD3+CD4+ T lymphocytes was positively correlated with RF, increased ACPA, ESR, and CRP levels. The frequency of TIGIT-expressing CD3+CD8+ T lymphocytes was positively correlated with RF and ESR levels. Furthermore, the expression level of TIGIT on CD3+CD4+ T lymphocytes was positively correlated with the DAS28 score in RA. CONCLUSIONS The expression levels of TIGIT on T lymphocytes were elevated and correlated with disease activity in RA.

T cell responses in senior patients with community-acquired pneumonia related to disease severity.

PubMed

Bian, Lu-Qin; Bi, Ying; Zhou, Shao-Wei; Chen, Zi-Dan; Wen, Jun; Shi, Jin; Mao, Ling; Wang, Ling

2017-12-01

Senior individuals older than 65 years of age are at a disproportionally higher risk of developing pneumonia. Impaired capacity to defend against airway infections may be one of the reasons. It is generally believed that weaker regulatory T cell responses may be beneficial to host defense against pathogens. In senior patients with community-acquired bacterial pneumonia, we investigated the frequencies and functions of regulatory T cells. Interestingly, we found that compared to age- and sex-matched healthy controls, senior pneumonia patients presented lower frequencies of Foxp3-expressing and Helios-expressing CD4 + T cells. The quantity of Foxp3 and Helios being expressed, measured by their mRNA transcription levels, was also lower in CD4 + T cells from pneumonia patients. Furthermore, following TCR and TGF-β stimulation, pneumonia patients presented impaired capacity to upregulate Foxp3 and Helios. Functional analyses revealed that CD4 + T cells from pneumonia patients secreted lower amounts of IL-10 and TGF-β, two cytokines critical to regulatory T cell-mediated suppression. Also, the expression of granzyme B and perforin, which were cytolytic molecules potentially utilized by regulatory T cells to mediate the elimination of antigen-presenting cells and effector T cells, were reduced in CD4 + CD25 + T cells from senior pneumonia patients. In addition, the CD4 + CD25 + T cells from senior pneumonia patients presented reduced capacity to suppress effector CD4 + and CD8 + T cell proliferation. Moreover, the value of pneumonia severity index was inversely correlated with several parameters of regulatory T cell function. Together, our results demonstrated that senior pneumonia patients presented a counterintuitive impairment in regulatory T cell responses that was associated with worse prognosis. Copyright © 2017 Elsevier Inc. All rights reserved.

Celiac Disease Does Not Influence Fracture Risk in Young Patients with Type 1 Diabetes

PubMed Central

Reilly, Norelle R; Lebwohl, Benjamin; Mollazadegan, Kaziwe; Michaëlsson, Karl; Green, Peter HR; Ludvigsson, Jonas F

2015-01-01

Objectives To examine the risk of any fractures in patients with both type 1 diabetes (T1D) and celiac disease (CD) vs patients with T1D only. Study design We performed a population-based cohort study. We defined T1D as individuals aged ≤30 years who had a diagnosis of diabetes recorded in the Swedish National Patient Register between 1964–2009. Individuals with CD were identified through biopsy report data between 1969–2008 from any of Sweden’s 28 pathology departments. Some 958 individuals had both T1D and CD and were matched for sex, age and calendar period with 4,598 reference individuals with T1D only. We then used a stratified Cox regression analysis, where CD was modeled as a time-dependent covariate, to estimate the risk of any fractures and osteoporotic fractures (hip, distal forearm, thoracic and lumbar spine, and proximal humerus) in patients with both T1D and CD compared with that in patients with T1D only. Results During follow-up, 12 patients with T1D and CD had a fracture (1 osteoporotic fracture). CD did not influence the risk of any fracture (adjusted Hazard Ratio=0.77; 95%CI=0.42–1.41) or osteoporotic fractures (adjusted Hazard Ratio=0.46; 95%CI=0.06–3.51) in patients with T1D. Stratification for time since CD diagnosis did not affect risk estimates. Conclusion Having a diagnosis of CD does not seem to influence fracture risk in young patients with T1D. Follow-up in this study was, however, too short to ascertain osteoporotic fractures which traditionally occur in old age. PMID:26589343

Increase in bone mineral density in strictly treated Crohn's disease patients with concomitant calcium and vitamin D supplementation.

PubMed

Bakker, Sjoerd F; Dik, Vincent K; Witte, Birgit I; Lips, Paul; Roos, Jan C; Van Bodegraven, Adriaan A

2013-06-01

Decreased bone mineral density (BMD) is common in Crohn's disease (CD) patients. This paper reports on the prevalence of decreased BMD in a referral cohort study of CD-patients next to the change of BMD over time in relation with CD-associated clinical characteristics. 205 CD patients of a referral hospital were enrolled between January1998-January 2010 when measurement of BMD by dual X-ray absorptiometry (DXA) was available. Follow-up DXA scan was performed in subjects with known risk factors besides Crohn indicative for low BMD. Treatment of CD patients was according to a protocol which is comparable to the current (inter)national guidelines. In osteopenic patients, supplemental vitamin D (800 IU) and Calcium (500-1000 mg) were prescribed. Mean BMD at baseline was 0.97 ± 0.16 gram/cm(2) in lumbar spine and 0.87 ± 0.12 gram/cm(2) in the total hip. At baseline, higher age and low Body Mass Index (BMI), were negatively correlated with BMD. Eighty-four patients underwent a second BMD assessment with a median interval period of 4 years (IQR 3-6). A mean annual increase of +0.76% (95%CI: -2.63%; +3.87%) in lumbar spine and +0.43% (95%CI: -2.65% ; +1.11%) in total hip was observed. Higher age, male sex, low BMI, and a higher age at diagnosis of CD were associated with low BMD. Follow-up of BMD in CD patients showed a contraintuitive small increase of BMD at lumbar spine and total hip in CD patients only using supplemental vitamin D and calcium next to strict treatment of CD. Copyright © 2012 European Crohn's and Colitis Organisation. Published by Elsevier B.V. All rights reserved.

Impact of surgery on quality of life in Crohn´s disease patients: final results of Czech cohort.

PubMed

Kunovský, Lumír; Mitas, Ladislav; Marek, Filip; Dolina, Jiri; Poredska, Karolina; Kucerova, Lenka; Benesova, Klara; Kala, Zdeněk

2018-01-01

Crohns disease (CD) belongs to chronic diseases that highly affect the patient´s quality of life (QoL). The effect of the disease and impairment of QoL in CD patients is already known. The aim was to assess how surgical treatment influences the patients QoL and determine factors that can affect postoperative QoL. We compared the QoL before and after surgery in patients who had undergone a bowel resection at our department due to CD between 2010-2016. The patients filled in a standardized QLQ-CR29 questionnaire to assess QoL in the preoperative period and the postoperative period after a 2-month interval. The control groups were CD patients who had not undergone surgical treatment (bowel resection) and a healthy cohort. In the QoL evaluation, 132 patients with CD who had undergone surgery (bowel resection), 83 patients with CD without an operation and 104 healthy subjects were enrolled. 104 of the operated patients experienced a postoperative improvement of the overall QoL (78.8 %), 2 patients did not register any changes in QoL (1.5 %) and 26 patients (19.7 %) experienced a worsening of their postoperative QoL. The results were statistically significant (p < 0.001). We detected a significant improvement of the overall QoL after surgical resection in CD patients (measured 2 months after surgery). Gender was identified as the only statistically relevant factor with influence on postoperative QoL.Key words: bowel resection - Crohn´s disease - Czech cohort - inflammatory bowel disease - quality of life - surgical treatment.

Fecal calprotectin in coeliac disease.

PubMed

Capone, Pietro; Rispo, Antonio; Imperatore, Nicola; Caporaso, Nicola; Tortora, Raffaella

2014-01-14

We would like to share with the readers the results of our experience in 50 celiac disease (CD) patients, enrolled between September 2012 and April 2013, who were referred to our third-level CD Unit. The fecal calprotectin (FC) concentration of 50 adults with newly diagnosed CD was compared to that of a control group of 50 healthy subjects. FC level was determined by enzyme linked immunosorbent assay with diagnostic cut-off of 75 μg/g. In addition, we tried to correlate the FC level with symptoms, histological severity of CD (Marsh grade) and level of tissue transglutaminase antibodies (aTg) in CD patients. Finally, FC level was increased in five CD patients and in four controls (10% vs 8%, P = NS); mean FC concentration of patients and controls were 57.7 (SD ± 29.1) and 45.1 (SD ± 38.4) respectively. Furthermore, no significant correlation was seen between FC levels and symptoms/Marsh grade/aTg. The five CD patients did not show inflammatory lesions (e.g., ulcers, erosions) at upper endoscopy. The four healthy controls with positive FC were followed-up for further six months; in this observational period they did not show clinical signs of any underlying disease. On these bases, we think that FC is not able to investigate the subclinical inflammatory changes of active CD and FC should be considered a useless tool in the diagnostic work-up of uncomplicated CD but it should be accompanied by aTg when ruling out organic disease in patients with irritable bowel syndrome.

Salivary and fecal microbiota and metabolome of celiac children under gluten-free diet.

PubMed

De Angelis, Maria; Vannini, Lucia; Di Cagno, Raffaella; Cavallo, Noemi; Minervini, Fabio; Francavilla, Ruggiero; Ercolini, Danilo; Gobbetti, Marco

2016-12-19

Celiac disease (CD) is an inflammatory autoimmune disorder resulting from the combination of genetic predisposition and gluten ingestion. A life-long gluten free diet (GFD) is the only therapeutic approach. Dysbiosis, which can precede the CD pathogenesis and/or persist when subjects are on GFD, is reviewed and discussed. Salivary microbiota and metabolome differed between healthy and celiac children treated under GFD (T-CD) for at least two years. The type of GFD (African- vs Italian-style) modified the microbiota and metabolome of Saharawi T-CD children. Different studies showed bacterial dysbiosis at duodenal and/or fecal level of patients with active untreated CD (U-CD) and T-CD compared to healthy subjects. The ratio of protective anti-inflammatory bacteria such as Lactobacillus-Bifidobacterium to potentially harmful Bacteroides-Enterobacteriaceae was the lowest in U-CD and T-CD children. In agreement with dysbiosis, serum, fecal and urinary metabolome from U-CD and T-CD patients showed altered levels of free amino acids and volatile organic compounds. However, consensus across studies defining specific bacteria and metabolites in U-CD or T-CD patients is still lacking. Future research efforts are required to determine the relationships between CD and oral and intestinal microbiotas to improve the composition of GFD for restoring the gut dysbiosis as a preventative or therapeutic approach for CD. Copyright © 2016 Elsevier B.V. All rights reserved.

The distribution of immunomodulatory cells in the lungs of patients with idiopathic pulmonary fibrosis

PubMed Central

Nuovo, Gerard J.; Hagood, James S.; Magro, Cynthia M.; Chin, Nena; Kapil, Rubina; Davis, Luke; Marsh, Clay B.; Folcik, Virginia A.

2011-01-01

We have characterized the immune system involvement in the disease processes of idiopathic pulmonary fibrosis in novel ways. To do so, we analyzed lung tissue from 21 cases of idiopathic pulmonary fibrosis and 21 (non-fibrotic, non-cancerous) controls for immune cell and inflammation-related markers. The immunohistochemical analysis of the tissue was grouped by patterns of severity in disease pathology. There were significantly greater numbers of CD68+ and CD80+ cells, and significantly fewer CD3+, CD4+, and CD45RO+ cells in areas of relatively (histologically) normal lung in biopsies from idiopathic pulmonary fibrosis patients compared to controls. In zones of active disease, characterized by epithelial cell regeneration and fibrosis, there were significantly more cells expressing CD4, CD8, CD20, CD68, CD80, CCR6, S100, IL-17, tumor necrosis factor-α, and retinoic acid-related orphan receptors compared to histologically normal lung areas from idiopathic pulmonary fibrosis patients. Inflammation was implicated in these active regions by the cells that expressed retinoid orphan receptor-α, -β, and -γ, CCR6, and IL-17. The regenerating epithelial cells predominantly expressed these pro-inflammatory molecules, as evidenced by co-expression analyses with epithelial cytokeratins. Macrophages in pseudo-alveoli and CD3+ T cells in the fibrotic interstitium also expressed IL-17. Co-expression of IL-17 with retinoid orphan receptors, and epithelial cytoskeletal proteins, CD68, and CD3 in epithelial cells, macrophages, and T-cells, respectively, confirmed the production of IL-17 by these cell types. There was little staining for Foxp3, CD56, or CD34 in any idiopathic pulmonary fibrosis lung regions. The fibrotic regions had fewer immune cells overall. In summary, our study shows participation of innate and adaptive mononuclear cells in active-disease regions of idiopathic pulmonary fibrosis lung, where the regenerating epithelial cells appear to propagate inflammation. The regenerative mechanisms become skewed to ultimately result in lethal, fibrotic restriction of lung function. PMID:22037258

Soluble CD30 in patients with antibody-mediated rejection of the kidney allograft.

PubMed

Slavcev, Antonij; Honsova, Eva; Lodererova, Alena; Pavlova, Yelena; Sajdlova, Helena; Vitko, Stefan; Skibova, Jelena; Striz, Ilja; Viklicky, Ondrej

2007-07-01

The aim of our retrospective study was to evaluate the clinical significance of measurement of the soluble CD30 (sCD30) molecule for the prediction of antibody-mediated (humoral) rejection (HR). Sixty-two kidney transplant recipients (thirty-one C4d-positive and thirty-one C4d-negative patients) were included into the study. Soluble CD30 levels were evaluated before transplantation and during periods of graft function deterioration. The median concentrations of the sCD30 molecule were identical in C4d-positive and C4d-negative patients before and after transplantation (65.5 vs. 65.0 and 28.2 vs. 36.0 U/ml, respectively). C4d+ patients who developed DSA de novo had a tendency to have higher sCD30 levels before transplantation (80.7+/-53.6 U/ml, n=8) compared with C4d-negative patients (65.0+/-33.4 U/ml, n=15). Soluble CD30 levels were evaluated as positive and negative (>or=100 U/ml and <100 U/ml respectively) and the sensitivity, specificity and accuracy of sCD30 estimation with regard to finding C4d deposits in peritubular capillaries were determined. The sensitivity of sCD30+ testing was generally below 40%, while the specificity of the test, i.e. the likelihood that if sCD30 testing is negative, C4d deposits would be absent, was 82%. C4d+ patients who developed DSA de novo were evaluated separately; the specificity of sCD30 testing for the incidence of HR in this cohort was 86%. We could not confirm in our study that high sCD30 levels (>or=100 U/ml) might be predictive for the incidence of HR. Negative sCD30 values might be however helpful for identifying patients with a low risk for development of DSA and antibody-mediated rejection.

Vitamin D effects on monocytes' CCL-2, IL6 and CD14 transcription in Addison's disease and HLA susceptibility.

PubMed

Kraus, A U; Penna-Martinez, M; Meyer, G; Badenhoop, K

2018-03-01

Addison's disease is a rare autoimmune disorder leading to adrenal insufficiency and life-long glucocorticoid dependency. Vitamin D receptor (VDR) polymorphisms and vitamin D deficiency predispose to Addison's disease. Aim of the current study was, to investigate potential anti-inflammatory vitamin D effects on monocytes in Addison's disease, focusing on inflammatory CCL-2 and IL6, as well on monocyte CD14 markers. Addison's disease is genetically linked to distinct HLA susceptibility alleles. Therefore we analyzed, whether HLA genotypes differed for vitamin D effects on monocyte markers. CD14 + monocytes were isolated from Addison's disease patients (AD, n=13) and healthy controls (HC, n=15) and stimulated with 1,25-dihydroxyvitamin D 3 and IL1β as an inflammatory stimulant. Cells were processed for mRNA expression of CCL-2, IL6 and CD14 and DNA samples were genotyped for major histocompatibility class (MHC) class II-encoded HLA- DQA1-DQB1 haplotypes. We found a downregulation of CCL-2 after vitamin D treatment in IL1β-stimulated monocytes both from AD patients and HC (AD p<0.001; HC p<0.0001). CD14 expression however, was upregulated in both HC and AD patients after vitamin D treatment (p<0.001, respectively). HC showed higher CD14 transcription level than AD patients after vitamin D treatment (p=0.04). Compared to IL1β-induced inflammation, HC have increased CD14 levels after vitamin D treatment (p<0.001), whereas the IL1β-induced CD14 expression of AD patients' monocytes did not change after vitamin D treatment (p=0.8). AD patients carrying HLA high-risk haplotypes showed an increased CCL-2 expression after IL1β-induced inflammation compared to intermediate-risk HLA carriers (p=0.05). Also HC monocytes' CD14 transcription after IL1β and vitamin D co-stimulation differed according to HLA risk profile. We show that vitamin D can exert anti-inflammatory effects on AD patients' monocytes which may be modulated by HLA risk genotypes. Copyright © 2017 Elsevier Ltd. All rights reserved.

Narcolepsy Type 1 Is Associated with a Systemic Increase and Activation of Regulatory T Cells and with a Systemic Activation of Global T Cells

PubMed Central

Pitoiset, Fabien; Regnault, Armelle; Tran, Tu Anh; Liblau, Roland; Klatzmann, David; Rosenzwajg, Michelle

2017-01-01

Narcolepsy is a rare neurologic disorder characterized by excessive daytime sleepiness, cataplexy and disturbed nocturnal sleep patterns. Narcolepsy type 1 (NT1) has been shown to result from a selective loss of hypothalamic hypocretin-secreting neurons with patients typically showing low CSF-hypocretin levels (<110 pg/ml). This specific loss of hypocretin and the strong association with the HLA-DQB1*06:02 allele led to the hypothesis that NT1 could be an immune-mediated pathology. Moreover, susceptibility to NT1 has recently been associated with several pathogens, particularly with influenza A H1N1 virus either through infection or vaccination. The goal of this study was to compare peripheral blood immune cell populations in recent onset pediatric NT1 subjects (post or non-post 2009-influenza A H1N1 vaccination) to healthy donors. We demonstrated an increased number of central memory CD4+ T cells (CD62L+ CD45RA-) associated to an activated phenotype (increase in CD69 and CD25 expression) in NT1 patients. Percentage and absolute count of regulatory T cells (Tregs) in NT1 patients were increased associated with an activated phenotype (increase in GITR and LAP expression), and of activated memory phenotype. Cytokine production by CD4+ and CD8+ T cells after activation was not modified in NT1 patients. In H1N1 vaccinated NT1 patients, absolute counts of CD3+, CD8+ T cells, and B cells were increased compared to non-vaccinated NT1 patients. These results support a global T cell activation in NT1 patients and thus support a T cell-mediated autoimmune origin of NT1, but do not demonstrate the pathological role of H1N1 prophylactic vaccination. They should prompt further studies of T cells, particularly of Tregs (such as suppression and proliferation antigen specific assays, and also T-cell receptor sequencing), in NT1. PMID:28107375

Salivary Gluten Degradation and Oral Microbial Profiles in Healthy Individuals and Celiac Disease Patients.

PubMed

Tian, Na; Faller, Lina; Leffler, Daniel A; Kelly, Ciaran P; Hansen, Joshua; Bosch, Jos A; Wei, Guoxian; Paster, Bruce J; Schuppan, Detlef; Helmerhorst, Eva J

2017-03-15

Celiac disease (CD) is a chronic immune-mediated enteropathy induced by dietary gluten in genetically predisposed individuals. Saliva harbors the second highest bacterial load of the gastrointestinal (GI) tract after the colon. We hypothesized that enzymes produced by oral bacteria may be involved in gluten processing in the intestine and susceptibility to celiac disease. The aim of this study was to investigate salivary enzymatic activities and oral microbial profiles in healthy subjects versus patients with classical and refractory CD. Stimulated whole saliva was collected from patients with CD in remission ( n = 21) and refractory CD (RCD; n = 8) and was compared to healthy controls (HC; n = 20) and subjects with functional GI complaints ( n = 12). Salivary gluten-degrading activities were monitored with the tripeptide substrate Z-Tyr-Pro-Gln-pNA and the α-gliadin-derived immunogenic 33-mer peptide. The oral microbiome was profiled by 16S rRNA-based MiSeq analysis. Salivary glutenase activities were higher in CD patients compared to controls, both before and after normalization for protein concentration or bacterial load. The oral microbiomes of CD and RCD patients showed significant differences from that of healthy subjects, e.g., higher salivary levels of lactobacilli ( P < 0.05), which may partly explain the observed higher gluten-degrading activities. While the pathophysiological link between the oral and gut microbiomes in CD needs further exploration, the presented data suggest that oral microbe-derived enzyme activities are elevated in subjects with CD, which may impact gluten processing and the presentation of immunogenic gluten epitopes to the immune system in the small intestine. IMPORTANCE Ingested gluten proteins are the triggers of intestinal inflammation in celiac disease (CD). Certain immunogenic gluten domains are resistant to intestinal proteases but can be hydrolyzed by oral microbial enzymes. Very little is known about the endogenous proteolytic processing of gluten proteins in the oral cavity. Given that this occurs prior to gluten reaching the small intestine, such enzymes are likely to contribute to the composition of the gluten digest that ultimately reaches the small intestine and causes CD. We demonstrated that endogenous salivary protease activities are incomplete, likely liberating peptides from larger gluten proteins. The potentially responsible microbes were identified. The study included refractory CD patients, who have been studied less with regard to CD pathogenesis. Copyright © 2017 American Society for Microbiology.

Immunophenotypic analysis of Waldenstrom's macroglobulinemia.

PubMed

San Miguel, J F; Vidriales, M B; Ocio, E; Mateo, G; Sánchez-Guijo, F; Sánchez, M L; Escribano, L; Bárez, A; Moro, M J; Hernández, J; Aguilera, C; Cuello, R; García-Frade, J; López, R; Portero, J; Orfao, A

2003-04-01

Immunophenotyping has become an essential tool for diagnosis of hematological malignancies. By contrast, for diagnosis of Waldenstrom's macroglobulinemia (WM) immunophenotyping is used only occasionally. From 150 patients with a IgM monoclonal gammopathy we have selected 60 cases with (1) morphological lymphoplasmocytoid bone marrow (BM) infiltration (>20%); (2) IgM paraprotein (>10g/L); and (3) absence of features of other lymphoma types. Immunophenotypic analysis was based on the use of the triple or quadruple monoclonal antibody (MoAb) combinations. To increase the sensitivity of the analysis of antigen expression, selected CD19(+)CD20(+) B cells were targeted. We have also explored the antigenic characteristics of both the plasma cell (PC) and mast cell (MC) compartments present in the BM from 15 WM patients. Clonal WM lymphocytes were characterized by the constant expression of pan-B markers (CD19, CD20, CD22, CD24) together with sIg, predominantly kappa (5:1, kappa:lambda ratio). A high proportion of cases (75%) were positive for FMC7 and CD25, but in contrast to hairy cell leukemia (HCL), these lymphocytes were always negative for CD103 and CD11c. CD10 antigen was also absent in all WM patients and less than one fifth of patients were positive for CD5 and CD23, while CD27, CD45RA, and BCL-2 were present in most malignant cells. In two cases, the coexistence of two different clones of B lymphocytes was identified, and in eight additional cases, intraclonal phenotypic heterogeneity was observed. As far as PCs are concerned, in most patients (85%) the number of PCs was within the normal range (median, 0.36%). The antigenic profile of these PCs differed from that observed in normal and myelomatous PC (CD38(++)CD19(++/-)CD56(-)CD45(++)CD20(+)). In three cases, PCs showed aberrant expression for CD5, CD22, or FMC7. Finally, the number of mast cells was significantly higher (0.058 +/- 0.13) as compared to normal BM (0.019 +/- 0.02) (P <.01), although they were immunophenotypically normal (CD117(+)CD2(-)CD25(-)). Copyright 2003 Elsevier Inc. All rights reserved.

Predominance of Th17 over regulatory T-cells in pleural effusions of patients with lung cancer implicates a proinflammatory profile.

PubMed

Prado-Garcia, Heriberto; Romero-Garcia, Susana; Rumbo-Nava, Uriel; Lopez-Gonzalez, Jose Sullivan

2015-03-01

Regulatory T-(Treg) and pro-inflammatory T-helper 17 (Th17) cells have been reported to be involved in the pathogenesis of pleural effusions caused by lung cancer. However, the presence of these subsets might not be a consequence of tumor pathogenesis, but rather a result of the pleural effusion itself, irrespective of its origin. In the present study, we analyzed the balance between these CD4+ T-cell subsets and compared them with those in non-malignant pleural effusions. We detected the frequencies of Treg and Th17 cells, identified as cluster of differentiation (CD)3+CD4+CD25+CD127low/- and CD3+CD4+ retinoid-related orphan receptor γt (RORγt)+ cells respectively, and proportions of interleukin (IL)17A-producing CD4+ cells in pleural effusions of patients with lung cancer, tuberculous and non-chronic pathologies by flow cytometry. The cytokine profile of stimulated CD4+ T-cells from tuberculosis and cancer groups was compared. The proportion of Th17 cells were increased whereas Tregs were decreased in both tuberculosis and cancer, but not in non-chronic pathologies. Nevertheless, CD4+ T-cells from lung cancer effusions secreted interferon (IFN)γ, IL6 and IL17A, whereas CD4+ T-cells from tuberculous effusions secreted IL10 and low levels of IFNγ. Although effusions from patients with chronic pathologies presented higher proportions of Th17 cells in comparison to those with non-chronic pathologies, only Th17 cells from malignant effusions maintained their proinflammatory profile after stimulation. Thus, in the pleural compartment of patients with lung cancer, a proinflammatory environment might be favored and possibly maintained by Th17 response. Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

Analysis of endoscopic brush samples identified mucosa-associated dysbiosis in inflammatory bowel disease.

PubMed

Nishino, Kyohei; Nishida, Atsushi; Inoue, Ryo; Kawada, Yuki; Ohno, Masashi; Sakai, Shigeki; Inatomi, Osamu; Bamba, Shigeki; Sugimoto, Mitsushige; Kawahara, Masahiro; Naito, Yuji; Andoh, Akira

2018-01-01

The mucosa-associated gut microbiota directly modulates epithelial and mucosal function. In this study, we investigated the mucosa-associated microbial community in patients with inflammatory bowel disease (IBD), using endoscopic brush samples. A total of 174 mucus samples from 43 patients with ulcerative colitis (UC), 26 with Crohn's disease (CD) and 14 non-IBD controls were obtained by gentle brushing of mucosal surfaces using endoscopic cytology brushes. The gut microbiome was analyzed using 16S rRNA gene sequencing. There were no significant differences in microbial structure among different anatomical sites (the ileum, cecum and sigmoid colon) within individuals. There was, however, a significant difference in microbial structure between CD, UC and non-IBD controls. The difference between CD and non-IBD controls was more marked than that between UC patients and non-IBD controls. α-Diversity was significantly lower in UC and CD patients than non-IBD controls. When comparing CD patients with non-IBD controls, the phylum Proteobacteria was significantly increased and the phyla Firmicutes and Bacteroidetes were significantly reduced. These included a significant increase in the genera Escherichia, Ruminococcus (R. gnavus), Cetobacterium, Actinobacillus and Enterococcus, and a significant decrease in the genera Faecalibacterium, Coprococcus, Prevotella and Roseburia. Comparisons between CD and UC patients revealed a greater abundance of the genera Escherichia, Ruminococcus (R. gnavus), Clostridium, Cetobacterium, Peptostreptococcus in CD patients, and the genera Faecalibacterium, Blautia, Bifidobacterium, Roseburia and Citrobacter in UC patients. Mucosa-associated dysbiosis was identified in IBD patients. CD and UC may be distinguishable from the mucosa-associated microbial community structure.

Adherence to On-Time ART Drug Pick-Up and Its Association with CD4 Changes and Clinical Outcomes Amongst HIV Infected Adults on First-Line Antiretroviral Therapy in Nigerian Hospitals.

PubMed

Anoje, Chukwuemeka; Agu, Kenneth Anene; Oladele, Edward A; Badru, Titilope; Adedokun, Oluwasanmi; Oqua, Dorothy; Khamofu, Hadiza; Adebayo, Olufunso; Torpey, Kwasi; Chabikuli, Otto Nzapfurundi

2017-02-01

Medication adherence is a major determinant of antiretroviral treatment (ART) success. Promptness in medication refill pick-ups may give an indication of medication adherence. This study determined medication refill adherence among HIV positive patients on ART and its association with treatment outcomes in HIV treatment centers in Nigeria. This retrospective multi-center cohort study involved a review of ART refill records for 3534 HIV-positive patients aged 18-60 years who initiated first-line ART between January 2008 and December 2009 and were on therapy for ≥18 months after ART initiation. Drug refill records of these patients for 10 consecutive refill visits after ART initiation were analyzed. The first ten consecutive refill appointment-keeping rates after ART initiation ranged from 64.3 % to 76.1 % which decreased with successive visits. Altogether, 743 (21.1 %) patients were deemed adherent, meaning they picked up their drugs within 7 days of the drug refill appointment date on at least nine out of ten refill visits. The adherent group of patients had a mean CD4 cells increase of 206 ± 6.1 cells/dl after 12 months of ART compared to 186 ± 7.1 cells/dl reported among the nonadherent group (p = 0.0145). The proportion of patients in the adherent category who showed no OIs after 12 months on ART (81 %) was significantly higher when compared to the proportion in the non-adherent category (23.5 %), (p = 0.008). The multivariate analysis showed that the odds of being adherent was 2-3 times more in patients who had a baseline CD4 count of less than 200 cells/dl compared to those with a baseline CD4 of >350 cells/dl. (AOR 2.43, 95 % CI 1.62-3.66). In addition, for patients with baseline CD4 cell count of 201-350 cells/dl, the odds of being adherent was found to be 1.9 compared to those with baseline CD4 of greater than 350 cells/dl (AOR 1.93, 95 % CI 1.27-2.94). Pharmacy refill data can serve as an adherence measure. Adherence to on-time drug pickup on ≥90 % of refill appointments was associated with a better CD4 count response and a reduction in the presence of opportunistic infections in ART patients after 12 months of treatment.

Robust interferon-α and IL-12 responses by dendritic cells are related to efficient CD4+ T-cell recovery in HIV patients on ART.

PubMed

Tan, Dino Bee Aik; Yong, Yean Kong; Lim, Andrew; Tan, Hong Yien; Kamarulzaman, Adeeba; French, Martyn; Price, Patricia

2011-05-01

Amongst HIV patients with successful virological responses to antiretroviral therapy (ART), poor CD4(+) T-cell recovery is associated with low nadir CD4(+) T-cell counts and persistent immune activation. These factors might be influenced by dendritic cell (DC) function. Interferon-α-producing plasmacytoid DC and IL-12-producing myeloid DC were quantified by flow cytometry after stimulation with agonists to TLR7/8 (CL075) or TLR9 (CpG-ODN). These were compared between patients who achieved CD4(+) T-cell counts above or below 200 cells/μL after 6 months on ART (High vs. Low groups). High Group patients had more DC producing interferon-α or IL-12 at Weeks 6 and 12 on ART than Low Group patients. The frequencies of cytokine-producing DC at Week 12 were directly correlated with CD4(+) T-cell counts at baseline and at Week 12. Patients with good recovery of CD4(+) T-cells had robust TLR-mediated interferon-α responses by plasmacytoid DC and IL-12 responses by myeloid DC during early ART (1-3 months). Copyright © 2011 Elsevier Inc. All rights reserved.

T- and NK-cell populations with regulatory phenotype and markers of apoptosis in circulating lymphocytes of patients with CIN3 or microcarcinoma of the cervix: evidence for potential mechanisms of immune suppression.

PubMed

Kurmyshkina, Olga V; Kovchur, Pavel I; Schegoleva, Ludmila V; Volkova, Tatyana O

2017-01-01

Processes and mechanisms responsible for systemic immune suppression in early-stage cervical cancer remain substantially underinvestigated. In this work, we focused on studying the frequencies of circulating regulatory T (CD4 and CD8 Tregs) and NK (NKregs) cells in parallel with assessment of apoptotic markers expression in T cells from patients with preinvasive and microinvasive cervical cancer, with the aim to determine whether up-regulation of apoptosis-associated markers in Т lymphocytes accompanies cervical cancer development and correlates with the change in percentages of regulatory cell populations at systemic level during the initial stages of invasive cervical cancer progression. Fourty two women with histologically confirmed cervical intraepithelial neoplasia grade 3 (CIN3, including carcinoma in situ) or cervical cancer (stage IA) and 30 healthy women (control) were enrolled in the study. Peripheral blood samples were taken immediately before surgery or any treatment and immediately subjected to multicolor flow cytometry. Analysis of a combination of CD4/CD8, CD25, CD127, and FoxP3 markers revealed a statistically significant increase in the frequencies of Tregs within both the CD4 and CD8 subsets of circulating lymphocytes in patients with CIN3 and stage IA cancer. In contrast, lower numbers of NKregs (defined as CD16 dim/neg CD56 bright subpopulation) and increased CD56 dim /CD56 bright NK ratio were found in patients compared to controls, with the percentage of CD16 bright CD56 dim cells (major subtype of circulating NKs) showing no difference. Patients also exhibited an increased expression of CD95 in total peripheral blood T lymphocytes, along with increased level of Annexin V binding to CD95-positive cells, suggesting higher susceptibility of T cells to apoptosis and potential involvement of CD95-dependent pathway in early-stage cervical cancer. Differential analysis of CD4 and CD8 T cells revealed different trends in the change of CD95 expression, confirming that this change likely has different functional significance for these two subsets. A search for correlations between the phenotypic parameters analyzed in this study was performed to demonstrate that women with early neoplastic lesions of the cervix, such as carcinoma in situ and microinvasive carcinoma, displayed a coordinated increase in expression of Treg markers in circulating lymphocytes, along with more pronounced cross-relationships between Treg numbers, CD95 expression on T cells, and apoptosis, compared to the control group. The results of this study suggest that a diversity of immune regulatory mechanisms that provide support for initial stages of invasive growth in cervical cancer patients includes systemic changes in the ratios between the principal regulatory and effector lymphocyte populations both within adaptive and innate immunity.

Increased Incidence of Thyroid Disease in Patients with Celiac Disease: A Systematic Review and Meta-Analysis

PubMed Central

Sun, Xin; Lu, Li; Yang, Rong; Li, Yanbin; Shan, Ling; Wang, Yang

2016-01-01

The prevalence of thyroid disease is likely increased among individuals with celiac disease (CD). In addition, exposure to gluten-free treatment may be associated with a risk of thyroid disease, but this association remains controversial. A systematic review was performed to evaluate the association between thyroid disease and CD. The articles were obtained from the PubMed, Web of Science, Embase, and Chinese WanFang bibliographical databases for the period up to May 2016. The results were analysed in a meta-analysis with odds ratios (ORs) and corresponding 95% confidence intervals (95% CIs). There were 13 articles in this meta-analysis, including 15629 CD cases and 79342 controls. Overall, the prevalence of thyroid disease in patients with CD was significantly increased compared with that in the control groups (OR 3.08, 95% CI 2.67–3.56, P<0.001). Moreover, there was no significant difference in the OR between the gluten-treated and untreated groups (OR 1.08, 95% CI 0.61–1.92, P = 0.786). The results of our meta-analysis support the hypothesis that the prevalence of thyroid disease in patients with CD is increased compared with that in controls, which suggests that CD patients should be screened for thyroid disease. The effect of gluten-free treatment on thyroid disease needs further investigation. PMID:28030626

Intraocular pressure and its correlation with midnight plasma cortisol level in Cushing's disease and other endogenous Cushing's syndrome.

PubMed

Mishra, Priyadarshini; Singh, Alok Pratap; Kanaujia, Vikas; Agarwal, Rachna; Mishra, Prabhaker; Guleria, Ashwani; Tripathi, Alka

2017-09-01

The purpose of this study is to measure intraocular pressure (IOP) and evaluate the correlation between IOP and midnight plasma cortisol (MPC) level in patients with Cushing's disease (CD) and other endogenous Cushing's syndrome (ECS). This is a cross-sectional study from a single center including newly diagnosed patients with CD or ECS. All patients underwent detailed ophthalmological evaluation. IOP was measured by Goldmann applanation tonometry in the morning and evening on two consecutive days. MPC value was obtained for each patient. The data were compared using paired and unpaired t-test, Mann-Whitney U-test, and Spearman's rank correlation coefficient. Among 32 patients, 22 were CD (68.75%) and 10 patients were other ECS (31.25%). A total of 25 patients (78.12%) in our study group had normal IOP (<22 mmHg), and seven patients (21.88%) had increased IOP (≥22 mmHg). The percentage of patients with normal IOP was found to be significantly higher compared to percentage of patients with high IOP (P = 0.001) using one-sample Chi-square test. Mean MPC value was 468.6 ± 388.3 nmol/L in patients having IOP ≥22 mmHg and 658.5 ± 584 nmol/L in those with IOP <22 mmHg from both CD and ECS groups, but the difference was not statistically significant. No correlation was found between IOP and MPC (Spearman's rank correlation rho = -0.16 [P = 0.38]). In CD and ECS patients, IOP elevation is an uncommon feature, and high IOP in either group does not correlate with MPC level.

HIV-DNA content in different CD4+ T-cell subsets correlates with CD4+ cell :  CD8+ cell ratio or length of efficient treatment.

PubMed

Gibellini, Lara; Pecorini, Simone; De Biasi, Sara; Bianchini, Elena; Digaetano, Margherita; Pinti, Marcello; Carnevale, Gianluca; Borghi, Vanni; Guaraldi, Giovanni; Mussini, Cristina; Cossarizza, Andrea; Nasi, Milena

2017-06-19

HIV establishes a latent infection at different degrees within naïve (TN) or central (TCM) and effector memory (TEM) CD4 T cell. Studying patients in whom HIV production was suppressed by combined antiretroviral therapy, our main aim was to find which factors are related or can influence intracellular viral reservoir in different CD4 T-cell subsets. We enrolled 32 HIV patients successfully treated for more than 2 years, with a CD4 T-cell count more than 500 cells/μl and plasma viremia undetectable from at least 1 year. Proviral HIV-DNA, the amount of cells expressing signal-joint T-cell receptor rearrangement excision circles and telomere length were quantified by droplet digital PCR in highly purified, sorted CD4 T-cell subsets; plasma IL-7 and IL-15 were measured by ELISA. HIV-DNA was significantly lower in TN cells compared with TCM or to TEM. Conversely, TN cells contained more signal-joint T-cell receptor rearrangement excision circles compared with TCM or to TEM; no appreciable changes were observed in telomere length. HIV-DNA content was significantly higher in TN and TCM cells, but not in TEM, from patients with shorter time of treatment, or in those with lower CD4 : CD8 ratio. Length of treatment or recovery of CD4 : CD8 ratio significantly influences viral reservoir in both TN and TCM. Measuring HIV-DNA in purified lymphocyte populations allows a better monitoring of HIV reservoir and could be useful for designing future eradication strategies.

Soluble CD30 and HLA antibodies as potential risk factors for kidney transplant rejection.

PubMed

Slavcev, Antonij; Lácha, Jiri; Honsová, Eva; Sajdlová, Helena; Lodererová, Alena; Vitko, Stefan; Skibová, Jelena; Striz, Ilja

2005-06-01

Recent literary data suggest that high pre- and post-transplant serum levels of the soluble CD30 (sCD30) molecule may be a risk factor for acute rejection and worse prognosis of the transplanted kidney. The aim of our study was to correlate the concentrations of sCD30 and the presence of HLA antibodies as defined by flow cytometry and ELISA with the clinical course and graft prognosis after transplantation. One hundred and seventeen kidney transplant patients were included into the study. The incidence of rejection episodes, graft function and graft survival for up to 1 year post-transplant were evaluated. Soluble CD30 levels before transplantation were virtually the same in patients who experienced rejection and in non-rejecting patients. In both patient groups, a significant decrease of sCD30 was detected 2 weeks after transplantation (104.4 U/ml before vs. 37.0 U/ml post-transplant, P < 0.001). However, there was a substantial difference in the level of decrease of sCD30 between rejecting and non-rejecting patients. Patients without rejection had lower sCD30 values (31.2 U/ml post-transplant) compared to patients who experienced rejection episodes (62.9 U/ml), P < 0.04. Multifactorial analysis showed that antibodies to HLA class II antigens and elevated concentrations of sCD30 shortly after transplantation were associated with increased risk for acute rejection in the first post-transplant year. Measurement of soluble CD30 after transplantation, taken into consideration with the presence of HLA class II antibodies, might be helpful for evaluating the potential risk for acute rejection.

A short-term increase of the postoperative naturally circulating dendritic cells subsets in flurbiprofen-treated patients with esophageal carcinoma undergoing thoracic surgery

PubMed Central

Chai, Xiao-qing; Shu, Shu-hua; Zhang, Xiao-lin; Xie, Yan-hu; Wei, Xin; Wu, Yu-jing; Wei, Wei

2016-01-01

The present study evaluated whether flurbiprofen increased the naturally circulating dendritic cells (DCs) subsets in patients with esophageal squamous cell carcinoma (ESCC) undergoing esophageal resection. Compared to healthy donors (n=20), the significantly depressed percentages of plasmacytoid DCs (pDCs), CD1c+ myeloid DCs (mDCs), and CD141+ mDCs among ESCC patients (n=60) were confirmed. Flurbiprofen was administered before skin incision and at the end of operation in group F (n=30), as well as placebo in group C (n=30). The postoperative suppressed percentages of pDCs, CD1c+ mDCs, and CD141+ mDCs increased significantly following the perioperative treatment with flurbiprofen. Flurbiprofen also significantly stimulated the postoperative IFN-f and IL-17 production, but inhibited the immunosuppressive IL-10 and TGF-β levels. Furthermore, flurbiprofen exerted a similar analgesic effect and brought a significantly less sufentanil consumption compared to group C. Taken together, flurbiprofen provided a short-term increase of postoperative naturally circulating DCs in ESCC patients. PMID:26959879

A short-term increase of the postoperative naturally circulating dendritic cells subsets in flurbiprofen-treated patients with esophageal carcinoma undergoing thoracic surgery.

PubMed

Wang, Di; Yang, Xin-lu; Chai, Xiao-qing; Shu, Shu-hua; Zhang, Xiao-lin; Xie, Yan-hu; Wei, Xin; Wu, Yu-jing; Wei, Wei

2016-04-05

The present study evaluated whether flurbiprofen increased the naturally circulating dendritic cells (DCs) subsets in patients with esophageal squamous cell carcinoma (ESCC) undergoing esophageal resection. Compared to healthy donors (n=20), the significantly depressed percentages of plasmacytoid DCs (pDCs), CD1c+ myeloid DCs (mDCs), and CD141+ mDCs among ESCC patients (n=60) were confirmed. Flurbiprofen was administered before skin incision and at the end of operation in group F (n=30), as well as placebo in group C (n=30). The postoperative suppressed percentages of pDCs, CD1c+ mDCs, and CD141+ mDCs increased significantly following the perioperative treatment with flurbiprofen. Flurbiprofen also significantly stimulated the postoperative IFN-f and IL-17 production, but inhibited the immunosuppressive IL-10 and TGF-β levels. Furthermore, flurbiprofen exerted a similar analgesic effect and brought a significantly less sufentanil consumption compared to group C. Taken together, flurbiprofen provided a short-term increase of postoperative naturally circulating DCs in ESCC patients.

Naturally occurring tolerance acquisition to foods in previously allergic children is characterized by antigen specificity and associated with increased subsets of regulatory T cells.

PubMed

Qamar, N; Fishbein, A B; Erickson, K A; Cai, M; Szychlinski, C; Bryce, P J; Schleimer, R P; Fuleihan, R L; Singh, A M

2015-11-01

Food allergy affects approximately 6-8% of children, and increasing in prevalence. Some children naturally outgrow their food allergy without intervention, but the mechanisms by which this occurs remain poorly understood. We sought to investigate the role of regulatory T cells in the development of naturally acquired tolerance. Fifty-eight children (1-18 years) with either egg or peanut allergy, recent acquisition of natural tolerance to egg or peanut, or no food allergy were studied. Peripheral blood mononuclear cells (PBMC) from these groups were stimulated with relevant antigen for 48 h and flow cytometry performed to characterize both surface (CD3, CD4, CD25, CD14, CD19, and CD127) and intracellular markers (IL-10, Foxp3, and IL-5). Resting PBMC from naturally tolerant patients had significantly increased CD3+CD4+CD25+CD127loFoxp3+ cells, when compared to allergic or control patients (mean 6.36 vs. 2.37 vs. 2.62%, respectively, P < 0.05). Upon stimulation with relevant antigen, naturally tolerant patients also had increased IL-10-expressing CD25+CD127lo cells (6.33 vs. 1.65 vs. 0.7, P < 0.01), Foxp3+ cells (mean 12.6 vs. 5.42 vs. 3%, P < 0.01), and CD4+ cells (mean 4.48 vs. 1.59 vs. 0.87%, P < 0.01); the increase was not observed in PBMCs from allergic or control patients. Additionally, this upregulation was only seen with relevant antigen stimulation and not upon stimulation with unrelated antigen. The increased CD3+CD4+CD25+CD127lo cells at baseline and upon stimulation and increased induction of IL-10-producing cells of several types, including Tr1 cells, from naturally tolerant patients suggests an important role for regulatory T cell subsets in the acquisition of natural tolerance. © 2015 John Wiley & Sons Ltd.

Naturally Occurring Tolerance Acquisition to Foods in Previously Allergic Children is Characterized by Antigen Specificity and Associated with Increased Subsets of Regulatory T cells

PubMed Central

Qamar, Nashmia; Fishbein, Anna B.; Erickson, Kristin A.; Cai, Miao; Szychlinski, Christine; Bryce, Paul J.; Schleimer, Robert P.; Fuleihan, Ramsay L.; Singh, Anne Marie

2015-01-01

Background Food allergy affects approximately 6–8% of children, and increasing in prevalence. Some children naturally outgrow their food allergy without intervention but the mechanisms by which this occurs remain poorly understood. We sought to investigate the role of regulatory T cells in the development of naturally acquired tolerance. Methods Fifty-eight children (1 to 18 years) with either egg or peanut allergy, recent acquisition of natural tolerance to egg or peanut, or no food allergy were studied. Peripheral blood mononuclear cells (PBMC) from these groups were stimulated with relevant antigen for 48 hours and flow cytometry performed to characterize both surface (CD3, CD4, CD25, CD14, CD19, CD127) and intracellular markers (IL-10, Foxp3, and IL-5). Results Resting PBMC from naturally tolerant patients had significantly increased CD3+CD4+CD25+CD127loFoxp3+ cells, when compared to allergic or control patients [mean 6.36 vs 2.37 vs 2.62%, respectively, p<0.05]. Upon stimulation with relevant antigen, naturally tolerant patients also had increased IL-10-expressing CD25+CD127lo cells [6.33 vs 1.65 vs 0.7, p<0.01], Foxp3+ cells [mean 12.6 vs 5.42 vs 3%, p<0.01] and CD4+ cells [mean 4.48 vs 1.59 vs 0.87%, p<0.01]; the increase was not observed in PBMCs from allergic or control patients. Additionally, this upregulation was only seen with relevant antigen stimulation and not upon stimulation with unrelated antigen. Conclusion The increased CD3+CD4+CD25+CD127lo cells at baseline and upon stimulation and increased induction of IL-10-producing cells of several types, including Tr1 cells, from naturally tolerant patients suggests an important role for regulatory T cell subsets in the acquisition of natural tolerance. PMID:25989379

Universal monitoring of minimal residual disease in acute myeloid leukemia.

PubMed

Coustan-Smith, Elaine; Song, Guangchun; Shurtleff, Sheila; Yeoh, Allen Eng-Juh; Chng, Wee Joo; Chen, Siew Peng; Rubnitz, Jeffrey E; Pui, Ching-Hon; Downing, James R; Campana, Dario

2018-05-03

Optimal management of acute myeloid leukemia (AML) requires monitoring of treatment response, but minimal residual disease (MRD) may escape detection. We sought to identify distinctive features of AML cells for universal MRD monitoring. We compared genome-wide gene expression of AML cells from 157 patients with that of normal myeloblasts. Markers encoded by aberrantly expressed genes, including some previously associated with leukemia stem cells, were studied by flow cytometry in 240 patients with AML and in nonleukemic myeloblasts from 63 bone marrow samples. Twenty-two (CD9, CD18, CD25, CD32, CD44, CD47, CD52, CD54, CD59, CD64, CD68, CD86, CD93, CD96, CD97, CD99, CD123, CD200, CD300a/c, CD366, CD371, and CX3CR1) markers were aberrantly expressed in AML. Leukemia-associated profiles defined by these markers extended to immature CD34+CD38- AML cells; expression remained stable during treatment. The markers yielded MRD measurements matching those of standard methods in 208 samples from 52 patients undergoing chemotherapy and revealed otherwise undetectable MRD. They allowed MRD monitoring in 129 consecutive patients, yielding prognostically significant results. Using a machine-learning algorithm to reduce high-dimensional data sets to 2-dimensional data, the markers allowed a clear visualization of MRD and could detect 1 leukemic cell among more than 100,000 normal cells. The markers uncovered in this study allow universal and sensitive monitoring of MRD in AML. In combination with contemporary analytical tools, the markers improve the discrimination between leukemic and normal cells, thus facilitating data interpretation and, hence, the reliability of MRD results. National Cancer Institute (CA60419 and CA21765); American Lebanese Syrian Associated Charities; National Medical Research Council of Singapore (1299/2011); Viva Foundation for Children with Cancer, Children's Cancer Foundation, Tote Board & Turf Club, and Lee Foundation of Singapore.

Fractures in pituitary adenoma patients from the Dutch National Registry of Growth Hormone Treatment in Adults.

PubMed

van Varsseveld, N C; van Bunderen, C C; Franken, A A M; Koppeschaar, H P F; van der Lely, A J; Drent, M L

2016-08-01

The effects of growth hormone (GH) replacement therapy on fracture risk in adult GH deficient (GHD) patients with different etiologies of pituitary GHD are not well known, due to limited data. The aim of this study was to investigate characteristics and fracture occurrence at start of (baseline) and during long-term GH replacement therapy in GHD adults previously treated for Cushing's disease (CD) or acromegaly, compared to patients with previous nonfunctioning pituitary adenoma (NFPA). From the Dutch National Registry of Growth Hormone Treatment in Adults, a nationwide surveillance study in severe GHD adults, all patients using ≥30 days of GH replacement therapy with previous NFPA (n = 783), CD (n = 180) and acromegaly (n = 65) were selected. Patient characteristics, fractures and potential influencing factors were investigated. At baseline, patients with previous CD were younger, more often female and had more often a history of osteopenia or osteoporosis, whereas patients with previous acromegaly had more often received cranial radiotherapy and a longer duration between treatment of their pituitary tumor and start of adult GH replacement therapy. During follow-up, a fracture occurred in 3.8 % (n = 39) of all patients. Compared to patients with previous NFPA, only patients with previous acromegaly had an increased fracture risk after 6 years of GH replacement therapy. During GH replacement therapy, an increased fracture risk was observed in severe GHD adult patients previously treated for acromegaly, but not in those previously treated for CD, compared to severe GHD adult patients using GH replacement therapy because of previous NFPA. Further studies are needed to confirm these findings and to elucidate potential underlying mechanisms.

Unique features of esophagogastric junction pressure topography in hiatus hernia patients with dysphagia.

PubMed

Pandolfino, John E; Kwiatek, Monika A; Ho, Kim; Scherer, John R; Kahrilas, Peter J

2010-01-01

Our aim was to assess pressure dynamics within the esophagogastric junction (EGJ) in sliding hiatus hernia (HH) during normal peristalsis and to compare the pressure profiles of HH patients with gastroesophageal reflux disease (GERD) symptoms (HH-GERD) to HH patients with dysphagia (HH-dysphagia). High-resolution manometry studies in 230 consecutive patients and 68 controls were reviewed. HH patients were defined by a >or=1.5 cm separation between the lower esophageal sphincter (LES) and crural diaphragm (CD) on pressure topography plots. The HH population was further culled to eliminate those patients with motor disorders or stricture. The study groups were composed of 18 HH patients with only reflux symptoms and 10 HH patients with only dysphagia. Analysis of the pressure dynamics within the EGJ was performed at rest and after swallowing to independently quantify the LES and CD contributions to residual EGJ pressure, as well as the magnitude and genesis of distal esophageal intrabolus pressure (IBP). Differences among study groups were analyzed with analysis of variance. After swallows, HH-dysphagia patients had greater residual CD pressure (9 mmHg; standard deviation [SD], 4) and IBP pressure (19 mmHg; SD, 4) compared to HH-GERD patients (5 mmHg; SD, 2; and 12 mmHg; SD, 2, respectively; P<.001) or normal subjects (NA; 11 mmHg; SD, 3; P<.001). Sliding HH alters the pressure dynamics through the EGJ and can lead to a functional obstruction. Patients with HH and dysphagia have greater pressures through the CD compared to HH patients with GERD symptoms, supporting the hypothesis that sliding HH in and of itself may be responsible for dysphagia. Copyright (c) 2010 Mosby, Inc. All rights reserved.

Mucosal Healing and Risk of Lymphoproliferative Malignancy in Celiac Disease

PubMed Central

Lebwohl, Benjamin; Granath, Fredrik; Ekbom, Anders; Smedby, Karin Ekström; Murray, Joseph A.; Neugut, Alfred I.; Green, Peter HR; Ludvigsson, Jonas F.

2013-01-01

Background Celiac disease (CD) is associated with an increased risk of lymphoproliferative malignancy (LPM). It is unknown whether this risk is affected by the results of the follow-up intestinal biopsy, performed to document mucosal healing. Objective To examine the association between mucosal healing in CD and later LPM. Design Population-based cohort study Setting We identified patients with CD from all of Sweden’s 28 pathology departments. Patients Individuals with CD who had a follow-up biopsy after initial diagnosis. Measurements We compared the risk of LPM to that of the general population using expected rates; and through Cox regression we compared the rate of LPM in those with persistent villous atrophy to those with mucosal healing. Results Among 7,625 patients with CD and a follow-up biopsy, persistent villous atrophy was present in 3,308 (43%). The overall risk of LPM was increased compared to the general population (Standardized incidence ratio, SIR 2.81; 95%CI 2.10–3.67), but this increase was greater among those with persistent villous atrophy (SIR 3.78; 95%CI 2.71–5.12) as compared to those with mucosal healing (SIR 1.50; 95%CI 0.77–2.62). Persistent villous atrophy compared to mucosal healing was associated with an increased risk of LPM (Hazard ratio, HR 2.26; 95%CI 1.18–4.34). We found an increased risk of T cell lymphoma (HR 3.51; 95%CI 0.75–16.34), but no excess risk of B cell lymphoma (HR 0.97; 95%CI 0.21–4.49). Limitation We had no data on dietary compliance. Conclusions The increased LPM risk in CD is associated with the results of the follow-up biopsy, with a higher risk among those with persistent villous atrophy. Follow-up biopsy may be a means to effectively stratify CD patients regarding subsequent LPM risk. Primary funding source the National Center for Advancing Translational Sciences, National Institutes of Health, The American Scandinavian Foundation, the Celiac Sprue Association, Örebro University Hospital, Karolinska Institutet, the Swedish Society of Medicine, the Swedish Research Council, and the Swedish Celiac Society. PMID:23922062

[Assessment of sulfasalazine and hydroxichloroqine hepatotoxicity in patients with rheumatic arthritis and isolated HBS-antigen positivity].

PubMed

Petrov, A V

2004-01-01

Findings were based on long-period survey (12-16 month) of 39 patients with rheumatoid arthritis (RA) and isolated persistent HBS-antigen. The patients were prescribed Hydroxichloroqine (H) and Sulfasolin (SF). Clinical data, laboratory tests, ultrasonic diagnostics to evaluate liver condition have been analyzed. HBs, Hbe-antigenes, DNA-virus B hepatitis blood test, nucleus dimensions, proliferative FGA response test and immune CD 8+, CD 14+ and CD 16+ cells to Fas-induced apoptosis were taken. SF therapy was found to be more hepatotoxic and likely to activate a latent virus B hepatitis as compared with Hydroxichloroqine and combine H and SF therapies. Triggering replication of virus B hepatitis occurs against a background of decreasing in functional activity of CD 14+ and CD 16+ cells. The immune critical level needed to activate VHB was determined.

High IFN-gamma and TNF production by peripheral NK cells of Colombian patients with different clinical presentation of Plasmodium falciparum

PubMed Central

2012-01-01

Background In Colombia, Plasmodium falciparum infection rarely results in severe disease or mortality compared to infections in African populations. During natural infection NK cells exhibit a cytolytic effect and regulate dendritic cells, macrophages, neutrophils as well as affect antigen specific T and B cell responses. To characterize the NK cells in P. falciparum infected patients of a highly endemic region of Colombia, the degree of NK proliferation and production of IFN gamma and TNF production in these cells were explored. Methods Seventeen patients with acute and three with severe P. falciparum malaria patients from the Northwest region of the country were recruited in the study. In addition, 20 healthy controls were included: 10 from Medellin (no-transmission area) and 10 from the Uraba region (a malaria endemic area). Immunophenotypic analysis of peripheral mononuclear cells was performed by FACS to detect total number of NK cells, subtypes and intracellular IFNγ and TNF production by NK cells in the different patient groups. Results The total mean CD56+/CD3- NK cell proportions in acute and severe malaria subjects were 9.14% (7.15%CD56dim, 2.01%CD56bright) and 19.62% (16.05%CD56dim, 3.58%CD56bright), respectively, in contrast to healthy controls from endemic (total mean CD56+/CD3-1.2%) and non-endemic area (total mean CD56+/CD3- 0.67%). Analysis of basal IFNγ and TNF levels confirmed the CD56bright NK population as the main cytokine producer (p < 0.0001) in the groups affected with malaria, with the CD56dim NK cell exhibiting the highest potential of TNF production after stimulus in the acute malaria group. Conclusions The results confirm the important role of not only CD56bright but also of CD56dim NK cell populations as producers of the two cytokines in malaria patients in Colombia. PMID:22316273

Early Course of Inflammatory Bowel Disease in a Population-Based Inception Cohort Study From 8 Countries in Asia and Australia.

PubMed

Ng, Siew C; Zeng, Zhirong; Niewiadomski, Ola; Tang, Whitney; Bell, Sally; Kamm, Michael A; Hu, Pinjin; de Silva, H Janaka; Niriella, Madunil A; Udara, W S A A Yasith; Ong, David; Ling, Khoon Lin; Ooi, Choon Jin; Hilmi, Ida; Lee Goh, Khean; Ouyang, Qin; Wang, Yu Fang; Wu, Kaichun; Wang, Xin; Pisespongsa, Pises; Manatsathit, Sathaporn; Aniwan, Satimai; Limsrivilai, Julajak; Gunawan, Jeffri; Simadibrata, Marcellus; Abdullah, Murdani; Tsang, Steve W C; Lo, Fu Hang; Hui, Aric J; Chow, Chung Mo; Yu, Hon Ho; Li, Mo Fong; Ng, Ka Kei; Ching, Jessica Y L; Chan, Victor; Wu, Justin C Y; Chan, Francis K L; Chen, Minhu; Sung, Joseph J Y

2016-01-01

The incidence of inflammatory bowel disease (IBD) is increasing in Asia, but little is known about disease progression in this region. The Asia-Pacific Crohn's and Colitis Epidemiology Study was initiated in 2011, enrolling subjects from 8 countries in Asia (China, Hong Kong, Indonesia, Sri Lanka, Macau, Malaysia, Singapore, and Thailand) and Australia. We present data from this ongoing study. We collected data on 413 patients diagnosed with IBD (222 with ulcerative colitis [UC], 181 with Crohn's disease [CD], 10 with IBD unclassified; median age, 37 y) from 2011 through 2013. We analyzed the disease course and severity and mortality. Risks for medical and surgical therapies were assessed using Kaplan-Meier analysis. The cumulative probability that CD would change from inflammatory to stricturing or penetrating disease was 19.6%. The cumulative probabilities for use of immunosuppressants or anti-tumor necrosis factor agents were 58.9% and 12.0% for patients with CD, and 12.7% and 0.9% for patients with UC, respectively. Perianal CD was associated with an increased risk of anti-tumor necrosis factor therapy within 1 year of its diagnosis (hazard ratio, 2.97; 95% confidence interval, 1.09-8.09). The cumulative probabilities for surgery 1 year after diagnosis were 9.1% for patients with CD and 0.9% for patients with UC. Patients with CD and penetrating disease had a 7-fold increase for risk of surgery, compared with patients with inflammatory disease (hazard ratio, 7.67; 95% confidence interval, 3.93-14.96). The overall mortality for patients with IBD was 0.7%. In a prospective population-based study, we found that the early course of disease in patients with IBD in Asia was comparable with that of the West. Patients with CD frequently progress to complicated disease and have accelerated use of immunosuppressants. Few patients with early stage UC undergo surgery in Asia. Increasing our understanding of IBD progression in different populations can help optimize therapy and improve outcomes. Copyright © 2016 AGA Institute. Published by Elsevier Inc. All rights reserved.

Validation of the Tuebingen CD-25 Inventory as a Measure of Postoperative Health-Related Quality of Life in Patients Treated for Cushing's Disease.

PubMed

Milian, Monika; Kreitschmann-Andermahr, Ilonka; Siegel, Sonja; Kleist, Bernadette; Führer-Sakel, Dagmar; Honegger, Juergen; Buchfelder, Michael; Psaras, Tsambika

2015-01-01

To evaluate the construct and criterion validity of the Tuebingen Cushing's disease quality of life inventory (Tuebingen CD-25) for application in patients treated for Cushing's disease (CD). A total of 176 patients with adrenocorticotropin hormone-dependent CD (144 of them female, overall mean age 46.1 ± 13.7 years) treated at 3 large tertiary referral centers in Germany were studied. Construct validity was assessed by hypothesis testing (self-perceived symptom reduction assessment) and contrasted groups (patients with vs. without hypercorticolism). For this purpose, already existing data from 55 CD patients was used, representing the hypercortisolemic group. Criterion validity (concurrent validity) was assessed in relation to the Cushing's quality of life questionnaire (CushingQoL), the Short Form 36 health survey (SF-36), and the body mass index (BMI). Patients with self-perceived remarkable symptom reduction had significant lower Tuebingen CD-25 scores (i.e. better health-related quality of life) than patients with self-perceived insufficient symptom reduction (p < 0.05). Similarly, the mean scores of the Tuebingen CD-25 scales were lower in patients without hypercortisolism (total score 27.0 ± 17.2) compared to those with hypercortisolism (total score 45.3 ± 22.1; each p < 0.05), providing evidence for construct validity. Criterion validity was confirmed by the correlations between the Tuebingen CD-25 total score and the CushingQoL (Spearman's coefficient -0.733), as well as all scales of the SF-36 (Spearman's coefficient between -0.447 and -0.700). The analyses presented in this large-sample study provide robust evidence for the construct and criterion validity of the Tuebingen CD-25. © 2015 S. Karger AG, Basel.

Parameters indicative of persistence of valvular pathology at initial diagnosis in acute rheumatic carditis: the role of albumin and CD19 expression.

PubMed

Oner, Taliha; Ozdemir, Rahmi; Genc, Dildar Bahar; Kucuk, Mehmet; Karadeniz, Cem; Demirpence, Savas; Yilmazer, Murat Muhtar; Mese, Timur; Tavli, Vedide; Genel, Ferah

The aim of this study is to define the predictors of chronic carditis in patients with acute rheumatic carditis (ARC). Patients diagnosed with ARC between May 2010 and May 2011 were included in the study. Echocardiography, electrocardiography, lymphocyte subset analysis, acute phase reactants, plasma albumin levels, and antistreptolysin-O (ASO) tests were performed at initial presentation. The echocardiographic assessments were repeated at the sixth month of follow-up. The patients were divided into two groups according to persistence of valvular pathology at 6th month as Group 1 and Group 2, and all clinical and laboratory parameters at admission were compared between two groups of valvular involvement. During the one-year study period, 22 patients had valvular disease. Seventeen (77.2%) patients showed regression in valvular pathology. An initial mild regurgitation disappeared in eight patients (36.3%). Among seven (31.8%) patients with moderate regurgitation initially, the regurgitation disappeared in three, and four patients improved to mild regurgitation. Two patients with a severe regurgitation initially improved to moderate regurgitation (9.1%). In five (22.8%) patients, the grade of regurgitation [moderate regurgitation in one (4.6%), and severe regurgitation in 4 (18.2%)] remained unchanged. The albumin level was significantly lower at diagnosis in Group 2 (2.6±0.48g/dL). Lymphocyte subset analysis showed a significant decrease in the CD8 percentage and a significant increase in CD19 percentage at diagnosis in Group 2 compared to Group 1. The blood albumin level and the percentage of CD8 and CD19 (+) lymphocytes at diagnosis may help to predict chronic valvular disease risk in patients with acute rheumatic carditis. Copyright © 2016. Published by Elsevier Editora Ltda.

Increased duodenal expression of miR-146a and -155 in pediatric Crohn’s disease

PubMed Central

Szűcs, Dániel; Béres, Nóra Judit; Rokonay, Réka; Boros, Kriszta; Borka, Katalin; Kiss, Zoltán; Arató, András; Szabó, Attila J; Vannay, Ádám; Sziksz, Erna; Bereczki, Csaba; Veres, Gábor

2016-01-01

AIM: To evaluate the role of microRNA (miR)-146a, -155 and -122 in the duodenal mucosa of pediatric patients with Crohn’s disease (CD) and the effect of transforming growth factor-β (TGF-β) on these miRs in duodenal epithelial and fibroblast cells. METHODS: Formalin-fixed, paraffin-embedded biopsies derived from the macroscopically inflamed (CD inflamed: n = 10) and intact (CD intact: n = 10) duodenal mucosa of pediatric CD patients and control children (C: n = 10) were examined. Expression of miR-146a, -155 and -122 was determined by real-time polymerase-chain reaction (PCR). The expression of the above miRs was investigated in recombinant human TGF-β (1 nmol/L, 24 h) or vehicle treated small intestinal epithelial cells (CCL-241) and primary duodenal fibroblast cells derived from healthy children as well. RESULTS: Expression of miR-146a was significantly higher in the inflamed duodenal mucosa compared to the intact duodenal mucosa of children with CD (CD inflamed: 3.21 ± 0.50 vs CD intact: 0.62 ± 0.26, P ≤ 0.01) and to the control group (CD inflamed: 3.21 ± 0.50 vs C: 1.00 ± 0.33, P ≤ 0.05). The expression of miR-155 was significantly increased in the inflamed region of the duodenum compared to the control group (CD inflamed: 4.87 ± 1.02 vs Control: 1.00 ± 0.40, P ≤ 0.001). The expression of miR-122 was unchanged in the inflamed or intact mucosa of CD patients compared to controls. TGF-β treatment significantly decreased the expression of miR-155 in small intestinal epithelial cells (TGF-β: 0.7 ± 0.083 vs Control: 1 ± 0.09, P ≤ 0.05) and also the expression of miR-146a (TGF-β: 0.67 ± 0.04 vs Control: 1 ± 0.15, P ≤ 0.01) and miR-155 (TGF-β: 0.72 ± 0.09 vs Control: 1 ± 0.06, P ≤ 0.05) in primary duodenal fibroblasts compared to corresponding vehicle treated controls. TGF-β treatment did not influence the expression of miR-122. CONCLUSION: The elevated expression of miR-146a and -155 in the inflamed duodenal mucosa of CD patients suggests the role of these miRs in the pathomechanism of inflammatory bowel disease. Anti-inflammatory TGF-β plays an important role in the regulation of the expression of these miRs. PMID:27468194

Celiac disease: Serologic prevalence in patients with irritable bowel syndrome

PubMed Central

Mehdi, Zobeiri; Sakineh, Ebrahimi; Mohammad, Farahvash; Mansour, Rezaei; Alireza, Abdollahi

2012-01-01

Background: The prevalence of irritable bowel syndrome (IBS) in the community is 10%–20% and have symptom based diagnostic criteria. Many symptoms of celiac disease (CD) with 1% prevalence in some communities can mimic IBS. Sensitive and specific serologic tests of CD can detect asymptomatic cases. The purpose of this study was to compare the level of anti-tissue-transglutaminase (tTG) IgA in IBS patients and controls group. Materials and Methods: This case-control study was performed at a University hospital in which 107 patients with IBS who met the Rome II criteria for their diagnosis were compared with 126 healthy age and sex-matched controls. Both groups were investigated for CD by analysis of their serum tTG IgA antibody with human recombinant antigen. Titers were positive containing over 10u/ml and borderline if they were between 4 and 10 u/ml. Result: 86 percent of IBS patients were female. The mean antibody level was 0.837 u/ml in IBS group and 0.933 u/ml in control group without any significant difference. Discussion and Conclusion: Results of this study may intensify disagreement on the situation of CD in IBS patients. PMID:23826010

Thiopurines are associated with a reduction in surgical re-resections in patients with Crohn's disease: a long-term follow-up study in a regional and academic cohort.

PubMed

van Loo, Ellen S; Vosseberg, Ninke W; van der Heide, Frans; Pierie, Jean-Pierre E N; van der Linde, Klaas; Ploeg, Rutger J; Dijkstra, Gerard; Nieuwenhuijs, Vincent B

2013-12-01

Combination therapy of thiopurines and anti-tumor necrosis factor alpha (TNF-α) antibodies is the most effective medical treatment of Crohn's disease (CD). Data on thiopurines and anti-TNF-α antibodies in preventing surgical recurrence (need for re-resection) of CD are scarce. Therefore, we analyzed which factors were involved in surgical recurrence of CD in a large cohort of patients with CD operated in a regional and a university hospital. This is a retrospective cohort study of 567 patients who underwent surgery for CD. Clinical data and risk factors for surgical recurrence were analyzed, focusing on medical therapy and hospital type. Overall, 237 (41.8%) patients developed a surgical recurrence, after a median of 70 (2-482) months. Before surgical recurrence, 235 patients (41.4%) and 116 patients (20.5%) used thiopurines and anti-TNF-α antibodies, respectively. Multivariate analysis identified 3 independent risk factors associated with surgical recurrence of CD. A higher risk was seen in patients with colonic disease compared with patients with ileal disease (hazard ratio, 1.56; 95% confidence interval, 1.10-2.21; P = 0.012) and in patients using multiple types of medication (hazard ratio, 1.38; 95% confidence interval, 1.25-1.54; P < 0.001). However, a lower risk was seen in patients using thiopurines (hazard ratio, 0.51; 95% confidence interval, 0.34-0.77; P = 0.001). Thiopurines are effective in preventing surgical recurrence of CD. The role of anti-TNF-α antibodies seems promising as well. Combination therapy of thiopurines and anti-TNF-α antibodies for prevention of surgical recurrence of CD should be studied in a randomized trial.

Association between serum soluble CD40 ligand levels and mortality in patients with severe sepsis

PubMed Central

2011-01-01

Introduction CD40 Ligand (CD40L) and its soluble counterpart (sCD40L) are proteins that exhibit prothrombotic and proinflammatory properties on binding to their cell surface receptor CD40. The results of small clinical studies suggest that sCD40L levels could play a role in sepsis; however, there are no data on the association between sCD40L levels and mortality of septic patients. Thus, the aim of this study was to determine whether circulating sCD40L levels could be a marker of adverse outcome in a large cohort of patients with severe sepsis. Methods This was a multicenter, observational and prospective study carried out in six Spanish intensive care units. Serum levels of sCD40L, tumour necrosis factor-alpha and interleukin-10, and plasma levels of tissue factor were measured in 186 patients with severe sepsis at the time of diagnosis. Serum sCD40L was also measured in 50 age- and sex-matched controls. Survival at 30 days was used as the endpoint. Results Circulating sCD40L levels were significantly higher in septic patients than in controls (P = 0.01), and in non-survivors (n = 62) compared to survivors (n = 124) (P = 0.04). However, the levels of CD40L were not different regarding sepsis severity. Logistic regression analysis showed that sCD40L levels >3.5 ng/mL were associated with higher mortality at 30 days (odds ratio = 2.89; 95% confidence interval = 1.37 to 6.07; P = 0.005). The area under the curve of sCD40L levels >3.5 ng/mL as predictor of mortality at 30 days was 0.58 (95% CI = 0.51 to 0.65; P = 0.03). Conclusions In conclusion, circulating sCD40L levels are increased in septic patients and are independently associated with mortality in these patients; thus, its modulation could represent an attractive therapeutic target. PMID:21406105

Integration and task shifting for TB/HIV care and treatment in highly resource-scarce settings: one size may not fit all.

PubMed

Van Rie, Annelies; Patel, Monita R; Nana, Mbonze; Vanden Driessche, Koen; Tabala, Martine; Yotebieng, Marcel; Behets, Frieda

2014-03-01

A crucial question in managing HIV-infected patients with tuberculosis (TB) concerns when and how to initiate antiretroviral therapy (ART). The effectiveness of CD4-stratified ART initiation in a nurse-centered, integrated TB/HIV program at primary care in Kinshasa, Democratic Republic of Congo, was assessed. Prospective cohort study was conducted to assess the effect of CD4-stratified ART initiation by primary care nurses (513 TB patients, August 2007 to November 2009). ART was to be initiated at 1 month of TB treatment if CD4 count is <100 cells per cubic millimeter, at 2 months if CD4 count is 100-350 cells per cubic millimeter, and at the end of TB treatment after CD4 count reassessment if CD4 count is >350 cells per cubic millimeter. ART uptake and mortality were compared with a historical prospective cohort of 373 HIV-infected TB patients referred for ART to a centralized facility and 3577 HIV-negative TB patients (January 2006 to May 2007). ART uptake increased (17%-69%, P < 0.0001) and mortality during TB treatment decreased (20.1% vs 9.8%, P < 0.0003) after decentralized, nurse-initiated, CD4-stratified ART. Mortality among TB patients with CD4 count >100 cells per cubic millimeter was similar to that of HIV-negative TB patients (5.6% vs 6.3%, P = 0.65), but mortality among those with CD4 count <100 cells per cubic millimeter remained high (18.8%). Nurse-centered, CD4-stratified ART initiation at primary care level was effective in increasing timely ART uptake and reducing mortality among TB patients but may not be adequate to prevent mortality among those presenting with severe immunosuppression. Further research is needed to determine the optimal management at primary care level of TB patients with CD4 counts <100 cells per cubic millimeter.

Increased PD-1+ and TIM-3+ TILs during cetuximab therapy inversely correlates with response in head and neck cancer patients

PubMed Central

Jie, Hyun-Bae; Srivastava, Raghvendra M.; Argiris, Athanassios; Bauman, Julie E.; Kane, Lawrence P.; Ferris, Robert L.

2017-01-01

Despite emerging appreciation for the important role of immune checkpoint receptors in regulating the effector functions of T cells, it is unknown whether their expression is involved in determining the clinical outcome in response to cetuximab therapy. We examined the expression patterns of immune checkpoint receptors (including PD-1, CTLA-4, and TIM-3) and cytolytic molecules (including granzyme B and perforin) of CD8+ tumor-infiltrating lymphocytes (TILs) and compared them to those of peripheral blood T lymphocytes (PBLs) in patients with head and neck cancer (HNSCC) during cetuximab therapy. The frequency of PD-1 and TIM-3 expression was significantly increased in CD8+ TILs compared to CD8+ PBLs (P = 0.008 and P = 0.02, respectively). This increased CD8+ TIL population co-expressed granzyme B/perforin and PD-1/TIM-3, which suggests a regulatory role for these immune checkpoint receptors in cetuximab-promoting cytolytic activities of CD8+ TIL. Indeed, the increased frequency of PD-1+ and TIM-3+ CD8+ TILs was inversely correlated with clinical outcome of cetuximab therapy. These findings support the use of PD-1 and TIM-3 as biomarkers to reflect immune status of CD8+ T cells in the tumor microenvironment during cetuximab therapy. Blockade of these immune checkpoint receptors might enhance cetuximab-based cancer immunotherapy to reverse CD8+ TIL dysfunction, thus potentially improving clinical outcomes of HNSCC patients. PMID:28408386

Voxel-based comparison of brain glucose metabolism between patients with Cushing's disease and healthy subjects.

PubMed

Liu, Shuai; Wang, Yinyan; Xu, Kaibin; Ping, Fan; Li, Fang; Wang, Renzhi; Cheng, Xin

2018-01-01

Cognitive impairment and psychiatric symptoms are common in patients with Cushing's disease (CD) owing to elevated levels of glucocorticoids. Molecular neuroimaging methods may help to detect changes in the brain of patients with CD. The aim of this study was to investigate the characteristics of brain metabolism and its association with serum cortisol level in CD. We compared brain metabolism, as measured using [ 18 F]-fluorodeoxyglucose positron emission tomography (FDG PET), between 92 patients with CD and 118 normal subjects on a voxel-wise basis. Pearson correlation was performed to evaluate the association between cerebral FDG uptake and serum cortisol level in patients with CD. We demonstrated that certain brain regions in patients with CD showed significantly increased FDG uptake, including the basal ganglia, anteromedial temporal lobe, thalamus, precentral cortex, and cerebellum. The clusters that demonstrated significantly decreased uptake were mainly located in the medial and lateral frontal cortex, superior and inferior parietal lobule, medial occipital cortex, and insular cortex. The metabolic rate of the majority of these regions was found to be significantly correlated with the serum cortisol level. Our findings may help to explain the underlying mechanisms of cognitive impairment and psychiatric symptoms in patients exposed to excessive glucocorticoids and evaluate the efficacy of treatments during follow-up.

Non-suppressive regulatory T cell subset expansion in pulmonary arterial hypertension.

PubMed

Sada, Yoshiharu; Dohi, Yoshihiro; Uga, Sayuri; Higashi, Akifumi; Kinoshita, Hiroki; Kihara, Yasuki

2016-08-01

Regulatory T cells (Tregs) have been reported to play a pivotal role in the vascular remodeling of pulmonary arterial hypertension (PAH). Recent studies have revealed that Tregs are heterogeneous and can be characterized by three phenotypically and functionally different subsets. In this study, we investigated the roles of Treg subsets in the pathogenesis of PAH in eight patients with PAH and 14 healthy controls. Tregs and their subsets in peripheral blood samples were analyzed by flow cytometry. Treg subsets were defined as CD4(+)CD45RA(+)FoxP3(low) resting Tregs (rTregs), CD4(+)CD45RA(-)FoxP3(high) activated Tregs (aTregs), and CD4(+)CD45RA(-)FoxP3(low) non-suppressive Tregs (non-Tregs). The proportion of Tregs among CD4(+) T cells was significantly higher in PAH patients than in controls (6.54 ± 1.10 vs. 3.81 ± 0.28 %, p < 0.05). Of the three subsets, the proportion of non-Tregs was significantly elevated in PAH patients compared with controls (4.06 ± 0.40 vs. 2.79 ± 0.14 %, p < 0.01), whereas those of rTregs and aTregs were not different between the two groups. Moreover, the expression levels of cytotoxic T lymphocyte antigen 4, a functional cell surface molecule, in aTregs (p < 0.05) and non-Tregs (p < 0.05) were significantly higher in PAH patients compared with controls. These results suggested the non-Treg subset was expanded and functionally activated in peripheral lymphocytes obtained from IPAH patients. We hypothesize that immunoreactions involving the specific activation of the non-Treg subset might play a role in the vascular remodeling of PAH.

Serological markers of enterocyte damage and apoptosis in patients with celiac disease, autoimmune diabetes mellitus and diabetes mellitus type 2.

PubMed

Hoffmanová, I; Sánchez, D; Hábová, V; Anděl, M; Tučková, L; Tlaskalová-Hogenová, H

2015-01-01

Impairment of mucosal barrier integrity of small intestine might be causative in immune-mediated gastrointestinal diseases. We tested the markers of epithelial apoptosis - cytokeratin 18 caspase-cleaved fragment (cCK-18), and enterocyte damage - intestinal fatty acid-binding protein (I-FABP) and soluble CD14 (sCD14) in sera of patients with untreated celiac disease (CLD), those on gluten-free diet (CLD-GFD), patients with autoimmune diabetes mellitus (T1D), T1D with insulitis (T1D/INS), and diabetes mellitus type 2 (T2D). We found elevated levels of cCK-18 (P<0.001), I-FABP (P<0.01) and sCD14 (P<0.05) in CLD when compared to healthy controls. However, the levels of cCK-18 (P<0.01) and I-FABP (P<0.01) in CLD-GFD were higher when compared with controls. Interestingly, elevated levels of cCK-18 and I-FABP were found in T2D and T1D (P<0.001), and T1D/INS (P<0.01, P<0.001). Twenty-two out of 43 CLD patients were seropositive for cCK-18, 19/43 for I-FABP and 11/43 for sCD14; 9/30 of T2D patients were positive for cCK-18 and 5/20 of T1D/INS for sCD14, while in controls only 3/41 were positive for cCK-18, 3/41 for I-FABP and 1/41 for sCD14. We documented for the first time seropositivity for sCD14 in CLD and potential usefulness of serum cCK-18 and I-FABP as markers of gut damage in CLD, CLD-GFD, and diabetes.

High Levels of IL-10 and CD4+CD25hi+ Treg Cells in Endemic Burkitt’s Lymphoma Patients

PubMed Central

Futagbi, Godfred; Gyan, Ben; Nunoo, Harriet; Tetteh, John K.A.; Welbeck, Jennifer E.; Renner, Lorna Awo; Ofori, Michael; Dodoo, Daniel; Edoh, Dominic A.; Akanmori, Bartholomew D.

2015-01-01

Background: The interplay between Epstein-Barr virus infection, malaria, and endemic Burkitt’s Lymphoma is not well understood. Reports show diminished EBV-specific Th1 responses in children living in malaria endemic areas and deficiency of EBNA1-specific IFN-γ T cell responses in children with endemic Burkitt’s Lymphoma (eBL). This study, therefore, examined some factors involved in the loss of EBNA-1-specific T cell responses in eBL. Methods: T-cell subset frequencies, activation, and IFN-γ- or IL-4-specific responses were analyzed by flow-cytometry. Plasma cytokine levels were measured by ELISA. Results: CD4+ and CD8+ cells in age- and sex-matched healthy controls (n = 3) expressed more IFN-γ in response to all immunostimulants than in pediatric endemic BL (eBL) patients (n = 4). In healthy controls, IFN-γ expression was higher than IL-4 expression, whereas in eBL patients the expression of IL-4 by CD4+ cells to EBNA-1 was slightly higher than IFN-γ. Moreover, the blood levels of TNF-α was significantly lower (p = 0.004) while IL-10 was significantly higher (p = 0.038), in eBL patients (n = 21) compared to controls (n = 16). Additionally, the frequency of CD4+CD25hi+ T cells was higher in both age-matched acute uncomplicated malaria (n = 26) and eBL (n = 14) patients compared to healthy controls (n = 19; p = 0.000 and p = 0.027, respectively). Conclusion: The data suggest that reduced Th1 response in eBL might be due to increased levels of IL-10 and T reg cells. PMID:28536409

High Levels of IL-10 and CD4+CD25hi+ Treg Cells in Endemic Burkitt's Lymphoma Patients.

PubMed

Futagbi, Godfred; Gyan, Ben; Nunoo, Harriet; Tetteh, John K A; Welbeck, Jennifer E; Renner, Lorna Awo; Ofori, Michael; Dodoo, Daniel; Edoh, Dominic A; Akanmori, Bartholomew D

2015-08-04

The interplay between Epstein-Barr virus infection, malaria, and endemic Burkitt's Lymphoma is not well understood. Reports show diminished EBV-specific Th1 responses in children living in malaria endemic areas and deficiency of EBNA1-specific IFN-γ T cell responses in children with endemic Burkitt's Lymphoma (eBL). This study, therefore, examined some factors involved in the loss of EBNA-1-specific T cell responses in eBL. T-cell subset frequencies, activation, and IFN-γ- or IL-4-specific responses were analyzed by flow-cytometry. Plasma cytokine levels were measured by ELISA. CD4+ and CD8+ cells in age- and sex-matched healthy controls ( n = 3) expressed more IFN-γ in response to all immunostimulants than in pediatric endemic BL (eBL) patients ( n = 4). In healthy controls, IFN-γ expression was higher than IL-4 expression, whereas in eBL patients the expression of IL-4 by CD4+ cells to EBNA-1 was slightly higher than IFN-γ. Moreover, the blood levels of TNF-α was significantly lower ( p = 0.004) while IL-10 was significantly higher ( p = 0.038), in eBL patients ( n = 21) compared to controls ( n = 16). Additionally, the frequency of CD4+CD25hi+ T cells was higher in both age-matched acute uncomplicated malaria ( n = 26) and eBL ( n = 14) patients compared to healthy controls ( n = 19; p = 0.000 and p = 0.027, respectively). The data suggest that reduced Th1 response in eBL might be due to increased levels of IL-10 and T reg cells.

Comparative effectiveness of infliximab and adalimumab in Crohn’s disease and ulcerative colitis

PubMed Central

Ananthakrishnan, Ashwin N.; Cagan, Andrew; Cai, Tianxi; Gainer, Vivian S.; Shaw, Stanley Y; Savova, Guergana; Churchill, Susanne; Karlson, Elizabeth W.; Kohane, Isaac; Liao, Katherine P.; Murphy, Shawn N.

2016-01-01

Introduction The availability of monoclonal antibodies to tumor necrosis factor α (anti-TNF) has revolutionized management of Crohn’s disease (CD) and ulcerative colitis (UC). However, limited data exists regarding comparative effectiveness of these agents to inform clinical practice. Methods This study consisted of patients with CD or UC initiation either infliximab (IFX) or adalimumab (ADA) between 1998 and 2010. A validated likelihood of non-response classification score utilizing frequency of narrative mentions of relevant symptoms in the electronic health record (EHR) was applied to assess comparative effectiveness at 1 year. IBD-related surgery, hospitalization, and use of steroids was determined during this period. Results Our final cohort included 1,060 new initiations of IFX (68% for CD) and 391 of ADA (79% for CD). In CD, the likelihood of non-response was higher in ADA than IFX (OR 1.62, 95% CI 1.21 – 2.17). Similar differences favoring efficacy of IFX was observed for the individual symptoms of diarrhea, pain, bleeding, and fatigue. However, there was no difference in IBD-related surgery, hospitalizations or prednisone use within 1 year after initiation of IFX or ADA in CD. There was no difference in narrative or codified outcomes between the two agents in UC. Conclusion We identified a modestly higher likelihood of symptomatic non-response at 1 year for ADA compared to IFX in patients with CD. However, there were no differences in IBD-related surgery or hospitalizations suggesting these treatments are broadly comparable in effectiveness in routine clinical practice. PMID:26933751

Development and Validation of an Inflammatory Bowel Diseases Monitoring Index for Use With Mobile Health Technologies.

PubMed

Van Deen, Welmoed K; van der Meulen-de Jong, Andrea E; Parekh, Nimisha K; Kane, Ellen; Zand, Aria; DiNicola, Courtney A; Hall, Laurin; Inserra, Elizabeth K; Choi, Jennifer M; Ha, Christina Y; Esrailian, Eric; van Oijen, Martijn G H; Hommes, Daniel W

2016-12-01

Mobile health technologies are advancing rapidly as smartphone use increases. Patients with inflammatory bowel disease (IBD) might be managed remotely through smartphone applications, but no tools are yet available. We tested the ability of an IBD monitoring tool, which can be used with mobile technologies, to assess disease activity in patients with Crohn's disease (CD) or ulcerative colitis (UC). We performed a prospective observational study to develop and validate a mobile health index for CD and UC, which monitors IBD disease activity using patient-reported outcomes. We collected data from disease-specific questionnaires completed by 110 patients with CD and 109 with UC who visited the University of California, Los Angeles, Center for IBD from May 2013 through January 2014. Patient-reported outcomes were compared with clinical disease activity index scores to identify factors associated with disease activity. Index scores were validated in 301 patients with CD and 265 with UC who visited 3 tertiary IBD referral centers (in California or Europe) from April 2014 through March 2015. We assessed activity of CD based on liquid stool frequency, abdominal pain, patient well-being, and patient-assessed disease control, and activity of UC based on stool frequency, abdominal pain, rectal bleeding, and patient-assessed disease control. The indices identified clinical disease activity with area under the receiver operating characteristic curve values of 0.90 in patients with CD and 0.91 in patients with UC. They identified endoscopic activity with area under the receiver operating characteristic values of 0.63 in patients with CD and 0.82 in patients with UC. Both scoring systems responded to changes in disease activity (P < .003). The intraclass correlation coefficient for test-retest reliability was 0.94 for CD and for UC. We developed and validated a scoring system to monitor disease activity in patients with CD and UC that can be used with mobile technologies. The indices identified clinical disease activity with area under the receiver operating characteristic curve values of 0.9 or higher in patients with CD or UC, and endoscopic activity in patients with UC but not CD. Copyright © 2016 AGA Institute. Published by Elsevier Inc. All rights reserved.

TGF-β1 related inflammation in the posterior longitudinal ligament of cervical spondylotic myelopathy patients.

PubMed

Wang, Jia-Zeng; Fang, Xiu-Tong; Lv, E; Yu, Fang; Wang, Zhen-Wei; Song, Hong-Xing

2015-01-01

This study aimed to elucidate the pathogenesis of posterior longitudinal ligament (PLL) hypertrophy. Cervical PLL specimens were collected from CSM patients during surgery (n = 30) and during routine autopsy (n = 14), and processed for histological examination (HE staining and Masson's Trichrome staining) and IHC (CD3, CD68, CD31, TGF-β1 and collagen II). In addition, the mRNA expression of collagen I was detected in cervical PLL specimens from 16 CSM patients (n = 16) and from routine autopsy (n = 16) by RT-PCR. Obvious fibrosis, cartilage metaplasia and calcification were found in the cervical PLL of CSM patients. In the degenerated PLL, CD68(+) macrophages were frequently identified, CD3(+) T lymphocytes were occasionally found, and many newly generated small vessels were also present. In the degenerated PLL, of the number of TGF-β1 positive cells increased markedly when compared with control group. IHC indicated TGF-β1 was secreted by macrophages. RT-PCR showed a significantly lower mRNA expression of collagen I in the PLL of CSM patients as compared to control group. Macrophages are the major type of inflammatory cells involved in the cervical PLL degeneration, and TGF-β1 is related to the cervical PLL degeneration. TGF-β1 is mainly secreted by macrophages. Anti-inflammation may serve as an alternative non-surgical treatment and prophylactic strategy for PLL degeneration.

Efficacy of adoptive cellular therapy in patients with gastric cancer: a meta-analysis.

PubMed

Shen, Dong; Liu, Zhi-Hao; Xu, Jia-Ning; Xu, Fang; Lin, Qin-Feng; Lin, Feng; Mao, Wei-Dong

2016-07-01

To systemically evaluate the efficacy and safety of adoptive cellular therapy for the treatment of gastric cancer (GC). We performed a systemic review and meta-analysis of nine eligible trials with GC and evaluated the effect of adoptive cellular therapy on the overall survival (OS) rate, T-cell subsets and adverse events. Overall, 829 patients were involved in the analysis. Adoptive cellular therapy significantly improved the OS rate compared with the control group. Meanwhile, we observed greatly increased percentages of CD3(+), CD4(+) and CD4(+)/CD8(+) in cellular therapy groups. Adoptive cellular therapy combined with adjuvant therapy resulted in significantly better OS rates, progression-free survival and T-lymphocyte responses in patients with GC.

Focal Defects of the Knee Articular Surface: Evidence of a Regenerative Potential Pattern in Osteochondritis Dissecans and Degenerative Lesions

PubMed Central

Gabusi, Elena; Manferdini, Cristina; Paolella, Francesca; Gambari, Laura; Mariani, Erminia

2017-01-01

The surgical treatment of knee articular focal lesions may offer heterogeneous clinical results. Osteochondritis dissecans (OCD) lesions showed to heal better than degenerative lesions (DL) but the underlying biological reasons are unknown. We evaluated the basal histological and immunohistochemical characteristics of these lesions analyzing a series of osteochondral fragments from young patients with similar age but presenting different etiology. Osteochondral tissue samples were stained with Safranin O and graded using a histological score. Markers of mesenchymal progenitor cells (CD146), osteoclasts (tartrate-resistant acid phosphatase, TRAP), and vessels (CD34) were evaluated. Histological score showed a higher degeneration of both cartilage and bone compartments in OCD compared to DL fragments. Only CD146-positive cells were found at the same percentage in cartilage compartment of both DL and OCD patients. By contrast, in the bone compartment a significantly higher percentage of CD146, TRAP, and CD34 markers was found in OCD compared to DL patients. These data showed distinct histological characteristics of osteochondral focal lesions located in the same anatomical region but having a different etiology. The higher percentages of these markers in OCD than in DL, mainly associated with a high bone turnover, could help to explain the higher clinical healing potential of OCD patients. PMID:28770227

The Selective Centrifugation Ensures a Better In Vitro Isolation of ASCs and Restores a Soft Tissue Regeneration In Vivo

PubMed Central

De Francesco, Francesco; Guastafierro, Antonio; Nicoletti, Gianfranco; Razzano, Sergio; Riccio, Michele; Ferraro, Giuseppe A.

2017-01-01

Autologous fat grafting procedures in plastic surgery have been extensively used to reinforce soft tissue in congenital or acquired tissue impairments. With this background, the aim of this study is firstly to examine the impact of a selective centrifugation on existing adipose stem cells (ASCs) in terms of stemness profile maintenance and, secondly, to investigate the effect of restoring volume in reconstruction on patients affected by soft tissue damage. After centrifugation, the fat graft products were separated into two layers and subsequently examined in vitro for the expression of CD34, CD90, CD117, CD105, CD29, CD31, CD44, CD73, CD133, CD14 and CD45 markers by flow cytometry and gene expression analyses were performed for Sox2, WNT3A, END, CD44, FUT4, COLL1, CTNNB1, hbEGF, KRTLG, MMP2 and VIM genes. The results showed that in the middle-high density (MHD) layer there was a peak concentration of ASCs, compared to another layer obtained after centrifugation. Research carried out on patients under treatment for soft tissue regeneration using cells obtained from MHD layer selection will be fundamental in comparative analysis. These studies will lead to an adequate standardization of outcomes, provided that treatment is performed through cell selection. Therefore, a unique procedure in tissue reconstruction and regeneration through fat grafting is presented here. PMID:28498335

Methylation of FOXP3 TSDR Underlies the Impaired Suppressive Function of Tregs from Long-term Belatacept-Treated Kidney Transplant Patients

PubMed Central

Alvarez Salazar, Evelyn Katy; Cortés-Hernández, Arimelek; Alemán-Muench, Germán Rodrigo; Alberú, Josefina; Rodríguez-Aguilera, Jesús R.; Recillas-Targa, Félix; Chagoya de Sánchez, Victoria; Cuevas, Eric; Mancilla-Urrea, Eduardo; Pérez García, María; Mondragón-Ramírez, Guillermo; Vilatobá, Mario; Bostock, Ian; Hernández-Méndez, Erick; De Rungs, David; García-Zepeda, Eduardo A.; Soldevila, Gloria

2017-01-01

Regulatory T cells (Tregs) are considered key players in the prevention of allograft rejection in transplanted patients. Belatacept (BLT) is an effective alternative to calcineurin inhibitors that appears to preserve graft survival and function; however, the impact of this drug in the homeostasis of Tregs in transplanted patients remains controversial. Here, we analyzed the phenotype, function, and the epigenetic status of the Treg-specific demethylated region (TSDR) in FOXP3 of circulating Tregs from long-term kidney transplant patients under BLT or Cyclosporine A treatment. We found a significant reduction in the proportion of CD4+CD25hiCD127lo/−FOXP3+ T cells in all patients compared to healthy individual (controls). Interestingly, only BLT-treated patients displayed an enrichment of the CD45RA+ “naïve” Tregs, while the expression of Helios, a marker used to identify stable FOXP3+ thymic Tregs remained unaffected. Functional analysis demonstrated that Tregs from transplanted patients displayed a significant reduction in their suppressive capacity compared to Tregs from controls, which is associated with decreased levels of FOXP3 and CD25. Analysis of the methylation status of the FOXP3 gene showed that BLT treatment results in methylation of CpG islands within the TSDR, which could be associated with the impaired Treg suppression function. Our data indicate that analysis of circulating Tregs cannot be used as a marker for assessing tolerance toward the allograft in long-term kidney transplant patients. Trial registration number IM103008. PMID:28316600

Circulating CXCR5+CD4+ T cells participate in the IgE accumulation in allergic asthma.

PubMed

Gong, Fang; Zhu, Hua-Yan; Zhu, Jie; Dong, Qiao-Jing; Huang, Xuan; Jiang, Dong-Jin

2018-05-01

The pathogenesis of allergic asthma is primarily characterized by abnormality in immunoglobin(Ig)E pathway, suggesting a possible role for follicular helper T cells (Tfh) in the genesis of excessive IgE accumulation. The blood chemokine (C-X-C motif) receptor 5 (CXCR)5 + CD4 + T cells, known as "circulating" Tfh, share common functional characteristics with Tfh cells from germinal centers. The aim of this study was to determine the phenotypes and functions of circulating CXCR5 + CD4 + T cells in allergic asthmatics. Here we found the frequency of the circulating CXCR5 + CD4 + T cells was raised in allergic asthma compared with healthy control (HC). Phenotypic assays showed that activated circulating CXCR5 + CD4 + T cells display the key features of Tfh cells, including invariably coexpressed programmed cell death (PD)-1 and inducible costimulator (ICOS). The frequency of interleukin IL-4 + -, IL-21 + -producing CXCR5 + CD4 + T cells was increased in allergic asthma patients compared with HC. Furthermore, sorted circulating CXCR5 + CD4 + T cells from allergic asthma patients boosted IgE production in coculture assay which could be inhibited by IL-4 or IL-21 blockage. Interestingly, IL-4 + -, IL-21 + -CXCR5 + CD4 + T cells positively correlated with total IgE in the blood. Our data indicated that circulating CXCR5 + CD4 + T cells may have a significant role in facilitating IgE production in allergic asthma patients. Copyright © 2018 European Federation of Immunological Societies. Published by Elsevier B.V. All rights reserved.

Drug-Coated Balloon vs. Conventional Balloon Angioplasty in Dialysis Patients With Symptomatic Femoropopliteal Disease　- A Matched Comparison.

PubMed

Chou, Hsin-Hua; Huang, Hsuan-Li; Hsieh, Chien-An; Jang, Shih-Jung; Tzeng, I-Shiang; Ko, Yu-Lin

2018-04-26

Recent randomized trials have shown the treatment benefits of use of a drug-coated balloon (DCB) over conventional percutaneous transluminal angioplasty (PTA) in patients with femoropopliteal disease. However, the effectiveness and safety of DCB for dialysis patients remain unclear.Methods and Results:Consecutive dialysis patients, who underwent PTA or DCB for femoropopliteal disease, were assessed retrospectively via 2:1 propensity score matching. Effectiveness and safety endpoints, including binary restenosis, clinically driven target lesion revascularization (CD-TLR), amputations, major adverse cardiac events (MACE), and deaths, were compared between groups. A total of 278 dialysis patients with 339 limbs were eligible for matching: 84 limbs from 77 patients treated with PTA and 46 limbs from 37 patients treated with DCB were compared after matching. Baseline patient and lesion characteristics were not different between groups. Patients treated with DCB had significantly higher rates of freedom from binary restenosis (52.4% vs. 18.6%, P<0.001) and CD-TLR (56.4% vs. 25.9%, P=0.001) at 2 years compared with patients treated with PTA. Both groups had similar outcomes for amputation, MACE, and death. Cox proportional analysis showed that treatment with DCB was independently associated with a reduction of binary restenosis (hazard ratio [HR] 0.368, P=0.001) and CD-TLR (HR 0.390, P=0.004). This study suggested superior 2-year outcomes using DCB compared with PTA and similar safety profiles in dialysis patients with femoropopliteal disease.

Deep sequencing and flow cytometric characterization of expanded effector memory CD8+CD57+ T cells frequently reveals T-cell receptor Vβ oligoclonality and CDR3 homology in acquired aplastic anemia.

PubMed

Giudice, Valentina; Feng, Xingmin; Lin, Zenghua; Hu, Wei; Zhang, Fanmao; Qiao, Wangmin; Ibanez, Maria Del Pilar Fernandez; Rios, Olga; Young, Neal S

2018-05-01

Oligoclonal expansion of CD8 + CD28 - lymphocytes has been considered indirect evidence for a pathogenic immune response in acquired aplastic anemia. A subset of CD8 + CD28 - cells with CD57 expression, termed effector memory cells, is expanded in several immune-mediated diseases and may have a role in immune surveillance. We hypothesized that effector memory CD8 + CD28 - CD57 + cells may drive aberrant oligoclonal expansion in aplastic anemia. We found CD8 + CD57 + cells frequently expanded in the blood of aplastic anemia patients, with oligoclonal characteristics by flow cytometric Vβ usage analysis: skewing in 1-5 Vβ families and frequencies of immunodominant clones ranging from 1.98% to 66.5%. Oligoclonal characteristics were also observed in total CD8 + cells from aplastic anemia patients with CD8 + CD57 + cell expansion by T-cell receptor deep sequencing, as well as the presence of 1-3 immunodominant clones. Oligoclonality was confirmed by T-cell receptor repertoire deep sequencing of enriched CD8 + CD57 + cells, which also showed decreased diversity compared to total CD4 + and CD8 + cell pools. From analysis of complementarity-determining region 3 sequences in the CD8 + cell pool, a total of 29 sequences were shared between patients and controls, but these sequences were highly expressed in aplastic anemia subjects and also present in their immunodominant clones. In summary, expansion of effector memory CD8 + T cells is frequent in aplastic anemia and mirrors Vβ oligoclonal expansion. Flow cytometric Vβ usage analysis combined with deep sequencing technologies allows high resolution characterization of the T-cell receptor repertoire, and might represent a useful tool in the diagnosis and periodic evaluation of aplastic anemia patients. (Registered at clinicaltrials.gov identifiers: 00001620, 01623167, 00001397, 00071045, 00081523, 00961064 ). Copyright © 2018 Ferrata Storti Foundation.

Extended flow cytometry characterization of normal bone marrow progenitor cells by simultaneous detection of aldehyde dehydrogenase and early hematopoietic antigens: implication for erythroid differentiation studies

PubMed Central

Mirabelli, Peppino; Di Noto, Rosa; Lo Pardo, Catia; Morabito, Paolo; Abate, Giovanna; Gorrese, Marisa; Raia, Maddalena; Pascariello, Caterina; Scalia, Giulia; Gemei, Marica; Mariotti, Elisabetta; Del Vecchio, Luigi

2008-01-01

Background Aldehyde dehydrogenase (ALDH) is a cytosolic enzyme highly expressed in hematopoietic precursors from cord blood and granulocyte-colony stimulating factor mobilized peripheral blood, as well as in bone marrow from patients with acute myeloblastic leukemia. As regards human normal bone marrow, detailed characterization of ALDH+ cells has been addressed by one single study (Gentry et al, 2007). The goal of our work was to provide new information about the dissection of normal bone marrow progenitor cells based upon the simultaneous detection by flow cytometry of ALDH and early hematopoietic antigens, with particular attention to the expression of ALDH on erythroid precursors. To this aim, we used three kinds of approach: i) multidimensional analytical flow cytometry, detecting ALDH and early hematopoietic antigens in normal bone marrow; ii) fluorescence activated cell sorting of distinct subpopulations of progenitor cells, followed by in vitro induction of erythroid differentiation; iii) detection of ALDH+ cellular subsets in bone marrow from pure red cell aplasia patients. Results In normal bone marrow, we identified three populations of cells, namely ALDH+CD34+, ALDH-CD34+ and ALDH+CD34- (median percentages were 0.52, 0.53 and 0.57, respectively). As compared to ALDH-CD34+ cells, ALDH+CD34+ cells expressed the phenotypic profile of primitive hematopoietic progenitor cells, with brighter expression of CD117 and CD133, accompanied by lower display of CD38 and CD45RA. Of interest, ALDH+CD34- population disclosed a straightforward erythroid commitment, on the basis of three orders of evidences. First of all, ALDH+CD34- cells showed a CD71bright, CD105+, CD45- phenotype. Secondly, induction of differentiation experiments evidenced a clear-cut expression of glycophorin A (CD235a). Finally, ALDH+CD34- precursors were not detectable in patients with pure red cell aplasia (PRCA). Conclusion Our study, comparing surface antigen expression of ALDH+/CD34+, ALDH-/CD34+ and ALDH+/CD34- progenitor cell subsets in human bone marrow, clearly indicated that ALDH+CD34- cells are mainly committed towards erythropoiesis. To the best of our knowledge this finding is new and could be useful for basic studies about normal erythropoietic differentiation as well as for enabling the employment of ALDH as a red cell marker in polychromatic flow cytometry characterization of bone marrow from patients with aplastic anemia and myelodysplasia. PMID:18510759

Comparison of surgical techniques for stoma closure: A retrospective study of purse-string skin closure versus conventional skin closure following ileostomy and colostomy reversal

PubMed Central

WADA, YUMA; MIYOSHI, NORIKATSU; OHUE, MASAYUKI; NOURA, SHINGO; FUJINO, SHIKI; SUGIMURA, KEIJIROU; AKITA, HIROFUMI; MOTOORI, MASAAKI; GOTOH, KUNIHITO; TAKAHASHI, HIDENORI; KOBAYASHI, SHOGO; OHMORI, TAKESHI; FUJIWARA, YOSHIYUKI; YANO, MASAHIKO

2015-01-01

The aim of this study was to compare the incidence of postoperative complications, including superficial incisional surgical site infection (SSI) following purse-string skin closure (PS) and conventional skin closure with a drainage tube (CD) following stoma closure. A total of 55 consecutive patients who underwent loop colostomy and loop ileostomy closures in our hospital between October, 2011 and September, 2014 were retrospectively assessed. The patients were divided into two groups, namely the PS group (26 patients) and the CD group (29 patients). There were no significant differences in the characteristics of the patients between the two groups. The baseline and operative characteristics also did not differ significantly between the two groups. However the incidence of superficial incisional SSI was lower in the PS group compared to that in the CD group (0 vs. 13.8%, respectively; P=0.049). The overall incidence of complications did not differ significantly between the two groups (P=0.313). The duration of postoperative hospital stay in the PS group was shorter compared to that in the CD group. In conclusion, the results of this study suggest that PS may an effective technique to reduce the incidence of superficial incisional SSI. This technique appears to be superior to the conventional technique, allowing for better cosmesis. PMID:26137277

Increase of endothelial progenitor cells in acute graft-versus-host disease after allogeneic haematopoietic stem cell transplantation for acute myeloid leukaemia.

PubMed

Medinger, Michael; Heim, Dominik; Gerull, Sabine; Halter, Jörg; Krenger, Werner; Buser, Andreas; Lengerke, Claudia; Bucher, Christoph; Passweg, Jakob

2016-08-01

Circulating endothelial progenitor cells (EPCs; CD31+ CD34(bright)CD133+ CD45(dim) cells) are novel markers of endothelial dysfunction and related to inflammatory processes such as acute graft-versus-host disease (aGvHD). 47 patients with acute myeloid leukaemia (AML) who were in complete remission as they underwent allogeneic hematopoietic stem cell transplantation with myeloablative conditioning with PBSC as stem cell source were enrolled in the study. Blood samples for the quantitative analysis of circulating EPC levels were drawn at different time points in patients with and without aGvHD. CD34+ VEGFR2/KDR+ CD133+ triple-positive cells identified among CD34+ cells by FACS. EPC were quantified and data are presented as cells/ml whole blood. Circulating EPC levels were not significantly different in patients with and without aGvHD prior to conditioning (baseline) and at the time of engraftment. However, at diagnosis of aGvHD≥grade 2, EPC levels increased whereas in patients without aGvHD the EPC levels remained significantly lower (3021±278 versus 2322±195 cells/ml; p<0.001). Patients with steroid-refractory aGvHD had high levels of EPC throughout. EPC levels fell in responding patients. Our results demonstrate that the number of circulating EPCs is increased in patients with aGvHD compared to patients without aGvHD. Copyright © 2016 Elsevier Ltd. All rights reserved.

EEG sleep in Cushing's disease and Cushing's syndrome: comparison with patients with major depressive disorder.

PubMed

Shipley, J E; Schteingart, D E; Tandon, R; Pande, A C; Grunhaus, L; Haskett, R F; Starkman, M N

1992-07-15

Because patients with Cushing' syndrome (CS) and Major depressive disorder (MDD) share features of hypercortisolism and the depressive syndrome, we compared electro-encephalographic (EEG) sleep in patients with pituitary-ACTH-dependent Cushing's syndrome (Cushing's disease, CD), patients with ACTH-independent Cushing's syndrome (AICS), patients with major depressive disorder (MDD), and normal subjects. There were substantial similarities in the abnormal polysomnography profiles of patients with CD, AICS, and MDD. All three patient groups demonstrated poorer sleep continuity, shortened rapid eye movement (REM) latency, and increased first REM period density compared with normal subjects. In addition, AICS patients and MDD patients had elevated REM activity and density. These findings are discussed in terms of models of pathophysiology that relate abnormalities in sleep, mood, and hypothalamic-pituitary-adrenal function.

Increased Incidence of Fatigue in Patients with Primary Immunodeficiency Disorders: Prevalence and Associations Within the US Immunodeficiency Network Registry.

PubMed

Hajjar, Joud; Guffey, Danielle; Minard, Charles G; Orange, Jordan S

2017-02-01

Patients with primary immunodeficiency (PID) often report fatigue, yet this symptom has not been studied in PID. Fatigue affects 6-7.5% of healthy adults. The goal of this study is to estimate the prevalence of fatigue in patients with PID and investigate its associated factors. We analyzed 2537 PID patients registered in USIDNET to determine responses to the field "fatigue" in the core registry form. Demographics, immune phenotypes, and comorbid conditions were compared between fatigued and non-fatigued patients to identify relevant associations and potential drivers. A focused analysis was performed for patients with predominantly antibody deficiency disorders (PADs). Fatigue was reported in 25.9% (95% CI 23.7-28.3) of PAD patients, compared to 6.4% (95% CI 4.9-8.2) of non-PAD. Patients with common variable immunodeficiency (CVID) had the highest prevalence of fatigue (p < 0.001) among all PID diagnoses. Other factors that were associated with a higher rate of fatigue among PAD patients included female sex, higher BMI, depression, bronchiectasis, and autoimmunity. Additionally, fatigued PAD patients had lower absolute lymphocyte, CD3, CD4, and CD8 counts compared to non-fatigued patients. Our findings suggest that fatigue is overrepresented in PAD patients. Prospective studies to estimate prevalence, risk factors, and fatigue etiology in PID are warranted, so therapeutic interventions can be considered.

Exome sequencing identifies novel compound heterozygous IFNA4 and IFNA10 mutations as a cause of impaired function in Crohn’s disease patients

PubMed Central

Xiao, Chuan-Xing; Xiao, Jing-Jing; Xu, Hong-Zhi; Wang, Huan-Huan; Chen, Xu; Liu, Yuan-Sheng; Li, Ping; Shi, Ying; Nie, Yong-Zhan; Li, Shao; Wu, Kai-Chun; Liu, Zhan-Ju; Ren, Jian-Lin; Guleng, Bayasi

2015-01-01

Previous studies have highlighted the role of genetic predispositions in disease, and several genes had been identified as important in Crohn’s disease (CD). However, many of these genes are likely rare and not associated with susceptibility in Chinese CD patients. We found 294 shared identical variants in the CD patients of which 26 were validated by Sanger sequencing. Two heterozygous IFN variants (IFNA10 c.60 T > A; IFNA4 c.60 A > T) were identified as significantly associated with CD susceptibility. The single-nucleotide changes alter a cysteine situated before the signal peptide cleavage site to a stop code (TGA) in IFNA10 result in the serum levels of IFNA10 were significantly decreased in the CD patients compared to the controls. Furthermore, the IFNA10 and IFNA4 mutants resulted in an impairment of the suppression of HCV RNA replication in HuH7 cells, and the administration of the recombinant IFN subtypes restored DSS-induced colonic inflammation through the upregulation of CD4+ Treg cells. We identified heterozygous IFNA10 and IFNA4 variants as a cause of impaired function and CD susceptibility genes in Chinese patients from multiple center based study. These findings might provide clues in the understanding of the genetic heterogeneity of CD and lead to better screening and improved treatment. PMID:26000985

Stimulated peripheral production of interferon-gamma is related to fatigue and depression in multiple sclerosis.

PubMed

Pokryszko-Dragan, A; Frydecka, I; Kosmaczewska, A; Ciszak, L; Bilińska, M; Gruszka, E; Podemski, R; Frydecka, D

2012-10-01

The aim of the study was to evaluate the stimulated production of interferon-gamma (IFNγ) by peripheral CD3+CD4+ T lymphocytes in patients with multiple sclerosis (MS) with regard to the degree of fatigue, and to investigate relationships between immunological parameters, level of depression and clinical variables. Forty MS patients (30 women, 10 men, aged 22-60 years): 20 fatigued and 20 non-fatigued were involved in the study. Fatigue was evaluated using the Fatigue Severity Scale (FSS) and Modified Fatigue Impact Scale (MFIS), depression level - using Beck Depression Inventory (BDI). Production of IFNγ by stimulated peripheral blood CD3+CD4+ T lymphocytes, assessed using flow cytometry, was compared between MS patients with different levels of fatigue and controls. Correlations were searched out between immunological findings and BDI, age, duration and course of MS, relapse rate, disability (assessed in Expanded Disability Status Scale - EDSS) and its progression. Stimulated production of IFNγ by CD3+CD4+ T lymphocytes was higher in severely fatigued patients in comparison with non-fatigued ones and controls, tended to correlate with FSS and MFIS, and correlated with BDI. No relationships were found between immunological findings and disease-related variables. Stimulated production of IFNγ by peripheral CD3+CD4+ T lymphocytes is related to fatigue and depression in MS patients. Copyright © 2012 Elsevier B.V. All rights reserved.

Circulating promyelocytes and low levels of CD16 expression on polymorphonuclear leukocytes accompany early-onset periodontitis.

PubMed Central

Nemoto, E; Nakamura, M; Shoji, S; Horiuchi, H

1997-01-01

Early-onset periodontitis (EOP) is characterized by rapidly progressive alveolar bone loss, chemotactic defects of neutrophils, and significant familial aggregation. We found immature myeloid lineage cells, defined as promyelocytes, in the peripheral blood in patients with EOP. A hematological examination of peripheral blood cells showed normal reference values regarding cell proportions. Flow cytometry revealed significantly lower expression of CD16, a glycosylphosphatidylinositol (GPI)-anchored protein, on peripheral neutrophils in patients compared with those in age- and sex-matched healthy controls, whereas the levels of CD11a and CD11b expression were similar. The chemotactic response of neutrophils was lower toward not only formyl-methionyl-leucyl-phenylalanine but also complement fragment C5a than that of healthy controls. The expression of another GPI-anchored protein, CD14, was equally expressed by controls and patients. Therefore, the low level of CD16 expression was not due to the incomplete synthesis of the GPI anchor. GPI anchors of CD16 on neutrophils from controls and patients were both partially resistant to phosphatidylinositol-specific phospholipase C. The presence of promyelocytes in peripheral blood, low expression of CD16, and low chemotactic response of neutrophils suggest that patients with EOP have an abnormal maturation system in myeloid lineage cells in the bone marrow, which may be associated with the onset and course of EOP. PMID:9284170

Socioeconomic Risk Factors for Celiac Disease Burden and Symptoms.

PubMed

Oza, Sveta S; Akbari, Mona; Kelly, Ciarán P; Hansen, Joshua; Theethira, Thimmaiah; Tariq, Sohaib; Dennis, Melinda; Leffler, Daniel A

2016-04-01

Celiac disease (CD) affects approximately 1% of the population and negatively affects aspects of life including physical and social function. The relationship between socioeconomic (SE) factors, symptom severity, and perceived burden of living with CD is not well understood. The objective of this study was to assess the relationships between income, symptoms, and perceived burden of CD. In this survey study conducted at a tertiary care center, 773 patients 18 years of age or more with biopsy confirmed CD were eligible to participate. Patients completed a survey with information on SE data, the validated Celiac Symptom Index (CSI), and visual analog scales (VAS) assessing overall health, CD-related health, difficulty in following a gluten-free diet (GFD), and importance of following a GFD. Three hundred forty one patients completed the survey. Higher income predicted better overall health, better CD related health, and fewer symptoms. In the logistic regression model, low income was associated with greater CD symptoms (odds ratio=6.04, P=0.002). Other factors associated with greater symptoms were younger age, poor overall health state, and more physician visits. Factors associated with increased burden of CD included hospitalizations, more symptoms, poor overall health state, and burden of following a GFD. Patients with lower incomes have worse CD-related health and greater symptoms. Those with low income had 6 times the odds of greater symptoms compared with those with high income. Our data suggest that income is associated with perceived overall health, CD-related health, and CD symptoms.

[Gene Mutation Spectrum of β-Thalassemia in Dai Ethinic Population of Two Border Region in Chinese Yunnan Province].

PubMed

Zhang, Jie; He, Jing; Zeng, Xiao-Hong; Su, Jie; Chen, Hong; Xu, Yong-Mei; Pu, Jian; Zhu, Bao-Sheng

2016-02-01

To investigate the gene mutation spectrum of β-thalassemia in Dai ethnic population of 2 border region in Chinese Yunnan Province. The patients with β-thalassemia in Dai ethnic population of Dehong and Xishuangbanna autonamic prefecture were screened by using blood routine detection and capillary electrophoresis. The β-globin gene mutation in patients with β-thalassemia were detected by using PCR reverse dot-blot hybridization (PCR-RDB), the constitutive rate of gene mutation in patients with β-thalassemia of Dai ethnic population in two border regions was analyzed and compared. A total of 186 patients with gene mutation of β-thalassemia were confirmed. Among them, 10 gene mutation were found, and the 5 main gene mutations were CD26 (62.56%), CD41-42 (18.97%), CD17 (14.36%), CD71-72 (2.05%) and IVS-II-654 (1.54%). Among Dai ethinic population in Dehong region, 4 gene mutations were found including CD26 (80.31%), CD17 (11.02%), CD41-42 (6.30%) and CD71-72 (2.36%). Among Dai ethinic population in Xishuangbanna region, 6 gene mutations were found, out of them the more common gene mutations were CD41-42 (42.64%), CD26 (29.41%) and CD17 (20.59%). The gene mutations of β-thalassemia in Dai ethinic population of Yunnan province has been confirmed to be more genetic heterogenicity, the spectrums of β-thalassemia mutations in Dai ethinic population of different regions were significant different.

A Bamboo Joint-Like Appearance is a Characteristic Finding in the Upper Gastrointestinal Tract of Crohn's Disease Patients: A Case-Control Study.

PubMed

Fujiya, Mikihiro; Sakatani, Aki; Dokoshi, Tatsuya; Tanaka, Kazuyuki; Ando, Katsuyoshi; Ueno, Nobuhiro; Gotoh, Takuma; Kashima, Shin; Tominaga, Motoya; Inaba, Yuhei; Ito, Takahiro; Moriichi, Kentaro; Tanabe, Hiroki; Ikuta, Katsuya; Ohtake, Takaaki; Yokota, Kinnichi; Watari, Jiro; Saitoh, Yusuke; Kohgo, Yutaka

2015-09-01

The clinical importance of Crohn's disease (CD)-specific lesions in the upper gastrointestinal tract (upper GIT) has not been sufficiently established. The aim of this case-control study is to investigate the characteristic findings of CD in the upper GIT. In 2740 patients who underwent gastroduodenoscopy at Asahikawa Medical University between April 2011 and December 2012, 81 CD patients, 81 gender- and age-matched non-IBD patients, and 66 ulcerative colitis (UC) patients were investigated in the present study. (1) The diagnostic ability and odds ratio of each endoscopic finding (a bamboo joint-like appearance in the cardia, erosions, and/or ulcers in the antrum, notched signs, and erosions and/or ulcers in the duodenum) were compared between the CD and non-IBD patients or UC patients. (2) The interobserver agreement of the diagnosis based on the endoscopic findings was evaluated by 3 experienced and 3 less-experienced endoscopists. The incidence of detecting a bamboo joint-like appearance, notched signs, and erosions and/or ulcers in the duodenum was significantly higher in the CD patients than in the non-IBD and UC patients. In addition, the diagnostic ability and odds ratio of a bamboo joint-like appearance for CD were higher than those for the other findings. Kendall's coefficients of concordance in the group of experienced and less-experienced endoscopists were relatively high for a bamboo joint-like appearance (0.748 and 0.692, respectively). A cardiac bamboo joint-like appearance is a useful finding for identifying high-risk groups of CD patients using only gastroduodenoscopy.

Potential contribution of a novel Tax epitope-specific CD4+ T cells to graft-versus-Tax effect in adult T cell leukemia patients after allogeneic hematopoietic stem cell transplantation.

PubMed

Tamai, Yotaro; Hasegawa, Atsuhiko; Takamori, Ayako; Sasada, Amane; Tanosaki, Ryuji; Choi, Ilseung; Utsunomiya, Atae; Maeda, Yasuhiro; Yamano, Yoshihisa; Eto, Tetsuya; Koh, Ki-Ryang; Nakamae, Hirohisa; Suehiro, Youko; Kato, Koji; Takemoto, Shigeki; Okamura, Jun; Uike, Naokuni; Kannagi, Mari

2013-04-15

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an effective treatment for adult T cell leukemia/lymphoma (ATL) caused by human T cell leukemia virus type 1 (HTLV-1). We previously reported that Tax-specific CD8(+) cytotoxic T lymphocyte (CTL) contributed to graft-versus-ATL effects in ATL patients after allo-HSCT. However, the role of HTLV-1-specific CD4(+) T cells in the effects remains unclear. In this study, we showed that Tax-specific CD4(+) as well as CD8(+) T cell responses were induced in some ATL patients following allo-HSCT. To further analyze HTLV-1-specific CD4(+) T cell responses, we identified a novel HLA-DRB1*0101-restricted epitope, Tax155-167, recognized by HTLV-1-specific CD4(+) Th1-like cells, a major population of HTLV-1-specific CD4(+) T cell line, which was established from an ATL patient at 180 d after allo-HSCT from an unrelated seronegative donor by in vitro stimulation with HTLV-1-infected cells from the same patient. Costimulation of PBMCs with both the identified epitope (Tax155-167) and known CTL epitope peptides markedly enhanced the expansion of Tax-specific CD8(+) T cells in PBMCs compared with stimulation with CTL epitope peptide alone in all three HLA-DRB1*0101(+) patients post-allo-HSCT tested. In addition, direct detection using newly generated HLA-DRB1*0101/Tax155-167 tetramers revealed that Tax155-167-specific CD4(+) T cells were present in all HTLV-1-infected individuals tested, regardless of HSCT. These results suggest that Tax155-167 may be the dominant epitope recognized by HTLV-1-specific CD4(+) T cells in HLA-DRB1*0101(+)-infected individuals and that Tax-specific CD4(+) T cells may augment the graft-versus-Tax effects via efficient induction of Tax-specific CD8(+) T cell responses.

Circulating CD147 predicts mortality in advanced hepatocellular carcinoma.

PubMed

Lee, Aimei; Rode, Anthony; Nicoll, Amanda; Maczurek, Annette E; Lim, Lucy; Lim, Seok; Angus, Peter; Kronborg, Ian; Arachchi, Niranjan; Gorelik, Alexandra; Liew, Danny; Warner, Fiona J; McCaughan, Geoffrey W; McLennan, Susan V; Shackel, Nicholas A

2016-02-01

The glycoprotein CD147 has a role in tumor progression, is readily detectable in the circulation, and is abundantly expressed in hepatocellular carcinoma (HCC). Advanced HCC patients are a heterogeneous group with some individuals having dismal survival. The aim of this study was to examine circulating soluble CD147 levels as a prognostic marker in HCC patients. CD147 was measured in 277 patients (110 HCC, 115 chronic liver disease, and 52 non-liver disease). Clinical data included etiology, tumor progression, Barcelona Clinic Liver Cancer (BCLC) stage, and treatment response. Patients with HCC were stratified into two groups based upon the 75th percentile of CD147 levels (24 ng/mL). CD147 in HCC correlated inversely with poor survival (P = 0.031). Increased CD147 predicted poor survival in BCLC stages C and D (P = 0.045), and CD147 levels >24 ng/mL predicted a significantly diminished 90-day and 180-day survival time (hazard ratio [HR] = 6.1; 95% confidence interval [CI]: 2.1-63.2; P = 0.0045 and HR = 2.8; 95% CI: 1.2-12.6; P = 0.028, respectively). In BCLC stage C, CD147 predicted prognosis; levels >24 ng/mL were associated with a median survival of 1.5 months compared with 6.5 months with CD147 levels ≤24 ng/mL (P = 0.03). CD147 also identified patients with a poor prognosis independent from treatment frequency, modality, and tumor size. Circulating CD147 is an independent marker of survival in advanced HCC. CD147 requires further evaluation as a potential new prognostic measure in HCC to identify patients with advanced disease who have a poor prognosis. © 2015 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.

Efficacy and Safety of Antiintegrin Antibody for Inflammatory Bowel Disease

PubMed Central

Lin, Lianjie; Liu, Xiang; Wang, Dongxu; Zheng, Changqing

2015-01-01

Abstract We sought to evaluate the safety and efficacy of available biologics that inhibit T-cell migration by blocking α4β7 integrins in inflammatory bowel diseases. The aim of this study is to evaluate whether Crohn disease (CD) patients receiving either vedolizumab or natalizumab have any different effect in CD Activity Index (CDAI). Using Medline, Excerpta Medica dataBASE, Cochrane Central Register of Controlled Trials (CENTRAL), and Google Scholar until October 31, 2013, we identified 10 studies examining the safety and efficacy of specific integrin inhibitors—vedolizumab, which targets an epitope comprising the α4β7 heterodimer; natalizumab, which recognizes the α4 integrin subunit; etrolizumab, which is specific for the β7 subunit—in the treatment of CD and ulcerative colitis (UC). CD patients receiving either vedolizumab or natalizumab demonstrated a modest increase in remission rate, when compared with that of the placebo group. Further, although both treatments reduced the CDAI slightly, the observed clinical response was less robust than that of the remission rate. UC patients treated with vedolizumab and natalizumab were found to show more prominent increases in both remission and clinical response, compared with placebo, than patients with CD. Etrolizumab, however, was not found to significantly affect either response or remission rates in UC patients. Biologics targeting integrins show promise as therapeutics in the treatment of inflammatory bowel disease in patients who are either nonresponsive or intolerant to traditional approaches, though further research is necessary to optimize treatment efficacies. PMID:25761174

CD56-enriched donor cell infusion after post-transplantation cyclophosphamide for haploidentical transplantation of advanced myeloid malignancies is associated with prompt reconstitution of mature natural killer cells and regulatory T cells with reduced incidence of acute graft versus host disease: A pilot study.

PubMed

Jaiswal, Sarita Rani; Zaman, Shamsur; Nedunchezhian, Murugaiyan; Chakrabarti, Aditi; Bhakuni, Prakash; Ahmed, Margoob; Sharma, Kanika; Rawat, Sheh; O'donnell, Paul; Chakrabarti, Suparno

2017-04-01

We conducted a pilot study on the feasibility of CD56-enriched donor cell infusion after post-transplantation cyclophosphamide (PTCy) for 10 patients with advanced myeloid malignancies undergoing haploidentical peripheral blood stem cell transplantation with cyclosporine alone as graft-versus-host disease (GVHD) prophylaxis and compared the outcome and immune reconstitution with a control group of 20 patients undergoing the same without CD56-enriched donor cell infusion. An early and rapid surge of mature NK cells as well as CD4 + T cells and regulatory T cells (Tregs) was noted compared with the control group. KIR of donor phenotype reconstituted as early as day 30 with expression of CD56 dim CD16 + NKG2A - KIR + phenotype. None experienced viral or fungal infections, and non-relapse mortality was 10% only. The incidence of grade 2-4 acute GVHD was 50% in the control group with none in the CD56 group (P = 0.01). Only two had de novo chronic GVHD in each group. Relapse occurred in five patients in CD56 group with a median follow-up of 12 months, similar to the control group. Our preliminary data show that CD56 + donor cell infusion after PTCy and short-course cyclosporine is feasible with prompt engraftment, rapid reconstitution of CD4 + T cells, Tregs and NK cells and reduced incidence of acute GVHD. Copyright © 2017 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.

Clinical relevance and suppressive capacity of human MDSC subsets.

PubMed

Lang, Stephan; Bruderek, Kirsten; Kaspar, Cordelia; Höing, Benedikt; Kanaan, Oliver; Dominas, Nina; Hussain, Timon; Droege, Freya; Eyth, Christian Peter; Hadaschik, Boris; Brandau, Sven

2018-06-18

Myeloid-derived suppressor cells (MDSC) are a heterogeneous group of pathologically expanded myeloid cells with immunosuppressive activity. In human disease three major MDSC subpopulations can be defined as monocytic M-MDSC, granulocytic PMN-MDSC and early stage e-MDSC, which lack myeloid lineage markers of the former two subsets. It was the purpose of this study to determine and compare the immunosuppressive capacity and clinical relevance of each of these subsets in patients with solid cancer. The frequency of MDSC subsets in the peripheral blood was determined by flow cytometry in a cohort of 49 patients with advanced head and neck cancer (HNC) and 22 patients with urological cancers. Sorted and purified MDSC subsets were tested in vitro for their T cell suppressive capacity. Frequency of circulating MDSC was correlated with overall survival of HNC patients. A high frequency of PMN-MDSC most strongly correlated with poor overall survival in HNC. T cell suppressive activity was higher in PMN-MDSC compared with M-MDSC and e-MDSC. A subset of CD66b+/CD11b+/CD16+ mature PMN-MDSC displayed high expression and activity of arginase I, and was superior to the other subsets in suppressing proliferation and cytokine production of T cells in both cancer types. High levels of this CD11b+/CD16+ PMN-MDSC, but not other PMN-MDSC subsets, strongly correlated with adverse outcome in HNC. A subset of mature CD11b+/CD16+ PMN-MDSC was identified as the MDSC subset with the strongest immunosuppressive activity and the highest clinical relevance. Copyright ©2018, American Association for Cancer Research.

Transcriptional network profile on synovial fluid T cells in psoriatic arthritis.

PubMed

Fiocco, Ugo; Martini, Veronica; Accordi, Benedetta; Caso, Francesco; Costa, Luisa; Oliviero, Francesca; Scanu, Anna; Facco, Monica; Boso, Daniele; Gatto, Mariele; Felicetti, Mara; Frallonardo, Paola; Ramonda, Roberta; Piva, Lucia; Zambello, Renato; Agostini, Carlo; Scarpa, Raffaele; Basso, Giuseppe; Semenzato, Gianpietro; Dayer, Jean-Michel; Punzi, Leonardo; Doria, Andrea

2015-09-01

The objective of the study was to quantify the transcriptional profile, as the main T cell lineage-transcription factors on synovial fluid (SF) T cells, in relation to SF cytokines and T cell frequencies (%) of psoriatic arthritis (PsA) patients. Reverse phase protein array was employed to identify interleukin (IL)-23Rp19-, FOXP3- and related orphan receptor gamma T (RORγt)- protein and Janus associated tyrosine kinases 1 (JAK1), signal transducer and activator and transcription 1 (STAT1), STAT3 and STAT5 phosphoproteins in total T cell lysates from SF of PsA patients. IL-1β, IL-2, IL-6, IL-21 and interferon (INF)-γ were measured using a multiplex bead immunoassay in SF from PsA patients and peripheral blood (PB) from healthy controls (HC). Frequencies of CD4(+)CD25(-), CD4(+)CD25(high) FOXP3(+) and CD4(+)CD25(high) CD127(low) Treg, and either mean fluorescence intensity (MFI) of FOXP3(+) on CD4(+) Treg or MFI of classic IL-6 receptor (IL-6R) α expression on CD4(+)CD25(-) helper/effector T cells (Th/eff) and Treg cells, were quantified in SF of PsA patients and in PB from HC by flow cytometry (FC). In PsA SF samples, IL-2, IL-21 and IFN-γ were not detectable, whereas IL-6 and IL-1β levels were higher than in SF of non-inflammatory osteoarthritis patients. Higher levels of IL-23R-, FOXP3- and RORγt proteins and JAK1, STAT1, STAT3 and STAT5 were found in total T cells from SF of PsA patients compared with PB from HC. Direct correlations between JAK1 Y1022/Y1023 and STAT5 Y694, and STAT3 Y705 and IL6, were found in SF of PsA patients. Increased proportion of CD4(+)CD25(high) FOXP3(+) and CD4(+)CD25(high) CD127(low) Treg cells and brighter MFI of IL-6Rα were observed both on CD4(+)CD25(high)- and CD4(+)CD25(-) T cells in PsA SF. The study showed a distinctive JAK1/STAT3/STAT5 transcriptional network on T cells in the joint microenvironment, outlining the interplay of IL-6, IL-23, IL-1β and γC cytokines in the polarization and plasticity of Th17 and Treg cells, which might participate in the perpetuation of joint inflammation in PsA patients.

Food antigen-induced immune responses in Crohn's disease patients and experimental colitis mice.

PubMed

Kawaguchi, Takaaki; Mori, Maiko; Saito, Keiko; Suga, Yasuyo; Hashimoto, Masaki; Sako, Minako; Yoshimura, Naoki; Uo, Michihide; Danjo, Keiko; Ikenoue, Yuka; Oomura, Kaori; Shinozaki, Junko; Mitsui, Akira; Kajiura, Takayuki; Suzuki, Manabu; Takazoe, Masakazu

2015-04-01

In Crohn's disease (CD), the involvement of food antigens in immune responses remains unclear. The objective of this study was to detect immune responses against food antigens in CD patients and examine the mechanism in a mouse model of colitis. We enrolled 98 CD patients, 50 ulcerative colitis patients, and 52 healthy controls (HCs) to compare the levels of serum immunoglobulin (Ig)Gs against 88 foods. The presence of serum IgGs against foods was also examined in interleukin (IL)-10 knockout (KO) mice in which CD4(+) T cell activation by antigenic food protein was assessed. Mice transferred with IL-10 KO cells received diets with or without food antigens, and the development of colitis was evaluated. The prevalence of IgGs against various foods, especially vegetables, grains, and nuts, was significantly higher in CD patients than in HCs. Similarly, the prevalence of IgGs against food proteins was higher in IL-10 KO mice than in BALB/c mice. Beta-conglycinin, identified as an antigenic food proteins in IL-10 KO mice, induced CD4(+) T cell production of interferon-γ and IL-17 through dendritic cell antigen presentation. Elimination of the food antigens ameliorated the development of colitis in mice without altering the composition of their intestinal microbiota. In CD colitis mice, intestinal inflammation via CD4(+) T cell hyperactivation was induced by food antigens associated with high serum IgG levels and was ameliorated by the elimination of food antigens. This disrupted immunological tolerance to food antigen, which might act as an exacerbating factor, remains to be elucidated in CD patients.

Decreased gene expression of CD2AP in Chinese patients with sporadic Alzheimer's disease.

PubMed

Tao, Qing-Qing; Liu, Zhi-Jun; Sun, Yi-Min; Li, Hong-Lei; Yang, Ping; Liu, De-Shan; Jiang, Bin; Li, Xiao-Yan; Xu, Jian-Feng; Wu, Zhi-Ying

2017-08-01

Many sporadic Alzheimer's disease (SAD) risk genes have been identified in the last decades, but most of them have not been consistently accepted. Here, we sought to identify SAD-associated genes and their potential mechanisms involved in SAD pathogenesis. A 2-stage design was employed. In stage 1, 95 variants in 75 genes that were previously reported as SAD-risk genes in Caucasian populations were evaluated in 1857 subjects (422 SAD patients and 1435 controls). In stage 2, a subset of promising variants found in stage 1 were further evaluated in an independent cohort of 1001 subjects (254 SAD and 747 controls). Variants in CD2AP were significantly associated with SAD risk in our subjects. Furthermore, CD2AP gene expression in peripheral blood lymphocytes (PBL) from 209 SAD patients and 213 controls was determined. CD2AP gene expression in PBL was significantly decreased in patients with SAD as compared with controls. Our study suggests that CD2AP is an SAD-risk gene in Chinese Han population and CD2AP gene expression is decreased in the PBL of patients with SAD, indicating its possible systemic involvement in SAD. Copyright © 2017 Elsevier Inc. All rights reserved.

The Quantitative and Functional Changes of Postoperative Peripheral Blood Immune Cell Subsets Relate to Prognosis of Patients with Subarachnoid Hemorrhage: A Preliminary Study.

PubMed

Zhou, Yu; Jiang, Yugang; Peng, Yong; Zhang, Mingming

2017-12-01

It has been suggested that the preoperative (PRE) and postoperative (POST) immune system alteration triggered by aneurysmal subarachnoid hemorrhage (SAH) and surgical treatment itself may affect patients' prognosis and contribute to POST complications. The mechanisms may be attributed to immune suppression-triggered infection or immune overreaction-triggered aseptic inflammation. In this study, we investigated the dynamic changes in peripheral immune cell subsets as well as the alterations of inflammatory cytokines in patients with aneurysmal SAH who received craniotomy and clipping surgery. In addition, we studied the association of those changes with POST complications and clinical prognosis. We investigated 27 patients who received craniotomy and clipping surgery for aneurysmal SAH. The operations were all performed within 24 hours after the occurrence of aneurysm rupture. Detailed immune monitoring (peripheral blood leukocytes and lymphocyte subsets and inflammatory cytokines) was performed on PRE (on admission), day 1, day 3, and day 6 after operation. Our data showed that the percentage of CD3+, CD8+, natural killer T (NKT), CD4+, and regulatory T (Treg) cells significantly decreased and the level of interleukin 4 (IL-4), interferon γ, and IL-2 significantly increased 1 day after surgery compared with the data in PRE. On the contrary, natural killer (NK), NK group 2 (NKG2D), and B cells increased and the level of IL-10 in plasma decreased. In study of the relationship between POST fever and the change in immune cell subgroups, the fever group had a lower percentage of CD3+, CD4+, NKT, Tregs, and B cells on day 1, day 3, and day 6 after surgery compared with the patients who did not have fever, whereas the CD8+, NK, and NKG2D subsets showed the opposite trend. Furthermore, we analyzed the association between immune profile changes and the prognosis of those patients. The patients were divided into those with an unfavorable prognosis (n = 6) and those with a favorable prognosis (n = 21) according to Glasgow Outcome Scale score and postoperation (POST) coma. Our results showed that except for B cells, patients with a favorable prognosis had a relatively higher percentage of CD3+, CD4+, CD8+, NK, NKT, NKG2D, and Treg cells compared with the unfavorable prognosis group from PRE to day 6 POST. Our results indicated that patients with aneurysmal SAH undergoing craniotomy and clipping surgery had a profound transient deterioration in immune function. In addition, the changes in immune cell subgroups had a strong association with POST fever. The changes in immune cell subgroups were also directly associated with clinical prognosis of the patients. These association findings might be attributable to a better biomarker to predict patient diagnosis. Copyright © 2017 Elsevier Inc. All rights reserved.

Comparison of monocyte-derived dendritic cells from colorectal cancer patients, non-small-cell-lung-cancer patients and healthy donors.

PubMed

Kvistborg, P; Bechmann, C M; Pedersen, A W; Toh, H C; Claesson, M H; Zocca, M B

2009-12-11

Dendritic cells (DCs) are bone marrow-derived professional antigen presenting cells. Due to their role as potent inducers of immune responses, these cells are widely used as adjuvant in experimental clinical settings for cancer immune therapy. We have developed a DC-based vaccine using autologous blood monocytes loaded with allogeneic tumor cell lysate rich in cancer/testis antigens. This vaccine has at present been tested for activity in three phase II clinical trials including two cohorts of patients with advanced colorectal cancer (CRC) and one cohort of patients with advanced non-small-cell-lung-cancer (NSCLC). In the present paper we retrospectively compare the maturation profile based on surface marker expression on DCs generated from the three patient cohorts and between cancer patient cohorts and a cohort of healthy donors. Vaccines were generated under cGMP conditions and phenotypic profiles of DC were analyzed by flow cytometry and the obtained data were used as a basis to set guideline values for our quality control of GMP produced DC vaccines. Each vaccine batch was analyzed for the expression of the surface maturation and differentiation molecules CD14, CD1a, CD83, CD86, MHC class II and CCR7, and the optimal expression pattern is considered as CD14(low), CD1a, CD83(high), CD86(high), MHC class II(high) and CCR7(high). In accordance with data from other studies including other types of cancer patients, especially breast cancer patients, we found that the maturation status of the DC batches depends on cancer type and correlates with clinical status of cancer patients included.

Short-term additional enfuvirtide therapy is associated with a greater immunological recovery in HIV very late presenters: a controlled pilot study.

PubMed

Bonora, S; Calcagno, A; Cometto, C; Fontana, S; Aguilar, D; D'Avolio, A; Gonzalez de Requena, D; Maiello, A; Dal Conte, I; Lucchini, A; Di Perri, G

2012-02-01

To evaluate whether the addition of enfuvirtide to standard highly active antiretroviral therapy (HAART) could confer immunovirological benefits in human immunodeficiency virus (HIV)-infected very late presenters. The current study is an open comparative therapeutic trial of standard protease inhibitor (PI)-based HAART ± additional enfuvirtide in treatment-naïve deeply immunologically impaired HIV-positive patients. Very late presenters (CD4 <50/mm(3)), without tuberculosis and neoplasms, were alternatively allocated to two nucleoside reverse transcriptase inhibitors (NRTIs) and lopinavir/ritonavir without (control arm, CO) or with (ENF arm) enfuvirtide 90 mg bid. Enfuvirtide was administered until the achievement of viral load <50 copies/ml and for at least 24 weeks. The primary objective was the magnitude of CD4+ cell recovery at 6 months. HIV RNA was intensively monitored in the first month, and, thereafter, monthly, as for CD4+ cell count and percentage, clinical data, and plasma drug concentrations. Of 22 enrolled patients (11 per arm), 19 completed the study (10 in the ENF arm). Baseline CD4+ cell counts and % were comparable, with 20 CD4+/mm(3) (12-37) and a percentage of 3.3 (1.7-7.1) in the ENF arm, and 16 CD4+/mm(3) (9-29) and a percentage of 3.1 (2.3-3.8) in the CO arm, respectively. The baseline viral load was also comparable between the two arms, with 5.77 log10 (5.42-6) and 5.39 log10 (5.06-6) in the ENF and CO arms, respectively. Enfuvirtide recipients had higher CD4+ percentage at week 8 (7.6 vs. 3.6%, p = 0.02) and at week 24 (10.7 vs. 5.9%, p = 0.02), and a greater CD4+ increase at week 24 (207 vs. 134 cells/mm(3), p = 0.04), with 70% of enfuvirtide intakers versus 12.5% of controls who achieved a CD4+ cell count >200/mm(3) (p = 0.01). At 48 weeks, patients in the ENF arm had CD4+ cell counts higher than controls (251 vs. 153cells/mm(3), p = 0.04) and were also found to be faster in reaching a CD4 cell count over 200/mm(3): 18 (8-24) versus 48 (36-108) weeks (p = 0.01). Viral load decay at week 4 was greater in the ENF arm (-3 vs. -2.2 log, p = 0.04), while the proportion of patients with viral load <50 copies/ml at week 24 was comparable. In this pilot study, the addition of enfuvirtide to a lopinavir-based HAART was shown to be associated with a significantly faster and greater immunological recovery in newly discovered HIV-positive patients with very low CD4+ cell counts. Induction strategies using an enfuvirtide-based approach in such subjects warrant further investigation.

Increased Enterococcus faecalis infection is associated with clinically active Crohn disease

PubMed Central

Zhou, Youlian; Chen, Huiting; He, Hanchang; Du, Yanlei; Hu, Jiaqi; Li, Yingfei; Li, Yuyuan; Zhou, Yongjian; Wang, Hong; Chen, Ye; Nie, Yuqiang

2016-01-01

Abstract This study was performed to investigate the relationship between the abundance of pathogenic gut microbes in Chinese patients with inflammatory bowel disease (IBD) and disease severity. We collected clinical data and fecal samples from 47 therapy-naive Chinese patients with ulcerative colitis (UC), 67 patients with Crohn disease (CD), and 48 healthy volunteers. Bacteria levels of Fusobacterium species (spp), enterotoxigenic Bacteroides fragilis (B fragilis), enteropathogenic Escherichia coli (E coli), and Enterococcus faecalis (E faecalis) were assessed by quantitative real-time PCR (qRT-PCR). Spearman correlation coefficients were calculated to test associations between bacterial content and clinical parameters. Compared to healthy controls, the levels of both Fusobacterium spp and E faecalis were significantly increased in the feces of patients with IBD (P < 0.01). B fragilis levels were higher (P < 0.05) and E faecalis levels lower (P < 0.05) in patients with CD compared to those with UC. Increased E faecalis colonization in CD associated positively with disease activity (P = 0.015), Crohn disease activity index (CDAI; R = 0.3118, P = 0.0108), and fecal calprotectin (P = 0.016). E faecalis and Fusobacterium spp are significantly enriched in patients with IBD, and increased E faecalis infection is associated with clinically active CD. PMID:27684872

Increased Enterococcus faecalis infection is associated with clinically active Crohn disease.

PubMed

Zhou, Youlian; Chen, Huiting; He, Hanchang; Du, Yanlei; Hu, Jiaqi; Li, Yingfei; Li, Yuyuan; Zhou, Yongjian; Wang, Hong; Chen, Ye; Nie, Yuqiang

2016-09-01

This study was performed to investigate the relationship between the abundance of pathogenic gut microbes in Chinese patients with inflammatory bowel disease (IBD) and disease severity.We collected clinical data and fecal samples from 47 therapy-naive Chinese patients with ulcerative colitis (UC), 67 patients with Crohn disease (CD), and 48 healthy volunteers. Bacteria levels of Fusobacterium species (spp), enterotoxigenic Bacteroides fragilis (B fragilis), enteropathogenic Escherichia coli (E coli), and Enterococcus faecalis (E faecalis) were assessed by quantitative real-time PCR (qRT-PCR). Spearman correlation coefficients were calculated to test associations between bacterial content and clinical parameters.Compared to healthy controls, the levels of both Fusobacterium spp and E faecalis were significantly increased in the feces of patients with IBD (P < 0.01). B fragilis levels were higher (P < 0.05) and E faecalis levels lower (P < 0.05) in patients with CD compared to those with UC. Increased E faecalis colonization in CD associated positively with disease activity (P = 0.015), Crohn disease activity index (CDAI; R = 0.3118, P = 0.0108), and fecal calprotectin (P = 0.016).E faecalis and Fusobacterium spp are significantly enriched in patients with IBD, and increased E faecalis infection is associated with clinically active CD.

Sensory tricks and brain excitability in cervical dystonia: a transcranial magnetic stimulation study.

PubMed

Amadio, Stefano; Houdayer, Elise; Bianchi, Francesca; Tesfaghebriel Tekle, Habtom; Urban, Ivan Pietro; Butera, Calogera; Guerriero, Roberta; Cursi, Marco; Leocani, Letizia; Comi, Giancarlo; Del Carro, Ubaldo

2014-08-01

Sensory tricks such as touching the face with fingertips often improve cervical dystonia [CD]. This study is to determine whether sensory tricks modulate motor cortex excitability, assessed by paired-pulse transcranial magnetic stimulation [p-pTMS]. Eight patients with rotational CD underwent p-pTMS, at rest and when the sensory trick was applied. To test intracortical inhibition [ICI] and facilitation [ICF], the amplitude ratio between conditioned and unconditioned cortical motor evoked potentials was measured at several interstimulus intervals (ISI 1, 3, 15, and 20 ms) and compared with controls mimicking patients' sensory tricks. At rest, a significant ICF enhancement was found at ISIs 15 through 20 in patients compared with controls, whereas no significant ICI changes were observed. Sensory tricks significantly reduced the abnormal ICF in patients and did not induce any change in controls. In our CD patients, sensory tricks seem to improve dystonia through an inhibitory effect on motor cortex excitability. © 2014 International Parkinson and Movement Disorder Society.

The Impact of Ostomy on Quality of Life and Functional Status of Crohn's Disease Patients.

PubMed

Abdalla, Maisa I; Sandler, Robert S; Kappelman, Michael D; Martin, Christopher F; Chen, Wenli; Anton, Kristen; Long, Millie D

2016-11-01

The potential need for an ostomy is a main concern for patients with inflammatory bowel disease. We performed this study to evaluate the impact of a long-term ostomy (≥6 mo duration) on the functional status and specific patient-reported outcomes in a population of patients with Crohn's disease (CD). We performed a cross-sectional analysis within the Crohn's and Colitis Foundation of America Partners cohort. Bivariate analyses and logistic regression models were used to investigate associations between ostomy and various demographic, disease factors, and patient-reported outcomes for health-related quality of life. A total of 402 CD patients with ostomy for a minimum duration of 6 months were compared with 4331 CD patients with no ostomy. Patients with ostomy were more likely to be in clinical remission compared with those without ostomy, 48.5% versus 31.3%, respectively. Having an ostomy did not impact the overall health-related quality of life and was not associated with anxiety, depression, sleep disturbances, or reduced sexual interest and satisfaction. However, the presence of ostomy was associated with reduced social role satisfaction in both patients with controlled and active disease. Additionally, in the subset of patients who did not achieve clinical remission, those with ostomy experienced greater pain interference (odds ratio, 1.63; 95% confidence interval, 1.12-2.35) and fatigue (odds ratio, 1.66; 95% confidence interval, 1.15-2.39). Ostomy is well tolerated in CD patients, particularly when clinical remission is achieved.

Circulating gluten-specific FOXP3+CD39+ regulatory T cells have impaired suppressive function in patients with celiac disease.

PubMed

Cook, Laura; Munier, C Mee Ling; Seddiki, Nabila; van Bockel, David; Ontiveros, Noé; Hardy, Melinda Y; Gillies, Jana K; Levings, Megan K; Reid, Hugh H; Petersen, Jan; Rossjohn, Jamie; Anderson, Robert P; Zaunders, John J; Tye-Din, Jason A; Kelleher, Anthony D

2017-12-01

Celiac disease is a chronic immune-mediated inflammatory disorder of the gut triggered by dietary gluten. Although the effector T-cell response in patients with celiac disease has been well characterized, the role of regulatory T (Treg) cells in the loss of tolerance to gluten remains poorly understood. We sought to define whether patients with celiac disease have a dysfunction or lack of gluten-specific forkhead box protein 3 (FOXP3) + Treg cells. Treated patients with celiac disease underwent oral wheat challenge to stimulate recirculation of gluten-specific T cells. Peripheral blood was collected before and after challenge. To comprehensively measure the gluten-specific CD4 + T-cell response, we paired traditional IFN-γ ELISpot with an assay to detect antigen-specific CD4 + T cells that does not rely on tetramers, antigen-stimulated cytokine production, or proliferation but rather on antigen-induced coexpression of CD25 and OX40 (CD134). Numbers of circulating gluten-specific Treg cells and effector T cells both increased significantly after oral wheat challenge, peaking at day 6. Surprisingly, we found that approximately 80% of the ex vivo circulating gluten-specific CD4 + T cells were FOXP3 + CD39 + Treg cells, which reside within the pool of memory CD4 + CD25 + CD127 low CD45RO + Treg cells. Although we observed normal suppressive function in peripheral polyclonal Treg cells from patients with celiac disease, after a short in vitro expansion, the gluten-specific FOXP3 + CD39 + Treg cells exhibited significantly reduced suppressive function compared with polyclonal Treg cells. This study provides the first estimation of FOXP3 + CD39 + Treg cell frequency within circulating gluten-specific CD4 + T cells after oral gluten challenge of patients with celiac disease. FOXP3 + CD39 + Treg cells comprised a major proportion of all circulating gluten-specific CD4 + T cells but had impaired suppressive function, indicating that Treg cell dysfunction might be a key contributor to disease pathogenesis. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Characteristics of Faecal Microbiota in Paediatric Crohn's Disease and Their Dynamic Changes During Infliximab Therapy.

PubMed

Wang, Yizhong; Gao, Xuefeng; Ghozlane, Amine; Hu, Hui; Li, Xiaolu; Xiao, Yongmei; Li, Dan; Yu, Guangjun; Zhang, Ting

2018-02-28

Crohn's disease [CD] is known to be associated with gut microbial dysbiosis. Infliximab [IFX] is increasingly used to treat paediatric CD; however, it is not clear how the gut microbiota is modified during IFX treatment. The aim of this study was to characterise the faecal microbiota community composition in paediatric CD patients and to assess its dynamic changes during IFX therapy. A 16S rRNA sequencing approach was applied to determine the compositions of microbial communities in faecal samples. The composition and function of the faecal microbiota were compared between CD patients and healthy controls. Characteristics of faecal microbiome composition in paediatric CD patients before IFX treatment were represented by a lower biodiversity, a gain in Enterococcus, and a significant loss in multiple short-chain fatty acid [SCFA]-producing bacteria, including Anaerostipes, Blautia, Coprococcus, Faecalibacterium, Lachnospira, Odoribacter, Roseburia, Ruminococcus, and Sutterella. Additionally, alterations were observed in metabolic functions of the gut microbial community in CD. IFX treatment increased the biodiversity of gut microbiota and shifted its composition as well as its functional capabilities in the paediatric CD patients toward a healthy status. However, multiple SCFA-producing taxa were not significantly expanded. The sustained response of paediatric CD patients to IFX was associated with abundance of SCFA-producing bacteria. A lower biodiversity with alterations in the composition and function of faecal microbial community, characterising gut microbial dysbiosis, was observed in Chinese paediatric CD patients. IFX diminished the CD-associated gut microbial dysbiosis but was deficient in increasing certain SCFA-producing taxa. Copyright © 2017 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com

Comparison of EpCAMhighCD44+ cancer stem cells with EpCAMhighCD44- tumor cells in colon cancer by single-cell sequencing.

PubMed

Liu, Mingshan; Di, Jiabo; Liu, Yang; Su, Zhe; Jiang, Beihai; Wang, Zaozao; Su, Xiangqian

2018-03-26

Cancer stem cells (CSCs) are considered to be responsible for tumorigenesis and cancer relapse. EpCAM high CD44 + tumor cells are putative colorectal CSCs that express high levels of stem cell genes, while the EpCAM high CD44 - population mostly contains differentiated tumor cells (DTCs). This study aims to determine whether single CSC (EpCAM high CD44 + ) and DTC (EpCAM high CD44 - ) can be distinguished in terms of somatic copy number alterations (SCNAs). We applied fluorescence-activated cell sorting to isolate the CD45 - EpCAM high CD44 + and CD45 - EpCAM high CD44 - populations from two primary colon tumors, on which low-coverage single-cell whole-genome sequencing (WGS) was then performed ∼0.1x depth. We compared the SCNAs of the CSCs and DTCs at single-cell resolution. In total, 47 qualified single cells of the two populations underwent WGS. The single-cell SCNA profiles showed that there were obvious SCNAs in both the CSCs and DTCs of each patient, and each patient had a specific copy number alteration pattern. Hierarchical clustering and correlation analysis both showed that the SCNA profiles of CSCs and DTCs from the same patient had similar SCNA pattern, while there were regional differences in the CSCs and DTCs in certain patient. SCNAs of CSCs in the same patient were highly reproducible. Our data suggest that major SCNAs occurred at an early stage and were inherited steadily. The similarity of ubiquitous SCNAs between the CSCs and DTCs might have arisen from lineage differentiation. CSCs from the same patient had reproducible SCNA profiles, indicating that gain or loss in certain chromosome is required for colon cancer development.

Increased circulating leukocyte-derived microparticles in ischemic cerebrovascular disease.

PubMed

He, Zhangping; Tang, Yanyan; Qin, Chao

2017-06-01

Circulating leukocyte-derived microparticles act as proinflammatory mediators that reflect vascular inflammation. In this study, we examined the hypothesis that the quantity of leukocyte-derived microparticles is increased in patients with ischemic cerebrovascular diseases, and investigated utility of various phenotypes of leukocyte-derived microparticles as specific biomarkers of vascular inflammation injury. Additionally we focused on identifying leukocyte-derived microparticles that may be correlated with stroke severity in acute ischemic stroke patients. The plasma concentration of leukocyte-derived microparticles obtained by a series of centrifugations of 76 consecutive patients with ischemic cerebrovascular diseases and 70 age-, sex-, and race-matched healthy controls were determined by flow cytometry. Significantly elevated numbers of leukocyte (CD45+), monocyte (CD14+), lymphocyte (CD4+), granulocyte (CD15+) derived microparticles were found in the plasma samples of patients ischemic cerebrovascular diseases, compared to healthy controls (p<0.05). Furthermore, the plasma levels of CD14+ microparticles were significantly correlated with stroke severity (r=0.355, p=0.019), cerebral vascular stenosis severity (r=0.255, p=0.025) and stroke subtype (r=0.242, p=0.036). No association with stroke was observed for other leukocyte-derived phenotypes. These results demonstrate that circulating leukocyte-derived microparticles amounts are increased in patients with ischemic cerebrovascular diseases, compared with healthy controls. As proinflammatory mediators, leukocyte-derived microparticles may contribute to vascular inflammatory and the inflammatory process in acute ischemic stroke. Levels of CD14+ microparticles may be a promising biomarker of ischemic severity and outcome of stroke in the clinic. Copyright © 2017 Elsevier Ltd. All rights reserved.

Bile duct regeneration and immune response by passenger lymphocytes signals biliary recovery versus complications after liver transplantation.

PubMed

Junger, Henrik H; Schlitt, Hans J; Geissler, Edward K; Fichtner-Feigl, Stefan; Brunner, Stefan M

2017-11-01

This study aimed to elucidate the impact of epithelial regenerative responses and immune cell infiltration on biliary complications after liver transplantation. Bile duct (BD) damage after cold storage was quantified by a BD damage score and correlated with patient outcome in 41 patients. Bacterial infiltration was determined by fluorescence in situ hybridization (FISH). BD samples were analyzed by immunohistochemistry for E-cadherin, cytokeratin, CD56, CD14, CD4, CD8, and double-immunofluorescence for cytokine production and by messenger RNA (mRNA) microarray. Increased mRNA levels of adherens junctions (P < 0.01) were detected in damaged BDs from patients without complications compared with damaged BDs from patients with biliary complications. Immunohistochemistry showed increased expression of E-cadherin and cytokeratin in BDs without biliary complications (P = 0.03; P = 0.047). FISH analysis demonstrated translocation of bacteria in BDs. However, mRNA analysis suggested an enhanced immune response in BDs without biliary complications (P < 0.01). Regarding immune cell infiltration, CD4 + and CD8 + cells were significantly increased in patients without complications compared with those with complications (P = 0.02; P = 0.01). In conclusion, following BD damage during cold storage, we hypothesize that the functional regenerative capacity of biliary epithelium and enhanced local adaptive immune cell infiltration are crucial for BD recovery. Such molecular immunological BD analyses therefore could help to predict biliary complications in cases of "major" epithelial damage after cold storage.Liver Transplantation 23 1422-1432 2017 AASLD. © 2017 by the American Association for the Study of Liver Diseases.

Regulatory T Cells in Peripheral Blood and Cerebrospinal Fluid of Syphilis Patients with and without Neurological Involvement

PubMed Central

Li, Kang; Wang, Cuini; Lu, Haikong; Gu, Xin; Guan, Zhifang; Zhou, Pingyu

2013-01-01

Background Syphilis, a sexually transmitted disease caused by spirochetal bacterium Treponema pallidum, can progress to affect the central nervous system, causing neurosyphilis. Accumulating evidence suggest that regulatory T cells (Tregs) may play an important role in the pathogenesis of syphilis. However, little is known about Treg response in neurosyphilis. Methodology/Principal Findings We analyzed Treg frequencies and Transforming Growth Factor-β (TGF-β) levels in the blood and CSF of 431 syphilis patients without neurological involvement, 100 neurosyphilis patients and 100 healthy donors. Suppressive function of Tregs in peripheral blood was also assessed. Among syphilis patients without neurological involvement, we found that secondary and serofast patients had increased Treg percentages, suppressive function and TGF-β levels in peripheral blood compared to healthy donors. Serum Rapid Plasma Reagin (RPR) titers were positively correlated with Treg numbers in these patients. Compared to these syphilis patients without neurological involvement, neurosyphilis patients had higher Treg frequency in peripheral blood. In the central nervous system, neurosyphilis patients had higher numbers of leukocytes in CSF compared to syphilis patients without neurological involvement. CD4+ T cells were the predominant cell type in the inflammatory infiltrates in CSF of neurosyphilis patients. Interestingly, among these neurosyphilis patients, a significant decrease in CSF CD4+ CD25high Treg percentage and number was observed in symptomatic neurosyphilis patients compared to those of asymptomatic neurosyphilis patients, which may be associated with low CSF TGF-β levels. Conclusions Our findings suggest that Tregs might play an important role in both bacterial persistence and neurologic compromise in the pathogenesis of syphilis. PMID:24244772

Patients with metabolic syndrome exhibit higher platelet activity than those with conventional risk factors for vascular disease.

PubMed

Serebruany, Victor L; Malinin, Alex; Ong, Stephen; Atar, Dan

2008-04-01

The metabolic syndrome is a matter of ongoing debate with regard to its existence, classification, clinical meaningfulness, and associated risks for vessel occlusion. Considering that persistent platelet activation is a cornerstone for the development of acute vascular events, and that patients with type 2 diabetes consistently exhibit high platelet activity, these characteristics may be critical for distinguishing and triageing specific features of metabolic syndrome among established risk factors for vascular disease. We assessed the platelet activity by conventional aggregation, expression of major surface receptors by flow cytometry, and quantitatively by rapid bedside analyzers in 20 aspirin-naïve patients with documented metabolic syndrome, and compared these with 20 untreated subjects with multiple cardiovascular risk factors. Closure time by the PFA-100 analyzer was significantly (P = 0.002) shorter in patients with metabolic syndrome indicating platelet inhibition under high shear conditions. Ultegra analyzer readings revealed increased fibrinogen binding (P = 0.0003) what in combination with the increased expression of PAC-1 (P = 0.32) strongly suggest activation of platelet glycoprotein IIb/IIIa receptor. Surface expression of CD107a (P = 0.014), and SPAN-12 (P = 0.003) were also higher in patients with metabolic syndrome. In contrast, platelet aggregation induced by collagen or ADP, CD31, CD41, CD42b, CD51/61, CD62p, CD63, CD154, CD165, so as formation of platelet-monocyte aggregates, PAR-1 thrombin receptor, and thrombospondin did not differ between groups. Patients with metabolic syndrome exhibited a higher degree of platelet activation than subjects with conventional risk factors for vascular disease. Conceptually, applying adequate antiplatelet strategies may reduce the risk of acute thrombotic events in these patients. Further prospective studies exploring this notion are encouraged.

Peripheral myeloid-derived suppressor and T regulatory PD-1 positive cells predict response to neoadjuvant short-course radiotherapy in rectal cancer patients

PubMed Central

Napolitano, Maria; D'Alterio, Crescenzo; Cardone, Eleonora; Trotta, Anna Maria; Pecori, Biagio; Rega, Daniela; Pace, Ugo; Scala, Dario; Scognamiglio, Giosuè; Tatangelo, Fabiana; Cacciapuoti, Carmela; Pacelli, Roberto; Delrio, Paolo; Scala, Stefania

2015-01-01

Short-course preoperative radiotherapy (SC-RT) followed by total mesorectal excision (TME) is one therapeutic option for locally advanced rectal cancer (LARC) patients. Since radio-induced DNA damage may affect tumor immunogenicity, Myeloid-derived suppressor cells (MDSCs) and T regulatory cells (Tregs) were evaluated in 13 patients undergoing SC-RT and TME for LARC. Peripheral Granulocytic-MDSCs (G-MDSC) [LIN−/HLA-DR−/CD11b+/CD14−/CD15+/CD33+], Monocytic (M-MDSC) [CD14+/HLA-DR−/lowCD11b+/CD33+] and Tregs [CD4+/CD25hi+/FOXP3+- CTLA-4/PD1] basal value was significantly higher in LARC patients compared to healthy donors (HD). Peripheral MDSC and Tregs were evaluated at time 0 (T0), after 2 and 5 weeks (T2-T5) from radiotherapy; before surgery (T8) and 6–12 months after surgery (T9, T10). G-MDSC decreased at T5 and further at T8 while M-MDSC cells decreased at T5; Tregs reached the lowest value at T5. LARC poor responder patients displayed a major decrease in M-MDSC after SC-RT and an increase of Treg-PD-1. In this pilot study MDSCs and Tregs decrease during the SC-RT treatment could represent a biomarker of response in LARC patients. Further studies are needed to confirm that the deepest M-MDSC reduction and increase in Treg-PD1 cells within 5–8 weeks from the beginning of treatment could discriminate LARC patients poor responding to SC-RT. PMID:25823653

Chagas cardiomyopathy is associated with higher incidence of stroke: a meta-analysis of observational studies.

PubMed

Cardoso, Rhanderson N; Macedo, Francisco Yuri B; Garcia, Melissa Nolan; Garcia, Daniel C; Benjo, Alexandre M; Aguilar, David; Jneid, Hani; Bozkurt, Biykem

2014-12-01

Chagas disease (CD) has been associated with an elevated risk of stroke, but current data are conflicting and prospective controlled studies are lacking. We performed a systematic review and meta-analysis examining the association between stroke and CD. Pubmed, Embase, Cochrane Central, Latin American database, and unpublished data were searched with the use of the following terms: ("Chagas" OR "American trypanosomiasis") AND ("dilated" OR "ischemic" OR "idiopathic" OR "nonChagasic" OR "stroke" OR "cerebrovascular"). We included studies that reported prevalence or incidence of stroke in a CD group compared with a non-CD control group. Odds ratios (ORs) and their 95% confidence intervals (CIs) were computed with the use of a random-effects model. A total of 8 studies and 4,158 patients were included, of whom 1,528 (36.7%) had CD. Risk of stroke was elevated in the group of patients with CD (OR 2.10, 95% CI 1.17-3.78). Similar results were observed in a subanalysis of cardiomyopathy patients (OR 1.74, 95% CI 1.02-3.00) and in sensitivity analysis with removal of each individual study. Furthermore, exclusion of studies at higher risk for bias also yielded consistent results (OR 1.70, 95% CI 1.06-2.71). Subanalysis restricted to studies that included patients with the indeterminate form found no significant difference in the stroke prevalence between CD and non-CD patients (OR 3.10, 95% CI 0.89-10.77). CD is significantly associated with cerebrovascular events, particularly among patients with cardiomyopathy. These findings underline the need for prospective controlled studies in patients with Chagas cardiomyopathy to ascertain the prognostic significance of cerebrovascular events and to evaluate the role of therapeutic anticoagulation in primary prevention. Published by Elsevier Inc.

Rapid point-of-care CD4 testing at mobile HIV testing sites to increase linkage to care: an evaluation of a pilot program in South Africa.

PubMed

Larson, Bruce A; Schnippel, Kathryn; Ndibongo, Buyiswa; Xulu, Thembisile; Brennan, Alana; Long, Lawrence; Fox, Matthew P; Rosen, Sydney

2012-10-01

A mobile HIV counseling and testing (HCT) program around Johannesburg piloted the integration of point-of-care (POC) CD4 testing, using the Pima analyzer, to improve linkages to HIV care. We report results from this pilot program for patients testing positive (n = 508) from May to October 2010. We analyzed 3 primary outcomes: assignment to testing group (offered POC CD4 or not), successful follow-up (by telephone), and completed the referral visit for HIV care within 8 weeks after HIV testing if successfully followed up. Proportions for each outcome were calculated, and relative risks were estimated using a modified Poisson approach. Three hundred eleven patients were offered the POC CD4 test, and 197 patients were not offered the test. No differences in patient characteristics were observed between the 2 groups. Approximately 62.7% of patients were successfully followed up 8 weeks after HIV testing, with no differences observed between testing groups. Among those followed up, 54.4% reported completing their referral visit. Patients offered the POC CD4 test were more likely to complete the referral visit for further HIV care (relative risk 1.25, 95% confidence interval: 1.00 to 1.57). In this mobile HCT setting, patients offered POC CD4 testing as part of the HCT services were more likely to visit a referral clinic after testing, suggesting that rapid CD4 testing technology may improve linkage to HIV care. Future research can evaluate options for adjusting HCT services if POC CD4 testing was included permanently and the cost-effectiveness of the POC CD4 testing compared with other approaches for improving linkage of care.

Elevated levels of IL-2 and IL-21 produced by CD4+ T cells in inflammatory bowel disease.

PubMed

Ebrahimpour, S; Shahbazi, M; Khalili, A; Tahoori, M T; Zavaran Hosseini, A; Amari, A; Aghili, B; Abediankenari, S; Mohammadizad, H; Mohammadnia-Afrouzi, M

2017-01-01

CD4+ T cells are considered as a subset of cells that play a pivotal role in the development of inflammatory bowel disease (IBD). The aim of this study was to assess the levels of interleukin (IL)-2, IL-21 and their receptors produced by CD4+ T cells in patients with inflammatory bowel disease. Thirty-two patients with ulcerative colitis (UC) and mean age of 37.93±10.37 years, as well as 22 patients with Crohn’s disease (CD) and mean age of 37.04±10.44 years, were studied. The healthy controls (HC) included 31 subjects with a mean age of 36.7±10.48 years. Peripheral blood mononuclear cells (PBMCs) were isolated from all the participants. The CD4+ T cells were isolated and the expression of IL-2 and IL-21 and also their receptors were examined by flow cytometry. The level of IL-2+ cells was significantly increased in UC patients compared with HC (40.71±6.04 vs 37.24±6.54, respectively, p=0.04). The level of IL-21+ cells was also significantly elevated in CD patients compared with HC (4.44±1 vs 3.83±0.74, respectively, p=0.02). Furthermore, we found a significant positive correlation between clinical activity index (CAI) and IL-21+ cells. According to the results, we hypothesize that the elevated level of IL-2+ and IL-21+ T cells and a positive correlation between IL-21+ cells with CAI in UC patients may contribute to the pathogenesis of disease. Moreover, the assessment of cells producing such cytokines constitutes a potential diagnostic and therapeutic strategy for IBD.

Prognostic implications of atrial fibrillation in patients undergoing myocardial perfusion single-photon emission computed tomography.

PubMed

Abidov, Aiden; Hachamovitch, Rory; Rozanski, Alan; Hayes, Sean W; Santos, Marcia M; Sciammarella, Maria G; Cohen, Ishac; Gerlach, James; Friedman, John D; Germano, Guido; Berman, Daniel S

2004-09-01

The aim of this research was to determine whether presence of atrial fibrillation (AF) provides incremental prognostic information relative to myocardial perfusion single-photon emission computed tomography (MPS) with respect to risk of cardiac death (CD). The prognostic significance of AF in patients undergoing MPS is not known. A total of 16,048 consecutive patients undergoing MPS were followed-up for a mean of 2.21 +/- 1.15 years for the development of CD. Of those, 384 patients (2.4%) had AF. Cox proportional hazards method was used to compare clinical and perfusion data for the prediction of CD in patients with and without AF. Atrial fibrillation was a significant predictor of CD in patients with normal (1.6% per year vs. 0.4% per year in non-AF patients), mildly abnormal (6.3% per year vs. 1.2% per year), and severely abnormal MPS (6.4% per year vs. 3.7% per year) (p < 0.001 for all). By multivariable analysis, AF patients had worse survival (p = 0.001) even after adjustment for the variables most predictive of CD: age, diabetes, shortness of breath, use of vasodilator stress, rest heart rate, and the nuclear variables. In the 4,239 patients with left ventricular ejection fraction evaluated by gated MPS, AF demonstrated incremental prognostic value not only over clinical and nuclear variables, but also over left ventricular ejection in predicting CD (p = 0.014). The presence of AF independently increases the risk of cardiac events over perfusion and function variables in patients undergoing MPS. Patients with AF have a high risk of CD, even when MPS is only mildly abnormal. Whether patients with AF and mildly abnormal MPS constitute a group more deserving of early referral to cardiac catheterization is a question warranting further study.

Prognostic relevance of miR-137 in patients with hepatocellular carcinoma.

PubMed

Sakabe, Tomohiko; Azumi, Junya; Umekita, Yoshihisa; Toriguchi, Kan; Hatano, Etsuro; Hirooka, Yasuaki; Shiota, Goshi

2017-02-01

Cancer stem cells (CSCs) play a pivotal role in progression, metastasis and recurrence of cancer. Therefore, it is clinically useful to identify the relevant CSC marker that is associated with prognosis of hepatocellular carcinoma (HCC) and clarify its genetic and biological characteristics. Expression of four CSC markers, CD13, EpCAM, CD44 and CD44v9, was examined in 99 HCC patients. Biological and cDNA/miRNA microarray data were compared among CD44-positive/-negative HCC cells and normal hepatic cells. The significance of the representative miRNAs was examined with regard to prognosis of additional 110 HCC patients. CD44-positive HuH7 cells proliferated faster and showed a greater sphere forming ability than CD44-negative HuH7 cells. CD44-positive HuH7 cells exhibited higher expression of specific genes involved in resistance to reactive oxygen species, anticancer drugs and tumour invasion than CD44-negative HCC cells. Higher expression of six miRNAs was observed in CD44-positive HuH7 cells, CD44-negative HuH7 cells, and human normal hepatic cells in that order. Of the six miRNAs, miR-137 was closely associated with overall and cancer-specific survivals, as well as with invasion of hepatic vein, hepatic artery, portal vein and bile duct, and alpha-foetoprotein in additional 110 HCC patients. miR-137 may serve as a prognostic marker in patients with HCC and may be a potential target for the elimination of liver CSCs. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Flow cytometry analysis of T-cell subsets in cerebrospinal fluid of narcolepsy type 1 patients with long-lasting disease.

PubMed

Moresco, Monica; Lecciso, Mariangela; Ocadlikova, Darina; Filardi, Marco; Melzi, Silvia; Kornum, Birgitte Rahbek; Antelmi, Elena; Pizza, Fabio; Mignot, Emmanuel; Curti, Antonio; Plazzi, Giuseppe

2018-04-01

Type 1 narcolepsy (NT1) is a central hypersomnia linked to the destruction of hypocretin-producing neurons. A great body of genetic and epidemiological data points to likely autoimmune disease aetiology. Recent reports have characterized peripheral blood T-cell subsets in NT1, whereas data regarding the cerebrospinal fluid (CSF) immune cell composition are lacking. The current study aimed to characterize the T-cell and natural killer (NK) cell subsets in NT1 patients with long disease course. Immune cell subsets from CSF and peripheral blood mononuclear cell (PBMC) samples were analysed by flow cytometry in two age-balanced and sex-balanced groups of 14 NT1 patients versus 14 healthy controls. The frequency of CSF cell groups was compared with PBMCs. Non-parametric tests were used for statistical analyses. The NT1 patients did not show significant differences of CSF immune cell subsets compared to controls, despite a trend towards higher CD4 + terminally differentiated effector memory T cells. T cells preferentially displayed a memory phenotype in the CSF compared to PBMCs. Furthermore, a reduced frequency of CD4 + terminally differentiated effector memory T cells and an increased frequency of NK CD56 bright cells was observed in PBMCs from patients compared to controls. Finally, the ratio between CSF and peripheral CD4 + terminally differentiated effector memory T cells was two-fold increased in NT1 patients versus controls. Significant differences in PBMCs and in CSF/PBMC ratios of immune cell profile were found in NT1 patients compared to healthy controls. These differences might have arisen from the different HLA status, or be primary or secondary to hypocretin deficiency. Further functional studies in patients close to disease onset are required to understand NT1 pathophysiology. Copyright © 2017 Elsevier B.V. All rights reserved.

PAR(2) expression in peripheral blood monocytes of patients with rheumatoid arthritis.

PubMed

Crilly, A; Burns, E; Nickdel, M B; Lockhart, J C; Perry, M E; Ferrell, P W; Baxter, D; Dale, J; Dunning, L; Wilson, H; Nijjar, J S; Gracie, J A; Ferrell, W R; McInnes, I B

2012-06-01

Proteinase-activated receptor 2 (PAR(2)) is a G protein-coupled receptor activated by serine proteinases with proinflammatory activity. A study was undertaken to investigate the presence and functional significance of PAR(2) expression on rheumatoid arthritis (RA)-derived leucocyte subsets. Venous blood was obtained from patients with RA and osteoarthritis (OA) as well as healthy control subjects. Surface expression of PAR(2) on peripheral blood mononuclear cells (PBMCs) was analysed by flow cytometry and interleukin 6 (IL-6) generation by ELISA. Patients with RA had elevated but variable surface expression of PAR(2) on CD14+ monocytes compared with control subjects (median (1st to 3rd quartiles) 1.76% (0.86-4.10%) vs 0.06% (0.03-0.81%), p<0.0001). CD3+ T cells showed a similar pattern with significantly higher PAR(2) expression in patients with RA compared with controls (3.05% (0.36-11.82%) vs 0.08% (0.02-0.28%), p<0.0001). For both subsets, PAR(2) expression was significantly higher (p<0.00001) in patients with high levels of disease activity: PAR(2) expression for both CD14+ and CD3+ cells correlated to C reactive protein and erythrocyte sedimentation rate. Furthermore, in a cohort of patients with newly diagnosed RA, elevated PAR(2) expression in both CD14+ and CD3+ cells was significantly reduced 3 months after methotrexate or sulfasalazine treatment and this reduction correlated significantly with the reduction in the 28-joint Disease Activity Scale score (p<0.05). PAR(2) expression on cells from patients with OA was low, similar to levels seen in control subjects. Generation of IL-6 by monocytes in response to a selective PAR(2) agonist was significantly greater in patients with RA than in patients with OA and control subjects (p<0.05). These findings are consistent with a pathogenic role for PAR(2) in RA.

PAR2 expression in peripheral blood monocytes of patients with rheumatoid arthritis

PubMed Central

Crilly, A; Burns, E; Nickdel, M B; Lockhart, J C; Perry, M E; Ferrell, P W; Baxter, D; Dale, J; Dunning, L; Wilson, H; Nijjar, J S; Gracie, J A; Ferrell, W R; McInnes, I B

2012-01-01

Objectives Proteinase-activated receptor 2 (PAR2) is a G protein-coupled receptor activated by serine proteinases with proinflammatory activity. A study was undertaken to investigate the presence and functional significance of PAR2 expression on rheumatoid arthritis (RA)-derived leucocyte subsets. Methods Venous blood was obtained from patients with RA and osteoarthritis (OA) as well as healthy control subjects. Surface expression of PAR2 on peripheral blood mononuclear cells (PBMCs) was analysed by flow cytometry and interleukin 6 (IL-6) generation by ELISA. Results Patients with RA had elevated but variable surface expression of PAR2 on CD14+ monocytes compared with control subjects (median (1st to 3rd quartiles) 1.76% (0.86–4.10%) vs 0.06% (0.03–0.81%), p<0.0001). CD3+ T cells showed a similar pattern with significantly higher PAR2 expression in patients with RA compared with controls (3.05% (0.36–11.82%) vs 0.08% (0.02–0.28%), p<0.0001). For both subsets, PAR2 expression was significantly higher (p<0.00001) in patients with high levels of disease activity: PAR2 expression for both CD14+ and CD3+ cells correlated to C reactive protein and erythrocyte sedimentation rate. Furthermore, in a cohort of patients with newly diagnosed RA, elevated PAR2 expression in both CD14+ and CD3+ cells was significantly reduced 3 months after methotrexate or sulfasalazine treatment and this reduction correlated significantly with the reduction in the 28-joint Disease Activity Scale score (p<0.05). PAR2 expression on cells from patients with OA was low, similar to levels seen in control subjects. Generation of IL-6 by monocytes in response to a selective PAR2 agonist was significantly greater in patients with RA than in patients with OA and control subjects (p<0.05). Conclusions These findings are consistent with a pathogenic role for PAR2 in RA. PMID:22294633

[Bone metabolism, biochemical markers of bone resorption and formation processes and interleukine 6 cytokin level during coeliac disease].

PubMed

Fekih, Monia; Sahli, Hela; Ben Mustapha, Nadia; Mestiri, Imen; Fekih, Moncef; Boubaker, Jalel; Kaabachi, Naziha; Sellami, Mohamed; Kallel, Lamia; Filali, Azza

2013-01-01

Celiac disease (CD) is characterized by a malabsorption syndrom. The bone anomalies are one of the principal complications of this disease. The osteoporosis frequency is high: 3.4% among patients having with CD versus 0.2% in the general population. To study the bone mineral density during the CD, to compare it to a control group and to determine the anomalies of biochemical markers of bone turn over and level of interleukin 6 cytokin (IL6) in these patients. All patients with CD have a measurement of bone mineral density by dual-energy x-ray absorptiometry (DXA), a biological exam with dosing calcemia, vitamin D, parathormone (PTH), the osteoblastic bone formation markers (serum osteocalcin, ALP phosphates alkaline), bone osteoclastic activity (C Télopeptide: CTX) and of the IL6. 42 patients were included, with a median age of 33.6 years. 52. 8% of the patients had a low level of D vitamine associated to a high level of PTH. An osteoporosis was noted in 21.5% of patients. No case of osteoporosis was detected in the control group. The mean level of the CTX, ostéocalcine and the IL6 was higher among patients having an osteoporosis or ostéopenia compared to patients with normal bone (p = 0,017). The factors associated with an bone loss (osteopenia or osteoporosis) were: an age > 30 years, a weight <50 kg, a level of ALP phosphates alkaline > 90 UI/ml, an hypo albuminemia < 40 g/l and a level of CTX higher than 1.2. Our study confirms the impact of the CD on the bone mineral statute. The relative risk to have an osteopenia or an osteoporosis was 5 in our series. The measurement of the osseous mineral density would be indicated among patients having a CD.

Endothelial adhesion molecules and leukocyte integrins in preeclamptic patients.

PubMed

Haller, H; Ziegler, E M; Homuth, V; Drab, M; Eichhorn, J; Nagy, Z; Busjahn, A; Vetter, K; Luft, F C

1997-01-01

Endothelial cell activation is important in the pathogenesis of preeclampsia; however, the nature of the activation is unknown. We investigated 22 patients with preeclampsia. 29 normotensive pregnancies, and 18 nonpregnant women to test the hypothesis that serum from preeclamptic patients induces expression of intercellular adhesion molecule-1 (ICAM-1) and vascular adhesion molecule-1 (VCAM-1) and stimulates intracellular free calcium concentrations [Ca2+]i in cultured endothelial cells. We then asked whether the corresponding integrin adhesive counter receptors lymphocyte function-associated antigen-1 (CD11a/CD18), macrophage-1 antigen (CD11b/CD18), p150,95 (CD11c/CD18), and very late activation antigen-4 (CD49/CD29) are increased in patients with preeclampsia. In the pregnant women, the measurements were conducted both before and after delivery. Integrin expression was measured by fluorescent antibody cell sorting analysis using monoclonal antibodies. ICAM-1 and VCAM-1 were analyzed on endothelial cells by enzyme-linked immunosorbent assay. [Ca2+]i was measured with fura 2. Serum from preeclamptic patients increased endothelial cell ICAM-1 expression but not VCAM-1 expression. Preeclamptic patients' serum also increased [Ca2+]i in endothelial cells compared with serum from normal nonpregnant or normal pregnant women. Endothelial cell [Ca2+]i concentrations were correlated with the ICAM-1 expression in preeclamptic patients (r = .80, P < .001) before but not after delivery. Expression of the integrin counter receptors on leukocytes was similarly increased in preclampsia and normal pregnancy compared with the nonpregnant state. The expression decreased significantly after delivery in both groups. Our results demonstrate that serum from preeclamptic women induces increased ICAM-1 surface expression on endothelial cells, while the expression of the integrin counterreceptors was not different. The effect on endothelial cells may be related to an increase in [Ca2+]i. The effect on cultured endothelial cells and the rapid decrease after delivery suggests the presence of a circulating serum factor which increases endothelial cell [Ca2+]i and enhances adhesion molecule expression.

Relationship between Vagal Tone, Cortisol, TNF-Alpha, Epinephrine and Negative Affects in Crohn’s Disease and Irritable Bowel Syndrome

PubMed Central

Pellissier, Sonia; Dantzer, Cécile; Mondillon, Laurie; Trocme, Candice; Gauchez, Anne-Sophie; Ducros, Véronique; Mathieu, Nicolas; Toussaint, Bertrand; Fournier, Alicia; Canini, Frédéric; Bonaz, Bruno

2014-01-01

Crohn’s disease (CD) and irritable bowel syndrome (IBS) involve brain-gut dysfunctions where vagus nerve is an important component. The aim of this work was to study the association between vagal tone and markers of stress and inflammation in patients with CD or IBS compared to healthy subjects (controls). The study was performed in 73 subjects (26 controls, 21 CD in remission and 26 IBS patients). The day prior to the experiment, salivary cortisol was measured at 8∶00 AM and 10∶00 PM. The day of the experiment, subjects completed questionnaires for anxiety (STAI) and depressive symptoms (CES-D). After 30 min of rest, ECG was recorded for heart rate variability (HRV) analysis. Plasma cortisol, epinephrine, norepinephrine, TNF-alpha and IL-6 were measured in blood samples taken at the end of ECG recording. Compared with controls, CD and IBS patients had higher scores of state-anxiety and depressive symptomatology. A subgroup classification based on HRV-normalized high frequency band (HFnu) as a marker of vagal tone, showed that control subjects with high vagal tone had significantly lower evening salivary cortisol levels than subjects with low vagal tone. Such an effect was not observed in CD and IBS patients. Moreover, an inverse association (r = −0.48; p<0.05) was observed between the vagal tone and TNF-alpha level in CD patients exclusively. In contrast, in IBS patients, vagal tone was inversely correlated with plasma epinephrine (r = −0.39; p<0.05). No relationship was observed between vagal tone and IL-6, norepinephrine or negative affects (anxiety and depressive symptomatology) in any group. In conclusion, these data argue for an imbalance between the hypothalamus-pituitary-adrenal axis and the vagal tone in CD and IBS patients. Furthermore, they highlight the specific homeostatic link between vagal tone and TNF-alpha in CD and epinephrine in IBS and argue for the relevance of vagus nerve reinforcement interventions in those diseases. PMID:25207649

Impaired function of CD4+/CD25+ T regulatory lymphocytes characterizes the self-limited hepatitis A virus infection.

PubMed

Perrella, Alessandro; Vitiello, Laura; Atripaldi, Luigi; Sbreglia, Costanza; Grattacaso, Stella; Bellopede, Pasquale; Patarino, Tommaso; Morelli, Giuseppe; Altamura, Simona; Racioppi, Luigi; Perrella, Oreste

2008-07-01

Hepatitis A virus (HAV) causes a transient illness leaving permanent protection against reinfection. Few data are available on the regulatory mechanisms involved in the CD4+ T helper activation. We aimed to investigate the frequency and function of CD3+/CD4+/CD25+ T cells with regulatory function (Tregs) during acute HAV infection. We enrolled 35 consecutive patients and 15 healthy donors, enumerated Tregs by flow cytometry assay and evaluated, after immunomagnetical sorting with magnetic beads, their ability to inhibit the proliferation of CD4+/CD25- T lymphocytes at different ratios (1:1, 1:10, 1:20). All patients had the usual course of infection. Our immunological analysis showed Tregs frequency in these patients (6.5% [range, 5-8.8%]; 36 [range, 10-87] cells) did not have any statistical difference compared with healthy donors (6% [range, 5-8%]; 48 (range, 23-71) cells), while their ability to suppress CD4+/CD25- was drastically reduced at different ratios (Mann-Whitney U-test; ratio 1:1, 93% vs 72%, z = -3.34, P < 0.0001; ratio 1:10, 86% vs 51%, z = -4.04, P < 0.001; ratio 1:20, 56% vs 30%, z = -3.43, P < 0.0001). After the seroconversion, CD4+/CD25+ frequency and function in HAV-infected patients did not differ from healthy individuals. CD4+/CD25+ T cells seem to be impaired in their function during the HAV acute infection. This evidence might help to determine an optimal T helper cell immune network that is a predisposing factor for a self-limiting disease.

Changes of regulatory T and B cells in patients with papillary thyroid carcinoma after 131I radioablation: a preliminary study.

PubMed

Jiang, Lei; Zhan, Yanxia; Gu, Yusen; Ye, Yi; Cheng, Yunfeng; Shi, Hongcheng

2013-01-01

Introduction. Lymphocytic infiltration and specific lymphocytes subsets may play important roles in papillary thyroid carcinoma (PTC) progression and prognosis. In this study, we try to understand the influence of (131)I radioablation on the important lymphocytes subtypes of regulatory T and B cells (Tregs and Bregs). Methods. Peripheral blood mononuclear cells from 30 PTC patients before and after (131)I therapy, and 20 healthy donors were collected. The expression of Tregs (CD4(+)CD25(+)CD127(-/low)) and B cell (CD5(+)CD19(+)) and production and secretion of interleukin 10 (IL-10) were analyzed by FACS and ELISA assay, respectively. Results. For Tregs percentage in peripheral blood lymphocytes, there was no difference between pretreatment and control and between posttreatment and control. Compared with pretherapy, increased Tregs infiltration was noted in posttherapy (P < 0.05). Although no difference was between pretreatment and control, compared with these two groups, decreased CD19(+) and CD5(+)CD19(+) B cell percentage in posttreatment was observed (P < 0.05). Among these groups, no significant difference was displayed in intracellular IL-10 production and extracellular IL-10 secretion. Conclusions. (131)I Radioablation increased Tregs and decreased CD19(+) and CD5(+)CD19(+) B cells percentage after treatment. However, it has no effect on IL-10 and lymphocytes in peripheral blood. Therefore, longer follow-up of Tregs and Bregs should be further investigated.

Function and regulation of LAG3 on CD4+CD25- T cells in non-small cell lung cancer.

PubMed

Ma, Qin-Yun; Huang, Da-Yu; Zhang, Hui-Jun; Wang, Shaohua; Chen, Xiao-Feng

2017-11-15

LAG3 is a surface molecule found on a subset of immune cells. The precise function of LAG3 appears to be context-dependent. In this study, we investigated the effect of LAG3 on CD4 + CD25 - T cells from non-small cell lung cancer (NSCLC) patients. We found that in the peripheral blood mononuclear cells of NSCLC patients, LAG3 was significantly increased in CD4 + T cells directly ex vivo and primarily in the CD4 + CD25 - fraction, which was regulated by prolonged TCR stimulation and the presence of IL-27. TCR stimulation also increased CD25 expression, but not Foxp3 expression, in LAG3-expressing CD4 + CD25 - cells Compared to LAG3-nonexpressing CD4 + CD25 - cells, LAG3-expressing CD4 + CD25 - cells presented significantly higher levels of PD1 and TIM3, two inhibitory receptors best described in exhausted CD8 + T effector cells. LAG3-expressing CD4 + CD25 - cells also presented impaired proliferation compared with LAG3-nonexpressing CD4 + CD25 - cells but could be partially rescued by inhibiting both PD1 and TIM3. Interestingly, CD8 + T cells co-incubated with LAG3-expressing CD4 + CD25 - cells at equal cell numbers demonstrated significantly lower proliferation than CD8 + T cells incubated alone. Co-culture with CD8 + T cell and LAG3-expressing CD4 + CD25 - T cell also upregulated soluble IL-10 level in the supernatant, of which the concentration was positively correlated with the number of LAG3-expressing CD4 + CD25 - T cells. In addition, we found that LAG3-expressing CD4 + CD25 - T cells infiltrated the resected tumors and were present at higher frequencies of in metastases than in primary tumors. Taken together, these data suggest that LAG3-expressing CD4 + CD25 - T cells represent another regulatory immune cell type with potential to interfere with anti-tumor immunity. Copyright © 2017 Elsevier Inc. All rights reserved.

Lower percentage of CD8+ T cells in peripheral blood of patients with sporotrichosis.

PubMed

Zhu, Mingji; Xu, Yaqin; An, Lin; Jiang, Jinlan; Zhang, Xu; Jiang, Rihua

2016-07-01

To characterize the peripheral immunity and immunity response of patients with sporotrichosis, in this study we determined the lymphocyte subsets in the peripheral blood of Chinese patients with sporotrichosis. In this retrospective study, peripheral blood was collected from 69 sporotrichosis patients (37, fixed cutaneous form; 32 lymphocutaneous) and 66 healthy controls. Lymphocyte subsets were analyzed using flow cytometry. Compared to controls, the percentage of CD8+ T cells was lower in sporotrichosis patients. The percentage of CD8+ T cells in peripheral blood tended to become lower with disease duration and disease severity, although the difference was not statistically significant for either acute, subacute and chronic patients or fixed cutaneous and lymphocutaneous patients. Our data indicate that the decrease of CD8+ T cells in peripheral blood of patients with sporotrichosis is associated with disease severity, although the difference was not statistically significant for either duration or clinical forms of the disease. Combining antifungal agents and immunomodulators in patients with long disease duration and lymphocutaneous may be more beneficial than antifungal monotherapy. Copyright © 2016. Published by Elsevier Inc.

Medical and surgical treatment of haemorrhoids and anal fissure in Crohn’s disease: a critical appraisal

PubMed Central

2013-01-01

Background The principle to avoid surgery for haemorrhoids and/or anal fissure in Crohn’s disease (CD) patients is still currently valid despite advances in medical and surgical treatments. In this study we report our prospectively recorded data on medical and surgical treatment of haemorrhoids and anal fissures in CD patients over a period of 8 years. Methods Clinical data of patients affected by perianal disease were routinely and prospectively inserted in a database between October 2003 and October 2011 at the Department of Surgery, Tor Vergata University Hospital, Rome. We reviewed and divided in two groups records on CD patients treated either medically or surgically according to the diagnosis of haemorrhoids or anal fissures. Moreover, we compared in each group the outcome in patients with prior diagnosis of CD and in patients diagnosed with CD only after perianal main treatment. Results Eighty-six CD patients were included in the study; 45 were treated for haemorrhoids and 41 presented with anal fissure. Conservative approach was initially adopted for all patients; in case of medical treatment failure, the presence of stable intestinal disease made them eligible for surgery. Fifteen patients underwent haemorrhoidectomy (open 11; closed 3; stapled 1), and two rubber band ligation. Fourteen patients required surgery for anal fissure (Botox ± fissurectomy 8; LIS 6). In both groups we observed high complication rate, 41.2% for haemorrhoids and 57.1% for anal fissure. Patients who underwent haemorrhoidectomy without certain diagnosis of CD had significantly higher risk of complications. Conclusions Conservative treatment of proctologic diseases in CD patients has been advocated given the high risk of complications and the evidence that spontaneous healing may also occur. From these preliminary results a role of surgery is conceivable in high selected patients, but definitve conclusions can’t be made. Further randomized trials are needed to establish the efficacy of the surgical approach, giving therapeutic recommendations and guidelines. PMID:23496835

Medical and surgical treatment of haemorrhoids and anal fissure in Crohn's disease: a critical appraisal.

PubMed

D'Ugo, Stefano; Franceschilli, Luana; Cadeddu, Federica; Leccesi, Laura; Blanco, Giovanna Del Vecchio; Calabrese, Emma; Milito, Giovanni; Di Lorenzo, Nicola; Gaspari, Achille L; Sileri, Pierpaolo

2013-03-11

The principle to avoid surgery for haemorrhoids and/or anal fissure in Crohn's disease (CD) patients is still currently valid despite advances in medical and surgical treatments. In this study we report our prospectively recorded data on medical and surgical treatment of haemorrhoids and anal fissures in CD patients over a period of 8 years. Clinical data of patients affected by perianal disease were routinely and prospectively inserted in a database between October 2003 and October 2011 at the Department of Surgery, Tor Vergata University Hospital, Rome. We reviewed and divided in two groups records on CD patients treated either medically or surgically according to the diagnosis of haemorrhoids or anal fissures. Moreover, we compared in each group the outcome in patients with prior diagnosis of CD and in patients diagnosed with CD only after perianal main treatment. Eighty-six CD patients were included in the study; 45 were treated for haemorrhoids and 41 presented with anal fissure. Conservative approach was initially adopted for all patients; in case of medical treatment failure, the presence of stable intestinal disease made them eligible for surgery. Fifteen patients underwent haemorrhoidectomy (open 11; closed 3; stapled 1), and two rubber band ligation. Fourteen patients required surgery for anal fissure (Botox ± fissurectomy 8; LIS 6). In both groups we observed high complication rate, 41.2% for haemorrhoids and 57.1% for anal fissure. Patients who underwent haemorrhoidectomy without certain diagnosis of CD had significantly higher risk of complications. Conservative treatment of proctologic diseases in CD patients has been advocated given the high risk of complications and the evidence that spontaneous healing may also occur. From these preliminary results a role of surgery is conceivable in high selected patients, but definitve conclusions can't be made. Further randomized trials are needed to establish the efficacy of the surgical approach, giving therapeutic recommendations and guidelines.

Ileal Crohn disease: mural microvascularity quantified with contrast-enhanced US correlates with disease activity.

PubMed

De Franco, Antonio; Di Veronica, Alessandra; Armuzzi, Alessandro; Roberto, Italia; Marzo, Manuela; De Pascalis, Barbara; De Vitis, Italo; Papa, Alfredo; Bock, Enrico; Danza, Francesco M; Bonomo, Lorenzo; Guidi, Luisa

2012-02-01

To quantitatively assess microvascular activation in the thickened ileal walls of patients with Crohn disease (CD) by using contrast-enhanced ultrasonography (US) and evaluate its correlation with widely used indexes of CD activity. This prospective study was approved by the ethics committee, and written informed consent was obtained from all patients. The authors examined 54 consecutively enrolled patients (mean age, 35.29 years; age range, 18-69 years; 39 men, 15 women) with endoscopically confirmed CD of the terminal ileum. Ileal wall segments thicker than 3 mm were examined with low-mechanical-index contrast-enhanced US and a second-generation US contrast agent. The authors analyzed software-plotted time-enhancement intensity curves to determine the maximum peak intensity (MPI) and wash-in slope coefficient (β) and evaluated their correlation with (a) the composite index of CD activity (CICDA), (b) the CD activity index (CDAI), and (c) the simplified endoscopic score for CD (SES-CD, evaluated in 37 patients) for the terminal ileum. Statistical analysis was performed with the Mann-Whitney test, Spearman rank test, and receiver operating characteristic (ROC) analysis. MPI and β coefficients were significantly increased in the 36 patients with a CICDA indicative of active disease (P<.0001 for both), the 33 patients with a CDAI of at least 150 (P<.032 and P<.0074, respectively), and the 26 patients with an SES-CD of at least 1 (P<.0001 and P<.002, respectively). ROC analysis revealed accurate identification (compared with CICDA) of active CD with an MPI threshold of 24 video intensity (VI) (sensitivity, 97%; specificity, 83%) and a β coefficient of 4.5 VI/sec (sensitivity, 86%; specificity, 83%). Contrast-enhanced US of the ileal wall is a promising method for objective, reproducible assessment of disease activity in patients with ileal CD. © RSNA, 2011

High soluble CD30 levels and associated anti-HLA antibodies in patients with failed renal allografts.

PubMed

Karahan, Gonca E; Caliskan, Yasar; Ozdilli, Kursat; Kekik, Cigdem; Bakkaloglu, Huseyin; Caliskan, Bahar; Turkmen, Aydin; Sever, Mehmet S; Oguz, Fatma S

2017-01-13

Serum soluble CD30 (sCD30), a 120-kD glycoprotein that belongs to the tumor necrosis factor receptor family, has been suggested as a marker of rejection in kidney transplant patients. The aim of this study was to evaluate the relationship between sCD30 levels and anti-HLA antibodies, and to compare sCD30 levels in patients undergoing hemodialysis (HD) with and without failed renal allografts and transplant recipients with functioning grafts. 100 patients undergoing HD with failed grafts (group 1), 100 patients undergoing HD who had never undergone transplantation (group 2), and 100 kidney transplant recipients (group 3) were included in this study. Associations of serum sCD30 levels and anti-HLA antibody status were analyzed in these groups. The sCD30 levels of group 1 and group 2 (154 ± 71 U/mL and 103 ± 55 U/mL, respectively) were significantly higher than those of the transplant recipients (group 3) (39 ± 21 U/mL) (p<0.001 and p<0.001). The serum sCD30 levels in group 1 (154 ± 71 U/mL) were also significantly higher than group 2 (103 ± 55 U/mL) (p<0.001). Anti-HLA antibodies were detected in 81 (81%) and 5 (5%) of patients in groups 1 and 2, respectively (p<0.001). When multiple regression analysis was performed to predict sCD30 levels, the independent variables in group 1 were the presence of class I anti-HLA antibodies (β = 0.295; p = 0.003) and age (β = -0.272; p = 0.005), and serum creatinine (β = 0.218; p = 0.027) and presence of class II anti-HLA antibodies (standardized β = 0.194; p = 0.046) in group 3. Higher sCD30 levels and anti-HLA antibodies in patients undergoing HD with failed renal allografts may be related to higher inflammatory status in these patients.

Soluble CD40 ligand in prediction of acute severe pancreatitis

PubMed Central

Frossard, Jean Louis; Morel, Philippe; Kwak, Brenda; Pastor, Catherine; Berney, Thierry; Buhler, Léo; Von Laufen, Alain; Demulder, Sandrine; Mach, Francois

2006-01-01

AIM: To assess the early predictability of the soluble CD40L (sCD40L) in pancreatitis severity. METHODS: Between February 2000 and February 2003, 279 consecutive patients with acute pancreatitis were prospectively enrolled in our study. In this report, 40 patients with mild and 40 patients with severe pancreatitis were randomly studied. sCD40L concentrations were measured 48 hours after admission. RESULTS: sCD40L levels were significantly higher 48 hours after admission in severe pancreatitis than in mild pancreatitis. Using a cutoff of 1 000 pg/L, the sensitivity and specificity of sCD40L to detect a severe course of the disease were 78% and 62% respectively compared to 72% and 81% for CRP. Logistic regression analysis found that CRP was the only statistically significant marker able to detect a severe course of the disease. CONCLUSION: These findings indicate that CRP remains a valuable marker to determine the severity and prognosis of acute pancreatitis whereas sCD40L levels should be assessed in further studies. PMID:16570356

Evaluation of serum sCD30 in renal transplantation patients with and without acute rejection.

PubMed

Cervelli, C; Fontecchio, G; Scimitarra, M; Azzarone, R; Famulari, A; Pisani, F; Battistoni, C; Di Iulio, B; Fracassi, D; Scarnecchia, M A; Papola, F

2009-05-01

Despite new immunosuppressive approaches, acute rejection episodes (ARE) are still a major cause of early kidney dysfunction with a negative impact on long-term allograft survival. Noninvasive markers able to identify renal ARE earlier than creatinine measurement include sCD30. We sought to establish whether circulating levels of sCD30 in pretransplantation and posttransplantation periods were of clinical relevance to avoid graft damage. Quantitative detection of serum sCD30 was performed using an enzyme-linked immunosorbent assay. Our results demonstrated that the mean concentrations of sCD30 were significantly higher in the sera of renal transplant recipients with ARE (30.04 U/mL) and in uremic patients on the waiting list (37.7 U/mL) compared with healthy controls (HC; 9.44 U/mL), but not nonrejecting patients (12.01 U/mL). Statistical analysis revealed a strong association between high sCD30 levels in posttransplantation sera and ARE risk. This study suggested that sCD30 levels were a reliable predictor of ARE among deceased-donor kidney recipients.

Dual CD19 and CD123 targeting prevents antigen-loss relapses after CD19-directed immunotherapies

PubMed Central

Barrett, David M.; Shestova, Olga; Hofmann, Ted J.; Perazzelli, Jessica; Klichinsky, Michael; Aikawa, Vania; Nazimuddin, Farzana; Kozlowski, Miroslaw; Scholler, John; Lacey, Simon F.; Melenhorst, Jan J.; Morrissette, Jennifer J.D.; Christian, David A.; Hunter, Christopher A.; Kalos, Michael; Porter, David L.; June, Carl H.; Grupp, Stephan A.

2016-01-01

Potent CD19-directed immunotherapies, such as chimeric antigen receptor T cells (CART) and blinatumomab, have drastically changed the outcome of patients with relapsed/refractory B cell acute lymphoblastic leukemia (B-ALL). However, CD19-negative relapses have emerged as a major problem that is observed in approximately 30% of treated patients. Developing approaches to preventing and treating antigen-loss escapes would therefore represent a vertical advance in the field. Here, we found that in primary patient samples, the IL-3 receptor α chain CD123 was highly expressed on leukemia-initiating cells and CD19-negative blasts in bulk B-ALL at baseline and at relapse after CART19 administration. Using intravital imaging in an antigen-loss CD19-negative relapse xenograft model, we determined that CART123, but not CART19, recognized leukemic blasts, established protracted synapses, and eradicated CD19-negative leukemia, leading to prolonged survival. Furthermore, combining CART19 and CART123 prevented antigen-loss relapses in xenograft models. Finally, we devised a dual CAR-expressing construct that combined CD19- and CD123-mediated T cell activation and demonstrated that it provides superior in vivo activity against B-ALL compared with single-expressing CART or pooled combination CART. In conclusion, these findings indicate that targeting CD19 and CD123 on leukemic blasts represents an effective strategy for treating and preventing antigen-loss relapses occurring after CD19-directed therapies PMID:27571406

The Impact of Ostomy on Quality of Life and Functional Status of Crohn’s Disease Patients within CCFA Partners

PubMed Central

Abdalla, Maisa I.; Sandler, Robert S.; Kappelman, Michael D.; Martin, Christopher F.; Chen, Wenli; Anton, Kristen; Long, Millie D.

2016-01-01

Background The potential need for an ostomy is a main concern for patients with inflammatory bowel disease. We performed this study to evaluate the impact of a long term ostomy (≥ 6 months duration) on the functional status and specific patient-reported outcomes (PRO) in a population of patients with Crohn’s disease (CD). Methods We performed a cross-sectional analysis within the CCFA Partners cohort Study. Bivariate analyses and logistic regression models were used to investigate associations between ostomy and various demographic, disease factors, and PROs for health related quality of life (HRQOL). Results A total of 402 CD patients with ostomy for a minimum duration of 6 months were compared to 4331 CD patients with no ostomy. Patients with ostomy were more likely to be in clinical remission compared to those without ostomy, 48.5% vs. 31.3%, respectively. Having an ostomy did not impact overall HRQOL and was not associated with anxiety, depression, sleep disturbances, or reduced sexual interest and satisfaction. However, the presence of ostomy was associated with reduced social role satisfaction in patients both with controlled and active disease. Additionally, in the subset of patients who did not achieve clinical remission, those with ostomy experienced greater pain interference (OR 1.63, 95% CI 1.12–2.35) and fatigue (OR 1.66 95% CI 1.15–2.39). Conclusion Ostomy is well-tolerated in CD patients, particularly when clinical remission is achieved. PMID:27661669