CD4/CD8 Ratio and KT Ratio Predict Yellow Fever Vaccine Immunogenicity in HIV-Infected Patients

PubMed Central

Hunt, Peter W.; Huang, Yong; Simoes, Marisol; Lima, Sheila B.; Freire, Marcos S.; Caiaffa-Filho, Helio H.; Hong, Marisa A.; Costa, Dayane Alves; Dias, Juliana Zanatta C.; Cerqueira, Natalia B.; Nishiya, Anna Shoko; Sabino, Ester Cerdeira; Sartori, Ana M.; Kallas, Esper G.

2016-01-01

Background HIV-infected individuals have deficient responses to Yellow Fever vaccine (YFV) and may be at higher risk for adverse events (AE). Chronic immune activation–characterized by low CD4/CD8 ratio or high indoleamine 2,3-dioxygenase-1 (IDO) activity—may influence vaccine response in this population. Methods We prospectively assessed AE, viremia by the YFV virus and YF-specific neutralizing antibodies (NAb) in HIV-infected (CD4>350) and -uninfected adults through 1 year after vaccination. The effect of HIV status on initial antibody response to YFV was measured during the first 3 months following vaccination, while the effect on persistence of antibody response was measured one year following vaccination. We explored CD4/CD8 ratio, IDO activity (plasma kynurenine/tryptophan [KT] ratio) and viremia by Human Pegivirus as potential predictors of NAb response to YFV among HIV-infected participants with linear mixed models. Results 12 HIV-infected and 45-uninfected participants were included in the final analysis. HIV was not significantly associated with AE, YFV viremia or NAb titers through the first 3 months following vaccination. However, HIV–infected participants had 0.32 times the NAb titers observed for HIV-uninfected participants at 1 year following YFV (95% CI 0.13 to 0.83, p = 0.021), independent of sex, age and prior vaccination. In HIV-infected participants, each 10% increase in CD4/CD8 ratio predicted a mean 21% higher post-baseline YFV Nab titer (p = 0.024). Similarly, each 10% increase in KT ratio predicted a mean 21% lower post-baseline YFV Nab titer (p = 0.009). Viremia by Human Pegivirus was not significantly associated with NAb titers. Conclusions HIV infection appears to decrease the durability of NAb responses to YFV, an effect that may be predicted by lower CD4/CD8 ratio or higher KT ratio. PMID:27941965

Distinctive roles of age, sex, and genetics in shaping transcriptional variation of human immune responses to microbial challenges.

PubMed

Piasecka, Barbara; Duffy, Darragh; Urrutia, Alejandra; Quach, Hélène; Patin, Etienne; Posseme, Céline; Bergstedt, Jacob; Charbit, Bruno; Rouilly, Vincent; MacPherson, Cameron R; Hasan, Milena; Albaud, Benoit; Gentien, David; Fellay, Jacques; Albert, Matthew L; Quintana-Murci, Lluis

2018-01-16

The contribution of host genetic and nongenetic factors to immunological differences in humans remains largely undefined. Here, we generated bacterial-, fungal-, and viral-induced immune transcriptional profiles in an age- and sex-balanced cohort of 1,000 healthy individuals and searched for the determinants of immune response variation. We found that age and sex affected the transcriptional response of most immune-related genes, with age effects being more stimulus-specific relative to sex effects, which were largely shared across conditions. Although specific cell populations mediated the effects of age and sex on gene expression, including CD8 + T cells for age and CD4 + T cells and monocytes for sex, we detected a direct effect of these intrinsic factors for the majority of immune genes. The mapping of expression quantitative trait loci (eQTLs) revealed that genetic factors had a stronger effect on immune gene regulation than age and sex, yet they affected a smaller number of genes. Importantly, we identified numerous genetic variants that manifested their regulatory effects exclusively on immune stimulation, including a Candida albicans -specific master regulator at the CR1 locus. These response eQTLs were enriched in disease-associated variants, particularly for autoimmune and inflammatory disorders, indicating that differences in disease risk may result from regulatory variants exerting their effects only in the presence of immune stress. Together, this study quantifies the respective effects of age, sex, genetics, and cellular heterogeneity on the interindividual variability of immune responses and constitutes a valuable resource for further exploration in the context of different infection risks or disease outcomes. Copyright © 2018 the Author(s). Published by PNAS.

IL-6 Production by TLR-Activated APC Broadly Enhances Aged Cognate CD4 Helper and B Cell Antibody Responses In Vivo.

PubMed

Brahmakshatriya, Vinayak; Kuang, Yi; Devarajan, Priyadharshini; Xia, Jingya; Zhang, Wenliang; Vong, Allen Minh; Swain, Susan L

2017-04-01

Naive CD4 T cell responses, especially their ability to help B cell responses, become compromised with aging. We find that using APC pretreated ex vivo with TLR agonists, polyinosinic-polycytidylic acid and CpG, to prime naive CD4 T cells in vivo, restores their ability to expand and become germinal center T follicular helpers and enhances B cell IgG Ab production. Enhanced helper responses are dependent on IL-6 production by the activated APC. Aged naive CD4 T cells respond suboptimally to IL-6 compared with young cells, such that higher doses are required to induce comparable signaling. Preactivating APC overcomes this deficiency. Responses of young CD4 T cells are also enhanced by preactivating APC with similar effects but with only partial IL-6 dependency. Strikingly, introducing just the activated APC into aged mice significantly enhances otherwise compromised Ab production to inactivated influenza vaccine. These findings reveal a central role for the production of IL-6 by APC during initial cognate interactions in the generation of effective CD4 T cell help, which becomes greater with age. Without APC activation, aging CD4 T cell responses shift toward IL-6-independent Th1 and CD4 cytotoxic Th cell responses. Thus, strategies that specifically activate and provide Ag to APC could potentially enhance Ab-mediated protection in vaccine responses. Copyright © 2017 by The American Association of Immunologists, Inc.

Leading causes of injury hospitalisation in children aged 0-4 years in New South Wales by injury submechanism: a brief profile by age and sex.

PubMed

Schmertmann, Marcia; Williamson, Ann; Black, Deborah

2012-11-01

To identify the leading causes of injury in children aged 0-4 years by single year of age using injury submechanisms and present a brief epidemiologic profile of each cause. Hospitalisation data for New South Wales from 1999 to 2009 were used to identify the leading causes of injury for children aged 0-4 years by single year of age. For each leading cause, rates over time and by sex were calculated by single year of age. Associated age and sex risk ratios were estimated. The leading causes of injury for children aged <1, 1 and 2 years were falls while being carried, burns by hot non-aqueous substances and poisoning by other and unspecified pharmaceutical substances, respectively. Falls involving playground equipment ranked first for children aged 3-4 years. Each leading injury cause exhibited an age pattern that remained stable over time and by sex. Age predicted falls while being carried and both age and sex predicted the remaining leading injury causes, with age and sex interacting to predict burns by hot non-aqueous substances. Epidemiologic analysis using single-year age intervals and injury submechanisms results in a clearer picture of injury risk for young children. The findings of this study provide detailed information regarding the leading causes of hospitalised injury in young children by age and sex. Child health-care providers can use this information to focus discussions of child development and injury risk with families of young children and suggest appropriate prevention measures in terms of a child's age and sex. © 2012 The Authors. Journal of Paediatrics and Child Health © 2012 Paediatrics and Child Health Division (Royal Australasian College of Physicians).

Salt preference: age and sex related variability.

PubMed

Verma, Punam; Mittal, Sunita; Ghildiyal, Archana; Chaudhary, Lalita; Mahajan, K K

2007-01-01

Salt preference was assessed in 60 adults of 18-21 yrs of age (30 males and 30 females) and in 60 children of 7-12 yrs of age (30 boys and 30 girls). Subjects rated the preference on Likert scale for popcorns of five salt concentrations (OM, 1M, 2M, 3M and +3M). Statistical analysis using Two way ANOVA revealed statistically significant effect of age and sex on salt preference (F4,100 = 15.027, P < 0.01) and One Way ANOVA revealed statistically significant sex difference in salt preference of adults (F4,50 = 16.26, P < 0.01) but no statistically significant sex difference in salt preference of children (F4,50 = 4.08, P > 0.05). Dietary experiences during development and more physical activity in children may be responsible for higher salt preference in children while finding no sex variability in children favours the role of sex hormones in salt preference of male and females.

CD200 Receptor Controls Sex-Specific TLR7 Responses to Viral Infection

PubMed Central

Raaben, Matthijs; Grinwis, Guy C. M.; Coenjaerts, Frank E.; Ressing, Maaike E.; Rottier, Peter J. M.; de Haan, Cornelis A. M.; Meyaard, Linde

2012-01-01

Immunological checkpoints, such as the inhibitory CD200 receptor (CD200R), play a dual role in balancing the immune system during microbial infection. On the one hand these inhibitory signals prevent excessive immune mediated pathology but on the other hand they may impair clearance of the pathogen. We studied the influence of the inhibitory CD200-CD200R axis on clearance and pathology in two different virus infection models. We find that lack of CD200R signaling strongly enhances type I interferon (IFN) production and viral clearance and improves the outcome of mouse hepatitis corona virus (MHV) infection, particularly in female mice. MHV clearance is known to be dependent on Toll like receptor 7 (TLR7)-mediated type I IFN production and sex differences in TLR7 responses previously have been reported for humans. We therefore hypothesize that CD200R ligation suppresses TLR7 responses and that release of this inhibition enlarges sex differences in TLR7 signaling. This hypothesis is supported by our findings that in vivo administration of synthetic TLR7 ligand leads to enhanced type I IFN production, particularly in female Cd200−/− mice and that CD200R ligation inhibits TLR7 signaling in vitro. In influenza A virus infection we show that viral clearance is determined by sex but not by CD200R signaling. However, absence of CD200R in influenza A virus infection results in enhanced lung neutrophil influx and pathology in females. Thus, CD200-CD200R and sex are host factors that together determine the outcome of viral infection. Our data predict a sex bias in both beneficial and pathological immune responses to virus infection upon therapeutic targeting of CD200-CD200R. PMID:22615569

Role of naturally occurring CD4+ CD25+ regulatory T cells in experimental atherosclerosis.

PubMed

Mor, Adi; Planer, David; Luboshits, Galia; Afek, Arnon; Metzger, Shula; Chajek-Shaul, Tova; Keren, Gad; George, Jacob

2007-04-01

Naturally occurring CD4+ CD25+ regulatory T cells (Tregs) exert suppressive effects on effector CD4 cells and downregulate experimental autoimmune disorders. We investigated the importance and potential role of Tregs in murine atherogenesis. Tregs were investigated comparatively between aged and young apolipoprotein E-knockout (ApoE-KO) mice and age-matched C57BL/6 littermates. The effect of oxidized LDL (oxLDL) was tested on the functional suppressive properties of Tregs from ApoE-KO and C57BL/6 mice. Tregs, CD4+ CD25- cells, and saline were infused into ApoE-KO mice to study their effects on atherogenesis. Treg numbers were reduced in atherosclerotic compared with nonatherosclerotic ApoE-KO mice. The functional suppressive properties of Tregs from ApoE-KO mice were compromised in comparison with those from their C57BL/6 littermates. Thus, oxLDL attenuated the suppressive properties of Tregs from C57BL/6 mice and more so in ApoE-KO mice. Transfer of Tregs from age-matched ApoE-KO mice resulted in significant attenuation of atherosclerosis compared with that after delivery of CD4+ CD25+/- T cells or phosphate-buffered saline. CD4+ CD25+ Tregs may play a protective role in the progression of atherosclerosis and could be considered a therapeutic tool if results from human studies can solidify observations in murine models.

Circulating CD4+CD28null and extra-thymic CD4+CD8+ double positive T cells are independently associated with disease damage in systemic lupus erythematosus patients.

PubMed

Ugarte-Gil, M F; Sánchez-Zúñiga, C; Gamboa-Cárdenas, R V; Aliaga-Zamudio, M; Zevallos, F; Tineo-Pozo, G; Cucho-Venegas, J M; Mosqueira-Riveros, A; Medina, M; Perich-Campos, R A; Alfaro-Lozano, J L; Rodriguez-Bellido, Z; Alarcón, G S; Pastor-Asurza, C A

2016-03-01

To determine whether circulating CD4+CD28null and extra-thymic CD4+CD8+ double positive (DP) T cells are independently associated with damage accrual in systemic lupus erythematosus (SLE) patients. This cross-sectional study was conducted between September 2013 and April 2014 in consecutive SLE patients from our Rheumatology Department. CD4+CD28null and CD4+CD8+ DP T-cell frequencies were analyzed by flow-cytometry. The association of damage (SLICC/ACR Damage Index, SDI) and CD4+CD28null and CD4+CD8+ DP T cells was examined by univariable and multivariable Poisson regression models, adjusting for possible confounders. All analyses were performed using SPSS 21.0. Patients' (n = 133) mean (SD) age at diagnosis was 35.5 (16.8) years, 124 (93.2%) were female; all were mestizo (mixed Caucasian and Amerindian ancestry). Disease duration was 7.4 (6.8) years. The SLE Disease Activity Index was 5.5 (4.2), and the SDI 0.9 (1.2). The percentages of CD4+CD28null and CD4+CD8+ DP T cells were 17.1 (14.4) and 0.4 (1.4), respectively. The percentage of CD4+CD28null and CD4+CD8+ DP T cells were positively associated with a higher SDI in both univariable (rate ratio (RR) 1.02, 95% confidence interval (CI): 1.01-1.03 and 1.17, 95% CI: 1.07-1.27, respectively; p < 0.001 for both) and multivariable analyses RR 1.02, 95% CI: 1.01-1.03, p = 0.001 for CD4+CD28null T cells and 1.28, 95% CI: 1.13-1.44, p < 0.001 for CD4+CD8+ DP T cells). Only the renal domain remained associated with CD4+CD28null in multivariable analyses (RR 1.023 (1.002-1.045); p = 0.034). In SLE patients, CD4+CD28null and CD4+CD8+ DP T cells are independently associated with disease damage. Longitudinal studies are warranted to determine the predictive value of these associations. © The Author(s) 2015.

Increased numbers of FoxP3-expressing CD4+ CD25+ regulatory T cells in peripheral blood from dogs with atopic dermatitis and its correlation with disease severity.

PubMed

Hauck, Verena; Hügli, Patrick; Meli, Marina L; Rostaher, Ana; Fischer, Nina; Hofmann-Lehmann, Regina; Favrot, Claude

2016-02-01

Atopic dermatitis (AD) is a common chronic inflammatory skin disease of humans and dogs. Regulatory T cells (Tregs) are essential controllers of immune homeostasis and have been shown to play a key role in human AD, even though frequencies of Tregs in atopic human patients vary greatly. Only two studies have reported Treg numbers in the peripheral blood of dogs with canine AD (CAD). This study aimed to assess the numbers of circulating Tregs in healthy and atopic dogs, and to determine whether Treg numbers correlate with age, sex, disease severity or pre-treatment. Client-owned dogs including 14 healthy dogs and 35 dogs with CAD. Expression of Tregs in peripheral blood mononuclear cells was evaluated by flow cytometry. Tregs were phenotypically identified as T cells triple positive for CD4, CD25 and FoxP3. The percentage of circulating CD4(+)  CD25(+)  FoxP3(+) Tregs in atopic dogs was increased significantly compared to healthy dogs (mean 2.1% versus 1%, P = 0.002) and correlated with disease severity (Pruritus Scale: r = 0.48, P = 0.003; CADESI-04: r = 0.34, P = 0.044). No significant differences in age or sex were found in either group and pre-treatment had no influence on results for atopic dogs. Data suggest that, as in humans, CD4(+)  CD25(+)  FoxP3(+) Tregs may contribute to the pathogenesis of CAD as indicated by an association between Treg frequency and disease severity. Further investigation is required to improve the understanding of the role of Tregs in atopic dogs. © 2015 ESVD and ACVD.

Role of ZnO photoanode nanostructures and sensitizer deposition approaches on the photovoltaic properties of CdS/CdSe and CdS1-xSex quantum dot-sensitized solar cells

NASA Astrophysics Data System (ADS)

Şişman, İlkay; Tekir, Oktay; Karaca, Hüseyin

2017-02-01

Hierarchical bundle-like ZnO nanorod arrays (BNRs) were synthesized by a one-pot hydrothermal method based on two consecutive temperature steps for cascade CdS/CdSe and ternary CdS1-xSex alloy quantum dot-sensitized solar cells (QDSSCs) as photoanode. The CdS/CdSe and CdS1-xSex QDs were deposited on the surface of the ZnO BNRs by conventional and modified successive ionic-layer adsorption and reaction (SILAR) methods, respectively. Using the ZnO BNRs/CdS/CdSe photoanode, the power conversion efficiency reaches 2.08%, which is 1.8 times higher than that of pristine ZnO nanorods/CdS/CdSe photoanode, while by applying ZnO BNRs/CdS1-xSex, the power conversion efficiency improves 2.52%. The remarkably improved photovoltaic performance is mainly derived from the bundle-like nanorod arrays structure, which increases the QDs loading amount and the scattering effect for light absorption, and the appropriate conduction band energy, sufficient Se amount and well coverage of the ternary CdS1-xSex QDs result in enhanced photogenerated electron injection, high light absorption and reduced recombination, respectively. As a result, ZnO BNRs/CdS1-xSex combination can significantly improve performance of QDSSCs.

T lymphocytes among HIV-infected and -uninfected infants: CD4/CD8 ratio as a potential tool in diagnosis of infection in infants under the age of 2 years.

PubMed

Zijenah, Lynn S; Katzenstein, David A; Nathoo, Kusum J; Rusakaniko, Simbarashe; Tobaiwa, Ocean; Gwanzura, Christine; Bikoue, Arsene; Nhembe, Margaret; Matibe, Petronella; Janossy, George

2005-02-01

BACKGROUND: Serologic tests for HIV infection in infants less than 18 months do not differentiate exposure and infection since maternally acquired IgG antibodies may be detected in infants. Thus, the gold standard for diagnosis of HIV-1 infection in infants under the age of 2 years is DNA or reverse transcriptase polymerase chain reaction. There is an urgent need to evaluate alternative and cost effective laboratory methods for early diagnosis of infant HIV-1 infection as well as identifying infected infants who may benefit from cotrimoxazole prophylaxis and/or initiation of highly active antiretroviral therapy. METHODS: Whole blood was collected in EDTA from 137 infants aged 0 to 18 months. DNA polymerase chain reaction was used as the reference standard for diagnosis of HIV-1 infection. T-cell subset profiles were determined by flow cytometry. RESULTS: Seventy-six infants were DNA PCR positive while 61 were negative. The median CD4 counts of PCR negative infants were significantly higher than those of the PCR positive infants, p < 0.001. The median CD4/CD8 ratio and the %CD4 of the PCR positive infants were both significantly lower than those of the negative infants, p < 0.001. The CD4/CD8 ratio had a >98% sensitivity for diagnosis of HIV-1 infection and a specificity of >98%. CONCLUSION: The CD4/CD8 ratio appears useful in identifying HIV-infected infants. The development of lower cost and more robust flow cytometric methods that provide both CD4/CD8 ratio and %CD4 may be cost-effective for HIV-1 diagnosis and identification of infants for cotrimoxazole prophylaxis and/or highly active antiretroviral therapy.

T lymphocytes among HIV-infected and -uninfected infants: CD4/CD8 ratio as a potential tool in diagnosis of infection in infants under the age of 2 years

PubMed Central

Zijenah, Lynn S; Katzenstein, David A; Nathoo, Kusum J; Rusakaniko, Simbarashe; Tobaiwa, Ocean; Gwanzura, Christine; Bikoue, Arsene; Nhembe, Margaret; Matibe, Petronella; Janossy, George

2005-01-01

Background Serologic tests for HIV infection in infants less than 18 months do not differentiate exposure and infection since maternally acquired IgG antibodies may be detected in infants. Thus, the gold standard for diagnosis of HIV-1 infection in infants under the age of 2 years is DNA or reverse transcriptase polymerase chain reaction. There is an urgent need to evaluate alternative and cost effective laboratory methods for early diagnosis of infant HIV-1 infection as well as identifying infected infants who may benefit from cotrimoxazole prophylaxis and/or initiation of highly active antiretroviral therapy. Methods Whole blood was collected in EDTA from 137 infants aged 0 to 18 months. DNA polymerase chain reaction was used as the reference standard for diagnosis of HIV-1 infection. T-cell subset profiles were determined by flow cytometry. Results Seventy-six infants were DNA PCR positive while 61 were negative. The median CD4 counts of PCR negative infants were significantly higher than those of the PCR positive infants, p < 0.001. The median CD4/CD8 ratio and the %CD4 of the PCR positive infants were both significantly lower than those of the negative infants, p < 0.001. The CD4/CD8 ratio had a >98% sensitivity for diagnosis of HIV-1 infection and a specificity of >98%. Conclusion The CD4/CD8 ratio appears useful in identifying HIV-infected infants. The development of lower cost and more robust flow cytometric methods that provide both CD4/CD8 ratio and %CD4 may be cost-effective for HIV-1 diagnosis and identification of infants for cotrimoxazole prophylaxis and/or highly active antiretroviral therapy. PMID:15683549

Changes in CD4 count among persons living with HIV/AIDS following Hurricane Katrina.

PubMed

Robinson, William T; Wendell, Deborah; Gruber, DeAnn

2011-07-01

To examine the effects of Hurricane Katrina on the disease progression of persons living with HIV/AIDS (PLWH/A), CD4 counts during the 18 months immediately prior and subsequent to Katrina were obtained from the Louisiana Office of Public Health. PLWH/A were determined to be either non-residents of the New Orleans area, returning evacuees or evacuees who had returned to the area within 18 months. A mixed model repeated measures ANOVA showed significant effects for race, sex, age, year of diagnosis, and mode of exposure. A significant main effect for residence was found, as well as an interaction of residence by time of CD4 count (pre-Katrina vs. post-Katrina), indicating that, while non-returning evacuees had lower overall CD4 counts, the change in CD4 counts of non-returning evacuees dropped more sharply than those of the returning PLWH/A or non-residents. While these results point to a potential need for the population of PLWH/A who continue to be affected by Katrina, they also provide important data on the effect that large-scale disasters and stressful life events may have on individuals with chronic disease.

CD137 ligand reverse signaling skews hematopoiesis towards myelopoiesis during aging.

PubMed

Tang, Qianqiao; Koh, Liang Kai; Jiang, Dongsheng; Schwarz, Herbert

2013-09-01

CD137 is a costimulatory molecule expressed on activated T cells. Its ligand, CD137L, is expressed on the surface of hematopoietic progenitor cells, and upon binding to CD137 induces reverse signaling into hematopoietic progenitor cells promoting their activation, proliferation and myeloid differentiation. Since aging is associated with an increasing number of myeloid cells we investigated the role of CD137 and CD137L on myelopoiesis during aging. Comparing 3 and 12 months old WT, CD137‐/‐ and CD137L‐/‐ mice we found significantly more granulocytes and monocytes in the bone marrow of older WT mice, while this age‐dependent increase was absent in CD137‐/‐ and CD137L‐/‐ mice. Instead, the bone marrow of 12 months old CD137‐/‐ and CD137L‐/‐ mice was characterized by an accumulation of hematopoietic progenitor cells, suggesting that the differentiation of hematopoietic progenitor cells became arrested in the absence of CD137L signaling. CD137L signaling is initiated by activated CD137‐expressing, CD4+ T cells. These data identify a novel molecular mechanisms underlying immune aging by demonstrating that CD137‐expressing CD4+ T cells in the bone marrow engage CD137L on hematopoietic progenitor cells, and that this CD137L signaling biases hematopoiesis towards myelopoiesis during aging.

Correlation of mucocutaneous manifestations of HIV-infected patients in an ART center with CD4 counts.

PubMed

Lahoti, Sonal; Rao, Kavita; Umadevi, H S; Mishra, Lakshmi

2017-01-01

As the search for reliable clinical indicators for management of human immunodeficiency virus/AIDS continues, mucocutaneous manifestations of HIV are considered among key clinical indicators for prediction of underlying degree of immunosuppression, systemic opportunistic infections, and disease progression. (1) To study the prevalence of mucocutaneous manifestations in HIV-seropositive patients attending the ART center of our hospital (2) To correlate mucocutaneous manifestations with CD4 cell counts. A total of 200 HIV-seropositive patients of adult age group visiting our hospital were included in the study. Information on demographics such as age, sex, transmission route, socioeconomic status, educational status, CD4 counts, and mucocutaneous findings was collected through interview administered survey and case records followed by oral and cutaneous examination. Mean CD4 cell count of asymptomatic HIV/AIDS patients was 580.96 cells/mm3. In comparison with the CD4 cell count of asymptomatic HIV-positive patients, (mean 580.96 cells/mm3) CD4 cell count of HIV-positive patients with various mucocutaneous manifestations (mean 409.65 cells/mm3) was correlated using student t-test and was statistically significant (P = 0.017). This study revealed maximum mucocutaneous lesions in the CD4 count range of 200-500. Nail changes accounted for the most common cutaneous manifestation with 53%, and pigmentation accounted for the most common oral manifestation with 39%. Mucocutaneous manifestations can arouse one to suspect the diagnosis of HIV infection in an otherwise healthy unwary patient. They can serve as a dependable marker of HIV disease.

Manual control age and sex differences in 4 to 11 year old children.

PubMed

Flatters, Ian; Hill, Liam J B; Williams, Justin H G; Barber, Sally E; Mon-Williams, Mark

2014-01-01

To what degree does being male or female influence the development of manual skills in pre-pubescent children? This question is important because of the emphasis placed on developing important new manual skills during this period of a child's education (e.g. writing, drawing, using computers). We investigated age and sex-differences in the ability of 422 children to control a handheld stylus. A task battery deployed using tablet PC technology presented interactive visual targets on a computer screen whilst simultaneously recording participant's objective kinematic responses, via their interactions with the on-screen stimuli using the handheld stylus. The battery required children use the stylus to: (i) make a series of aiming movements, (ii) trace a series of abstract shapes and (iii) track a moving object. The tasks were not familiar to the children, allowing measurement of a general ability that might be meaningfully labelled 'manual control', whilst minimising culturally determined differences in experience (as much as possible). A reliable interaction between sex and age was found on the aiming task, with girls' movement times being faster than boys in younger age groups (e.g. 4-5 years) but with this pattern reversing in older children (10-11 years). The improved performance in older boys on the aiming task is consistent with prior evidence of a male advantage for gross-motor aiming tasks, which begins to emerge during adolescence. A small but reliable sex difference was found in tracing skill, with girls showing a slightly higher level of performance than boys irrespective of age. There were no reliable sex differences between boys and girls on the tracking task. Overall, the findings suggest that prepubescent girls are more likely to have superior manual control abilities for performing novel tasks. However, these small population differences do not suggest that the sexes require different educational support whilst developing their manual skills.

Investigation of associations of ARMS2, CD14, and TLR4 gene polymorphisms with wet age-related macular degeneration in a Greek population

PubMed Central

Sarli, Antonia; Skalidakis, Iosif; Velissari, Aliki; Koutsandrea, Chryssanthi; Stefaniotou, Maria; Petersen, Michael B; Kroupis, Christos; Kitsos, George; Moschos, Marilita M

2017-01-01

Background Age-related macular degeneration (AMD) is a multifactorial degenerative ocular disease that leads to loss of central vision. Functional gene polymorphisms have already been associated with the disease (for example, ARMS2 A69S, rs10490924). Aim The goal of our study was to verify the correlation of the aforementioned ARMS2 variation with the disease, to examine, for the first time, the role of the CD14 C260T variation (rs2569190), and to investigate the association of two TLR4 polymorphisms (Asp299Gly or rs4986790 and Thr399Ile or rs4986791) in a Greek population with the wet form of AMD. Patients and methods Genomic DNAs were isolated from blood samples of 103 healthy controls and 120 Greek patients with wet AMD who were age- and sex-matched, and all of whom were clinically evaluated. For the genotyping of all selected polymorphisms, polymerase chain reaction–restriction fragment length polymorphism analysis was performed. Results and conclusions This study confirmed the association between the ARMS2 variation and AMD, detecting the T risk allele in a significantly higher frequency in the patient group, compared with the control subjects (45% vs 29.13%, P<0.001, odds ratio [OR] 1.99, confidence interval 1.34–2.95). For the CD14 polymorphism, no statistically significant correlation was observed. As for the TLR4 polymorphisms, the percentage of heterozygotes increased from 2.9% to 11.7% in the patient population for Asp299Gly and from 1.9% to 10% for the Thr399Ile polymorphism (ORs 4.40 [P=0.01] and 5.61 [P=0.0088], respectively). Although our ARMS2 and CD14 results provided definite conclusions, the role of innate immunity TLR4 gene awaits further investigation in larger AMD populations with more clinical data collected on past microbial infections. PMID:28794612

Ageing & long-term CD4 cell count trends in HIV-positive patients with 5 years or more combination antiretroviral therapy experience

PubMed Central

WRIGHT, ST; PETOUMENOS, K; BOYD, M; CARR, A; DOWNING, S; O’CONNOR, CC; GROTOWSKI, M; LAW, MG

2012-01-01

Background The aim of this analysis is to describe the long-term changes in CD4 cell counts beyond 5 years of combination antiretroviral therapy (cART). If natural ageing leads to a long-term decline in the immune system via low-grade chronic immune activation/inflammation, then one might expect to see a greater or earlier decline in CD4 counts in older HIV-positive patients with increasing duration of cART. Methods Retrospective and prospective data were examined from long-term virologically stable HIV-positive adults from the Australian HIV Observational Database. We estimated mean CD4 cell counts changes following the completion of 5 years of cART using linear mixed models. Results A total of 37,916 CD4 measurements were observed for 892 patients over a combined total of 9,753 patient years. Older patients (>50 years) at cART initiation had estimated mean(95% confidence interval) change in CD4 counts by Year-5 CD4 count strata (<500, 501–750 and >750 cells/μL) of 14(7 to 21), 3(−5 to 11) and −6(−17 to 4) cells/μL/year. Of the CD4 cell count rates of change estimated, none were indicative of long-term declines in CD4 cell counts. Conclusions Our results suggest that duration of cART and increasing age does not result in decreasing mean changes in CD4 cell counts for long-term virologically suppressed patients. Indicating that level of immune recovery achieved during the first 5 years of treatment are sustained through long-term cART. PMID:23036045

Determining age and sex of American coots

USGS Publications Warehouse

Eddleman, William R.; Knopf, Fritz L.

1985-01-01

Reliable techniques for age and sex determination of migrating and wintering American Coots (Fulica americana) have not been available. Breeding coots can be ages through age 3 by tarsal color (birds 4 years and older were placed in a 4+ age class) (Crawford 1978), and males and females have sex-specific behaviors and calls while on breeding territories (Gullion 1950, 1952). Externally, juvenile coots differ from adults in having gray (as opposed to white) bills and brown (as opposed to red) eyes to an age of 75 days (Gullion 1954-394). Bill color changes to white by about 120 days. No quantitative data have been available, however, on the proportion of juveniles retaining these traits throughout fall and early winter. Nonbreeding coots can be ages as juvenile or adult by internal examination of the thickness of the wall of the bursa of Fabricius, although bursal depth does not predictably decline with age (Fredrickson 1968). Attempts to sex coots by single external measurements of combinations of measurements have met with mixed success. Eight-five percent of 101 fall migrants in Wisconsin could be sexed by the length of the metatarsus-midtoe including claw by using 139.5 mm as a cutoff point (Burton 1959), whereas 88% of 67 coots in California were correctly sexed by the length of the metatarsus-midtoe without claw using 127.5 mm as the cutoff point (Gullion 1952). Two-hundred-thirty-two of 291 coots collected in Iowa, however, were in the zone of overlap between the sexes for this measurement (Fredrickson 1968). Previous studies attempting to develop aging and sexing techniques for American Coots have been limited to a few study sites or to 1 season or year, often failing to take geographical, annual, and seasonal morphological variation into account (e.g., Visser 1976, Fjeldsa 1977). We designed the present study to refine and quantify external and internal age and sex criteria for postbreeding coots, with the objective of defining techniques applicable for all

Impact on life expectancy of HIV-1 positive individuals of CD4+ cell count and viral load response to antiretroviral therapy

PubMed Central

May, Margaret T.; Gompels, Mark; Delpech, Valerie; Porter, Kholoud; Orkin, Chloe; Kegg, Stephen; Hay, Phillip; Johnson, Margaret; Palfreeman, Adrian; Gilson, Richard; Chadwick, David; Martin, Fabiola; Hill, Teresa; Walsh, John; Post, Frank; Fisher, Martin; Ainsworth, Jonathan; Jose, Sophie; Leen, Clifford; Nelson, Mark; Anderson, Jane; Sabin, Caroline

2014-01-01

Objective: The objective of this study is to estimate life expectancies of HIV-positive patients conditional on response to antiretroviral therapy (ART). Methods: Patients aged more than 20 years who started ART during 2000–2010 (excluding IDU) in HIV clinics contributing to the UK CHIC Study were followed for mortality until 2012. We determined the latest CD4+ cell count and viral load before ART and in each of years 1–5 of ART. For each duration of ART, life tables based on estimated mortality rates by sex, age, latest CD4+ cell count and viral suppression (HIV-1 RNA <400 copies/ml), were used to estimate expected age at death for ages 20–85 years. Results: Of 21 388 patients who started ART, 961 (4.5%) died during 110 697 person-years. At start of ART, expected age at death [95% confidence interval (CI)] of 35-year-old men with CD4+ cell count less than 200, 200–349, at least 350 cells/μl was 71 (68–73), 78 (74–82) and 77 (72–81) years, respectively, compared with 78 years for men in the general UK population. Thirty-five-year-old men who increased their CD4+ cell count in the first year of ART from less than 200 to 200–349 or at least 350 cells/μl and achieved viral suppression gained 7 and 10 years, respectively. After 5 years on ART, expected age at death of 35-year-old men varied from 54 (48–61) (CD4+ cell count <200 cells/μl and no viral suppression) to 80 (76–83) years (CD4+ cell count ≥350 cells/μl and viral suppression). Conclusion: Successfully treated HIV-positive individuals have a normal life expectancy. Patients who started ART with a low CD4+ cell count significantly improve their life expectancy if they have a good CD4+ cell count response and undetectable viral load. PMID:24556869

Long terms trends in CD4+ cell counts, CD8+ cell counts, and the CD4+ : CD8+ ratio

PubMed Central

Hughes, Rachael A.; May, Margaret T.; Tilling, Kate; Taylor, Ninon; Wittkop, Linda; Reiss, Peter; Gill, John; Schommers, Philipp; Costagliola, Dominique; Guest, Jodie L.; Lima, Viviane D.; d’Arminio Monforte, Antonella; Smith, Colette; Cavassini, Matthias; Saag, Michael; Castilho, Jessica L.; Sterne, Jonathan A.C.

2018-01-01

Objective: Model trajectories of CD4+ and CD8+ cell counts after starting combination antiretroviral therapy (ART) and use the model to predict trends in these counts and the CD4+ : CD8+ ratio. Design: Cohort study of antiretroviral-naïve HIV-positive adults who started ART after 1997 (ART Cohort Collaboration) with more than 6 months of follow-up data. Methods: We jointly estimated CD4+ and CD8+ cell count trends and their correlation using a bivariate random effects model, with linear splines describing their population trends, and predicted the CD4+ : CD8+ ratio trend from this model. We assessed whether CD4+ and CD8+ cell count trends and the CD4+ : CD8+ ratio trend varied according to CD4+ cell count at start of ART (baseline), and, whether these trends differed in patients with and without virological failure more than 6 months after starting ART. Results: A total of 39 979 patients were included (median follow-up was 53 months). Among patients with baseline CD4+ cell count at least 50 cells/μl, predicted mean CD8+ cell counts continued to decrease between 3 and 15 years post-ART, partly driving increases in the predicted mean CD4+ : CD8+ ratio. During 15 years of follow-up, normalization of the predicted mean CD4+ : CD8+ ratio (to >1) was only observed among patients with baseline CD4+ cell count at least 200 cells/μl. A higher baseline CD4+ cell count predicted a shorter time to normalization. Conclusion: Declines in CD8+ cell count and increases in CD4+ : CD8+ ratio occurred up to 15 years after starting ART. The likelihood of normalization of the CD4+ : CD8+ ratio is strongly related to baseline CD4+ cell count. PMID:29851663

NADPH oxidase deficiency underlies dysfunction of aged CD8+ Tregs

PubMed Central

Wen, Zhenke; Shimojima, Yasuhiro; Shirai, Tsuyoshi; Li, Yinyin; Ju, Jihang; Yang, Zhen; Tian, Lu; Goronzy, Jörg J.

2016-01-01

Immune aging results in progressive loss of both protective immunity and T cell–mediated suppression, thereby conferring susceptibility to a combination of immunodeficiency and chronic inflammatory disease. Here, we determined that older individuals fail to generate immunosuppressive CD8+CCR7+ Tregs, a defect that is even more pronounced in the age-related vasculitic syndrome giant cell arteritis. In young, healthy individuals, CD8+CCR7+ Tregs are localized in T cell zones of secondary lymphoid organs, suppress activation and expansion of CD4 T cells by inhibiting the phosphorylation of membrane-proximal signaling molecules, and effectively inhibit proliferative expansion of CD4 T cells in vitro and in vivo. We identified deficiency of NADPH oxidase 2 (NOX2) as the molecular underpinning of CD8 Treg failure in the older individuals and in patients with giant cell arteritis. CD8 Tregs suppress by releasing exosomes that carry preassembled NOX2 membrane clusters and are taken up by CD4 T cells. Overexpression of NOX2 in aged CD8 Tregs promptly restored suppressive function. Together, our data support NOX2 as a critical component of the suppressive machinery of CD8 Tregs and suggest that repairing NOX2 deficiency in these cells may protect older individuals from tissue-destructive inflammatory disease, such as large-vessel vasculitis. PMID:27088800

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

Normal CD4 Count Range among Healthy Nigerian Population in Ilorin.

PubMed

Afolabi, J K; Fadeyi, A; Desalu, O O; Durotoye, I A; Fawibe, A E; Adeboye, M A N; Olawumi, H O; Babatunde, A S; Ernest, S K; Aderibigbe, S A; Saadu, R; Salami, A K; Aboyeji, A P

For the establishment and monitoring of the immune status, CD4 count is critical. To determine the CD4 count range of apparently healthy Nigerians resident in Ilorin and compare with the national value. An automated blood analyzer was used to determine the full blood count and CD4 count. The percentage of CD4 count was derived by using other variables. Of the 1205 participants, the reference CD4 count (percentage of CD4) range for adult was 400 to 1288 cells/mm 3 (19%-48%) and for children was 582 to 3652 cells/mm 3 (17%-50%). CD4 count and percentage of CD4 were significantly ( P = .001) higher in females than in males, and the CD4 count declined significantly with increasing age ( r = -.174, P ≤ .0001). The percentage of CD4 count shows less variation with age ( r = -.051, P = .076). Adult residents of Ilorin had significantly lower absolute mean CD4 count (808 ± 260) than that of the national reference values of 847.0 ± 307.0 cells/mm 3 ( P = .001). We therefore advocate the use of CD4 count range derived in this study is lower than that of the national reference values.

Manual Control Age and Sex Differences in 4 to 11 Year Old Children

PubMed Central

Flatters, Ian; Hill, Liam J. B.; Williams, Justin H. G.; Barber, Sally E.; Mon-Williams, Mark

2014-01-01

To what degree does being male or female influence the development of manual skills in pre-pubescent children? This question is important because of the emphasis placed on developing important new manual skills during this period of a child's education (e.g. writing, drawing, using computers). We investigated age and sex-differences in the ability of 422 children to control a handheld stylus. A task battery deployed using tablet PC technology presented interactive visual targets on a computer screen whilst simultaneously recording participant's objective kinematic responses, via their interactions with the on-screen stimuli using the handheld stylus. The battery required children use the stylus to: (i) make a series of aiming movements, (ii) trace a series of abstract shapes and (iii) track a moving object. The tasks were not familiar to the children, allowing measurement of a general ability that might be meaningfully labelled ‘manual control’, whilst minimising culturally determined differences in experience (as much as possible). A reliable interaction between sex and age was found on the aiming task, with girls' movement times being faster than boys in younger age groups (e.g. 4–5 years) but with this pattern reversing in older children (10–11 years). The improved performance in older boys on the aiming task is consistent with prior evidence of a male advantage for gross-motor aiming tasks, which begins to emerge during adolescence. A small but reliable sex difference was found in tracing skill, with girls showing a slightly higher level of performance than boys irrespective of age. There were no reliable sex differences between boys and girls on the tracking task. Overall, the findings suggest that prepubescent girls are more likely to have superior manual control abilities for performing novel tasks. However, these small population differences do not suggest that the sexes require different educational support whilst developing their manual skills

The effect of age, sex and obesity on fundamental motor skills among 4 to 6 years-old children.

PubMed

Vameghi, Roshanak; Shams, Amir; Shamsipour Dehkordi, Parvane

2013-04-01

To examine the effect of age, sex and obesity on Fundamental Motor Skills (FMS) in 4 to 6 years-old children. A total of 400 preschool children (200 boys and 200 girls) between the ages of 4 to 6 years old participated in this research. Subjects were selected through multi-stage cluster random sampling. Fundamental motor skills (FMS) were assessed with using the OSU-SIGMA scale. Body mass index (BMI) was directly measured from height(m)(2)/weight(kg) for each child and based on CDC growth charts, normal weight, overweight and obesity were defined. The results showed that age and sex variables were a significant effect on walking and running skills, but BMI was not significant (P>0.05). Also, these variables had a significant effect on jumping, skipping, hopping and ladder climbing. In both ages, boys in jumping and ladder climbing skills were better than girls, but the girls were better in skipping and hopping skills (P<0.05). Moreover, the results showed that age and BMI variables have a significant effect on stair climbing skill, but sex was not significant (P>0.05). For object control skills, the results showed that age and sex variables were a significant effect on catching and throwing skills, but BMI was not significant (P>0.05). Finally, the age, sex and BMI variables were a significant effect on kicking and sticking skills. This research demonstrated that boys performed better than girls, and both overweight and obese children have lower performance than normal children.

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.

CD4+CD25+ T-Cells Control Autoimmunity in the Absence of B-Cells

PubMed Central

Mariño, Eliana; Villanueva, Jeanette; Walters, Stacey; Liuwantara, David; Mackay, Fabienne; Grey, Shane T.

2009-01-01

OBJECTIVE Tumor necrosis factor ligand family members B-cell–activating factor (BAFF) and a proliferation-inducing ligand (APRIL) can exert powerful effects on B-cell activation and development, type 1 T-helper cell (Th1) immune responses, and autoimmunity. We examined the effect of blocking BAFF and APRIL on the development of autoimmune diabetes. RESEARCH DESIGN AND METHODS Female NOD mice were administered B-cell maturation antigen (BCMA)-Fc from 9 to 15 weeks of age. Diabetes incidence, islet pathology, and T- and B-cell populations were examined. RESULTS BCMA-Fc treatment reduced the severity of insulitis and prevented diabetes development in NOD mice. BCMA-Fc–treated mice showed reduced follicular, marginal-zone, and T2MZ B-cells. B-cell reduction was accompanied by decreased frequencies of pathogenic CD4+CD40+ T-cells and reduced Th1 cytokines IL-7, IL-15, and IL-17. Thus, T-cell activation was blunted with reduced B-cells. However, BCMA-Fc–treated mice still harbored detectable diabetogenic T-cells, suggesting that regulatory mechanisms contributed to diabetes prevention. Indeed, BCMA-Fc–treated mice accumulated increased CD4+CD25+ regulatory T-cells (Tregs) with age. CD4+CD25+ cells were essential for maintaining euglycemia because their depletion abrogated BCMA-Fc–mediated protection. BCMA-Fc did not directly affect Treg homeostasis given that CD4+CD25+Foxp3+ T-cells did not express TACI or BR3 receptors and that CD4+CD25+Foxp3+ T-cell frequencies were equivalent in wild-type, BAFF−/−, TACI−/−, BCMA−/−, and BR3−/− mice. Rather, B-cell depletion resulted in CD4+CD25+ T-cell–mediated protection from diabetes because anti-CD25 monoclonal antibody treatment precipitated diabetes in both diabetes-resistant NOD.μMT−/− and BCMA-Fc–treated mice. CONCLUSIONS BAFF/APRIL blockade prevents diabetes. BCMA-Fc reduces B-cells, subsequently blunting autoimmune activity and allowing endogenous regulatory mechanisms to preserve a

Apolipoprotein E4 Causes Age- and Sex-Dependent Impairments of Hilar GABAergic Interneurons and Learning and Memory Deficits in Mice

PubMed Central

Leung, Laura; Andrews-Zwilling, Yaisa; Yoon, Seo Yeon; Jain, Sachi; Ring, Karen; Dai, Jessica; Wang, Max Mu; Tong, Leslie; Walker, David; Huang, Yadong

2012-01-01

Apolipoprotein (apo) E4 is the major genetic risk factor for Alzheimer's disease (AD). ApoE4 has sex-dependent effects, whereby the risk of developing AD is higher in apoE4-expressing females than males. However, the mechanism underlying the sex difference, in relation to apoE4, is unknown. Previous findings indicate that apoE4 causes age-dependent impairments of hilar GABAergic interneurons in female mice, leading to learning and memory deficits. Here, we investigate whether the detrimental effects of apoE4 on hilar GABAergic interneurons are sex-dependent using apoE knock-in (KI) mice across different ages. We found that in female apoE-KI mice, there was an age-dependent depletion of hilar GABAergic interneurons, whereby GAD67- or somatostatin-positive–but not NPY- or parvalbumin-positive–interneuron loss was exacerbated by apoE4. Loss of these neuronal populations was correlated with the severity of spatial learning deficits at 16 months of age in female apoE4-KI mice; however, this effect was not observed in female apoE3-KI mice. In contrast, we found an increase in the numbers of hilar GABAergic interneurons with advancing age in male apoE-KI mice, regardless of apoE genotype. Moreover, male apoE-KI mice showed a consistent ratio of hilar inhibitory GABAergic interneurons to excitatory mossy cells approximating 1.5 that is independent of apoE genotype and age, whereas female apoE-KI mice exhibited an age-dependent decrease in this ratio, which was exacerbated by apoE4. Interestingly, there are no apoE genotype effects on GABAergic interneurons in the CA1 and CA3 subregions of the hippocampus as well as the entorhinal and auditory cortexes. These findings suggest that the sex-dependent effects of apoE4 on developing AD is in part attributable to inherent sex-based differences in the numbers of hilar GABAergic interneurons, which is further modulated by apoE genotype. PMID:23300939

Ageing and long-term CD4 cell count trends in HIV-positive patients with 5 years or more combination antiretroviral therapy experience.

PubMed

Wright, S T; Petoumenos, K; Boyd, M; Carr, A; Downing, S; O'Connor, C C; Grotowski, M; Law, M G

2013-04-01

The aim of this study was to describe the long-term changes in CD4 cell counts beyond 5 years of combination antiretroviral therapy (cART). If natural ageing leads to a long-term decline in the immune system via low-grade chronic immune activation/inflammation, then one might expect to see a greater or earlier decline in CD4 counts in older HIV-positive patients with increasing duration of cART. Retrospective and prospective data were examined from long-term virologically stable HIV-positive adults from the Australian HIV Observational Database. We estimated mean CD4 cell count changes following the completion of 5 years of cART using linear mixed models. A total of 37 916 CD4 measurements were observed for 892 patients over a combined total of 9753 patient-years. Older patients (> 50 years old) at cART initiation had estimated mean (95% confidence interval) changes in CD4 counts by year-5 CD4 count strata (< 500, 500-750 and > 750 cells/μL) of 14 (7 to 21), 3 (-5 to 11) and -6 (-17 to 4) cells/μL/year. Of the CD4 cell count rates of change estimated, none were indicative of long-term declines in CD4 cell counts. Our results suggest that duration of cART and increasing age do not result in decreasing mean changes in CD4 cell counts for long-term virologically suppressed patients, indicating that the level of immune recovery achieved during the first 5 years of treatment is sustained through long-term cART. © 2012 British HIV Association.

Novel teleost CD4-bearing cell populations provide insights into the evolutionary origins and primordial roles of CD4+ lymphocytes and CD4+ macrophages

PubMed Central

Takizawa, Fumio; Magadan, Susana; Parra, David; Xu, Zhen; Korytář, Tomáš; Boudinot, Pierre; Sunyer, J. Oriol

2016-01-01

Tetrapods contain a single CD4 co-receptor with four immunoglobulin domains that likely arose from a primordial two-domain ancestor. Notably, teleost fish contain two CD4 genes. Like tetrapod CD4, CD4-1 of rainbow trout includes four immunoglobulin domains while CD4-2 contains only two. Since CD4-2 is reminiscent of the prototypic two-domain CD4 co-receptor, we hypothesized that by characterizing the cell types bearing CD4-1 and CD4-2, we would shed light into the evolution and primordial roles of CD4-bearing cells. Using newly established monoclonal antibodies against CD4-1 and CD4-2, we identified two bona fide CD4+ T-cell populations, a predominant lymphocyte population co-expressing surface CD4-1 and CD4-2 (CD4 DP), and a minor subset expressing only CD4-2 (CD4-2 SP). While both subsets produced equivalent levels of Th1, Th17, and Treg cytokines upon bacterial infection, CD4-2 SP lymphocytes were less proliferative and displayed a more restricted TCRβ repertoire. These data suggest that CD4-2 SP cells represent a functionally distinct population and may embody a vestigial CD4+ T cell subset, the roles of which reflect those of primeval CD4+ T cells. Importantly, we also describe the first CD4+ monocyte/macrophage population in a non-mammalian species. Of all myeloid subsets, we found the CD4+ population to be the most phagocytic, while CD4+ lymphocytes lacked this capacity. This study fills in an important gap in the knowledge of teleost CD4-bearing leukocytes thus revealing critical insights into the evolutionary origins and primordial roles of CD4+ lymphocytes and CD4+ monocyte/macrophages. PMID:27183628

Sex Differences in Antiretroviral Therapy Initiation in Pediatric HIV Infection

PubMed Central

Swordy, Alice; Mori, Luisa; Laker, Leana; Muenchhoff, Maximilian; Matthews, Philippa C.; Tudor-Williams, Gareth; Lavandier, Nora; van Zyl, Anriette; Hurst, Jacob; Walker, Bruce D.; Ndung’u, Thumbi; Prendergast, Andrew; Goulder, Philip; Jooste, Pieter

2015-01-01

The incidence and severity of infections in childhood is typically greater in males. The basis for these observed sex differences is not well understood, and potentially may facilitate novel approaches to reducing disease from a range of conditions. We here investigated sex differences in HIV-infected children in relation to antiretroviral therapy (ART) initiation and post-treatment outcome. In a South African cohort of 2,101 HIV-infected children, we observed that absolute CD4+ count and CD4% were significantly higher in ART-naïve female, compared to age-matched male, HIV-infected children. Absolute CD4 count and CD4% were also significantly higher in HIV-uninfected female versus male neonates. We next showed that significantly more male than female children were initiated on ART (47% female); and children not meeting criteria to start ART by >5yrs were more frequently female (59%; p<0.001). Among ART-treated children, immune reconstitution of CD4 T-cells was more rapid and more complete in female children, even after adjustment for pre-ART absolute CD4 count or CD4% (p=0.011, p=0.030, respectively). However, while ART was initiated as a result of meeting CD4 criteria less often in females (45%), ART initiation as a result of clinical disease in children whose CD4 counts were above treatment thresholds occurred more often in females (57%, p<0.001). The main sex difference in morbidity observed in children initiating ART above CD4 thresholds, above that of TB disease, was as a result of wasting and stunting observed in females with above-threshold CD4 counts (p=0.002). These findings suggest the possibility that optimal treatment of HIV-infected children might incorporate differential CD4 treatment thresholds for ART initiation according to sex. PMID:26151555

In Utero Exposure to Histological Chorioamnionitis Primes the Exometabolomic Profiles of Preterm CD4+ T Lymphocytes.

PubMed

Matta, Poojitha; Sherrod, Stacy D; Marasco, Christina C; Moore, Daniel J; McLean, John A; Weitkamp, Joern-Hendrik

2017-11-01

Histological chorioamnionitis (HCA) is an intrauterine inflammatory condition that increases the risk for preterm birth, death, and disability because of persistent systemic and localized inflammation. The immunological mechanisms sustaining this response in the preterm newborn remain unclear. We sought to determine the consequences of HCA exposure on the fetal CD4 + T lymphocyte exometabolome. We cultured naive CD4 + T lymphocytes from HCA-positive and -negative preterm infants matched for gestational age, sex, race, prenatal steroid exposure, and delivery mode. We collected conditioned media samples before and after a 6-h in vitro activation of naive CD4 + T lymphocytes with soluble staphylococcal enterotoxin B and anti-CD28. We analyzed samples by ultraperformance liquid chromatography ion mobility-mass spectrometry. We determined the impact of HCA on the CD4 + T lymphocyte exometabolome and identified potential biomarker metabolites by multivariate statistical analyses. We discovered that: 1) CD4 + T lymphocytes exposed to HCA exhibit divergent exometabolomic profiles in both naive and activated states; 2) ∼30% of detected metabolites differentially expressed in response to activation were unique to HCA-positive CD4 + T lymphocytes; 3) metabolic pathways associated with glutathione detoxification and tryptophan degradation were altered in HCA-positive CD4 + T lymphocytes; and 4) flow cytometry and cytokine analyses suggested a bias toward a T H 1-biased immune response in HCA-positive samples. HCA exposure primes the neonatal adaptive immune processes by inducing changes to the exometabolomic profile of fetal CD4 + T lymphocytes. These exometabolomic changes may link HCA exposure to T H 1 polarization of the neonatal adaptive immune response. Copyright © 2017 by The American Association of Immunologists, Inc.

Changes in Reactivity In Vitro of CD4+CD25+ and CD4+CD25− T Cell Subsets in Transplant Tolerance

PubMed Central

Hall, Bruce M.; Robinson, Catherine M.; Plain, Karren M.; Verma, Nirupama D.; Tran, Giang T.; Nomura, Masaru; Carter, Nicole; Boyd, Rochelle; Hodgkinson, Suzanne J.

2017-01-01

Transplant tolerance induced in adult animals is mediated by alloantigen-specific CD4+CD25+ T cells, yet in many models, proliferation of CD4+ T cells from hosts tolerant to specific-alloantigen in vitro is not impaired. To identify changes that may diagnose tolerance, changes in the patterns of proliferation of CD4+, CD4+CD25+, and CD4+CD25− T cells from DA rats tolerant to Piebald Virol Glaxo rat strain (PVG) cardiac allografts and from naïve DA rats were examined. Proliferation of CD4+ T cells from both naïve and tolerant hosts was similar to both PVG and Lewis stimulator cells. In mixed lymphocyte culture to PVG, proliferation of naïve CD4+CD25− T cells was greater than naïve CD4+ T cells. In contrast, proliferation of CD4+CD25− T cells from tolerant hosts to specific-donor PVG was not greater than CD4+ T cells, whereas their response to Lewis and self-DA was greater than CD4+ T cells. Paradoxically, CD4+CD25+ T cells from tolerant hosts did not proliferate to PVG, but did to Lewis, whereas naïve CD4+CD25+ T cells proliferate to both PVG and Lewis but not to self-DA. CD4+CD25+ T cells from tolerant, but not naïve hosts, expressed receptors for interferon (IFN)-γ and IL-5 and these cytokines promoted their proliferation to specific-alloantigen PVG but not to Lewis or self-DA. We identified several differences in the patterns of proliferation to specific-donor alloantigen between cells from tolerant and naïve hosts. Most relevant is that CD4+CD25+ T cells from tolerant hosts failed to proliferate or suppress to specific donor in the absence of either IFN-γ or IL-5. The proliferation to third-party and self of each cell population from tolerant and naïve hosts was similar and not affected by IFN-γ or IL-5. Our findings suggest CD4+CD25+ T cells that mediate transplant tolerance depend on IFN−γ or IL-5 from alloactivated Th1 and Th2 cells. PMID:28878770

CD4+ T Lymphocytes count in sickle cell anaemia patients attending a tertiary hospital.

PubMed

Ojo, Omotola Toyin; Shokunbi, Wuraola Adebola

2014-05-01

Sickle cell haemoglobin (HbS) is the commonest abnormal haemoglobin and it has a worldwide distribution. Reports have shown that patients with sickle cell anaemia (HbSS) have an increased susceptibility to infection leading to increased morbidity and mortality. Impaired leucocyte function and loss of both humoral and cell-mediated immunity are some of the mechanisms that have been reported to account for the immunocompromised state in patients with sickle cell disease. This study was carried out to determine the CD4+ T lymphocytes count in patients with sickle cell anaemia. A comparative cross-sectional study of 40 sickle cell anaemia patients in steady state (asymptomatic for at least 4 weeks) attending haematology clinic and 40 age and sex-matched healthy HbA control were recruited into the study. Both HbS patients and the controls were HIV negative. The blood samples obtained were analyzed for CD4+ T cell by Flow cytometry. The study found that there was no significant difference in the number of CD4+ T lymphocyte count between individuals with sickle cell anaemia and HbA (1016 ± 513 cells/μL vs 920 ± 364cells/μL). It is recommended that the functionality of CD4+ T lymphocyte should be considered rather than the number in further attempt to elucidate the cellular immune dysfunction in patients with sickle cell anaemia.

CDC staging based on absolute CD4 count and CD4 percentage in an HIV-1-infected Indian population: treatment implications

PubMed Central

Vajpayee, M; Kaushik, S; Sreenivas, V; Wig, N; Seth, P

2005-01-01

CD4+ T-cell levels are an important criterion for categorizing HIV-related clinical conditions according to the CDC classification system and are therefore important in the management of HIV by initiating antiretroviral therapy and prophylaxis for opportunistic infections due to HIV among HIV-infected individuals. However, it has been observed that the CD4 counts are affected by the geographical location, race, ethnic origin, age, gender and changes in total and differential leucocyte counts. In the light of this knowledge, we classified 600 HIV seropositive antiretroviral treatment (ART)-naïve Indian individuals belonging to different CDC groups A, B and C on the basis of CDC criteria of both CD4% and CD4 counts and receiver operating characteristic (ROC) curves were generated. Importantly, CDC staging on the basis of CD4% indicated significant clinical implications, requiring an early implementation of effective antiretroviral treatment regimen in HIV-infected individuals deprived of treatment when classified on the basis of CD4 counts. PMID:16045738

Expression of CTLA-4 (CD152) on human medullary CD4+ thymocytes.

PubMed

Castan, J; Klauenberg, U; Kalmár, P; Fleischer, B; Bröker, B M

1998-06-01

CTLA-4 (CD152) is a T cell surface receptor with sequence homology to the co-stimulatory molecule CD28. The molecule, which is essential for the inhibitory regulation of the immune response, becomes transiently expressed on mature T cells after stimulation in vitro. In situ, CTLA-4+ T cells are enriched in the light zones of the germinal centers in human peripheral lymphoid organs. In this study we have studied expression of CTLA-4 in human thymus in situ. CTLA-4 was expressed on about one third of CD4+/CD8-/CD1- medullary thymocytes. CTLA-4 was acquired by a subset of immature (CD1+) thymocytes and lost from the mature (CD1-) subpopulation within 48 h of cell culture, suggesting that the expression on medullary thymocytes is transient. The demonstration of CTLA-4 on a substantial subpopulation of mature CD4+ thymocytes adds a new dimension to the understanding of this important molecule. When contemplating application of anti-CTLA-4 for therapy its potential influence on T cell maturation has to be taken into account.

Age-dependent changes in the sphingolipid composition of CD4+ T cell membranes and immune synapses implicate glucosylceramides in age-related T cell dysfunction

USDA-ARS?s Scientific Manuscript database

Sphingolipid (SL4) composition can influence the biophysical properties of cell membranes. Additionally, specific SL modulate signaling pathways involved in proliferation, senescence, and apoptosis. We investigated age-dependent changes in the SL composition of CD4+ T cells, and the impact of these ...

Cross-sectional study of CD4: CD8 ratio recovery in young adults with perinatally acquired HIV-1 infection.

PubMed

Pollock, Katrina M; Pintilie, Hannah; Foster, Caroline; Fidler, Sarah

2018-02-01

Antiretroviral therapy (ART) has improved survival into adulthood for young people with perinatally acquired HIV-1 (yp-PaHIV), but long-term prognosis remains unclear. We hypothesized that on-going immune activation, reflected in the failure of CD4:CD8 ratio normalization would be observed in yp-PaHIV, despite ART.A cross-sectional study of routinely collected clinical data from a cohort of yp-PaHIV (≥16 years).Data were collected from records of individuals attending a specialist clinic for yp-PaHIV transitioning to adult care. CD4:CD8 ratio and proportion with CD4:CD8 ratio ≥1, demographic data and viral parameters, including HIV-1 viral load (VL) and human cytomegalovirus (CMV) IgG, were analyzed with IBM SPSS Statistics v22.A total of 115 yp-PaHIV, median (IQR) age 22.0 (20.0-24.0) years, were studied, of whom 59 were females, and the majority were Black African 75/115 (65.2%). Where measured, CMV antibodies were frequently detected (71/74, 95.9%) and CMV IgG titre was inversely associated with CD4:CD8 ratio, (Rho -0.383, P = .012). Of those taking ART, 69 out of 90 (76.7%) yp-PaHIV had suppressed HIV viremia (<50 RNA copies/mL) and recovery of CD4:CD8 ratio to ≥1 was seen in 26 out of 69 (37.7%) with suppressed HIV viremia. Persistence of low CD4:CD8 ratio was observed even in those with a CD4 count ≥500 cells/μL, where 28/52 (53.8%) had a CD4:CD8 ratio <1. Of those with suppressed viremia, the median (IQR) age for starting ART was 8.0 (5.0-12.8) years and CD4:CD8 ratio was inversely associated with age at ART start, Rho -0.348, (P = .028).In this cohort of yp-PaHIV, despite lifelong HIV infection and widespread CMV coinfection, CD4:CD8 ratio recovery rate was comparable to adults treated in acute infection. Where persistence of CD4:CD8 ratio abnormality was observed, on-going immune activation may have significance for non-AIDS outcomes. Taken together our findings indicate immune resilience to be a feature of these adult survivors of

Measuring trends in age at first sex and age at marriage in Manicaland, Zimbabwe.

PubMed

Cremin, I; Mushati, P; Hallett, T; Mupambireyi, Z; Nyamukapa, C; Garnett, G P; Gregson, S

2009-04-01

To identify reporting biases and to determine the influence of inconsistent reporting on observed trends in the timing of age at first sex and age at marriage. Longitudinal data from three rounds of a population-based cohort in eastern Zimbabwe were analysed. Reports of age at first sex and age at marriage from 6837 individuals attending multiple rounds were classified according to consistency. Survival analysis was used to identify trends in the timing of first sex and marriage. In this population, women initiate sex and enter marriage at younger ages than men but spend much less time between first sex and marriage. Among those surveyed between 1998 and 2005, median ages at first sex and first marriage were 18.5 years and 21.4 years for men and 18.2 years and 18.5 years, respectively, for women aged 15-54 years. High levels of reports of both age at first sex and age at marriage among those attending multiple surveys were found to be unreliable. Excluding reports identified as unreliable from these analyses did not alter the observed trends in either age at first sex or age at marriage. Tracing birth cohorts as they aged revealed reporting biases, particularly among the youngest cohorts. Comparisons by birth cohorts, which span a period of >40 years, indicate that median age at first sex has remained constant over time for women but has declined gradually for men. Although many reports of age at first sex and age at marriage were found to be unreliable, inclusion of such reports did not result in artificial generation or suppression of trends.

Different thresholds of T cell activation regulate FIV infection of CD4{sup +}CD25{sup +} and CD4{sup +}CD25{sup -} cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Joshi, Anjali; Garg, Himanshu; Tompkins, Mary B.

2005-05-10

Cellular activation plays an important role in retroviral replication. Previously, we have shown that CD4{sup +}CD25{sup +} T cells by the virtue of their partially activated phenotype represent ideal candidates for a productive feline immunodeficiency virus (FIV) infection. In the present study, we extended our previous observations with regard to FIV replication in CD4{sup +}CD25{sup +} and CD4{sup +}CD25{sup -} cells under different stimulation conditions. Both CD4{sup +}CD25{sup +} and CD4{sup +}CD25{sup -} cells remain latently infected in the absence of IL-2 or concanvalinA (ConA), respectively; harboring a replication competent provirus capable of reactivation several days post-infection. While CD4{sup +}CD25{supmore » +} cells require low levels of exogenous IL-2 and virus inputs for an efficient FIV replication, CD4{sup +}CD25{sup -} T cells can only be productively infected in the presence of either high concentrations of IL-2 or high virus titers, even in the absence of mitogenic stimulation. Interestingly, while high virus input activates CD4{sup +}CD25{sup -} cells to replicate FIV, it induces apoptosis in a high percentage of CD4{sup +}CD25{sup +} T cells. High IL-2 concentrations but not high virus inputs lead to surface upregulation of CD25 and significant cellular proliferation in CD4{sup +}CD25{sup -} cells. These results suggest that CD4{sup +}CD25{sup +} and CD4{sup +}CD25{sup -} T cells have different activation requirements which can be modulated by both viral and cytokine stimuli to reach threshold activation levels in order to harbor a productive FIV infection. This holds implications in vivo for CD4{sup +}CD25{sup +} and CD4{sup +}CD25{sup -} cells to serve as potential reservoirs of a productive and latent FIV infection.« less

An age-related numerical and functional deficit in CD19(+) CD24(hi) CD38(hi) B cells is associated with an increase in systemic autoimmunity.

PubMed

Duggal, Niharika A; Upton, Jane; Phillips, Anna C; Sapey, Elizabeth; Lord, Janet M

2013-10-01

Autoimmunity increases with aging indicative of reduced immune tolerance, but the mechanisms involved are poorly defined. In recent years, subsets of B cells with immunoregulatory properties have been identified in murine models of autoimmune disorders, and these cells downregulate immune responses via secretion of IL10. In humans, immature transitional B cells with a CD19(+) CD24(hi) CD38(hi) phenotype have been reported to regulate immune responses via IL10 production. We found the frequency and numbers of CD19(+) CD24(hi) CD38(hi) cells were reduced in the PBMC pool with age. IL10 expression and secretion following activation via either CD40, or Toll-like receptors was also impaired in CD19(+) CD24(hi) CD38(hi) B cells from healthy older donors. When investigating the mechanisms involved, we found that CD19(+) CD24(hi) CD38(hi) B-cell function was compromised by age-related effects on both T cells and B cells: specifically, CD40 ligand expression was lower in CD4 T cells from older donors following CD3 stimulation, and signalling through CD40 was impaired in CD19(+) CD24(hi) CD38(hi) B cells from elders as evidenced by reduced phosphorylation (Y705) and activation of STAT3. However, there was no age-associated change in expression of costimulatory molecules CD80 and CD86 on CD19(+) CD24(hi) CD38(hi) cells, suggesting IL10-dependent immune suppression is impaired, but contact-dependent suppressive capacity is intact with age. Finally, we found a negative correlation between CD19(+) CD24(hi) CD38(hi) B-cell IL10 production and autoantibody (Rheumatoid factor) levels in older adults. We therefore propose that an age-related decline in CD19(+) CD24(hi) CD38(hi) B cell number and function may contribute towards the increased autoimmunity and reduced immune tolerance seen with aging. © 2013 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

C/EBPα is dispensable for the ontogeny of PD-1+ CD4+ memory T cells but restricts their expansion in an age-dependent manner.

PubMed

Norrie, Ida Christine; Ohlsson, Ewa; Nielsen, Olaf; Hasemann, Marie Sigurd; Porse, Bo T

2014-01-01

Ageing and cancer is often associated with altered T cell distributions and this phenomenon has been suggested to be the main driver in the development of immunosenescence. Memory phenotype PD-1+ CD4+ T cells accumulate with age and during leukemic development, and they might account for the attenuated T cell response in elderly or diseased individuals. The transcription factor C/EBPα has been suggested to be responsible for the accumulation as well as for the senescent features of these cells including impaired TCR signaling and decreased proliferation. Thus modulating the activity of C/EBPα could potentially target PD-1+ CD4+ T cells and consequently, impede the development of immunosenescence. To exploit this possibility we tested the importance of C/EBPα for the development of age-dependent PD-1+ CD4+ T cells as well as its role in the accumulation of PD-1+ CD4+ T cells during leukemic progression. In contrast to earlier suggestions, we find that loss of C/EBPα expression in the lymphoid compartment led to an increase of PD-1+ CD4+ T cells specifically in old mice, suggesting that C/EBPα repress the accumulation of these cells in elderly by inhibiting their proliferation. Furthermore, C/EBPα-deficiency in the lymphoid compartment had no effect on leukemic development and did not affect the accumulation of PD-1+ CD4+ T cells. Thus, in addition to contradict earlier suggestions of a role for C/EBPα in immunosenescence, these findings efficiently discard the potential of using C/EBPα as a target for the alleviation of ageing/cancer-associated immunosenescence.

Increased numbers of CD4+ and CD8+ T cells in lesional skin of cats with allergic dermatitis.

PubMed

Roosje, P J; van Kooten, P J; Thepen, T; Bihari, I C; Rutten, V P; Koeman, J P; Willemse, T

1998-07-01

The aim of this study was to characterize T cells in the skin of cats with an allergic dermatitis histologically compatible with atopic dermatitis, since T cells play an important role in the pathogenesis of atopic dermatitis in humans. We observed a significantly greater number of T cells in lesional skin of domestic short-haired cats with allergic dermatitis (n = 10; median age 5.8 years) than in the skin of healthy control animals (n = 10; median age 5.0 years). In the skin of the healthy control animals, one or two CD4+ cells and no CD8+ cells were found. A predominant increase of CD4+ T cells and a CD4+/CD8+ ratio (mean +/- SD: 3.9 +/- 2.0) was found in the lesional skin of 10 cats with allergic dermatitis. The CD4+/CD8+ cell ratio in the skin of healthy control animals could not be determined because of the absence of CD8+ cells. The CD4+/CD8+ cell ratio in the peripheral blood of 10 cats with allergic dermatitis (mean +/- SD: 1.9 +/- 0.4) did not differ significantly from that in 10 healthy control animals (2.2 +/- 0.4). The CD4+/CD8+ cell ratio and predominance of CD4+ T cells in the lesional skin of cats with allergic dermatitis is comparable to that found in atopic dermatitis in humans. In addition, the observed increase of CD4+ T cells in the nonlesional skin of cats with allergic dermatitis compared to the skin of healthy cats is similar to what is seen in humans. Cytokines produced by T cells and antigen-specific T cells are important mediators in the inflammatory cascade resulting in atopic dermatitis in humans. This study is a first step to investigate their role in feline allergic dermatitis.

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.

Ability of HIV-1 Nef to downregulate CD4 and HLA class I differs among viral subtypes

PubMed Central

2013-01-01

Background The highly genetically diverse HIV-1 group M subtypes may differ in their biological properties. Nef is an important mediator of viral pathogenicity; however, to date, a comprehensive inter-subtype comparison of Nef in vitro function has not been undertaken. Here, we investigate two of Nef’s most well-characterized activities, CD4 and HLA class I downregulation, for clones obtained from 360 chronic patients infected with HIV-1 subtypes A, B, C or D. Results Single HIV-1 plasma RNA Nef clones were obtained from N=360 antiretroviral-naïve, chronically infected patients from Africa and North America: 96 (subtype A), 93 (B), 85 (C), and 86 (D). Nef clones were expressed by transfection in an immortalized CD4+ T-cell line. CD4 and HLA class I surface levels were assessed by flow cytometry. Nef expression was verified by Western blot. Subset analyses and multivariable linear regression were used to adjust for differences in age, sex and clinical parameters between cohorts. Consensus HIV-1 subtype B and C Nef sequences were synthesized and functionally assessed. Exploratory sequence analyses were performed to identify potential genotypic correlates of Nef function. Subtype B Nef clones displayed marginally greater CD4 downregulation activity (p = 0.03) and markedly greater HLA class I downregulation activity (p < 0.0001) than clones from other subtypes. Subtype C Nefs displayed the lowest in vitro functionality. Inter-subtype differences in HLA class I downregulation remained statistically significant after controlling for differences in age, sex, and clinical parameters (p < 0.0001). The synthesized consensus subtype B Nef showed higher activities compared to consensus C Nef, which was most pronounced in cells expressing lower protein levels. Nef clones exhibited substantial inter-subtype diversity: cohort consensus residues differed at 25% of codons, while a similar proportion of codons exhibited substantial inter-subtype differences in major

Phenotypic and functional characteristics of CD4+ CD39+ FOXP3+ and CD4+ CD39+ FOXP3neg T-cell subsets in cancer patients.

PubMed

Schuler, Patrick J; Schilling, Bastian; Harasymczuk, Malgorzata; Hoffmann, Thomas K; Johnson, Jonas; Lang, Stephan; Whiteside, Theresa L

2012-07-01

Human CD4(+) CD39(+) regulatory T (Treg) cells hydrolyze exogenous adenosine triphosphate (ATP) and participate in immunosuppressive adenosine production. They contain two T-cell subsets whose role in mediating suppression is not understood. Frequencies of both CD4(+) CD39(+) subsets were evaluated in peripheral blood lymphocytes of 57 cancer patients and in tumor infiltrating lymphocytes (TILs) of 6 patients. CD4(+) CD39(+) and CD4(+) CD39(neg) T cells isolated using immunobeads and cell sorting were cultured under various conditions. Their conversion into CD39(+) FOXP3(+) CD25(+) or CD39(+) FOX(neg) CD25(neg) cells was monitored by multiparameter flow cytometry. Hydrolysis of exogenous ATP was measured in luminescence assays. Two CD4(+) CD39(+) cell subsets differing in expression of CD25, FOXP3, CTLA-4, CD121a, PD-1, latency associated peptide (LAP), glycoprotein A repetitions predominant (GARP), and the cytokine profile accumulated with equal frequencies in the blood and tumor tissues of cancer patients. The frequency of both subsets was significantly increased in cancer. CD39 expression levels correlated with the subsets' ability to hydrolyze ATP. Conventional CD4(+) CD39(neg) T cells incubated with IL-2 + TGF-β expanded to generate CD4(+) CD39(+) FOXP3(+) Treg cells, while CD4(+) CD39(+) FOXP3(neg) CD25(neg) subset cells stimulated via the TCR and IL-2 converted to FOXP3(+) CTLA4(+) CD25(+) TGF-β-expressing Treg cells. Among CD4(+) CD39(+) Treg cells, the CD4(+) CD39(+) FOXP3(neg) CD25(neg) subset serves as a reservoir of cells able to convert to Treg cells upon activation by environmental signals. © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Comprehensive circular RNA profiling reveals that circular RNA100783 is involved in chronic CD28-associated CD8(+)T cell ageing.

PubMed

Wang, Yu-Hong; Yu, Xu-Hui; Luo, Shan-Shun; Han, Hui

2015-01-01

Ageing brings about the gradual deterioration of the immune system, also known as immunosenescence. The role of non-coding circular RNA in immunosenescence is under studied. Using circular RNA microarray data, we assembled Comparison groups (C1, C2, C3 and C4) that allowed us to compare the circular RNA expression profiles between CD28(+)CD8(+) T cells and CD28(-)CD8(+) T cells isolated from healthy elderly or adult control subjects. Using a step-wise biomathematical strategy, the differentially-expressed circRNAs were identified in C1 (CD28(+)CD8(+) vs CD28(-)CD8(+)T cells in the elderly) and C4 (CD28(-)CD8(+)T cells in the elderly vs in the adult), and the commonly-expressed circRNA species from these profiles were optimized as immunosenescence biomarkers. Four overlapping upregulated circular RNAs (100550, 100783, 101328 and 102592) expressed in cross-comparison between C1 and C4 were validated using quantitative polymerase chain reaction. Of these, only circular RNA100783 exhibited significant validation. None of the down-regulated circular RNAs were expressed in the C1 and the C4 cross-comparisons. Therefore, we further predicted circular RNA100783-targeted miRNA-gene interactions using online DAVID annotation. The analysis revealed that a circular RNA100783-targeted miRNA-mRNA network may be involved in alternative splicing, the production of splice variants, and in the regulation of phosphoprotein expression. Considering the hypothesis of splicing-related biogenesis of circRNAs, we propose that circular RNA100783 may play a role in phosphoprotein-associated functions duringCD28-related CD8(+) T cell ageing. This study is the first to employ circular RNA profiling to investigate circular RNA-micro RNA interactions in ageing human CD8(+)T cell populations and the accompanying loss of CD28 expression. The overlapping expression of circular RNA100783 may represent a novel biomarker for the longitudinal tracking ofCD28-related CD8(+) T cell ageing and global

C/EBPα Is Dispensable for the Ontogeny of PD-1+ CD4+ Memory T Cells but Restricts Their Expansion in an Age-Dependent Manner

PubMed Central

Norrie, Ida Christine; Ohlsson, Ewa; Nielsen, Olaf

2014-01-01

Ageing and cancer is often associated with altered T cell distributions and this phenomenon has been suggested to be the main driver in the development of immunosenescence. Memory phenotype PD-1+ CD4+ T cells accumulate with age and during leukemic development, and they might account for the attenuated T cell response in elderly or diseased individuals. The transcription factor C/EBPα has been suggested to be responsible for the accumulation as well as for the senescent features of these cells including impaired TCR signaling and decreased proliferation. Thus modulating the activity of C/EBPα could potentially target PD-1+ CD4+ T cells and consequently, impede the development of immunosenescence. To exploit this possibility we tested the importance of C/EBPα for the development of age-dependent PD-1+ CD4+ T cells as well as its role in the accumulation of PD-1+ CD4+ T cells during leukemic progression. In contrast to earlier suggestions, we find that loss of C/EBPα expression in the lymphoid compartment led to an increase of PD-1+ CD4+ T cells specifically in old mice, suggesting that C/EBPα repress the accumulation of these cells in elderly by inhibiting their proliferation. Furthermore, C/EBPα-deficiency in the lymphoid compartment had no effect on leukemic development and did not affect the accumulation of PD-1+ CD4+ T cells. Thus, in addition to contradict earlier suggestions of a role for C/EBPα in immunosenescence, these findings efficiently discard the potential of using C/EBPα as a target for the alleviation of ageing/cancer-associated immunosenescence. PMID:24404186

Repeated irradiation from micro-computed tomography scanning at 2, 4 and 6 months of age does not induce damage to tibial bone microstructure in male and female CD-1 mice.

PubMed

Sacco, Sandra M; Saint, Caitlin; Longo, Amanda B; Wakefield, Charles B; Salmon, Phil L; LeBlanc, Paul J; Ward, Wendy E

2017-01-01

Long-term effects of repeated i n vivo micro-computed tomography (μCT) scanning at key stages of growth and bone development (ages 2, 4 and 6 months) on trabecular and cortical bone structure, as well as developmental patterns, have not been studied. We determined the effect of repetitive μCT scanning at age 2, 4 and 6 months on tibia bone structure of male and female CD-1 mice and characterized developmental changes. At 2, 4 and 6 months of age, right tibias were scanned using in vivo μCT (Skyscan 1176) at one of three doses of radiation per scan: 222, 261 or 460 mGy. Left tibias of the same mice were scanned only at 6 months to serve as non-irradiated controls to determine whether recurrent radiation exposure alters trabecular and cortical bone structure at the proximal tibia. In males, eccentricity was lower ( P <0.05) in irradiated compared with non-irradiated tibias (222 mGy group). Within each sex, all other structural outcomes were similar between irradiated and non-irradiated tibias regardless of dose. Trabecular bone loss occurred in all mice due to age while cortical development continued to age 6 months. In conclusion, repetitive μCT scans at various radiation doses did not damage trabecular or cortical bone structure of proximal tibia in male and female CD-1 mice. Moreover, scanning at 2, 4 and 6 months of age highlight the different developmental time course between trabecular and cortical bone. These scanning protocols can be used to investigate longitudinal responses of bone structures to an intervention.

Task-shifting of CD4 T cell count monitoring by the touchscreen-based Muse™ Auto CD4/CD4% single-platform system for CD4 T cell numeration: Implication for decentralization in resource-constrained settings.

PubMed

Kouabosso, André; Mossoro-Kpinde, Christian Diamant; Bouassa, Ralph-Sydney Mboumba; Longo, Jean De Dieu; Mbeko Simaleko, Marcel; Grésenguet, Gérard; Bélec, Laurent

2018-04-01

The accuracy of CD4 T cell monitoring by the recently developed flow cytometry-based CD4 T cell counting Muse™ Auto CD4/CD4% Assay analyzer (EMD Millipore Corporation, Merck Life Sciences, KGaA, Darmstadt, Germany) was evaluated in trained lay providers against laboratory technicians. After 2 days of training on the Muse™ Auto CD4/CD4% analyzer, EDTA-blood samples from 6 HIV-positive and 4 HIV-negative individuals were used for CD4 T cell counting in triplicate in parallel by 12 trained lay providers as compared to 10 lab technicians. Mean number of CD4 T cells in absolute number was 829 ± 380 cells/μl by lay providers and 794 ± 409 cells/μl by technicians (P > 0.05); and in percentage 36.2 ± 14.8%CD4 by lay providers and 36.1 ± 15.0%CD4 by laboratory technician (P > 0.05). The unweighted linear regression and Passing-Bablok regression analyses on CD4 T cell results expressed in absolute count revealed moderate correlation between CD4 T cell counts obtained by lay providers and lab technicians. The mean absolute bias measured by Bland-Altman analysis between CD4 T cell/μl obtained by lay providers and lab technicians was -3.41 cells/μl. Intra-assay coefficient of variance (CV) of Muse™ Auto CD4/CD4% in absolute number was 10.1% by lay providers and 8.5% by lab technicians (P > 0.05), and in percentage 5.5% by lay providers and 4.4% by lab technicians (P > 0.05). The inter-assay CV of Muse™ Auto CD4/CD4% in absolute number was 13.4% by lay providers and 10.3% by lab technicians (P > 0.05), and in percentage 7.8% by lay providers and 6.9% by lab technicians (P > 0.05). The study demonstrates the feasibility of CD4 T cell counting using the alternative flow cytometer Muse™ Auto CD4/CD4% analyzer by trained lay providers and therefore the practical possibility of decentralization CD4 T cell counting to health community centers. Copyright © 2018. Published by Elsevier B.V.

The Impact of Sex Work Interruption on Blood-Derived T Cells in Sex Workers from Nairobi, Kenya.

PubMed

Omollo, Kenneth; Boily-Larouche, Geneviève; Lajoie, Julie; Kimani, Makobu; Cheruiyot, Julianna; Kimani, Joshua; Oyugi, Julius; Fowke, Keith Raymond

Unprotected sexual intercourse exposes the female genital tract (FGT) to semen-derived antigens, which leads to a proinflammatory response. Studies have shown that this postcoital inflammatory response can lead to recruitment of activated T cells to the FGT, thereby increasing risk of HIV infection. The purpose of this study was to evaluate the impact of sex work on activation and memory phenotypes of peripheral T cells among female sex workers (FSW) from Nairobi, Kenya. Thirty FSW were recruited from the Pumwani Sex Workers Cohort, 10 in each of the following groups: HIV-exposed seronegative (at least 7 years in active sex work), HIV positive, and New Negative (HIV negative, less than 3 years in active sex work). Blood was obtained at three different phases (active sex work, abstinence from sex work-sex break, and following resumption of sex work). Peripheral blood mononuclear cells were isolated and stained for phenotypic markers (CD3, CD4, CD8, and CD161), memory phenotype markers (CD45RA and CCR7), activation markers (CD69, HLA-DR, and CD95), and the HIV coreceptor (CCR5). T-cell populations were compared between groups. In HIV-positive women, CD8+CCR5+ T cells declined at the sex break period, while CD4+CD161+ T cells increased when returning to sex work. All groups showed no significant changes in systemic T-cell activation markers following the interruption of sex work, however, significant reductions in naive CD8+ T cells were noted. For each of the study points, HIV positives had higher effector memory and CD8+CD95+ T cells and lower naive CD8+ T cells than the HIV-uninfected groups. Interruption of sex work had subtle effects on systemic T-cell memory phenotypes.

Association among oral health, apical periodontitis, CD14 polymorphisms, and coronary heart disease in middle-aged adults.

PubMed

Pasqualini, Damiano; Bergandi, Loredana; Palumbo, Luigi; Borraccino, Alberto; Dambra, Valentina; Alovisi, Mario; Migliaretti, Giuseppe; Ferraro, Gaetana; Ghigo, Dario; Bergerone, Serena; Scotti, Nicola; Aimetti, Mario; Berutti, Elio

2012-12-01

There is evidence to suggest that an association exists between oral infections and coronary heart disease (CHD). Subjects presenting lesions of endodontic origin (LEOs) or pulpal inflammation had an increased risk of developing CHD. However, findings concerning systemic manifestations of apical periodontitis (AP) remain controversial. An association between CD14 gene polymorphisms and atherosclerosis-associated diseases has been shown, but there are no data regarding an association between CD14 polymorphism and AP. This study evaluated associations between clinical oral health status, CD14 polymorphisms, and CHD. A case-controlled clinical trial was designed to compare middle-aged adults with acute myocardial infarction or unstable angina (n = 51) within 12 months of the acute event defined as first manifestation with healthy controls (n = 49). Participants were matched for age, sex, and socioeconomic status. Indicators of oral disease and compliance were evaluated. CD14 polymorphisms were analyzed by restriction fragment length polymorphism-polymerase chain reaction. CHD subjects had a higher prevalence of oral diseases and lower compliance to oral preventive strategies than healthy controls. Multivariate analysis showed a positive association between missing teeth (odds ratio [OR] = 1.37; 95% confidence interval [CI], 1.02-1.85), the number of LEOs (OR = 4.37; 95% CI, 1.69-11.28), chronic periodontitis (OR = 5.87; 95% CI, 1.17-29.4), and CHD. No statistically significant association emerged between the CD14 C(-260)T and the CD14 C(-159)T polymorphism, endodontic or periodontal disease, and CHD. Chronic oral diseases may increase the risk of CHD and may be an unconventional risk factor for CHD. Copyright © 2012 American Association of Endodontists. Published by Elsevier Inc. All rights reserved.

CD4/CD8/Dendritic cell complexes in the spleen: CD8+ T cells can directly bind CD4+ T cells and modulate their response

PubMed Central

Barinov, Aleksandr; Galgano, Alessia; Krenn, Gerald; Tanchot, Corinne; Vasseur, Florence

2017-01-01

CD4+ T cell help to CD8+ T cell responses requires that CD4+ and CD8+ T cells interact with the same antigen presenting dendritic cell (Ag+DC), but it remains controversial whether helper signals are delivered indirectly through a licensed DC and/or involve direct CD4+/CD8+ T cell contacts and/or the formation of ternary complexes. We here describe the first in vivo imaging of the intact spleen, aiming to evaluate the first interactions between antigen-specific CD4+, CD8+ T cells and Ag+DCs. We show that in contrast to CD4+ T cells which form transient contacts with Ag+DC, CD8+ T cells form immediate stable contacts and activate the Ag+DC, acquire fragments of the DC membranes by trogocytosis, leading to their acquisition of some of the DC properties. They express MHC class II, and become able to present the specific Marilyn peptide to naïve Marilyn CD4+ T cells, inducing their extensive division. In vivo, these CD8+ T cells form direct stable contacts with motile naïve CD4+ T cells, recruiting them to Ag+DC binding and to the formation of ternary complexes, where CD4+ and CD8+ T cells interact with the DC and with one another. The presence of CD8+ T cells during in vivo immune responses leads to the early activation and up-regulation of multiple functions by CD4+ T lymphocytes. Thus, while CD4+ T cell help is important to CD8+ T cell responses, CD8+ T cells can interact directly with naïve CD4+ T cells impacting their recruitment and differentiation. PMID:28686740

Sex-specific phenotypes of hyperthyroidism and hypothyroidism in aged mice.

PubMed

Rakov, Helena; Engels, Kathrin; Hönes, Georg Sebastian; Brix, Klaudia; Köhrle, Josef; Moeller, Lars Christian; Zwanziger, Denise; Führer, Dagmar

2017-12-22

Sex and age play a role in the prevalence of thyroid dysfunction (TD), but their interrelationship for manifestation of hyper- and hypothyroidism is still not well understood. Using a murine model, we asked whether sex impacts the phenotypes of hyper- and hypothyroidism at two life stages. Hyper- and hypothyroidism were induced by i.p. T4 or MMI/ClO 4 -/LoI treatment over 7 weeks in 12- and 20-months-old female and male C57BL/6N mice. Control animals underwent PBS treatment (n = 7-11 animals/sex/treatment). Animals were investigated for impact of sex on body weight, food and water intake, body temperature, heart rate, behaviour (locomotor activity, motor coordination and strength) and serum thyroid hormone (TH) status. Distinct sex impact was found in eu- and hyperthyroid mice, while phenotypic traits of hypothyroidism were similar in male and female mice. No sex difference was found in TH status of euthyroid mice; however, T4 treatment resulted in twofold higher TT4, FT4 and FT3 serum concentrations in adult and old females compared to male animals. Hyperthyroid females consistently showed higher locomotor activity and better coordination but more impairment of muscle function by TH excess at adult age. Importantly and in contrast to male mice, adult and old hyperthyroid female mice showed increased body weight. Higher body temperature in female mice was confirmed in all age groups. No sex impact was found on heart rate irrespective of TH status in adult and old mice. By comparison of male and female mice with TD at two life stages, we found that sex modulates TH action in an organ- and function-specific manner. Sex differences were more pronounced under hyperthyroid conditions. Importantly, sex-specific differences in features of TD in adult and old mice were not conclusively explained by serum TH status in mice.

Aging Converts Innate B1a Cells into Potent CD8+ T Cell Inducers

PubMed Central

Lee-Chang, Catalina; Bodogai, Monica; Moritoh, Kanako; Chen, Xin; Wersto, Robert; Sen, Ranjan; Young, Howard A.; Croft, Michael; Ferrucci, Luigi; Biragyn, Arya

2016-01-01

B-cell dysregulation in aging is thought to mostly occur in conventional B2 cells without affecting innate B1 cells. Elderly humans and mice also accumulate 4-1BBL+ MHC class-IHi CD86Hi B cells of unknown origin. Here we report that these cells, termed 4BL cells, are activated murine and possibly human B1a cells. The activation is mediated by aging human monocytes and murine peritoneal macrophages. The 4BL cells induce expression of 4-1BBL and IFNγR1 on B1a cells resulting in subsequent up regulation of membrane TNFα (mTNFα) and CD86. As a result, B1a cells induce expression of granzyme B in CD8+T cells by targeting TNFR2 via mTNFα while providing co-stimulation with CD86. Thus, for the first time, these results indicate that aging affects the function of B1a cells. Upon aging, these cells lose their tumor-supporting activity and become inducers of potentially antitumor and autoimmune CD8+T cells. PMID:26983789

CD4+ T cell count, HIV-1 viral loads and demographic variables of newly identified patients with HIV infection in Wuhan, China.

PubMed

Liu, Man-Qing; Tang, Li; Kong, Wen-Hua; Zhu, Ze-Rong; Peng, Jin-Song; Wang, Xia; Yao, Zhong-Zhao; Schilling, Robert; Zhou, Wang

2013-10-01

In China, the rate of human immunodeficiency virus (HIV) testing is increasing among men who have sex with men. The purpose of the present study was to describe HIV-related biomarkers and selected demographic variables of persons with newly diagnosed HIV/AIDS, among men who have sex with men in particular, in Wuhan China. Demographic indicators, and CD4+ T cell counts and HIV-1 viral load were collected from individuals newly identified as HIV-1 antibody positive during 2011. Of 176 enrolled patients, 132 (75.0%) were men who have sex with men. This group was significantly younger and had higher CD4+ T cell counts than patients who were likely infected through heterosexual contact. Most men who have sex with men (56.6%) were discovered by initiative investigation. Among heterosexual patients CD4+ T cell counts and HIV-1 viral load were significantly correlated; among the group of men who have sex with men, no such association was found. Copyright © 2013 Wiley Periodicals, Inc.

Rationally Controlled Synthesis of CdSexTe1−x Alloy Nanocrystals and Their Application in Efficient Graded Bandgap Solar Cells

PubMed Central

Wen, Shiya; Li, Miaozi; Yang, Junyu; Mei, Xianglin; Wu, Bin; Liu, Xiaolin; Heng, Jingxuan; Hou, Lintao; Xu, Wei; Wang, Dan

2017-01-01

CdSexTe1−x semiconductor nanocrystals (NCs), being rod-shaped/irregular dot-shaped in morphology, have been fabricated via a simple hot-injection method. The NCs composition is well controlled through varying molar ratios of Se to Te precursors. Through changing the composition of the CdSexTe1−x NCs, the spectral absorption of the NC thin film between 570–800 nm is proved to be tunable. It is shown that the bandgap of homogeneously alloyed CdSexTe1−x active thin film is nonlinearly correlated with the different compositions, which is perceived as optical bowing. The solar cell devices based on CdSexTe1−x NCs with the structure of ITO/ZnO/CdSe/CdSexTe1−x/MoOx/Au and the graded bandgap ITO/ZnO/CdSe(w/o)/CdSexTe1−x/CdTe/MoOx/Au are systematically evaluated. It was found that the performance of solar cells degrades almost linearly with the increase of alloy NC film thickness with respect to ITO/ZnO/CdSe/CdSe0.2Te0.8/MoOx/Au. From another perspective, in terms of the graded bandgap structure of ITO/ZnO/CdSe/CdSexTe1−x/CdTe/MoOx/Au, the performance is improved in contrast with its single-junction analogues. The graded bandgap structure is proved to be efficient when absorbing spectrum and the solar cells fabricated under the structure of ITO/ZnO/CdSe0.8Te0.2/CdSe0.2Te0.8/CdTe/MoOx/Au indicate power conversion efficiency (PCE) of 6.37%, a value among the highest for solution-processed inversely-structured CdSexTe1−x NC solar cells. As the NC solar cells are solution-processed under environmental conditions, they are promising for fabricating solar cells at low cost, roll by roll and in large area. PMID:29117132

Fusion proteins of HIV-1 envelope glycoprotein gp120 with CD4-induced antibodies showed enhanced binding to CD4 and CD4 binding site antibodies

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chen, Weizao, E-mail: chenw3@mail.nih.gov; Feng, Yang; Wang, Yanping

Highlights: Black-Right-Pointing-Pointer Some recombinant HIV-1 gp120s do not preserve their conformations on gp140s. Black-Right-Pointing-Pointer We hypothesize that CD4i antibodies could induce conformational changes in gp120. Black-Right-Pointing-Pointer CD4i antibodies enhance binding of CD4 and CD4bs antibodies to gp120. Black-Right-Pointing-Pointer CD4i antibody-gp120 fusion proteins could have potential as vaccine immunogens. -- Abstract: Development of successful AIDS vaccine immunogens continues to be a major challenge. One of the mechanisms by which HIV-1 evades antibody-mediated neutralizing responses is the remarkable conformational flexibility of its envelope glycoprotein (Env) gp120. Some recombinant gp120s do not preserve their conformations on gp140s and functional viral spikes, and exhibitmore » decreased recognition by CD4 and neutralizing antibodies. CD4 binding induces conformational changes in gp120 leading to exposure of the coreceptor-binding site (CoRbs). In this study, we test our hypothesis that CD4-induced (CD4i) antibodies, which target the CoRbs, could also induce conformational changes in gp120 leading to better exposed conserved neutralizing antibody epitopes including the CD4-binding site (CD4bs). We found that a mixture of CD4i antibodies with gp120 only weakly enhanced CD4 binding. However, such interactions in single-chain fusion proteins resulted in gp120 conformations which bound to CD4 and CD4bs antibodies better than the original or mutagenically stabilized gp120s. Moreover, the two molecules in the fusion proteins synergized with each other in neutralizing HIV-1. Therefore, fusion proteins of gp120 with CD4i antibodies could have potential as components of HIV-1 vaccines and inhibitors of HIV-1 entry, and could be used as reagents to explore the conformational flexibility of gp120 and mechanisms of entry and immune evasion.« less

Sex and Age Differences in Trail Half Marathon Running.

PubMed

Navalta, James W; Montes, Jeffrey; Tanner, Elizabeth A; Bodell, Nathaniel G; Young, John C

2018-01-01

Female participation is growing in trail running races. The purpose was to evaluate sex and age differences in top finishers of a trail running half marathon. Velocity differences between males (M) and females (F) were determined for the top 10 finishers of the Moab Trail Half Marathon from 2012 - 2015 across age, and by finishing place. Differences between age category and between sexes were determined through ANOVA with significance accepted at P < 0.05. A significant difference for running velocity was present between sexes at each age category (20-29 yr F = 2.9±0.3, M = 3.4±0.4 m·sec -1 ; 30-39 yr F = 2.8±0.3, M = 3.3±0.3; 40-49 yr F = 2.7±0.3, M = 3.0±0.5; 50-59 yr F = 2.3±0.2, M = 2.8±0.3; 60-69 yr F = 1.6±0.3, M = 2.2±0.4; P < 0.0001). Sex difference in trail running velocity was consistent (~13%) among all age categories with exception of the oldest group (33%, P = 0.0001). There were significantly greater female finishers in every age category (20 - 29 yr F = 107±18, M = 56±1;, 30 - 39 yr F = 150±34, M = 84±21; 40 - 49 yr F = 112±17, M = 64±16; P < 0.01) until 50 - 59 yr (F = 48±13, M = 41±14; P = 0.50). These data indicate that the widening gap in sex differences observed in road races are ameliorated in a trail running environment that has a larger number of female participants.

The role of gluten consumption at an early age in celiac disease development: a further analysis of the prospective PreventCD cohort study.

PubMed

Crespo-Escobar, Paula; Mearin, Maria Luisa; Hervás, David; Auricchio, Renata; Castillejo, Gemma; Gyimesi, Judit; Martinez-Ojinaga, Eva; Werkstetter, Katharina; Vriezinga, Sabine Lisa; Korponay-Szabo, Ilma Rita; Polanco, Isabel; Troncone, Riccardo; Stoopman, Els; Kolaček, Sanja; Shamir, Raanan; Szajewska, Hania; Koletzko, Sibylle; Ribes-Koninckx, Carmen

2017-04-01

Background: We previously found that the introduction of small quantities of gluten at 4-6 mo of age did not reduce the risk of celiac disease (CD) in a group of high-risk children. However, the consumption of high amounts of gluten early in life has been suggested to increase CD risk. Objective: The aim of this study was to evaluate this hypothesis by using data from the previous study of the PreventCD trial (www.preventcd.com). Design: Gluten intake was prospectively quantified by using specific food records between 11 and 36 mo of age in 715 children positive for the human leukocyte antigen ( HLA )- DQ2 and/or HLA -DQ8 from 5 European countries. According to the PreventCD protocol, infants received 100 mg immunologically active gluten/d or placebo from 4 to 6 mo of age, with a stepwise and fixed gluten increase until age 10 mo and unrestricted intake thereafter. The primary outcome of the present study was the impact of the amount of gluten consumed from age 10 mo onward on CD development. Results: Mean daily gluten intakes from 10 mo onward were significantly different between countries for children at all ages ( P < 0.001) but not between children who developed CD and those who did not within the same country ( P > 0.05). The variables country, sex, intervention group, and gluten consumption pattern did not show significant associations with CD development risk (HRs not significant). In addition, the interaction between HLA risk group and gluten consumption pattern showed no significant risk on CD development, except for the DQ2.2/DQ7 haplotype (HR: 5.81; 95% CI: 1.18, 28.74; P = 0.031). Conclusions: Gluten consumption patterns as well as the amount of gluten consumed at 11-36 mo of age do not influence CD development for most related HLA genotypes in children with a genetic risk. This study reports the gluten consumption pattern in children at risk of CD from different European countries. This trial was registered at www.controlled-trials.com as ISRCTN

Aging Converts Innate B1a Cells into Potent CD8+ T Cell Inducers.

PubMed

Lee-Chang, Catalina; Bodogai, Monica; Moritoh, Kanako; Chen, Xin; Wersto, Robert; Sen, Ranjan; Young, Howard A; Croft, Michael; Ferrucci, Luigi; Biragyn, Arya

2016-04-15

B cell dysregulation in aging is thought to mostly occur in conventional B2 cells without affecting innate B1 cells. Elderly humans and mice also accumulate 4-1BBL(+)MHC class-I(Hi)CD86(Hi)B cells of unknown origin. In this article, we report that these cells, termed 4BL cells, are activated murine and possibly human B1a cells. The activation is mediated by aging human monocytes and murine peritoneal macrophages. They induce expression and activation of 4-1BBL and IFN-γR1 on B1a cells to subsequently upregulate membrane TNF-α and CD86. As a result, activated B1a/4BL cells induce expression of granzyme B in CD8(+)T cells by targeting TNFR2 via membrane TNF-α and providing costimulation with CD86. Thus, for the first time, to our knowledge, these results indicate that aging affects the function of B1a cells. Upon aging, these cells lose their tumor-supporting activity and become inducers of potentially antitumor and autoimmune CD8(+)T cells. Copyright © 2016 by The American Association of Immunologists, Inc.

Non-calcified coronary plaque volume inversely related to CD4 count in HIV infection

PubMed Central

Duarte, Horacio; Matta, Jatin R.; Muldoon, Nancy; Masur, Henry; Hadigan, Colleen; Gharib, Ahmed M.

2013-01-01

Background Non-calcified coronary artery plaque (NCAP) may be an important predictor of cardiovascular events, however, few studies have directly measured NCAP in HIV-infected individuals. Methods We completed a prospective cross-sectional evaluation of NCAP and coronary calcium scores using CT angiography in HIV-infected subjects (n=26) without known coronary artery disease (CAD), but who had one or more CAD risk factor and compared them to controls matched on age, race, sex, body mass index and Framingham risk score (n=26). Results There was no difference in coronary calcium scores (114 ± 218 vs. 124 ± 298 p=0.89) or NCAP volume (65 ± 86 mm3 vs. 63 ± 82 mm3, p=0.38) between HIV-infected subjects and controls, respectively. Among HIV-infected subjects, lower CD4 count was associated with increased NCAP volume (r=-0.52, p=0.006). CD4 count remained a significant predictor of NCAP in a multivariate analysis that adjusted for age and duration of antiretroviral therapy. Conclusion Plaque burden is similar between HIV-infected and uninfected individuals when matched on traditional CAD risk factors, however immune function may mediate the development of atherosclerosis in HIV infection. PMID:22293714

Quantifying CD4 receptor protein in two human CD4+ lymphocyte preparations for quantitative flow cytometry.

PubMed

Wang, Meiyao; Misakian, Martin; He, Hua-Jun; Bajcsy, Peter; Abbasi, Fatima; Davis, Jeffrey M; Cole, Kenneth D; Turko, Illarion V; Wang, Lili

2014-01-01

In our previous study that characterized different human CD4+ lymphocyte preparations, it was found that both commercially available cryopreserved peripheral blood mononuclear cells (PBMC) and a commercially available lyophilized PBMC (Cyto-Trol™) preparation fulfilled a set of criteria for serving as biological calibrators for quantitative flow cytometry. However, the biomarker CD4 protein expression level measured for T helper cells from Cyto-Trol was about 16% lower than those for cryopreserved PBMC and fresh whole blood using flow cytometry and mass cytometry. A primary reason was hypothesized to be due to steric interference in anti- CD4 antibody binding to the smaller sized lyophilized control cells. Targeted multiple reaction monitoring (MRM) mass spectrometry (MS) is used to quantify the copy number of CD4 receptor protein per CD4+ lymphocyte. Scanning electron microscopy (SEM) is utilized to assist searching the underlying reasons for the observed difference in CD4 receptor copy number per cell determined by MRM MS and CD4 expression measured previously by flow cytometry. The copy number of CD4 receptor proteins on the surface of the CD4+ lymphocyte in cryopreserved PBMCs and in lyophilized control cells is determined to be (1.45 ± 0.09) × 10(5) and (0.85 ± 0.11) × 10(5), respectively, averaged over four signature peptides using MRM MS. In comparison with cryopreserved PBMCs, there are more variations in the CD4 copy number in lyophilized control cells determined based on each signature peptide. SEM images of CD4+ lymphocytes from lyophilized control cells are very different when compared to the CD4+ T cells from whole blood and cryopreserved PBMC. Because of the lyophilization process applied to Cyto-Trol control cells, a lower CD4 density value, defined as the copy number of CD4 receptors per CD4+ lymphocyte, averaged over three different production lots is most likely explained by the loss of the CD4 receptors on damaged and

High Cell Surface Expression of CD4 Allows Distinction of CD4+CD25+ Antigen-specific Effector T Cells from CD4+CD25+ Regulatory T Cells in Murine Experimental Autoimmune Encephalomyelitis

PubMed Central

Li, Jinzhu; Ridgway, William; Fathman, C. Garrison; Tse, Harley Y.; Shaw, Michael K.

2008-01-01

Analysis of T regulatory cells (Treg) and T effector cells (Teff) in experimental autoimmune encephalomyelitis is complicated by the fact that both cell types express CD4 and CD25. We demonstrate that encephalitogenic T cells, following antigen recognition, up regulate cell surface expression of CD4. The CD4high sub-population contains all of the antigen response as shown by proliferation and cytokine secretion, and only these cells are capable of transferring EAE to naive animals. On the other hand, a FACS separable CD25+ sub-population of cells displayed consistent levels of CD4 prior to and after antigen stimulation. These cells displayed characteristics of Treg, such as expressing high levels of the Foxp3 gene and the ability to suppress mitogenic T cell responses. PMID:17920698

Morphologic examination of CD3-CD4(bright) cells in rat liver.

PubMed

Yamamoto, Satoshi; Sato, Yosinobu; Abo, Toru; Hatakeyama, Katsuyosi

2002-01-01

Recently, we found CD3-CD4(bright) cells with comparative specificity for normal rat liver. In the current study, we investigated the type and form of both CD3-CD4(bright) cells and CD3-CD4(dull) cells in the rat liver. The surface phenotype of hepatic mononuclear cells in Lewis rats was identified by using monoclonal antibodies including anti-CD4, anti-CD3, and antimacrophage in conjunction with two- or three-color immunofluorescence analysis. CD3-CD4(bright) cells and CD3-CD4(dull) cells were examined morphologically using May-Giemsa staining and scanning electron microscopy. The distribution of CD3-CD4(bright) cells and CD3-CD4(dull) cells 48 hours after intravenous administration of liposome-encapsulated dichloromethylene diphosphate was also investigated. In comparison to CD3-CD4(dull) cells, CD3-CD4(bright) cells were slightly larger macrophages with abundant cytoplasmic granules, being present with comparative specificity for normal rat liver and showing negligible effects by intravenous liposome-encapsulated dichloromethylene diphosphate administration. These data suggest that in normal young rat liver these CD3-CD4(dull) and CD3-CD4(bright) cells may be dendritic cells and Kupffer cells that shift from the liver to the spleen or vice versa. These cells may also be able to locally proliferate in liver or spleen due to changes in the developing liver.

Regulatory function of cytomegalovirus-specific CD4{sup +}CD27{sup -}CD28{sup -} T cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tovar-Salazar, Adriana; Patterson-Bartlett, Julie; Jesser, Renee

2010-03-15

CMV infection is characterized by high of frequencies of CD27{sup -}CD28{sup -} T cells. Here we demonstrate that CMV-specific CD4{sup +}CD27{sup -}CD28{sup -} cells are regulatory T cells (T{sub R}). CD4{sup +}CD27{sup -}CD28{sup -} cells sorted from CMV-stimulated PBMC of CMV-seropositive donors inhibited de novo CMV-specific proliferation of autologous PBMC in a dose-dependent fashion. Compared with the entire CMV-stimulated CD4{sup +} T-cell population, higher proportions of CD4{sup +}CD27{sup -}CD28{sup -} T{sub R} expressed FoxP3, TGFbeta, granzyme B, perforin, GITR and PD-1, lower proportions expressed CD127 and PD1-L and similar proportions expressed CD25, CTLA4, Fas-L and GITR-L. CMV-CD4{sup +}CD27{sup -}CD28{sup -}more » T{sub R} expanded in response to IL-2, but not to CMV antigenic restimulation. The anti-proliferative effect of CMV-CD4{sup +}CD27{sup -}CD28{sup -} T{sub R} significantly decreased after granzyme B or TGFbeta inhibition. The CMV-CD4{sup +}CD27{sup -}CD28{sup -} T{sub R} of HIV-infected and uninfected donors had similar phenotypes and anti-proliferative potency, but HIV-infected individuals had higher proportions of CMV-CD4{sup +}CD27{sup -}CD28{sup -} T{sub R}. The CMV-CD4{sup +}CD27{sup -}CD28{sup -} T{sub R} may contribute to the downregulation of CMV-specific and nonspecific immune responses of CMV-infected individuals.« less

Specific interaction of CXCR4 with CD4 and CD8{alpha}: Functional analysis of the CD4/CXCR4 interaction in the context of HIV-1 envelope glycoprotein-mediated membrane fusion

DOE Office of Scientific and Technical Information (OSTI.GOV)

Basmaciogullari, Stephane; Pacheco, Beatriz; Department of Pathology, Division of AIDS, Harvard Medical School, Boston, MA 02115

2006-09-15

We investigated possible interactions between HIV-1 receptor (CD4) and the main coreceptors CXCR4 and CCR5. We found that CD4 and CXCR4 coexpressed in 293T cells form a complex that can be immunoprecipitated with antibodies directed against the extracellular domain of either protein. Mutagenesis revealed that the CD4/CXCR4 interaction maps to two previously uncharacterized basic motifs in the cytoplasmic domain of CD4. HIV-1 envelope glycoprotein-mediated membrane fusion was found to be independent of the ability of CD4 and CXCR4 to interact, whether fusion was studied in a virus-cell or a cell-cell model. However, this interaction might explain the adaptation of HIV-1more » to CXCR4 as an alternative to CCR5. We found that CXCR4 also interacts with the cytoplasmic domain of CD8{alpha} in a way that is similar to the CD4/CXCR4 interaction. The CD4/CXCR4 and CD8{alpha}/CXCR4 interactions may thus be involved in cellular signaling pathways shared by the CD4 and CD8{alpha} molecules.« less

Apoptotic depletion of CD4+ T cells in idiopathic CD4+ T lymphocytopenia.

PubMed Central

Laurence, J; Mitra, D; Steiner, M; Lynch, D H; Siegal, F P; Staiano-Coico, L

1996-01-01

Progressive loss of CD4+ T lymphocytes, accompanied by opportunistic infections characteristic of the acquired immune deficiency syndrome, ahs been reported in the absence of any known etiology. The pathogenesis of this syndrome, a subset of idiopathic CD4+ T lymphocytopenia (ICL), is uncertain. We report that CD4+ T cells from seven of eight ICL patients underwent accelerated programmed cell death, a process facilitated by T cell receptor cross-linking. Apoptosis was associated with enhanced expression of Fas and Fas ligand in unstimulated cell populations, and partially inhibited by soluble anti-Fas mAb. In addition, apoptosis was suppressed by aurintricarboxylic acid, an inhibitor of calcium-dependent endonucleases and proteases, in cells from four of seven patients, The in vivo significance of these findings was supported by three factors: the absence of accelerated apoptosis in persons with stable, physiologic CD4 lymphopenia without clinical immune deficiency; detection of serum antihistone H2B autoantibodies, one consequence of DNA fragmentation, in some patients; and its selectivity, with apoptosis limited to the CD4 population in some, and occurring among CD8+ T cells predominantly in those individuals with marked depletion of both CD4+ T lymphocytes linked to clinical immune suppression have evidence for accelerated T cell apoptosis in vitro that may be pathophysiologic and amenable to therapy with apoptosis inhibitors. PMID:8609222

Age, sex and reproductive status affect boldness in dogs.

PubMed

Starling, Melissa J; Branson, Nicholas; Thomson, Peter C; McGreevy, Paul D

2013-09-01

Boldness in dogs is believed to be one end of the shy-bold axis, representing a super-trait. Several personality traits fall under the influence of this super-trait. Previous studies have found that boldness is affected by breed and breed groups, influences performance in sporting dogs, and is affected in some cases by the sex of the dogs. This study investigated the effects of dog age, sex and reproductive status on boldness in dogs by way of a dog personality survey circulated amongst Australian dog owners. Age had a significant effect on boldness (F=4.476; DF=16,758; P<0.001), with boldness decreasing with age in years. Males were bolder than females (F=19.219; DF=1,758; P<0.001) and entire dogs were bolder than neutered dogs (F=4.330; DF=1,758; P<0.038). The study indicates how behaviour may change in adult dogs as they age and adds to the literature on how sex and reproductive status may affect personality in dogs. Copyright © 2013 Elsevier Ltd. All rights reserved.

Age and CD161 Expression Contribute to Inter-Individual Variation in Interleukin-23 Response in CD8+ Memory Human T Cells

PubMed Central

Abraham, Clara; Cho, Judy H.

2013-01-01

The interleukin-23 (IL-23) pathway plays a critical role in the pathogenesis of multiple chronic inflammatory disorders, however, inter-individual variability in IL-23-induced signal transduction in circulating human lymphocytes has not been well-defined. In this study, we observed marked, reproducible inter-individual differences in IL-23 responsiveness (measured by STAT3 phosphorylation) in peripheral blood CD8+CD45RO+ memory T and CD3+CD56+ NKT cells. Age, but not gender, was a significant (Pearson’s correlation coefficient, r = −0.37, p = 0.001) source of variability observed in CD8+CD45RO+ memory T cells, with IL-23 responsiveness gradually decreasing with increasing age. Relative to cells from individuals demonstrating low responsiveness to IL-23 stimulation, CD8+CD45RO+ memory T cells from individuals demonstrating high responsiveness to IL-23 stimulation showed increased gene expression for IL-23 receptor (IL-23R), RORC (RORγt) and CD161 (KLRB1), whereas RORA (RORα) and STAT3 expression were equivalent. Similar to CD4+ memory T cells, IL-23 responsiveness is confined to the CD161+ subset in CD8+CD45RO+ memory T cells, suggesting a similar CD161+ precursor as has been reported for CD4+ Th17 cells. We observed a very strong positive correlation between IL-23 responsiveness and the fraction of CD161+, CD8+CD45RO+ memory T cells (r = 0.80, p<0.001). Moreover, the fraction of CD161+, CD8+CD45RO+ memory T cells gradually decreases with aging (r = −0.34, p = 0.05). Our data define the inter-individual differences in IL-23 responsiveness in peripheral blood lymphocytes from the general population. Variable expression of CD161, IL-23R and RORC affects IL-23 responsiveness and contributes to the inter-individual susceptibility to IL-23-mediated defenses and inflammatory processes. PMID:23469228

Relationship of ethnicity and CD4 Count with glucose metabolism among HIV patients on Highly-Active Antiretroviral Therapy (HAART)

PubMed Central

2013-01-01

Background HIV patients on HAART are prone to metabolic abnormalities, including insulin resistance, lipodystrophy and diabetes. This study purports to investigate the relationship of ethnicity and CD4+ T cell count attained after stable highly-active antiretroviral treatment (HAART) with glucose metabolism in hyperrtriglyceridemic HIV patients without a history of diabetes. Methods Demographic, anthropometric, clinical, endocrinologic, energy expenditure and metabolic measures were obtained in 199 multiethnic, healthy but hypertriglyceridemic HIV-infected patients [46% Hispanic, 17% African-American, 37% Non-Hispanic White (NHW)] on stable HAART without a history of diabetes. The relationship of glucose and insulin responses to ethnicity, CD4 strata (low (<300/cc) or moderate-to-high (≥ 300/cc)), and their interaction was determined. Results African-Americans had significantly greater impairment of glucose tolerance (P < 0.05) and HbA1c levels (P < .001) than either Hispanics or NHWs. In multivariate models, after adjusting for confounders (age, sex, HIV/HAART duration, smoking, obesity, glucose, insulin and lipids), African-Americans and Hispanics had significantly higher HbA1c and 2-hour glucose levels than NHW’s. Demonstrating a significant interaction between ethnicity and CD4 count (P = 0.023), African Americans with CD4 <300/cc and Hispanics with CD4 ≥300/cc had the most impaired glucose response following oral glucose challenge. Conclusions Among hypertriglyceridemic HIV patients on HAART, African-Americans and Hispanics are at increased risk of developing diabetes. Ethnicity also interacts with CD4+ T cell count attained on stable HAART to affect post-challenge glycemic response. PMID:23607267

CD4+CD25hiFOXP3+ cells in cord blood of neonates born from filaria infected mother are negatively associated with CD4+Tbet+ and CD4+RORγt+ T cells.

PubMed

Ateba-Ngoa, Ulysse; Mombo-Ngoma, Ghyslain; Zettlmeissl, Eva; van der Vlugt, Luciën E P M; de Jong, Sanne E; de Jong, Sanne; Matsiegui, Pierre-Blaise; Ramharter, Michael; Kremsner, Peter G; Yazdanbakhsh, Maria; Adegnika, Ayola Akim

2014-01-01

Children who have been exposed in utero to maternal filarial infection are immunologically less responsive to filarial antigens, have less pathology, and are more susceptible to acquire infection than offspring of uninfected mothers. Moreover children from filaria infected mothers have been shown to be less responsive to vaccination as a consequence of an impairment of their immune response. However, it is not well known how in utero exposure to parasite antigens affects cellular immune responses. Here, 30 pregnant women were examined for the presence of microfilaria of Loa loa and Mansonella perstans in peripheral blood. At delivery, cord blood mononuclear cells (CBMC) were obtained and the CD4+T cells were phenotyped by expression of the transcription factors Tbet, RORγt, and FOXP3. No significant difference was observed between newborns from infected versus uninfected mothers in the frequencies of total CD4+T cells and CD4+T cells subsets including CD4+Tbet+, CD4+RORγt+ T and CD4+CD25hiFOXP3+ T cells. However, there was a negative association between CD4+CD25hiFOXP3+T cells and CD4+Tbet+ as well as CD4+RORγt+ T cells in the infected group only (B = -0.242, P = 0.002; B = -0.178, P = 0.013 respectively). Our results suggest that filarial infection during pregnancy leads to an expansion of functionally active regulatory T cells that keep TH1 and TH17 in check.

Phenotypic and Functional Characterization of Peripheral Blood Lymphocytes from Various Age- and Sex-Specific Groups of Owl Monkeys (Aotus nancymaae).

PubMed

Nehete, Pramod N; Nehete, Bharti P; Chitta, Sriram; Williams, Lawrence E; Abee, Christian R

2017-02-01

Owl monkeys (Aotus nancymaae) are New World NHP that serve an important role in vaccine development and as a model for human disease conditions such as malaria. Despite the past contributions of this animal model, limited information is available about the phenotype and functional properties of peripheral blood lymphocytes in reference to sex and age. Using a panel of human antibodies and a set of standardized human immune assays, we identified and characterized various peripheral blood lymphocyte subsets, evaluated the immune functions of T cells, and analyzed cytokines relative to sex and age in healthy owl monkeys. We noted age- and sex-dependent changes in CD28+ (an essential T cell costimulatory molecule) and CD95+ (an apoptotic surface marker) T cells and various levels of cytokines in the plasma. In immune assays of freshly isolated peripheral blood mononuclear cells, IFNγ and perforin responses were significantly higher in female than in male monkeys and in young adults than in juvenile and geriatric groups, despite similar lymphocyte (particularly T cell) populations in these groups. Our current findings may be useful in exploring Aotus monkeys as a model system for the study of aging, susceptibility to infectious diseases, and age-associated differences in vaccine efficacy, and other challenges particular to pediatric and geriatric patients.

Sex differences and sex hormones in anxiety-like behavior of aging rats.

PubMed

Domonkos, Emese; Borbélyová, Veronika; Csongová, Melinda; Bosý, Martin; Kačmárová, Mária; Ostatníková, Daniela; Hodosy, Július; Celec, Peter

2017-07-01

Sex differences in the prevalence of affective disorders might be attributable to different sex hormone milieu. The effects of short-term sex hormone deficiency on behavior, especially on anxiety have been studied in numerous animal experiments, mainly on young adult rats and mice. However, sex differences in aged animals and the effects of long-term hypogonadism are understudied. The aim of our study was to analyze sex differences in anxiety-like behavior in aged rats and to prove whether they can be attributed to endogenous sex hormone production in males. A battery of tests was performed to assess anxiety-like behavior in aged female, male and gonadectomized male rats castrated before puberty. In addition, the aged gonadectomized male rats were treated with a single injection of estradiol or testosterone or supplemented with estradiol for two-weeks. Female rats displayed a less anxious behavior than male rats in most of the conducted behavioral tests except the light-dark box. Long-term androgen deficiency decreased the sex difference in anxiety either partially (open field, PhenoTyper cage) or completely (elevated plus maze). Neither single injection of sex hormones, nor two-week supplementation of estradiol in gonadectomized aged male rats significantly affected their anxiety-like behavior in the elevated plus maze. In conclusion, our results confirm sex differences in anxiety in aged rats likely mediated by endogenous testosterone production in males. Whether long-term supplementation with exogenous sex hormones could affect anxiety-like behavior in elderly individuals remains to be elucidated. Copyright © 2017 Elsevier Inc. All rights reserved.

CD4+CD25hiFOXP3+ Cells in Cord Blood of Neonates Born from Filaria Infected Mother Are Negatively Associated with CD4+Tbet+ and CD4+RORγt+ T Cells

PubMed Central

Zettlmeissl, Eva; van der Vlugt, Luciën E. P. M.; de Jong, Sanne; Matsiegui, Pierre-Blaise; Ramharter, Michael; Kremsner, Peter G.; Yazdanbakhsh, Maria; Adegnika, Ayola Akim

2014-01-01

Background Children who have been exposed in utero to maternal filarial infection are immunologically less responsive to filarial antigens, have less pathology, and are more susceptible to acquire infection than offspring of uninfected mothers. Moreover children from filaria infected mothers have been shown to be less responsive to vaccination as a consequence of an impairment of their immune response. However, it is not well known how in utero exposure to parasite antigens affects cellular immune responses. Methodology Here, 30 pregnant women were examined for the presence of microfilaria of Loa loa and Mansonella perstans in peripheral blood. At delivery, cord blood mononuclear cells (CBMC) were obtained and the CD4+T cells were phenotyped by expression of the transcription factors Tbet, RORγt, and FOXP3. Results No significant difference was observed between newborns from infected versus uninfected mothers in the frequencies of total CD4+T cells and CD4+T cells subsets including CD4+Tbet+, CD4+RORγt+ T and CD4+CD25hiFOXP3+ T cells. However, there was a negative association between CD4+CD25hiFOXP3+T cells and CD4+Tbet+ as well as CD4+RORγt+ T cells in the infected group only (B = −0.242, P = 0.002; B = −0.178, P = 0.013 respectively). Conclusion Our results suggest that filarial infection during pregnancy leads to an expansion of functionally active regulatory T cells that keep TH1 and TH17 in check. PMID:25531674

Isolation of CD4+CD25+ regulatory T cells for clinical trials.

PubMed

Hoffmann, Petra; Boeld, Tina J; Eder, Ruediger; Albrecht, Julia; Doser, Kristina; Piseshka, Biserka; Dada, Ashraf; Niemand, Claudia; Assenmacher, Mario; Orsó, Evelyn; Andreesen, Reinhard; Holler, Ernst; Edinger, Matthias

2006-03-01

The adoptive transfer of donor CD4+CD25+ regulatory T cells has been shown to protect from lethal graft-versus-host disease after allogeneic bone marrow transplantation in murine disease models. Efficient isolation strategies that comply with good manufacturing practice (GMP) guidelines are prerequisites for the clinical application of human CD4+CD25+ regulatory T cells. Here we describe the isolation of CD4+CD25+ T cells with regulatory function from standard leukapheresis products by using a 2-step magnetic cell-separation protocol performed under GMP conditions. The generated cell products contained on average 49.5% CD4+CD25high T cells that phenotypically and functionally represented natural CD4+CD25+ regulatory T cells and showed a suppressive activity comparable to that of CD4+CD25+ regulatory T-cell preparations purified by non-GMP-approved fluorescence-activated cell sorting.

Sex- and age-dependent effects of celiac disease on growth and weight gain in children with type 1 diabetes: Analysis of the type 1 diabetes Exchange Clinic Registry.

PubMed

Simmons, Jill H; Foster, Nicole C; Riddlesworth, Tonya D; DuBose, Stephanie N; Redondo, Maria J; Liu, Edwin; Freemark, Michael

2018-06-01

Celiac disease (CD) is common in patients with type 1 diabetes (T1D) and effects of CD on growth in children with T1D remain unclear. We analyzed heights, weights, and body mass index (BMI) in 215 matched pediatric CD/control pairs in the T1D Exchange Clinic Registry. CD was defined by a clinic-reported diagnosis and positive celiac serology (n = 80) and/or positive small bowel biopsy (n = 135). Cases and controls were matched by age (mean: 14 years), diabetes duration (median: 7 years), sex (57% female), and clinic site. There were 5569 height/weight measurements. Gluten was restricted for varying periods of time in 61% of females and 51% of males with CD. Females with CD were shorter than female controls at all ages (P = 0.01). Weight z-scores were initially lower in preschool females with CD but similar to controls by middle childhood. Males with CD were initially shorter but adult heights were similar. Height in both sexes and weight in males were lower in CD participants diagnosed at younger age. Growth in T1D children with biopsy-proven CD, 76% of them were gluten-restricted, was comparable to that of T1D controls. Concurrent CD impairs linear growth in T1D females at all stages of development and in young T1D males. Young females with CD have lower weights, but both sexes have similar weights by middle childhood. Children younger at CD onset remain shorter throughout childhood; males younger at CD onset have persistently lower weights. Long-term gluten restriction may restore weight gain and linear growth in children with CD and T1D. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

CMV induces expansion of highly polyfunctional CD4+ T cell subset coexpressing CD57 and CD154.

PubMed

Pera, Alejandra; Vasudev, Anusha; Tan, Crystal; Kared, Hassen; Solana, Rafael; Larbi, Anis

2017-02-01

CD4 + T cells are essential for human CMV infection control. CMV-specific CD4 + T cells possess antiviral functions and participate in anti-CMV humoral/cellular responses. In the elderly, CMV infection impairs immunity to other viruses and has been traditionally associated with T cell senescence; however, recent results suggest that, in younger people, CMV confers immune protection against other pathogens (heterologous immunity). To shed light on this controversy, we analyzed latent CMV infection effects on the quality of young individuals' immune response, specifically, the presence of polyfunctional T cells through an extensive phenotypic and functional characterization of the CD4 + T cell subset. CD154 expression, degranulation (CD107a), and cytokine production (IFN-γ, TNF-α, and IL-2) as well as T cell phenotype markers (CD57, CD28, and CD27) were analyzed. We demonstrate that CD4 + T cells that coexpress CD57 and CD154, which are exclusively present in CMV-positive individuals, are the most polyfunctional CD4 + subset, whereas CD4 + CD27 + CD28 - T cells associate with lower polyfunctionality. Conversely, the frequency of CD4 + CD28 + T cells correlates with higher polyfunctionality of CD4 + CD57 - T cells from CMV-seronegative individuals and CD4 + CD57 + CD154 + T cells from CMV-seropositive individuals. Thus, polyfunctionality is a property of central memory CD4 + T cells in CMV-seronegative individuals, whereas after CMV infection, polyfunctional T cells become highly differentiated, which allows efficient eradication of infections. We extend previous observations of the impact of CMV on CD8 + T cell functionality to the CD4 + T cell compartment, revealing CD57 as a polyfunctionality marker of T cells which expands after CMV infection. CD57 + T cells have been associated with inflammatory conditions, but their potential role in the response against infectious disease and vaccination should now be investigated. © Society for Leukocyte Biology.

Trends in and correlates of CD4+ cell count at antiretroviral therapy initiation after changes in national ART guidelines in Rwanda

PubMed Central

Mutimura, Eugene; Addison, Diane; Anastos, Kathryn; Hoover, Donald; Dusingize, Jean Claude; Karenzie, Ben; Izimukwiye, Isabelle; Mutesa, Leo; Nsanzimana, Sabin; Nashi, Denis

2015-01-01

Background Initiation of antiretroviral therapy (ART) in the advanced stages of HIV infection remains a major challenge in sub-Saharan Africa. This study was conducted to better understand barriers and enablers to timely ART initiation in Rwanda where ART coverage is high and national ART eligibility guidelines first expanded in 2007–2008. Methods Using data on 6326 patients (≥15 years) at five Rwandan clinics, we assessed trends and correlates of CD4+ cell count at ART initiation and the proportion initiating ART with advanced HIV disease (CD4+ <200 cells/µl or WHO stage IV). Results Out of 6326 patients, 4486 enrolling in HIV care initiated ART with median CD4+ cell count of 211 cells/µl [interquartile range: 131–300]. Median CD4+ cell counts at ART initiation increased from 183 cells/µl in 2007 to 293 cells/µl in 2011–2012, and the proportion with advanced HIV disease decreased from 66.2 to 29.4%. Factors associated with a higher odds of advanced HIV disease at ART initiation were male sex [adjusted odds ratios (AOR) = 1.7; 95% confidence interval (CI): 1.3–2.1] and older age (AOR46–55+ vs. <25 = 2.3; 95% CI: 1.2–4.3). Among those initiating ART more than 1 year after enrollment in care, those who had a gap in care of 12 or more months prior to ART initiation had higher odds of advanced HIV disease (AOR = 5.2; 95% CI: 1.2–21.1). Conclusion Marked improvements in the median CD4+ cell count at ART initiation and proportion initiating ART with advanced HIV disease were observed following the expansion of ART eligibility criteria in Rwanda. However, sex disparities in late treatment initiation persisted through 2011–2012, and appeared to be driven by later diagnosis and/or delayed linkage to care among men. PMID:25562492

CD4 cell responses to combination antiretroviral therapy in patients starting therapy at high CD4 cell counts.

PubMed

Wright, Stephen T; Carr, Andrew; Woolley, Ian; Giles, Michelle; Hoy, Jennifer; Cooper, David A; Law, Matthew G

2011-09-01

To examine CD4 cell responses to combination antiretroviral therapy (cART) in patients enrolled in the Australian HIV Observational Database who commenced cART at CD4 cell counts >350 cells per microliter. CD4 cell counts were modelled using random effects, repeated measurement models in 432 HIV-infected adults from Australian HIV Observational Database who commenced their first cART regimen and had a baseline CD4 count >350 cells per microliter. Using published AIDS and/or death incidence rates combined with the data summarized by time and predicted CD4 cell count, we calculated the expected reduction in risk of an event for different starting baseline CD4 strata. Mean CD4 counts increased above 500 cells per microliter in all baseline CD4 strata by 12 months (means of 596, 717, and 881 cells/μL in baseline CD4 strata 351-500, 501-650, and >650 cells/μL, respectively) and after 72 months since initiating cART, mean CD4 cell counts (by increasing baseline CD4 strata) were 689, 746, 742 cells per microliter. The expected reduction in risk of mortality for baseline CD4 counts >650 cells per microliter relative to 351-500 cells per microliter was approximately 8%, an absolute risk reduction 0.33 per 1000 treated patient-years. Patients starting cART at high CD4 cell counts (>650 cells/μL) tend to maintain this immunological level over 6 years of follow-up. Patients starting from 351 to 500 CD4 cells per microliter achieve levels of >650 cells per microliter after approximately 3 years of cART. Initiating cART with a baseline CD4 count 501-650 or >650 cells per microliter relative to 351-500 cells per microliter indicated a minimal reduction in risk of AIDS incidence and/or death.

Identification of CD4+ T-cell-derived CD161+ CD39+ and CD39+CD73+ microparticles as new biomarkers for rheumatoid arthritis.

PubMed

Fan, Wenqiang; Wang, Wenxiang; Wu, Jie; Ma, Ling; Guo, Jinyan

2017-02-01

This study aimed to identify CD4 + T-cell-derived microparticles (MPs) and investigate their roles in rheumatoid arthritis (RA). Synovial fluids from 34 RA, 33 osteoarthritis patients and 42 healthy individuals were analyzed by flow cytometry. Human fibroblast-like synoviocytes and peripheral blood mononuclear cells were cultured with or without isolated MPs, chemokines and cytokines were measured by ELISA. CD4 + CD161 + CD39 + and CD4 + CD39 + CD73 + MPs were abundantly present in RA patients, which were positively or negatively correlated with RA features, respectively. Chemokines CCL20, CCL17 and CCL22, and cytokines IL-17 and IL-10 were influenced by these MPs in human fibroblast-like synoviocytes (HFLS) or PMBCs. CD4 + T-cell-derived CD161 + CD39 + and CD39 + CD73 + MPs could serve as new reciprocal biomarkers for RA evaluation.

Non-calcified coronary plaque volume inversely related to CD4(+) T-cell count in HIV infection.

PubMed

Duarte, Horacio; Matta, Jatin R; Muldoon, Nancy; Masur, Henry; Hadigan, Colleen; Gharib, Ahmed M

2012-01-01

Non-calcified coronary artery plaque (NCAP) might be an important predictor of cardiovascular events; however, few studies have directly measured NCAP in HIV-infected individuals. We completed a prospective cross-sectional evaluation of NCAP and coronary calcium scores using computed tomography angiography in HIV-infected patients (n=26) without known coronary artery disease (CAD), but who had one or more CAD risk factor(s), and compared them with controls matched on age, race, sex, body mass index and Framingham Risk Score (n=26). There was no difference in coronary calcium scores (114 ± 218 versus 124 ± 298; P=0.89) or NCAP volume (65 ± 86 mm(3) versus 63 ± 82 mm(3); P=0.38) between HIV-infected patients and controls, respectively. Among HIV-infected patients, lower CD4(+) T-cell count was associated with increased NCAP volume (r=-0.52, P=0.006). The CD4(+) T-cell count remained a significant predictor of NCAP in a multivariate analysis that adjusted for age and duration of antiretroviral therapy. Plaque burden is similar between HIV-infected and uninfected individuals when matched on traditional CAD risk factors; however, immune function might mediate the development of atherosclerosis in HIV infection.

Opioid maintenance therapy restores CD4+ T cell function by normalizing CD4+CD25(high) regulatory T cell frequencies in heroin user.

PubMed

Riss, Gina-Lucia; Chang, Dae-In; Wevers, Carolin; Westendorf, Astrid M; Buer, Jan; Scherbaum, Norbert; Hansen, Wiebke

2012-08-01

There is an increasing body of evidence that heroin addiction is associated with severe alterations in immune function, which might contribute to an increased risk to contract infectious diseases like hepatitis B and C or HIV. However, the impact of heroin consumption on the CD4(+) T cell compartment is not well understood. Therefore, we analyzed the frequency and functional phenotype of CD4(+) T cells as well as immune-suppressive CD4(+)CD25(high) regulatory T cells (Tregs) isolated from the peripheral blood of opiate addicts currently abusing heroin (n=27) in comparison to healthy controls (n=25) and opiate addicts currently in opioid maintenance treatment (OMT; n=27). Interestingly, we detected a significant increase in the percentage of CD4(+)CD25(high) Tregs in the peripheral blood of heroin addicted patients in contrast to patients in OMT. The proliferative response of CD4(+) T cells upon stimulation with anti-CD3 and anti-CD28 antibodies was significantly decreased in heroin users, but could be restored by depletion of CD25(high) regulatory T cells from CD4(+) T cells to similar values as observed from healthy controls and patients in OMT. These results suggest that impaired immune responses observed in heroin users are related to the expansion of CD4(+)CD25(high) Tregs and more importantly, can be restored by OMT. Copyright © 2012 Elsevier Inc. All rights reserved.

Characterization of circulating CD4+ CD8+ double positive and CD4- CD8- double negative T-lymphocyte in children with β-thalassemia major.

PubMed

Zahran, Asmaa M; Saad, Khaled; Elsayh, Khalid I; Alblihed, Mohamd A

2017-03-01

Infectious complications represent the second most common cause of mortality and a major cause of morbidity in β-thalassemia major (BTM), with a prevalence of 12-13%. The data on unconventional T-lymphocyte subsets in BTM children are limited. The aim of the present study was to investigate and evaluate phenotypic alterations in CD4 + CD8 + double positive (DP), CD4 - CD8 - double negative (DN), and natural killer T-lymphocytes (NKT) in BTM children in comparison to healthy controls. Our case control study included 80 children with BTM and 40 healthy children as controls. Assessment of unconventional T-lymphocyte populations was done using sensitive four-color flow cytometry (FACSCalibur). Our analysis of the data showed a significantly higher frequency CD4 + CD8 + (double-positive) T cells, CD4 - CD8 - (double negative) T cells, and natural killer T cells in the peripheral blood of both BTM groups (splenectomized and non-splenectomized) as compared to healthy controls, suggesting that these cells may play a role in the clinical course of BTM. The relationship of the unconventional T-lymphocytes to immune disorders in BTM children remains to be determined. Further longitudinal study with a larger sample size is warranted to elucidate the role these cells in BTM. TRIAL NUMBER: UMIN000018950.

CD4+ Primary T Cells Expressing HCV-Core Protein Upregulate Foxp3 and IL-10, Suppressing CD4 and CD8 T Cells

PubMed Central

Aguado, Enrique; Garcia-Cozar, Francisco

2014-01-01

Adaptive T cell responses are critical for controlling HCV infection. While there is clinical evidence of a relevant role for regulatory T cells in chronic HCV-infected patients, based on their increased number and function; mechanisms underlying such a phenomena are still poorly understood. Accumulating evidence suggests that proteins from Hepatitis C virus can suppress host immune responses. We and others have shown that HCV is present in CD4+ lymphocytes from chronically infected patients and that HCV-core protein induces a state of unresponsiveness in the CD4+ tumor cell line Jurkat. Here we show that CD4+ primary T cells lentivirally transduced with HCV-core, not only acquire an anergic phenotype but also inhibit IL-2 production and proliferation of bystander CD4+ or CD8+ T cells in response to anti-CD3 plus anti-CD28 stimulation. Core-transduced CD4+ T cells show a phenotype characterized by an increased basal secretion of the regulatory cytokine IL-10, a decreased IFN-γ production upon stimulation, as well as expression of regulatory T cell markers, CTLA-4, and Foxp3. A significant induction of CD4+CD25+CD127lowPD-1highTIM-3high regulatory T cells with an exhausted phenotype was also observed. Moreover, CCR7 expression decreased in HCV-core expressing CD4+ T cells explaining their sequestration in inflamed tissues such as the infected liver. This work provides a new perspective on de novo generation of regulatory CD4+ T cells in the periphery, induced by the expression of a single viral protein. PMID:24465502

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

Most Do, but Some Do Not: CD4+CD25− T Cells, but Not CD4+CD25+ Treg Cells, Are Cytolytic When Redirected by a Chimeric Antigen Receptor (CAR)

PubMed Central

Hombach, Andreas A.; Abken, Hinrich

2017-01-01

Evidences are accumulating that CD4+ T cells can physiologically mediate antigen specific target cell lysis. By circumventing major histocompatibility complex (MHC)-restrictions through an engineered chimeric antigen receptor (CAR), CD4+ T cells lyse defined target cells as efficiently as do CD8+ T cells. However, the cytolytic capacity of redirected CD4+CD25− T cells, in comparison with CD4+CD25+ regulatory T (Treg) cells was so far not thoroughly defined. Treg cells require a strong CD28 signal together with CD3ζ for activation. We consequently used a CAR with combined CD28­CD3ζ signalling for redirecting CD4+CD25− T cells and CD4+CD25+ Treg cells from the same donor. CAR redirected activation of these T cell subsets and induced a distinct cytokine pattern with high IL-10 and a lack of IL-2 release by Treg cells. Despite strong antigen-specific activation, CAR Treg cells produced only weak target cell lysis, whereas CD4+CD25− CAR T cells were potent killers. Cytolysis did not correlate with the target cell sensitivity to Fas/FasL mediated killing; CD4+CD25− T cells upregulated perforin and granzyme B upon CAR activation, whereas Treg cells did less. The different cytolytic capacities of CAR redirected conventional CD4+ cells and Treg cells imply their use for different purposes in cell therapy. PMID:28850063

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

CD127 and CD25 expression defines CD4+ T cell subsets that are differentially depleted during HIV infection.

PubMed

Dunham, Richard M; Cervasi, Barbara; Brenchley, Jason M; Albrecht, Helmut; Weintrob, Amy; Sumpter, Beth; Engram, Jessica; Gordon, Shari; Klatt, Nichole R; Frank, Ian; Sodora, Donald L; Douek, Daniel C; Paiardini, Mirko; Silvestri, Guido

2008-04-15

Decreased CD4(+) T cell counts are the best marker of disease progression during HIV infection. However, CD4(+) T cells are heterogeneous in phenotype and function, and it is unknown how preferential depletion of specific CD4(+) T cell subsets influences disease severity. CD4(+) T cells can be classified into three subsets by the expression of receptors for two T cell-tropic cytokines, IL-2 (CD25) and IL-7 (CD127). The CD127(+)CD25(low/-) subset includes IL-2-producing naive and central memory T cells; the CD127(-)CD25(-) subset includes mainly effector T cells expressing perforin and IFN-gamma; and the CD127(low)CD25(high) subset includes FoxP3-expressing regulatory T cells. Herein we investigated how the proportions of these T cell subsets are changed during HIV infection. When compared with healthy controls, HIV-infected patients show a relative increase in CD4(+)CD127(-)CD25(-) T cells that is related to an absolute decline of CD4(+)CD127(+)CD25(low/-) T cells. Interestingly, this expansion of CD4(+)CD127(-) T cells was not observed in naturally SIV-infected sooty mangabeys. The relative expansion of CD4(+)CD127(-)CD25(-) T cells correlated directly with the levels of total CD4(+) T cell depletion and immune activation. CD4(+)CD127(-)CD25(-) T cells were not selectively resistant to HIV infection as levels of cell-associated virus were similar in all non-naive CD4(+) T cell subsets. These data indicate that, during HIV infection, specific changes in the fraction of CD4(+) T cells expressing CD25 and/or CD127 are associated with disease progression. Further studies will determine whether monitoring the three subsets of CD4(+) T cells defined based on the expression of CD25 and CD127 should be used in the clinical management of HIV-infected individuals.

In ovo injection of anti-chicken CD25 monoclonal antibodies depletes CD4+CD25+ T cells in chickens.

PubMed

Shanmugasundaram, Revathi; Selvaraj, Ramesh K

2013-01-01

The CD4(+)CD25(+) cells have T regulatory cell properties in chickens. This study investigated the effect of in ovo injection of anti-chicken CD25 monoclonal antibodies (0.5 mg/egg) on CD4(+)CD25(+) cell depletion and on amounts of interleukin-2 mRNA and interferon-γ mRNA in CD4(+)CD25(-) cells posthatch. Anti-chicken CD25 or PBS (control) was injected into 16-d-old embryos. Chicks hatched from eggs injected with anti-chicken CD25 antibodies had a lower CD4(+)CD25(+) cell percentage in the blood until 25 d posthatch. The anti-chicken CD25 antibody injection nearly depleted CD4(+)CD25(+) cells in the blood until 16 d posthatch. At 30 d posthatch, the CD4(+)CD25(+) cell percentage in the anti-CD25-antibody-injected group was comparable with the percentage in the control group. At 16 d posthatch, the anti-chicken CD25 antibody injection decreased CD4(+)CD25(+) cell percentages in the thymus, spleen, and cecal tonsils. Chickens hatched from anti-CD25-antibody-injected eggs had approximately 25% of CD4(+)CD25(+) cells in the cecal tonsils and thymus compared with those in the cecal tonsils and thymus of the control group. The CD4(+)CD25(-) cells from the spleen and cecal tonsils of chicks hatched from anti-chicken-CD25-injected eggs had higher amounts of interferon-γ and interleukin-2 mRNA than CD4(+)CD25(-) cells from the control group. It could be concluded that injecting anti-chicken CD25 antibodies in ovo at 16 d of incubation nearly depleted the CD4(+)CD25(+) cells until 25 d posthatch.

CD147-mediated chemotaxis of CD4+CD161+ T cells may contribute to local inflammation in rheumatoid arthritis.

PubMed

Lv, Minghua; Miao, Jinlin; Zhao, Peng; Luo, Xing; Han, Qing; Wu, Zhenbiao; Zhang, Kui; Zhu, Ping

2018-01-01

CD161 is used as a surrogate marker for Th17 cells, which are implicated in the pathogenesis of rheumatoid arthritis (RA). In this study, we evaluated the percentage, clinical significance, and CD98 and CD147 expression of CD4 + CD161 + T cells. The potential role of CD147 and CD98 in cyclophilin A-induced chemotaxis of CD4 + CD161 + T cells was analyzed. Thirty-seven RA patients, 15 paired synovial fluid (SF) of RA, and 22 healthy controls were recruited. The cell populations and surface expression of CD98 and CD147 were analyzed by flow cytometry. Spearman's rank correlation coefficient and multiple linear regression were applied to calculate the correlations. Chemotaxis assay was used to investigate CD4 + CD161 + T cell migration. We found that the percentage of CD4 + CD161 + T cells and their expression of CD147 and CD98 in SF were higher than in the peripheral blood of RA patients. Percentage of SF CD4 + CD161 + T cells was positively correlated with 28-Joint Disease Activity Score (DAS28). CD147 monoclonal antibody (HAb18) attenuated the chemotactic ability of CD4 + CD161 + T cells. An increased CD4 + CD161 + T cell percentage and expression of CD147 and CD98 were shown in RA SF. Percentage of SF CD4 + CD161 + T cells can be used as a predictive marker of disease activity in RA. CD147 block significantly decreased the chemotactic index of CD4 + CD161 + cells induced by cyclophilin A (CypA). These results imply that the accumulation of CD4 + CD161 + T cells in SF and their high expression of CD147 may be associated with CypA-mediated chemotaxis and contribute to local inflammation in RA.

Apolipoprotein E and Alzheimer disease: Genotype-specific risks by age and sex

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bickeboeller, H.; Babron, M.C.; Clerget-Darpoux, F.

1997-02-01

The distribution of apolipoprotein E (APOE) genotypes as a function of age and sex has been examined in a French population of 417 Alzheimer disease (AD) patients and 1,030 control subjects. When compared to the APOE {epsilon}3 allele, an increased risk associated with the APOE {epsilon}4 allele (odds ratio [OR] [{epsilon}4] = 2.7 with 95% confidence interval [CI] = 2.0-3.6; P < .001) and a protective effect of the APOE {epsilon}2 allele (OR[{epsilon}2] = 0.5 with 95% CI = 0.3-0.98; P = .012) were retrieved. An effect of the {epsilon}4 allele dosage on susceptibility was confirmed (OR[{epsilon}4/{epsilon}4] vs. the {epsilon}3/{epsilon}3more » genotype = 11.2 [95% CI = 4.0-31.6]; OR[{epsilon}3/{epsilon}4] vs. the {epsilon}3/{epsilon}3 genotype = 2.2 [95% Cl = 1.5-3.5]). The frequency of the {epsilon}4 allele was lower in male cases than in female cases, but, since a similar difference was found in controls, this does not lead to a difference in OR between sex. ORs for the {epsilon}4 allele versus the {epsilon}3 allele, OR({epsilon}4), were not equal in all age classes: OR({epsilon}4) in the extreme groups with onset at < 60 years or > 79 years were significantly lower than those from the age groups 60-79 years. In {epsilon}3/{epsilon}4 individuals, sex-specific lifetime risk estimates by age 85 years (i.e., sex-specific penetrances by age 85 years) were 0.14 (95% CI 0.04-0.30) for men and 0.17 (95% CI 0.09-0.28) for women. 53 refs., 1 fig., 3 tabs.« less

Age difference asymmetry and a two-sex perspective.

PubMed

Ni Bhrolchain, M

1992-01-01

-83, the age differences in women's 1st marriages increased and men's decreases; and 4) the low of 1.6 years' age difference for bachelors was the same in 1987 and 1901-5. A summary in table form is provided of the studies conducted which show variation over time in the average age difference between spouses. The implications of age differences are that calculations of the probability of widowhood will be affected as well as simulations of family and household processes. It is concluded that accurate demographic accounting requires a 2-sex perspective. Retrospective surveys should collect marital histories of men and women, particularly due to the high rates of divorce and remarriage.

Theoretical investigation of the structural, electronic, and thermodynamic properties of CdS1-xSex alloys

NASA Astrophysics Data System (ADS)

Long, Debing; Li, Mingkai; Meng, Dongxue; Ahuja, Rajeev; He, Yunbin

2018-03-01

In this work, the structural, electronic, and thermodynamic properties of wurtzite (WZ) and zincblende (ZB) CdS1-xSex alloys are investigated using the density functional theory (DFT) and the cluster expansion method. A special quasirandom structure containing 16 atoms is constructed to calculate the band structures of random alloys. The band gaps of CdS1-xSex alloys are direct and decrease as the Se content increases. The delta self-consistent-field method is applied to correct band gaps that are underestimated by DFT. The band offsets clearly reflect the variation in valence band maxima and conduction band minima, thus providing information useful to the design of relevant quantum well structures. The positive formation enthalpies of both phases imply that CdS1-xSex is an immiscible system and tends to phase separate. The influence of lattice vibrations on the phase diagram is investigated by calculating the phonon density of states. Lattice vibration effects can reduce the critical temperature Tc and increase alloy solid solubilities. This influence is especially significant in the ZB structure. When only chemical interactions are present, the Tc values for WZ- and ZB-CdS1-xSex are 260 K and 249 K, respectively. The lattice vibration enthalpy and entropy lower the Tc to 255 K and 233 K, respectively.

Sex differences in elite swimming with advanced age are less than marathon running.

PubMed

Senefeld, J; Joyner, M J; Stevens, A; Hunter, S K

2016-01-01

The sex difference in marathon performance increases with finishing place and age of the runner but whether this occurs among swimmers is unknown. The purpose was to compare sex differences in swimming velocity across world record place (1st-10th), age group (25-89 years), and event distance. We also compared sex differences between freestyle swimming and marathon running. The world's top 10 swimming times of both sexes for World Championship freestyle stroke, backstroke, breaststroke, and butterfly events and the world's top 10 marathon times in 5-year age groups were obtained. Men were faster than women for freestyle (12.4 ± 4.2%), backstroke (12.8 ± 3.0%), and breaststroke (14.5 ± 3.2%), with the greatest sex differences for butterfly (16.7 ± 5.5%). The sex difference in swimming velocity increased across world record place for freestyle (P < 0.001), breaststroke, and butterfly for all age groups and distances (P < 0.001) because of a greater relative drop-off between first and 10th place for women. The sex difference in marathon running increased with the world record place and the sex difference for marathon running was greater than for swimming (P < 0.001). The sex difference in swimming increased with world record place and age, but was less than for marathon running. Collectively, these results suggest more depth in women's swimming than marathon running. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Tumor evasion of the immune system by converting CD4+CD25- T cells into CD4+CD25+ T regulatory cells: role of tumor-derived TGF-beta.

PubMed

Liu, Victoria C; Wong, Larry Y; Jang, Thomas; Shah, Ali H; Park, Irwin; Yang, Ximing; Zhang, Qiang; Lonning, Scott; Teicher, Beverly A; Lee, Chung

2007-03-01

CD4+CD25+ T regulatory (T(reg)) cells were initially described for their ability to suppress autoimmune diseases in animal models. An emerging interest is the potential role of T(reg) cells in cancer development and progression because they have been shown to suppress antitumor immunity. In this study, CD4+CD25- T cells cultured in conditioned medium (CM) derived from tumor cells, RENCA or TRAMP-C2, possess similar characteristics as those of naturally occurring T(reg) cells, including expression of Foxp3, a crucial transcription factor of T(reg) cells, production of low levels of IL-2, high levels of IL-10 and TGF-beta, and the ability to suppress CD4+CD25- T cell proliferation. Further investigation revealed a critical role of tumor-derived TGF-beta in converting CD4+CD25- T cells into T(reg) cells because a neutralizing Ab against TGF-beta, 1D11, completely abrogated the induction of T(reg) cells. CM from a nontumorigenic cell line, NRP-152, or irradiated tumor cells did not convert CD4+CD25- T cells to T(reg) cells because they produce low levels of TGF-beta in CM. Finally, we observed a reduced tumor burden in animals receiving 1D11. The reduction in tumor burden correlated with a decrease in tumor-derived TGF-beta. Treatment of 1D11 also reduced the conversion of CD4+ T cells into T(reg) cells and subsequent T(reg) cell-mediated suppression of antitumor immunity. In summary, we have demonstrated that tumor cells directly convert CD4+CD25- T cells to T(reg) cells through production of high levels of TGF-beta, suggesting a possible mechanism through which tumor cells evade the immune system.

CD4(+)/CD8(+) T-lymphocyte Ratio: Effects of Rehydration before Exercise in Dehydrated Men

NASA Technical Reports Server (NTRS)

Greenleaf, John E.; Jackson, Catherine G. R.; Lawless, Desales

1995-01-01

Effects of fluid ingestion on CD4+/CD8+ T-lymphocyte cell ratios were measured in four dehydrated men (ages 30-46 yr) before and after 70 min of supine submaximal (71 % VO(sub 2max) lower extremity cycle exercise. Just before exercise, Evans blue dye was injected for measurement of plasma volume. The subjects then drank one of six fluid formulations (12 ml/kg) in 3-4 min. All six mean post-hydration (pre-exercise) CD4+/CD8+ ratios (Becton-Dickinson Fluorescence Activated Cell Sorter and FACScan Consort-30 software program were below the normal range of 1.2-1.5; mean (+/- SE) and range were 0.77 +/- 0.12 and 0.39-1.15, respectively. The post-exercise ratios increased: mean = 1.36 =/- 0.15 (P less than 0.05) and range = 0.98-1.98. Regression of mean CD4+/CD8+ ratios on mean plasma osmolality resulted in pre- and post-exercise correlation coefficients of -0.76 (P less than 0.10) and -0.92 (P less than 0.01), respectively. The decreased pre-exercise ratios (after drinking) were probably not caused by the Evans blue dye but appeared to be associated more with the stress (osmotic) of dehydration. The increased post-exercise ratios to normal levels accompanied the rehydration and were not due to the varied electrolyte and osmotic concentrations of the ingested fluids or to the varied vascular volume shifts during exercise. Thus, the level of subject hydration and plasma osmotality may be factors involved in the mechanism of immune system modulation induced by exercise.

Evidence for sex differences in cardiovascular aging and adaptive responses to physical activity.

PubMed

Parker, Beth A; Kalasky, Martha J; Proctor, David N

2010-09-01

There are considerable data addressing sex-related differences in cardiovascular system aging and disease risk/progression. Sex differences in cardiovascular aging are evident during resting conditions, exercise, and other acute physiological challenges (e.g., orthostasis). In conjunction with these sex-related differences-or perhaps even as an underlying cause-the impact of cardiorespiratory fitness and/or physical activity on the aging cardiovascular system also appears to be sex-specific. Potential mechanisms contributing to sex-related differences in cardiovascular aging and adaptability include changes in sex hormones with age as well as sex differences in baseline fitness and the dose of activity needed to elicit cardiovascular adaptations. The purpose of the present paper is thus to review the primary research regarding sex-specific plasticity of the cardiovascular system to fitness and physical activity in older adults. Specifically, the paper will (1) briefly review known sex differences in cardiovascular aging, (2) detail emerging evidence regarding observed cardiovascular outcomes in investigations of exercise and physical activity in older men versus women, (3) explore mechanisms underlying the differing adaptations to exercise and habitual activity in men versus women, and (4) discuss implications of these findings with respect to chronic disease risk and exercise prescription.

Evidence for sex differences in cardiovascular aging and adaptive responses to physical activity

PubMed Central

Parker, Beth A.; Kalasky, Martha J.; Proctor, David N.

2010-01-01

There are considerable data addressing sex-related differences in cardiovascular system aging and disease risk/progression. Sex differences in cardiovascular aging are evident during resting conditions, exercise, and other acute physiological challenges (e.g., orthostasis). In conjunction with these sex-related differences—or perhaps even as an underlying cause—the impact of cardiorespiratory fitness and/or physical activity on the aging cardiovascular system also appears to be sex-specific. Potential mechanisms contributing to sex-related differences in cardiovascular aging and adaptability include changes in sex hormones with age as well as sex differences in baseline fitness and the dose of activity needed to elicit cardiovascular adaptations. The purpose of the present paper is thus to review the primary research regarding sex-specific plasticity of the cardiovascular system to fitness and physical activity in older adults. Specifically, the paper will (1) briefly review known sex differences in cardiovascular aging, (2) detail emerging evidence regarding observed cardiovascular outcomes in investigations of exercise and physical activity in older men versus women, (3) explore mechanisms underlying the differing adaptations to exercise and habitual activity in men versus women, and (4) discuss implications of these findings with respect to chronic disease risk and exercise prescription. PMID:20480371

Co-Occurrence of ODD and CD in Preschool Children With Symptoms of ADHD.

PubMed

Bendiksen, Bothild; Svensson, Elisabeth; Aase, Heidi; Reichborn-Kjennerud, Ted; Friis, Svein; Myhre, Anne M; Zeiner, Pål

2017-07-01

Patterns of co-occurrence between ADHD, Oppositional Defiant Disorder (ODD), and Conduct Disorder (CD) were examined in a sample of non-referred preschool children. ADHD subtypes and sex differences were also explored. Children aged 3.5 years ( n = 1,048) with high scores on ADHD characteristics were recruited from the Norwegian Mother and Child Cohort Study and clinically assessed, including a semi-structured psychiatric interview. In children with ADHD, concurrent ODD was present more often than CD (31% vs. 10%), but having ADHD gave higher increase in the odds of CD than of ODD (ODD: odds ratio [OR] = 6.7, 95% confidence interval [CI] = [4.2, 10.8]; CD: OR = 17.6, 95% CI = [5.9, 52.9]). We found a greater proportion of children having the combined ADHD subtype as well as more severe inattentiveness among children with co-occurring CD compared with ODD. Sex differences were minor. There are important differences in co-occurring patterns of ODD and CD in preschool children with ADHD.

Correlation between Lymphocyte CD4 Count, Treatment Duration, Opportunistic Infection and Cognitive Function in Human Immunodeficiency Virus-Acquired Immunodeficiency Syndrome (HIV-AIDS) Patients.

PubMed

Fitri, Fasihah Irfani; Rambe, Aldy Safruddin; Fitri, Aida

2018-04-15

Human immunodeficiency virus (HIV) infection is an epidemic worldwide, despite the marked benefits of antiretroviral therapy (ARV) in reducing severe HIV-associated dementia. A milder form of neurocognitive disorders are still prevalent and remain a challenge. This study aimed to determine the correlation between plasma cluster of differentiation 4 (CD4) lymphocyte, duration of ARV treatment, opportunistic infections, and cognitive function in HIV-AIDS patients. A cross-sectional study involving 85 HIV-AIDS patients was conducted at Adam Malik General Hospital Medan, Indonesia. All subjects were subjected to physical, neurologic examination and Montreal Cognitive Assessment-Indonesian Version (MoCA-INA) to assess cognitive function and measurement of lymphocyte CD4 counts. Out of the 85 subjects evaluated, the proportion concerning sexes include 52 males (61.2 %) and 33 females (38.8%). The mean age was 38.53 ± 9.77 years old. There was a significant correlation between CD4 lymphocyte counts and MoCA-INA score (r = 0.271, p = 0.012), but there was no significant correlation between duration of ARV treatment and MoCA-INA score. There was also no difference in MoCA-INA score based on the presence of opportunistic infection. Lymphocyte CD4 count was independently correlated with cognitive function in HIV-AIDS patients.

CD127 and CD25 Expression Defines CD4+ T Cell Subsets That Are Differentially Depleted during HIV Infection1

PubMed Central

Dunham, Richard M.; Cervasi, Barbara; Brenchley, Jason M.; Albrecht, Helmut; Weintrob, Amy; Sumpter, Beth; Engram, Jessica; Gordon, Shari; Klatt, Nichole R.; Frank, Ian; Sodora, Donald L.; Douek, Daniel C.; Paiardini, Mirko; Silvestri, Guido

2009-01-01

Decreased CD4+ T cell counts are the best marker of disease progression during HIV infection. However, CD4+ T cells are heterogeneous in phenotype and function, and it is unknown how preferential depletion of specific CD4+ T cell subsets influences disease severity. CD4+ T cells can be classified into three subsets by the expression of receptors for two T cell-tropic cytokines, IL-2 (CD25) and IL-7 (CD127). The CD127+CD25low/− subset includes IL-2-producing naive and central memory T cells; the CD127−CD25− subset includes mainly effector T cells expressing perforin and IFN-γ; and the CD127lowCD25high subset includes FoxP3-expressing regulatory T cells. Herein we investigated how the proportions of these T cell subsets are changed during HIV infection. When compared with healthy controls, HIV-infected patients show a relative increase in CD4+CD127−CD25− T cells that is related to an absolute decline of CD4+CD127+CD25low/− T cells. Interestingly, this expansion of CD4+CD127− T cells was not observed in naturally SIV-infected sooty mangabeys. The relative expansion of CD4+CD127−CD25− T cells correlated directly with the levels of total CD4+ T cell depletion and immune activation. CD4+CD127−CD25− T cells were not selectively resistant to HIV infection as levels of cell-associated virus were similar in all non-naive CD4+ T cell subsets. These data indicate that, during HIV infection, specific changes in the fraction of CD4+ T cells expressing CD25 and/or CD127 are associated with disease progression. Further studies will determine whether monitoring the three subsets of CD4+ T cells defined based on the expression of CD25 and CD127 should be used in the clinical management of HIV-infected individuals. PMID:18390743

TCRαβ+/CD4+ Large Granular Lymphocytosis

PubMed Central

Lima, Margarida; Almeida, Julia; dos Anjos Teixeira, Maria; Alguero, Maria del Carmen; Santos, Ana Helena; Balanzategui, Ana; Queirós, Maria Luís; Bárcena, Paloma; Izarra, Antonio; Fonseca, Sónia; Bueno, Clara; Justiça, Benvindo; Gonzalez, Marcos; San Miguel, Jesús F.; Orfao, Alberto

2003-01-01

Large granular lymphocyte (LGL) leukemia is a well-recognized disease of mature T-CD8+ or less frequently natural killer cells; in contrast, monoclonal expansions of CD4+ T-LGL have only been sporadically reported in the literature. In the present article we have explored throughout a period of 56 months the incidence of monoclonal expansions of CD4+ T-LGL in a population of 2.2 million inhabitants and analyzed the immunophenotype and the pattern of cytokine production of clonal CD4+ T cells of a series of 34 consecutive cases. Like CD8+ T-LGL leukemias, CD4+ T-LGL leukemia patients have an indolent disease; however, in contrast to CD8+ T-LGL leukemias, they do not show cytopenias and autoimmune phenomena and they frequently have associated neoplasias, which is usually determining the clinical course of the disease. Monoclonal CD4+ T-LGLshowed expression of TCRαβ, variable levels of CD8 (CD8−/+dim) and a homogeneous typical cytotoxic (granzyme B+, CD56+, CD57+, CD11b+/−) and activated/memory T cell (CD2+bright, CD7−/+dim, CD11a+bright, CD28−, CD62L− HLA-DR+) immunophenotype. In addition, they exhibited a Th1 pattern of cytokine production [interferon-γ++, tumor necrosis factor-α++, interleukin (IL-2)−/+, IL-4−, IL-10−, IL-13−]. Phenotypic analysis of the TCR-Vβ repertoire revealed large monoclonal TCR-Vβ expansions; only a restricted number of TCR-Vβ families were represented in the 34 cases analyzed. These findings suggest that monoclonal TCRαβ+/CD4+/NKa+/CD8−/+dim T-LGL represent a subgroup of monoclonal LGL lymphoproliferative disorders different from both CD8+ T-LGL and natural killer cell-type LGL leukemias. Longer follow-up periods are necessary to determine the exact significance of this clonal disorder. PMID:12875995

Are Mucosa CD4+/CD8+ T-Cells Expressions Correlated with the Endoscopic Appearance of Chronic Gastritis Related with Helicobacter pylori Infection?

PubMed

Ratnasari, Neneng; Bayupurnama, Putut; Maduseno, Sutanto; Indrarti, Fahmi; Triwikatmani, Catharina; Harijadi, Achmad; Nurdjanah, Siti

2016-06-01

Local inflammatory processes in the gastric mucosa are followed by extensive immune cell infiltration, resulting in chronic active gastritis characterized by a marked infiltration of T(h)1 cytokine-producing CD4+ and CD8+T-cells Objective. To investigate the correlation between CD4+/CD8+ T-cells in gastric mucosa with endoscopic appearance in chronic gastritis with or without H.pylori infection. Prospective, cross sectional study is performed in a chronic dyspepsia population in July-November 2009 at Dr. Sardjito General Hospital Yogyakarta, Indonesia. The update Sydney system was used to analyze the gastroscopy appearance. Biopsy specimens were stained with HE-stain and IHC-stain. Data were analyzed by t-test, Mann-Whitney and Spearman correlation test. Number of 88 consecutive subjects are enrolled the study (50% male; 50% female), age 46±15 years; 25% H.pylori positive. The expression of CD4+ and CD8+ were higher in H.pylori negative subjects, but only the CD4+ was significant (P=0.011). A significant correlation was found between CD4+ and CD8+ in both subjects (r(Hp+)=0.62 and r(Hp-)=0.68; P<0.05). The expression of CD4+ and CD8+ in H.pylori positive showed a significant correlation with gastric lesions (r(CD4+)=-0.60; r(CD8+)=-0.42 ; P<0.05), only erosion showed a significant difference in both subjects. A positive correlation was found between CD4+ and CD8+ infiltration in both subjects with or without H.pylori infection, and a negative correlation was only found between gastric lesion with CD4+ and CD8+ infiltration in H.pylori subject.

Joint longitudinal data analysis in detecting determinants of CD4 cell count change and adherence to highly active antiretroviral therapy at Felege Hiwot Teaching and Specialized Hospital, North-west Ethiopia (Amhara Region).

PubMed

Seyoum, Awoke; Ndlovu, Principal; Temesgen, Zewotir

2017-03-16

Adherence and CD4 cell count change measure the progression of the disease in HIV patients after the commencement of HAART. Lack of information about associated factors on adherence to HAART and CD4 cell count reduction is a challenge for the improvement of cells in HIV positive adults. The main objective of adopting joint modeling was to compare separate and joint models of longitudinal repeated measures in identifying long-term predictors of the two longitudinal outcomes: CD4 cell count and adherence to HAART. A longitudinal retrospective cohort study was conducted to examine the joint predictors of CD4 cell count change and adherence to HAART among HIV adult patients enrolled in the first 10 months of the year 2008 and followed-up to June 2012. Joint model was employed to determine joint predictors of two longitudinal response variables over time. Furthermore, the generalized linear mixed effect model had been used for specification of the marginal distribution, conditional to correlated random effect. A total of 792 adult HIV patients were studied to analyze the longitudinal joint model study. The result from this investigation revealed that age, weight, baseline CD4 cell count, ownership of cell phone, visiting times, marital status, residence area and level of disclosure of the disease to family members had significantly affected both outcomes. From the two-way interactions, time * owner of cell phone, time * sex, age * sex, age * level of education as well as time * level of education were significant for CD4 cell count change in the longitudinal data analysis. The multivariate joint model with linear predictor indicates that CD4 cell count change was positively correlated (p ≤ 0.0001) with adherence to HAART. Hence, as adherence to HAART increased, CD4 cell count also increased; and those patients who had significant CD4 cell count change at each visiting time had been encouraged to be good adherents. Joint model analysis was more

CD4-binding site alterations in CCR5-using HIV-1 envelopes influencing gp120-CD4 interactions and fusogenicity

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sterjovski, Jasminka; Churchill, Melissa J.; Roche, Michael

2011-02-20

CD4-binding site (CD4bs) alterations in gp120 contribute to different pathophysiological phenotypes of CCR5-using (R5) HIV-1 strains, but the potential structural basis is unknown. Here, we characterized functionally diverse R5 envelope (Env) clones (n = 16) to elucidate potential structural alterations within the gp120 CD4bs that influence Env function. Initially, we showed that the magnitude of gp120-CD4-binding correlates with increased fusogenicity and reduced CD4 dependence. Analysis of three-dimensional gp120 structural models revealed two CD4bs variants, D279 and N362, that were associated with reduced CD4 dependence. Further structural analysis showed that a wider aperture of the predicted CD4bs cavity, as constrained bymore » the inner-most atoms at the gp120 V1V2 stem and the V5 loop, was associated with amino acid alterations within V5 and correlated with increased gp120-CD4 binding and increased fusogenicity. Our results provide evidence that the gp120 V5 loop may alter CD4bs conformation and contribute to increased gp120-CD4 interactions and Env fusogenicity.« less

Percentage and function of CD4+CD25+ regulatory T cells in patients with hyperthyroidism

PubMed Central

Jiang, Ting-Jun; Cao, Xue-Liang; Luan, Sha; Cui, Wan-Hui; Qiu, Si-Huang; Wang, Yi-Chao; Zhao, Chang-Jiu; Fu, Peng

2018-01-01

The current study observed the percentage of peripheral blood (PB) CD4+CD25+ regulatory T cells (Tregs) and the influence of CD4+CD25+ Tregs on the proliferation of naïve CD4 T cells in patients with hyperthyroidism. Furthermore, preliminary discussions are presented on the action mechanism of CD4+CD25+ Tregs on hyperthyroidism attacks. The present study identified that compared with the percentage of PB CD4+CD25+ Tregs in healthy control subjects, no significant changes were observed in the percentage of PB CD4+CD25+ Tregs in patients with hyperthyroidism (P>0.05). For patients with hyperthyroidism, CD4+CD25+ Tregs exhibited significantly reduced inhibition of the proliferation of naïve CD4 T cells and decreased secretion capacity on the cytokines of CD4 T cells, compared with those of healthy control subjects (P<0.05). In addition, it was demonstrated that thyroid function of patients with hyperthyroidism was significantly improved (P<0.05) subsequent to receiving medication. Compared with the percentage of PB CD4+CD25+ Tregs in patients with hyperthyroidism before treatment, no significant changes were observed in the percentage of PB CD4+CD25+ Tregs in hyperthyroidism patients following treatment (P>0.05). In the patients with hyperthyroidism, following treatment, CD4+CD25+ Tregs exhibited significantly increased inhibition of the proliferation of naïve CD4 T cells and increased secretion capacity of CD4 T cell cytokines, compared with those of the patients with hyperthyroidism prior to treatment (P<0.05). PB CD4+CD25+ Tregs function was decreased in patients with hyperthyroidism, and its non-proportional decrease may be closely associated with the occurrence and progression of hyperthyroidism. PMID:29207121

Selective epitaxial growth of zinc blende-derivative on wurtzite-derivative: the case of polytypic Cu2CdSn(S1-xSex)4 nanocrystals

NASA Astrophysics Data System (ADS)

Wu, Liang; Fan, Feng-Jia; Gong, Ming; Ge, Jin; Yu, Shu-Hong

2014-02-01

Polytypic nanocrystals with zinc blende (ZB) cores and wurtzite (WZ) arms, such as tetrapod and octopod nanocrystals, have been widely reported. However, polytypic nanocrystals with WZ cores and ZB arms or ends have been rarely reported. Here, we report a facile, solution-based approach to the synthesis of polytypic Cu2CdSn(S1-xSex)4 (CCTSSe) nanocrystals with ZB-derivative selectively engineered on (000+/-2)WZ facets of WZ-derived cores. Accordingly, two typical morphologies, i.e., bullet-like nanocrystals with a WZ-derivative core and one ZB-derivative end, and rugby ball-like nanocrystals with a WZ-derivative core and two ZB-derivative ends, can be selectively prepared. The epitaxial growth mechanism is confirmed by the time-dependent experiments. The ratio of rugby ball-like and bullet-like polytypic CCTSSe nanocrystals can be tuned through changing the amount of Cd precursor to adjust the reactivity difference between (0002)WZ and (000-2)WZ facets. These unique polytypic CCTSSe nanocrystals may find applications in energetic semiconducting materials for energy conversion in the future.Polytypic nanocrystals with zinc blende (ZB) cores and wurtzite (WZ) arms, such as tetrapod and octopod nanocrystals, have been widely reported. However, polytypic nanocrystals with WZ cores and ZB arms or ends have been rarely reported. Here, we report a facile, solution-based approach to the synthesis of polytypic Cu2CdSn(S1-xSex)4 (CCTSSe) nanocrystals with ZB-derivative selectively engineered on (000+/-2)WZ facets of WZ-derived cores. Accordingly, two typical morphologies, i.e., bullet-like nanocrystals with a WZ-derivative core and one ZB-derivative end, and rugby ball-like nanocrystals with a WZ-derivative core and two ZB-derivative ends, can be selectively prepared. The epitaxial growth mechanism is confirmed by the time-dependent experiments. The ratio of rugby ball-like and bullet-like polytypic CCTSSe nanocrystals can be tuned through changing the amount of Cd precursor

Age and Sex Related Differences in Subcortical Brain Iron Concentrations among Healthy Adults

PubMed Central

Persson, Ninni; Wu, Jianlin; Zhang, Qing; Liu, Ting; Shen, Jing; Bao, Ruyi; Ni, Mingfei; Liu, Tian; Wang, Yi; Spincemaille, Pascal

2015-01-01

Age and sex can influence brain iron levels. We studied the influence of these variables on deep gray matter magnetic susceptibilities. In 183 healthy volunteers (44.7 ± 14.2 years, range 20-69, ♀ 49%), in vivo Quantitative Susceptibility Mapping (QSM) at 1.5T was performed to estimate brain iron accumulation in the following regions of interest (ROIs): caudate nucleus (Cd), putamen (Pt), globus pallidus (Gp), thalamus (Th), pulvinar (Pul), red nucleus (Rn), substantia nigra (Sn) and the cerebellar dentate nuclei (Dn). We gauged the influence of age and sex on magnetic susceptibility by specifying a series of Structural Equation Models. The distributions of susceptibility varied in degree across the structures, conforming to histologic findings (Hallgren & Sourander, 1958), with the highest degree of susceptibility in the Gp and the lowest in the Th. Iron increase correlated across several ROIs, which may reflect an underlying age-related process. Advanced age was associated with a particularly strong linear rise of susceptibility in the striatum. Nonlinear age trends were found in the Rn, where they were the most pronounced, followed by the Pul and Sn, while minimal nonlinear trends were observed for the Pt, Th, and Dn. Moreover, sex related variations were observed, so that women showed lower levels of susceptibility in the Sn after accounting for age. Regional susceptibility of the Pul increased linearly with age in men but exhibited a nonlinear association with age in women with a leveling off starting from midlife. Women expected to be post menopause (+51 years) showed lower total magnetic susceptibility in the subcortical gray matter. The current report is consistent with previous reports of age related variations of brain iron, but also adds to the current knowledge by reporting age-related changes in less studied, smaller subcortical nuclei. This is the first in-vivo report to show lower total subcortical brain iron levels selectively in women from

Age and sex related differences in subcortical brain iron concentrations among healthy adults.

PubMed

Persson, Ninni; Wu, Jianlin; Zhang, Qing; Liu, Ting; Shen, Jing; Bao, Ruyi; Ni, Mingfei; Liu, Tian; Wang, Yi; Spincemaille, Pascal

2015-11-15

Age and sex can influence brain iron levels. We studied the influence of these variables on deep gray matter magnetic susceptibilities. In 183 healthy volunteers (44.7 ± 14.2 years, range 20-69, ♀ 49%), in vivo quantitative susceptibility mapping (QSM) at 1.5T was performed to estimate brain iron accumulation in the following regions of interest (ROIs): caudate nucleus (Cd), putamen (Pt), globus pallidus (Gp), thalamus (Th), pulvinar (Pul), red nucleus (Rn), substantia nigra (Sn) and the cerebellar dentate nuclei (Dn). We gauged the influence of age and sex on magnetic susceptibility by specifying a series of structural equation models. The distributions of susceptibility varied in degree across the structures, conforming to histologic findings (Hallgren and Sourander, 1958), with the highest degree of susceptibility in the Gp and the lowest in the Th. Iron increase correlated across several ROIs, which may reflect an underlying age-related process. Advanced age was associated with a particularly strong linear rise of susceptibility in the striatum. Nonlinear age trends were found in the Rn, where they were the most pronounced, followed by the Pul and Sn, while minimal nonlinear trends were observed for the Pt, Th, and Dn. Moreover, sex related variations were observed, so that women showed lower levels of susceptibility in the Sn after accounting for age. Regional susceptibility of the Pul increased linearly with age in men but exhibited a nonlinear association with age in women with a leveling off starting from midlife. Women expected to be post menopause (+51 years) showed lower total magnetic susceptibility in the subcortical gray matter. The current report not only is consistent with previous reports of age related variations of brain iron, but also adds to the current knowledge by reporting age-related changes in less studied, smaller subcortical nuclei. This is the first in-vivo report to show lower total subcortical brain iron levels selectively in women

Influence of sex on the number of circulating endothelial microparticles and microRNA expression in middle-aged adults.

PubMed

Bammert, Tyler D; Hijmans, Jamie G; Kavlich, Philip J; Lincenberg, Grace M; Reiakvam, Whitney R; Fay, Ryan T; Greiner, Jared J; Stauffer, Brian L; DeSouza, Christopher A

2017-08-01

What is the central question of this study? Are there sex-related differences in the number of circulating endothelial microparticles (EMPs) and microparticle microRNA expression in middle-aged adult humans? What is the main finding and its importance? Although the numbers of circulating endothelial microparticles do not differ between middle-aged men and women, there are sex-related differences in the expression of miR-125a in activation-derived EMPs and miR-34a in apoptosis-derived EMPs. Differences in circulating endothelial microparticle microRNA content may provide new insight into the sex-related disparity in the risk and prevalence of vascular disease in middle-aged adults. The aims of this study were to determine: (i) whether circulating concentrations of endothelial microparticles (EMPs) differ in middle-aged men compared with women; and (ii) whether there are sex-related differences in microRNA expression in EMPs. Peripheral blood was collected from 30 sedentary adults: 15 men (56 ± 6 years old) and 15 women (56 ± 5 years old). Endothelial microparticles were defined by markers of activation (CD62e + ) or apoptosis (CD31 + /CD42b - ) by flow cytometry. Expression of microRNA (miR-34a, 92a, 125a and 126) in activation- and apoptosis-derived EMPs was measured by RT-PCR. Circulating activation- (33 ± 31 versus 39 ± 35 microparticles μl -1 ) and apoptosis-derived EMPs (49 ± 54 versus 42 ± 43 microparticles μl -1 ) were not significantly different between men and women. Expression of miR-125a (2.23 ± 2.01 versus 6.95 ± 3.99 a.u.) was lower (∼215%; P < 0.05) in activation-derived EMPs, whereas expression of miR-34a (1.17 ± 1.43 versus 0.38 ± 0.35 a.u.) was higher (∼210%; P < 0.05) in apoptosis-derived EMPs from men compared with women. Expression of microRNA in circulating EMPs may provide new insight into sex-related differences in cardiovascular disease. © 2017 The Authors. Experimental Physiology © 2017 The

Requirement for CD4 T Cell Help in Generating Functional CD8 T Cell Memory

NASA Astrophysics Data System (ADS)

Shedlock, Devon J.; Shen, Hao

2003-04-01

Although primary CD8 responses to acute infections are independent of CD4 help, it is unknown whether a similar situation applies to secondary responses. We show that depletion of CD4 cells during the recall response has minimal effect, whereas depletion during the priming phase leads to reduced responses by memory CD8 cells to reinfection. Memory CD8 cells generated in CD4+/+ mice responded normally when transferred into CD4-/- hosts, whereas memory CD8 cells generated in CD4-/- mice mounted defective recall responses in CD4+/+ adoptive hosts. These results demonstrate a previously undescribed role for CD4 help in the development of functional CD8 memory.

Viruses within the Flaviviridae Decrease CD4 Expression and Inhibit HIV Replication in Human CD4+ Cells1

PubMed Central

Xiang, Jinhua; McLinden, James H.; Rydze, Robert A.; Chang, Qing; Kaufman, Thomas M.; Klinzman, Donna; Stapleton, Jack T.

2013-01-01

Viral infections alter host cell homeostasis and this may lead to immune evasion and/or interfere with the replication of other microbes in coinfected hosts. Two flaviviruses are associated with a reduction in HIV replication or improved survival in HIV-infected people (dengue virus (DV) and GB virus type C (GBV-C)). GBV-C infection and expression of the GBV-C nonstructural protein 5A (NS5A) and the DV NS5 protein in CD4+ T cells inhibit HIV replication in vitro. To determine whether the inhibitory effect on HIV replication is conserved among other flaviviruses and to characterize mechanism(s) of HIV inhibition, the NS5 proteins of GBV-C, DV, hepatitis C virus, West Nile virus, and yellow fever virus (YFV; vaccine strain 17D) were expressed in CD4+ T cells. All NS5 proteins inhibited HIV replication. This correlated with decreased steady-state CD4 mRNA levels and reduced cell surface CD4 protein expression. Infection of CD4+ T cells and macrophages with YFV (17D vaccine strain) also inhibited HIV replication and decreased CD4 gene expression. In contrast, mumps virus was not inhibited by the expression of flavivirus NS5 protein or by YFV infection, and mumps infection did not alter CD4 mRNA or protein levels. In summary, CD4 gene expression is decreased by all human flavivirus NS5 proteins studied. CD4 regulation by flaviviruses may interfere with innate and adaptive immunity and contribute to in vitro HIV replication inhibition. Characterization of the mechanisms by which flaviviruses regulate CD4 expression may lead to novel therapeutic strategies for HIV and immunological diseases. PMID:19923460

Cd4As2Br3

PubMed Central

Kars, Mohammed; Roisnel, Thierry; Dorcet, Vincent; Rebbah, Allaoua; Otero-Diáz, L. Carlos

2014-01-01

Single crystals of Cd4As2Br3 (tetra­cadmium biarsenide tri­bromide) were grown by a chemical transport reaction. The structure is isotypic with the members of the cadmium and mercury pnictidohalides family with general formula M 4 A 2 X 3 (M = Cd, Hg; A = P, As, Sb; X = Cl, Br, I) and contains two independent As atoms on special positions with site symmetry -3 and two independent Cd atoms, of which one is on a special position with site symmetry -3. The Cd4As2Br3 structure consists of AsCd4 tetra­hedra sharing vertices with isolated As2Cd6 octa­hedra that contain As–As dumbbells in the centre of the octahedron. The Br atoms are located in the voids of this three-dimensional arrangement and bridge the different polyhedra through Cd⋯Br contacts. PMID:24764933

Cyclic adenosine 5'-monophosphate and calcium induce CD152 (CTLA-4) up-regulation in resting CD4+ T lymphocytes.

PubMed

Vendetti, Silvia; Riccomi, Antonella; Sacchi, Alessandra; Gatta, Lucia; Pioli, Claudio; De Magistris, Maria Teresa

2002-12-01

The CTLA-4 (CD152) molecule is up-regulated upon T cell activation and proliferation, and plays a critical role in the inhibition of immune responses. We show in this study that cAMP induces up-regulation of CD152 in human CD4(+) T lymphocytes. This effect occurs in the absence of the up-regulation of CD69 and CD25 activation markers and T cell proliferation. In addition, we found that the Ca(2+) ionophore ionomycin also up-regulates CD152, and that the combination of a cAMP analog or cAMP inducers with ionomycin further enhances the expression of CD152 in resting CD4(+) T lymphocytes. However, cyclosporin A, which inhibits Ca(2+)/calcineurin signaling pathway, fully prevented the ionomycin- but not the cAMP-induced up-regulation of CD152. The effects of cAMP and ionomycin involve increase of both CD152 mRNA transcripts, coding for the membrane and the soluble forms of CD152. Furthermore, we show that CD152 molecules are translocated to the membrane and are functional, as their engagement by specific mAbs prevented NF-kappaB activation by anti-CD3/CD28 stimulation. These findings demonstrate that at least two novel signal pathways regulate CTLA-4 gene expression and CD152 molecule up-regulation in human CD4(+) T lymphocytes, in the absence of full T cell activation.

[CD4 lymphocytopenia in systemic lupus erythematosus].

PubMed

Ferreira, Sofia; Vasconcelos, Júlia; Marinho, António; Farinha, Fátima; Almeida, Isabel; Correia, João; Barbosa, Paulo; Mendonça, Teresa; Vasconcelos, Carlos

2009-01-01

Systemic Lupus Erythematosus (SLE) is an inflammatory chronic disease characterized by the presence of autoantibodies, immunocomplex production and organ injury. Several alterations of the immune system have been described, namely of CD4 T cells, with particular focus on regulatory subgroup. Quantify peripheral CD4 T cells in a population of patients with SLE and correlate it with lupus activity, affected organs, therapeutics and infections. Retrospective study involving all SLE patients seen in the clinical immunology outpatient clinic of the Hospital Geral Santo António, Porto that has done some peripheral blood flow cytometry study. Twenty-nine patients have been evaluated, 16 were taking glucocorticoids and six immunossupressors. The mean SLEDAI at the study time was nine and the ECLAM was three. Thirty-one percent of the patients had leukopenia, 76% lymphocytopenia and the same number CD4 depletion. Fifty-five percent of the patients had CD4 levels lower than 500/mm3, 31% lower than 200/mm3. All patients with SLEDAI > or = 20 and ECLAM > or = 4 had CD4 counts inferior to 500/mm3 and all patients with inactive disease had CD4 superior to 500/mm3. There have been three opportunistic infections: cryptococcal meningitis, pulmonary aspergilosis, Pneumocystis jirovecii pneumonia, all in patients with CD4 counts lower than 500/mm3. Decreased CD4 T cells counts have been very common in this study population. There is an inverse relation between CD4 cells counts and disease activity. Opportunistic infections occurred in patients with severe CD4 depletion.

Long-term patterns in CD4 response are determined by an interaction between baseline CD4 cell count, viral load, and time: The Asia Pacific HIV Observational Database (APHOD).

PubMed

Egger, Sam; Petoumenos, Kathy; Kamarulzaman, Adeeba; Hoy, Jennifer; Sungkanuparph, Somnuek; Chuah, John; Falster, Kathleen; Zhou, Jialun; Law, Matthew G

2009-04-15

Random effects models were used to explore how the shape of CD4 cell count responses after commencing combination antiretroviral therapy (cART) develop over time and, in particular, the role of baseline and follow-up covariates. Patients in Asia Pacific HIV Observational Database who first commenced cART after January 1, 1997, and who had a baseline CD4 cell count and viral load measure and at least 1 follow-up measure between 6 and 24 months, were included. CD4 cell counts were determined at every 6-month period after the commencement of cART for up to 6 years. A total of 1638 patients fulfilled the inclusion criteria with a median follow-up time of 58 months. Lower post-cART mean CD4 cell counts were found to be associated with increasing age (P < 0.001), pre-cART hepatitis C coinfection (P = 0.038), prior AIDS (P = 0.019), baseline viral load < or equal to 100,000 copies per milliliter (P < 0.001), and the Asia Pacific region compared with Australia (P = 0.005). A highly significant 3-way interaction between the effects of time, baseline CD4 cell count, and post-cART viral burden (P < 0.0001) was demonstrated. Higher long-term mean CD4 cell counts were associated with lower baseline CD4 cell count and consistently undetectable viral loads. Among patients with consistently detectable viral load, CD4 cell counts seemed to converge for all baseline CD4 levels. Our analysis suggest that the long-term shape of post-cART CD4 cell count changes depends only on a 3-way interaction between baseline CD4 cell count, viral load response, and time.

Influence of female sex and fertile age on neuromyelitis optica spectrum disorders.

PubMed

Borisow, Nadja; Kleiter, Ingo; Gahlen, Anna; Fischer, Katrin; Wernecke, Klaus-Dieter; Pache, Florence; Ruprecht, Klemens; Havla, Joachim; Krumbholz, Markus; Kümpfel, Tania; Aktas, Orhan; Ringelstein, Marius; Geis, Christian; Kleinschnitz, Christoph; Berthele, Achim; Hemmer, Bernhard; Angstwurm, Klemens; Weissert, Robert; Stellmann, Jan-Patrick; Schuster, Simon; Stangel, Martin; Lauda, Florian; Tumani, Hayrettin; Mayer, Christoph; Zeltner, Lena; Ziemann, Ulf; Linker, Ralf A; Schwab, Matthias; Marziniak, Martin; Then Bergh, Florian; Hofstadt-van Oy, Ulrich; Neuhaus, Oliver; Winkelmann, Alexander; Marouf, Wael; Rückriem, Lioba; Faiss, Jürgen; Wildemann, Brigitte; Paul, Friedemann; Jarius, Sven; Trebst, Corinna; Hellwig, Kerstin

2017-07-01

Gender and age at onset are important epidemiological factors influencing prevalence, clinical presentation, and treatment response in autoimmune diseases. To evaluate the impact of female sex and fertile age on aquaporin-4-antibody (AQP4-ab) status, attack localization, and response to attack treatment in patients with neuromyelitis optica (NMO) and its spectrum disorders (neuromyelitis optica spectrum disorder (NMOSD)). Female-to-male ratios, diagnosis at last visit (NMO vs NMOSD), attack localization, attack treatment, and outcome were compared according to sex and age at disease or attack onset. A total of 186 NMO/SD patients (82% female) were included. In AQP4-ab-positive patients, female predominance was most pronounced during fertile age (female-to-male ratio 23:1). Female patients were more likely to be positive for AQP4-abs (92% vs 55%; p < 0.001). Interval between onset and diagnosis of NMO/SD was longer in women than in men (mean 54 vs 27 months; p = 0.023). In women, attacks occurring ⩽40 years of age were more likely to show complete remission ( p = 0.003) and better response to high-dose intravenous steroids ( p = 0.005) compared to woman at >40 years. Our data suggest an influence of sex and age on susceptibility to AQP4-ab-positive NMO/SD. Genetic and hormonal factors might contribute to pathophysiology of NMO/SD.

Impact of exposure to intimate partner violence on CD4+ and CD8+ T cell decay in HIV infected women: longitudinal study.

PubMed

Jewkes, Rachel; Dunkle, Kristin; Jama-Shai, Nwabisa; Gray, Glenda

2015-01-01

Intimate partner violence (IPV) is a risk factor for HIV acquisition in many settings, but little is known about its impact on cellular immunity especially in HIV infected women, and if any impact differs according to the form of IPV. We tested hypotheses that exposure to IPV, non-partner rape, hunger, pregnancy, depression and substance abuse predicted change in CD4+ and CD8+ T-cell count in a dataset of 103 HIV infected young women aged 15-26 enrolled in a cluster randomised controlled trial. Multiple regression models were fitted to measure rate of change in CD4 and CD8 and including terms for age, person years of CD4+/CD8+ T-cell observation, HIV positivity at baseline, and stratum. Exposure variables included drug use, emotional, physical or sexual IPV exposure, non-partner rape, pregnancy and food insecurity. Mean CD4+ T cell count at baseline (or first HIV+ test) was 567.6 (range 1121-114). Participants were followed for an average of 1.3 years. The magnitude of change in CD4 T-cells was significantly associated with having ever experienced emotional abuse from a current partner at baseline or first HIV+ test (Coeff -132.9 95% CI -196.4, -69.4 p<0.0001) and drug use (Coeff -129.9 95% CI -238.7, -21.2 p=0.02). It was not associated with other measures. The change in CD8 T-cells was associated with having ever experienced emotional abuse at baseline or prior to the first HIV+ test (Coeff -178.4 95%CI -330.2, -26.5 p=0.02). In young ART-naive HIV positive women gender-based violence exposure in the form of emotional abuse is associated with a faster rate of decline in markers of cellular immunity. This highlights the importance of attending to emotional abuse when studying the physiological impact of IPV experience and the mechanisms of its impact on women's health.

Limited CD4+ T cell proliferation leads to preservation of CD4+ T cell counts in SIV-infected sooty mangabeys.

PubMed

Chan, Ming Liang; Petravic, Janka; Ortiz, Alexandra M; Engram, Jessica; Paiardini, Mirko; Cromer, Deborah; Silvestri, Guido; Davenport, Miles P

2010-12-22

Human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) infections result in chronic virus replication and progressive depletion of CD4+ T cells, leading to immunodeficiency and death. In contrast, 'natural hosts' of SIV experience persistent infection with high virus replication but no severe CD4+ T cell depletion, and remain AIDS-free. One important difference between pathogenic and non-pathogenic infections is the level of activation and proliferation of CD4+ T cells. We analysed the relationship between CD4+ T cell number and proliferation in HIV, pathogenic SIV in macaques, and non-pathogenic SIV in sooty mangabeys (SMs) and mandrills. We found that CD4+ T cell proliferation was negatively correlated with CD4+ T cell number, suggesting that animals respond to the loss of CD4+ T cells by increasing the proliferation of remaining cells. However, the level of proliferation seen in pathogenic infections (SIV in rhesus macaques and HIV) was much greater than in non-pathogenic infections (SMs and mandrills). We then used a modelling approach to understand how the host proliferative response to CD4+ T cell depletion may impact the outcome of infection. This modelling demonstrates that the rapid proliferation of CD4+ T cells in humans and macaques associated with low CD4+ T cell levels can act to 'fuel the fire' of infection by providing more proliferating cells for infection. Natural host species, on the other hand, have limited proliferation of CD4+ T cells at low CD4+ T cell levels, which allows them to restrict the number of proliferating cells susceptible to infection.

Comprehensive RNA-Seq transcriptomic profiling across 11 organs, 4 ages, and 2 sexes of Fischer 344 rats.

PubMed

Yu, Ying; Zhao, Chen; Su, Zhenqiang; Wang, Charles; Fuscoe, James C; Tong, Weida; Shi, Leming

2014-01-01

The rat is used extensively by the pharmaceutical, regulatory, and academic communities for safety assessment of drugs and chemicals and for studying human diseases; however, its transcriptome has not been well studied. As part of the SEQC (i.e., MAQC-III) consortium efforts, a comprehensive RNA-Seq data set was constructed using 320 RNA samples isolated from 10 organs (adrenal gland, brain, heart, kidney, liver, lung, muscle, spleen, thymus, and testes or uterus) from both sexes of Fischer 344 rats across four ages (2-, 6-, 21-, and 104-week-old) with four biological replicates for each of the 80 sample groups (organ-sex-age). With the Ribo-Zero rRNA removal and Illumina RNA-Seq protocols, 41 million 50 bp single-end reads were generated per sample, yielding a total of 13.4 billion reads. This data set could be used to identify and validate new rat genes and transcripts, develop a more comprehensive rat transcriptome annotation system, identify novel gene regulatory networks related to tissue specific gene expression and development, and discover genes responsible for disease and drug toxicity and efficacy.

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.

TLR4 signaling in effector CD4+ T cells regulates TCR activation and experimental colitis in mice

PubMed Central

González-Navajas, José M.; Fine, Sean; Law, Jason; Datta, Sandip K.; Nguyen, Kim P.; Yu, Mandy; Corr, Maripat; Katakura, Kyoko; Eckman, Lars; Lee, Jongdae; Raz, Eyal

2010-01-01

TLRs sense various microbial products. Their function has been best characterized in DCs and macrophages, where they act as important mediators of innate immunity. TLR4 is also expressed on CD4+ T cells, but its physiological function on these cells remains unknown. Here, we have shown that TLR4 triggering on CD4+ T cells affects their phenotype and their ability to provoke intestinal inflammation. In a model of spontaneous colitis, Il10–/–Tlr4–/– mice displayed accelerated development of disease, with signs of overt colitis as early as 8 weeks of age, when compared with Il10–/– and Il10–/–Tlr9–/– mice, which did not develop colitis by 8 months. Similar results were obtained in a second model of colitis in which transfer of naive Il10–/–Tlr4–/– CD4+ T cells into Rag1–/– recipients sufficient for both IL-10 and TLR4 induced more aggressive colitis than the transfer of naive Il10–/– CD4+ T cells. Mechanistically, LPS stimulation of TLR4-bearing CD4+ T cells inhibited ERK1/2 activation upon subsequent TCR stimulation via the induction of MAPK phosphatase 3 (MKP-3). Our data therefore reveal a tonic inhibitory role for TLR4 signaling on subsequent TCR-dependent CD4+ T cell responses. PMID:20051628

Transporters for Antiretroviral Drugs in Colorectal CD4+ T Cells and Circulating α4β7 Integrin CD4+ T Cells: Implications for HIV Microbicides.

PubMed

Mukhopadhya, Indrani; Murray, Graeme I; Duncan, Linda; Yuecel, Raif; Shattock, Robin; Kelly, Charles; Iannelli, Francesco; Pozzi, Gianni; El-Omar, Emad M; Hold, Georgina L; Hijazi, Karolin

2016-09-06

CD4+ T lymphocytes in the colorectal mucosa are key in HIV-1 transmission and dissemination. As such they are also the primary target for antiretroviral (ARV)-based rectal microbicides for pre-exposure prophylaxis. Drug transporters expressed in mucosal CD4+ T cells determine ARV distribution across the cell membrane and, most likely, efficacy of microbicides. We describe transporters for antiretroviral drugs in colorectal mucosal CD4+ T lymphocytes and compare gene expression with circulating α4β7+CD4+ T cells, which traffic to the intestine and have been shown to be preferentially infected by HIV-1. Purified total CD4+ T cells were obtained from colorectal tissue and blood samples by magnetic separation. CD4+ T cells expressing α4β7 integrin were isolated by fluorescence-activated cell sorting from peripheral blood mononuclear cells of healthy volunteers. Expressions of 15 efflux and uptake drug transporter genes were quantified using Taqman qPCR assays. Expression of efflux transporters MRP3, MRP5, and BCRP and uptake transporter CNT2 were significantly higher in colorectal CD4+ T cells compared to circulating CD4+ T cells (p = 0.01-0.03). Conversely, circulating α4β7+CD4+ T cells demonstrated significantly higher expression of OATPD compared to colorectal CD4+ T cells (p = 0.001). To the best of our knowledge this is the first report of drug transporter gene expression in colorectal CD4+ and peripheral α4β7+CD4+ T cells. The qualitative and quantitative differences in drug transporter gene expression profiles between α4β7+CD4+ T cells and total mucosal CD4+ T cells may have significant implications for the efficacy of rectally delivered ARV-microbicides. Most notably, we have identified efflux drug transporters that could be targeted by selective inhibitors or beneficial drug-drug interactions to enhance intracellular accumulation of antiretroviral drugs.

Limited CD4+ T cell proliferation leads to preservation of CD4+ T cell counts in SIV-infected sooty mangabeys

PubMed Central

Chan, Ming Liang; Petravic, Janka; Ortiz, Alexandra M.; Engram, Jessica; Paiardini, Mirko; Cromer, Deborah; Silvestri, Guido; Davenport, Miles P.

2010-01-01

Human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) infections result in chronic virus replication and progressive depletion of CD4+ T cells, leading to immunodeficiency and death. In contrast, ‘natural hosts’ of SIV experience persistent infection with high virus replication but no severe CD4+ T cell depletion, and remain AIDS-free. One important difference between pathogenic and non-pathogenic infections is the level of activation and proliferation of CD4+ T cells. We analysed the relationship between CD4+ T cell number and proliferation in HIV, pathogenic SIV in macaques, and non-pathogenic SIV in sooty mangabeys (SMs) and mandrills. We found that CD4+ T cell proliferation was negatively correlated with CD4+ T cell number, suggesting that animals respond to the loss of CD4+ T cells by increasing the proliferation of remaining cells. However, the level of proliferation seen in pathogenic infections (SIV in rhesus macaques and HIV) was much greater than in non-pathogenic infections (SMs and mandrills). We then used a modelling approach to understand how the host proliferative response to CD4+ T cell depletion may impact the outcome of infection. This modelling demonstrates that the rapid proliferation of CD4+ T cells in humans and macaques associated with low CD4+ T cell levels can act to ‘fuel the fire’ of infection by providing more proliferating cells for infection. Natural host species, on the other hand, have limited proliferation of CD4+ T cells at low CD4+ T cell levels, which allows them to restrict the number of proliferating cells susceptible to infection. PMID:20591864

Joint estimation of CD4+ cell progression and survival in untreated individuals with HIV-1 infection.

PubMed

Mangal, Tara D

2017-05-15

We compiled the largest dataset of seroconverter cohorts to date from 25 countries across Africa, North America, Europe, and Southeast/East (SE/E) Asia to simultaneously estimate transition rates between CD4 cell stages and death, in antiretroviral therapy (ART)-naive HIV-1-infected individuals. A hidden Markov model incorporating a misclassification matrix was used to represent natural short-term fluctuations and measurement errors in CD4 cell counts. Covariates were included to estimate the transition rates and survival probabilities for each subgroup. The median follow-up time for 16 373 eligible individuals was 4.1 years (interquartile range 1.7-7.1), and the mean age at seroconversion was 31.1 years (SD 8.8). A total of 14 525 individuals had recorded CD4 cell counts pre-ART, 1885 died, and 6947 initiated ART. Median (interquartile range) survival for men aged 20 years at seroconversion was 13.0 (12.4-13.4), 11.6 (10.9-12.3), and 8.3 years (7.9-8.9) in Europe/North America, Africa, and SE/E Asia, respectively. Mortality rates increase with age (hazard ratio 2.22, 95% confidence interval 1.84-2.67 for >45 years compared with <25 years) and vary by region (hazard ratio 2.68, 1.75-4.12 for Africa and 1.88, 1.50-2.35 for Asia compared with Europe/North America). CD4 cell decline was significantly faster in Asian cohorts compared with Europe/North America (hazard ratio 1.45, 1.36-1.54). Mortality and CD4 cell progression rates exhibited regional and age-specific differences, with decreased survival in African and SE/E Asian cohorts compared with Europe/North America and in older age groups. This extensive dataset reveals heterogeneities between regions and ages, which should be incorporated into future HIV models.

Chimpanzees Immunized with Recombinant Soluble CD4 Develop Anti-Self CD4 Antibody Responses with Anti-Human Immunodeficiency Virus Activity

NASA Astrophysics Data System (ADS)

Watanabe, Mamoru; Boyson, Jonathan E.; Lord, Carol I.; Letvin, Norman L.

1992-06-01

In view of the efficiency with which human immunodeficiency virus replication can be blocked in vitro with anti-CD4 antibodies, the elicitation of an anti-CD4 antibody response through active immunization might represent a useful therapeutic strategy for AIDS. Here we demonstrate that immunization of chimpanzees with recombinant soluble human CD4 elicited an anti-CD4 antibody response. The elicited antibody bound self CD4 on digitonin-treated but not freshly isolated lymphocytes. Nevertheless, this antibody blocked human immunodeficiency virus replication in chimpanzee and human lymphocytes. These observations suggest that immunization with recombinant soluble CD4 from human immunodeficiency virus-infected humans may be feasible and therapeutically beneficial.

Stability and change in same-sex attraction, experience, and identity by sex and age in a New Zealand birth cohort.

PubMed

Dickson, Nigel; van Roode, Thea; Cameron, Claire; Paul, Charlotte

2013-07-01

Gaps remain in knowledge of changes in sexual orientation past adolescence and early adulthood. A longitudinal study of a New Zealand birth cohort was used to examine differences by age and sex in change in sexual attraction between 21 (1993/1994) and 38 years (2010/2011), sexual experiences between 26 and 38 years, and sexual identity between 32 and 38 years. Any same-sex attraction was significantly more common among women than men at all ages. Among women, any same-sex attraction increased up to age 26 (from 8.8 to 16.6 %), then decreased slightly by age 38 (12.0 %); among men, prevalence was significantly higher at age 38 (6.5 %) than 21 (4.2 %), but not in the intermediate assessments. It is likely that the social environment becoming more tolerant was responsible for some of the changes. Same-sex attraction was much more common than same-sex experiences or a same-sex identity, especially among women, with no major sex differences in these latter dimensions. Women exhibited much greater change in sexual attraction between assessments than men; for change in experiences and identity, sex differences were less marked and not statistically confirmed. Changes in the respective dimensions appeared more likely among those initially with mixed attraction and experiences, and among those initially identifying as bisexual, but this did not account for the sex difference in likelihood of change. These results provide contemporary information about the extent and variation of reported sexual attraction, experiences, and identity that we show continues across early and mid-adulthood.

T-cell differentiation and CD56+ levels in polypoidal choroidal vasculopathy and neovascular age-related macular degeneration.

PubMed

Subhi, Yousif; Nielsen, Marie Krogh; Molbech, Christopher Rue; Oishi, Akio; Singh, Amardeep; Nissen, Mogens Holst; Sørensen, Torben Lykke

2017-11-20

Polypoidal choroidal vasculopathy (PCV) and neovascular age-related macular degeneration (AMD) are prevalent age-related diseases characterized by exudative changes in the macula. Although they share anatomical and clinical similarities, they are also distinctly characterized by their own features, e.g. vascular abnormalities in PCV and drusen-mediated progression in neovascular AMD. PCV remains etiologically uncharacterized, and ongoing discussion is whether PCV and neovascular AMD share the same etiology or constitute two substantially different diseases. In this study, we investigated T-cell differentiation and aging profile in human patients with PCV, patients with neovascular AMD, and age-matched healthy control individuals. Fresh venous blood was prepared for flow cytometry to investigate CD4 + and CD8 + T-cell differentiation (naïve, central memory, effector memory, effector memory CD45ra + ), loss of differentiation markers CD27 and CD28, and expression of aging marker CD56. Patients with PCV were similar to the healthy controls in all aspects. In patients with neovascular AMD we found significantly accelerated T-cell differentiation (more CD28 - CD27 - cells) and aging (more CD56 + cells) in the CD8 + T-cell compartment. These findings suggest that PCV and neovascular AMD are etiologically different in terms of T cell immunity, and that neovascular AMD is associated with T-cell immunosenescence.

Sex, age, and tissue specific accumulation of eight metals, arsenic, and selenium in the European hedgehog (Erinaceus europaeus).

PubMed

Rautio, Anni; Kunnasranta, Mervi; Valtonen, Anu; Ikonen, Mirva; Hyvärinen, Heikki; Holopainen, Ismo J; Kukkonen, Jussi V K

2010-11-01

Many insectivores have been shown to be sensitive to heavy metals and therefore suitable for biomonitoring purposes. In Finland, the hibernation period of the European hedgehog (Erinaceus europaeus) is long, and during hibernation the stress caused by environmental toxins may be crucial. Concentrations of cadmium (Cd), copper (Cu), iron (Fe), magnesium (Mg), manganese (Mn), molybdenum (Mo), nickel (Ni), lead (Pb), arsenic (As), and selenium (Se) were measured in a population of hedgehogs in the town of Joensuu in eastern Finland during the summers of 2004 and 2005. The analyzed tissues were kidney, liver, hair, and spine. The sampled hedgehogs (n = 65) were mainly road-killed animals. As expected, the concentrations of heavy metals were low because the hedgehogs were living in a comparatively unpolluted area. Significant increases with age were found in Cd concentrations (kidney, liver, and spine) and some essential elements (Se in spine, kidney, and liver; Mo in kidney and liver; Cu in spine; Fe in liver; and Mn in spine). Age accumulation and correlations between Se and Cd and between Mo and Cd may indicate the protective roles of Se and Mo against Cd toxicity in hedgehogs, in which Cd is already at comparatively low concentrations. Sex had no significant effect on concentrations of the elements studied. In conclusion, age is an important parameter to be taken into account when studying heavy-metal concentrations in hedgehogs and other insectivores.

Distribution of HIV RNA in CSF and Blood is linked to CD4/CD8 Ratio During Acute HIV.

PubMed

Chan, Phillip; Patel, Payal; Hellmuth, Joanna; Colby, Donn J; Kroon, Eugène; Sacdalan, Carlo; Pinyakorn, Suteeraporn; Jagodzinski, Linda; Krebs, Shelly; Ananworanich, Jintanat; Valcour, Victor; Spudich, Serena

2018-05-07

HIV RNA levels in the plasma and cerebrospinal fluid (CSF) are correlated in chronic HIV infection but their dynamics have not been characterized during acute infection. This study analyzed predictors of CSF HIV RNA and relative degree of CNS viral transmigration expressed as plasma minus CSF HIV log10 RNA (PCratio) during untreated acute HIV infection. CSF immune markers were compared between groups with different PCratio. 117 mostly male (97%) participants in the RV254 cohort in Bangkok, Thailand, had median age 28 years and an estimated median 18 days duration of infection; forty-three (37%) were Fiebig stages I/II. Twenty-seven (23%) had CSF HIV RNA <80 copies/ml. Those with quantifiable levels (n=90) had median CSF HIV RNA and PCratio of 3.76 and 2.36 Log10 copies/mL, respectively. HIV RNA peaked at Fiebig III in plasma and Fiebig IV in CSF. In multivariable analyses, plasma HIV RNA and CD4/CD8 ratio independently correlated with CSF HIV RNA (p<0.001) while CD4/CD8 ratio predicted PCratio (p=0.018). Participants with PCratio<1 had higher CSF neopterin, sCD163, IL-6 and sCD14 levels (all p<0.05). CD4/CD8 ratio independently correlated with CSF HIV RNA and PCratio, suggesting that immune responses modulate CNS viral entry at early infection.

Evaluation of CD4+ CD25+ FoxP3+ regulatory T cells during treatment of patients with brucellosis.

PubMed

Hasanjani Roushan, M R; Bayani, M; Soleimani Amiri, S; Mohammadnia-Afrouzi, M; Nouri, H R; Ebrahimpour, S

2016-01-01

Cell-mediated immunity (CMI) plays a critical role in the control of brucellosis. Regulatory T cells (Tregs) have a functional character in modulating the balance between host immune response and tolerance, which can eventually lead to chronic infection or relapse. The aim of this study was to assess the alteration of Tregs in cases of brucellosis before and after treatment. Thirty cases of acute brucellosis with the mean age of 41.03±15.15 years (case group) and 30 healthy persons with the mean age of 40.63±13.95 years (control group) were selected and assessed. Peripheral blood mononuclear cells (PBMCs) were isolated from peripheral blood of all individuals. We analyzed the alteration of Treg cell count using flow cytometry for CD4, CD25, and FoxP3 markers. The level of CD4+ CD25+ FoxP3+ Treg cells was increased in active patients compared with controls (2.5±0.99% vs 1.6±0.84%, p= 0.0004), but it had declined in the treated cases (1.83±0.73%, p=0.02). The level of Tregs was elevated in three relapsed cases. The frequency of Tregs and Treg/Teff (effector T cell) ratio was correlated with inverse serum agglutination test (SAT) and, 2-mercaptoethanol (2-ME) titers as markers of treatment in brucellosis. Based on our findings, we suggest that regulatory cells, such as CD4+ CD25+ FoxP3+ Treg cells, may contribute to the development of infection processes involving immune responses in brucellosis, and evaluation of regulatory T-cell levels may be a potential diagnostic strategy for the treatment outcome in chronic and relapsed cases of brucellosis.

Evolution of the CD4 family: teleost fish possess two divergent forms of CD4 in addition to lymphocyte activation gene-3

USGS Publications Warehouse

Laing, K.J.; Zou, J.J.; Purcell, M.K.; Phillips, R.; Secombes, C.J.; Hansen, J.D.

2006-01-01

The T cell coreceptor CD4 is a transmembrane glycoprotein belonging to the Ig superfamily and is essential for cell-mediated immunity. Two different genes were identified in rainbow trout that resemble mammalian CD4. One (trout CD4) encodes four extracellular Ig domains reminiscent off mammalian CD4, whereas the other (CD4REL) codes for two Ig domains. Structural motifs within the amino acid sequences suggest that the two Ig domains of CD4REL duplicated to generate the four-domain molecule of CD4 and the related gene, lymphocyte activation gene-3. Here we present evidence that both of these molecules in trout are homologous to mammalian CD4 and that teleosts encode an additional CD4 family member, lymphocyte activation gene-3, which is a marker for activated T cells. The syntenic relationships of similar genes in other teleost and non-fish genomes provide evidence for the likely evolution of CD4-related molecules in vertebrates, with CD4REL likely representing the primordial form in fish. Expression of both CD4 genes is highest in the thymus and spleen, and mRNA expression of these genes is limited to surface IgM- lymphocytes, consistent with a role for T cell functionality. Finally, the intracellular regions of both CD4 and CD4REL possess the canonical CXC motif involved in the interaction off CD4 with p56LCK, implying that similar mechanisms for CD4 + T cell activation are present in all vertebrates. Our results therefore raise new questions about T cell development and functionality in lower vertebrates that cannot be answered by current mammalian models and, thus, is of fundamental importance for understanding the evolution of cell-mediated immunity in gnathosomes. Copyright ?? 2006 by The American Association of Immunologists, Inc.

Simian immunodeficiency virus selectively infects proliferating CD4+ T cells in neonatal rhesus macaques.

PubMed

Wang, Xiaolei; Xu, Huanbin; Pahar, Bapi; Alvarez, Xavier; Green, Linda C; Dufour, Jason; Moroney-Rasmussen, Terri; Lackner, Andrew A; Veazey, Ronald S

2010-11-18

Infants infected with HIV have a more severe course of disease and persistently higher viral loads than HIV-infected adults. However, the underlying pathogenesis of this exacerbation remains obscure. Here we compared the rate of CD4(+) and CD8(+) T-cell proliferation in intestinal and systemic lymphoid tissues of neonatal and adult rhesus macaques, and of normal and age-matched simian immunodeficiency virus (SIV)-infected neonates. The results demonstrate infant primates have much greater rates of CD4(+) T-cell proliferation than adult macaques, and that these proliferating, recently "activated" CD4(+) T cells are infected in intestinal and other lymphoid tissues of neonates, resulting in selective depletion of proliferating CD4(+) T cells in acute infection. This depletion is accompanied by a marked increase in CD8(+) T-cell activation and production, particularly in the intestinal tract. The data indicate intestinal CD4(+) T cells of infant primates have a markedly accelerated rate of proliferation and maturation resulting in more rapid and sustained production of optimal target cells (activated memory CD4(+) T cells), which may explain the sustained "peak" viremia characteristic of pediatric HIV infection. Eventual failure of CD4(+) T-cell turnover in intestinal tissues may indicate a poorer prognosis for HIV-infected infants.

Characterization of the CD4+ and CD8+ tumor infiltrating lymphocytes propagated with bispecific monoclonal antibodies.

PubMed

Wong, J T; Pinto, C E; Gifford, J D; Kurnick, J T; Kradin, R L

1989-11-15

To study the CD4+ and CD8+ tumor infiltrating lymphocytes (TIL) in the antitumor response, we propagated these subsets directly from tumor tissues with anti-CD3:anti-CD8 (CD3,8) and anti-CD3:anti-CD4 (CD3,4) bispecific mAb (BSMAB). CD3,8 BSMAB cause selective cytolysis of CD8+ lymphocytes by bridging the CD8 molecules of target lymphocytes to the CD3 molecular complex of cytolytic T lymphocytes with concurrent activation and proliferation of residual CD3+CD4+ T lymphocytes. Similarly, CD3,4 BSMAB cause selective lysis of CD4+ lymphocytes whereas concurrently activating the residual CD3+CD8+ T cells. Small tumor fragments from four malignant melanoma and three renal cell carcinoma patients were cultured in medium containing CD3,8 + IL-2, CD3,4 + IL-2, or IL-2 alone. CD3,8 led to selective propagation of the CD4+ TIL whereas CD3,4 led to selective propagation of the CD8+ TIL from each of the tumors. The phenotypes of the TIL subset cultures were generally stable when assayed over a 1 to 3 months period and after further expansion with anti-CD3 mAb or lectins. Specific 51Cr release of labeled target cells that were bridged to the CD3 molecular complexes of TIL suggested that both CD4+ and CD8+ TIL cultures have the capacity of mediating cytolysis via their Ti/CD3 TCR complexes. In addition, both CD4+ and CD8+ TIL cultures from most patients caused substantial (greater than 20%) lysis of the NK-sensitive K562 cell line. The majority of CD4+ but not CD8+ TIL cultures also produced substantial lysis of the NK-resistant Daudi cell line. Lysis of the autologous tumor by the TIL subsets was assessed in two patients with malignant melanoma. The CD8+ TIL from one tumor demonstrated cytotoxic activity against the autologous tumor but negligible lysis of allogeneic melanoma targets. In conclusion, immunocompetent CD4+ and CD8+ TIL subsets can be isolated and expanded directly from small tumor fragments of malignant melanoma and renal cell carcinoma using BSMAB. The resultant

Measurements of exciton diffusion by degenerate four-wave mixing in CdS1-xSex

NASA Astrophysics Data System (ADS)

Schwab, H.; Pantke, K.-H.; Hvam, J. M.; Klingshirn, C.

1992-09-01

We performed transient-grating experiments to study the diffusion of excitons in CdS1-xSex mixed crystals. The decay of the initially created exciton density grating is well described for t<=1 ns by a stretched-exponential function. For later times this decay changes over to a behavior that is well fitted by a simple exponential function. During resonant excitation of the localized states, we find the diffusion coefficient (D) to be considerably smaller than in the binary compounds CdSe and CdS. At 4.2 K, D is below our experimental resolution which is about 0.025 cm2/s. With increasing lattice temperature (Tlattice) the diffusion coefficient increases. It was therefore possible to prove, in a diffusion experiment, that at Tlattice<=5 K the excitons are localized, while the exciton-phonon interaction leads to a delocalization and thus to the onset of diffusion. It was possible to deduce the diffusion coefficient of the extended excitons as well as the energetic position of the mobility edge.

Hyperostosis frontalis interna: criteria for sexing and aging a skeleton.

PubMed

May, Hila; Peled, Nathan; Dar, Gali; Cohen, Haim; Abbas, Janan; Medlej, Bahaa; Hershkovitz, Israel

2011-09-01

Estimation of sex and age in skeletons is essential in anthropological and forensic medicine investigations. The aim of the current study was to examine the potential of hyperostosis frontalis interna (HFI) as a criterion for determining sex and age in forensic cases. Macroscopic examination of the inner aspect of the frontal bone of 768 skulls (326 males and 442 females) aged 1 to 103, which had undergone a head computerized tomography scan, was carried out using the volume rendering technique. HFI was divided into two categories: minor and major. HFI is a sex- and age-dependent phenomena, with females manifesting significantly higher prevalence than males (p<0.01). In both females and males, prevalence of HFI increases as age increases (p<0.01). We present herein the probabilities of designating an unknown skull to a specific sex and age cohort according to the presence of HFI (standardized to age distribution in an Israeli population). Moreover, we present the probability of an individual belonging to a specific sex or age cohort according to age or sex (respectively) and severity of HFI. We suggest a valid, reliable, and easy method for sex and age identification of unknown skulls.

Ex Vivo Restimulation of Human PBMC Expands a CD3+CD4−CD8− γδ + T Cell Population That Can Confound the Evaluation of CD4 and CD8 T Cell Responses to Vaccination

PubMed Central

Sedgmen, B. J.; Papalia, L.; Wang, L.; Dyson, A. R.; McCallum, H. A.; Simson, C. M.; Pearse, M. J.; Maraskovsky, E.; Hung, D.; Eomois, P. P.; Hartel, G.; Barnden, M. J.; Rockman, S. P.

2013-01-01

The measurement of vaccine-induced humoral and CD4+ and CD8+ cellular immune responses represents an important correlate of vaccine efficacy. Accurate and reliable assays evaluating such responses are therefore critical during the clinical development phase of vaccines. T cells play a pivotal role both in coordinating the adaptive and innate immune responses and as effectors. During the assessment of cell-mediated immunity (CMI) in subjects participating in a large-scale influenza vaccine trial, we identified the expansion of an IFN-γ-producing CD3+CD4−CD8− γδ + T cell population in the peripheral blood of 90/610 (15%) healthy subjects. The appearance of CD3+CD4−CD8− γδ + T cells in the blood of subjects was transient and found to be independent of the study cohort, vaccine group, subject gender and ethnicity, and ex vivo restimulation conditions. Although the function of this population and relevance to vaccination are unclear, their inclusion in the total vaccine-specific T-cell response has the potential to confound data interpretation. It is thus recommended that when evaluating the induction of IFN-γ-producing CD4+ and CD8+ immune responses following vaccination, the CD3+CD4−CD8− γδ + T cells are either excluded or separately enumerated from the overall frequency determination. PMID:24066003

Development of a Healthy Aging Score in the Population-Based Rotterdam Study: Evaluating Age and Sex Differences.

PubMed

Jaspers, Loes; Schoufour, Josje D; Erler, Nicole S; Darweesh, Sirwan K L; Portegies, Marileen L P; Sedaghat, Sanaz; Lahousse, Lies; Brusselle, Guy G; Stricker, Bruno H; Tiemeier, Henning; Ikram, M Arfan; Laven, Joop S E; Franco, Oscar H; Kavousi, Maryam

2017-03-01

To develop a healthy aging score (HAS), to assess age and sex differences in HAS, and to evaluate the association of the HAS with survival. Prospective population-based cohort. Inhabitants of Ommoord, Rotterdam, The Netherlands. A total of 1405 men and 2122 women, mean (standard deviation) age 75.9 (6.4) years. We included 7 domains in the total score of HAS: chronic diseases, mental health, cognitive function, physical function, pain, social support, and quality of life; each scored 0, 1, or 2 in each domain. A total score (range 0-14) was constructed and was assessed continuously and in tertiles (13-14: healthy aging, 11-12: intermediate aging, 0-10: poor aging). Sex-specific change in the mean HAS was computed for the age categories of 65-69, 70-74, 75-79, 80-84, and ≥85 years. The association between HAS and mortality was assessed with Cox proportional hazards models. Mean follow-up was 8.6 (3.4) years. Men had poorer scores in the chronic disease domain than women. However, women had poorer mental health, worse physical function, more pain, and lower quality of life compared with men. The prevalence of healthy aging was higher in men (n = 396, 28.2%), than in women (n = 526, 24.8%). The mean (standard deviation) HAS was 11.1 (2.2) in men and 10.7 (2.3) in women. Mean HAS was higher in men than in women for all age categories. The β for change in mean HAS across the 5 increasing age categories was -0.55 (-0.65 to -0.45) in men and -0.65 (-0.73 to -0.57) in women. The age-adjusted hazard ratio per unit increase in HAS with mortality was 0.86 (0.83-0.89) in men, and 0.89 (0.87-0.91) in women. Levels of HAS were lower in women compared with men, in all age categories. The HAS declined with increasing age for both sexes, albeit slightly steeper in women. The HAS was strongly associated with mortality in both sexes. A better understanding of population healthy aging and sex differences in this regard could aid to implement strategies for sustainable

Partial reconstitution of the CD4+-T-cell compartment in CD4 gene knockout mice restores responses to tuberculosis DNA vaccines.

PubMed

D'Souza, Sushila; Romano, Marta; Korf, Johanna; Wang, Xiao-Ming; Adnet, Pierre-Yves; Huygen, Kris

2006-05-01

Reactivation tuberculosis (TB) is a serious problem in immunocompromised individuals, especially those with human immunodeficiency virus (HIV) coinfection. The adaptive immune response mediated by CD4+ and CD8+ T cells is known to confer protection against TB. Hence, vaccines against TB are designed to activate these two components of the immune system. Anti-TB DNA vaccines encoding the immunodominant proteins Ag85A, Ag85B, and PstS-3 from Mycobacterium tuberculosis are ineffective in mice lacking CD4+ T cells (CD4-/- mice). In this study, we demonstrate that reconstitution of the T-cell compartment in CD4-/- mice restores vaccine-specific antibody and gamma interferon (IFN-gamma) responses to these DNA vaccines. The magnitude of the immune responses correlated with the extent of reconstitution of the CD4+-T-cell compartment. Reconstituted mice vaccinated with DNA encoding PstS-3, known to encode a dominant D(b)-restricted CD8+-T-cell epitope, displayed CD8+-T-cell responses not observed in CD4-/- mice. M. tuberculosis challenge in reconstituted mice led to the extravasation of IFN-gamma-producing CD4+ and CD8+ T cells into lungs, the primary site of bacterial replication. Importantly, a reconstitution of 12 to 15% of the CD4+-T-cell compartment resulted in Ag85B plasmid DNA-mediated protection against a challenge M. tuberculosis infection. Our findings provide evidence that anti-TB DNA vaccines could be effective in immunodeficient individuals after CD4+-T-lymphocyte reconstitution, as may occur following antiretroviral therapy in HIV+ patients.

Peripheral Frequency of CD4+ CD28− Cells in Acute Ischemic Stroke

PubMed Central

Tuttolomondo, Antonino; Pecoraro, Rosaria; Casuccio, Alessandra; Di Raimondo, Domenico; Buttà, Carmelo; Clemente, Giuseppe; Corte, Vittoriano della; Guggino, Giuliana; Arnao, Valentina; Maida, Carlo; Simonetta, Irene; Maugeri, Rosario; Squatrito, Rosario; Pinto, Antonio

2015-01-01

Abstract CD4+ CD28− T cells also called CD28 null cells have been reported as increased in the clinical setting of acute coronary syndrome. Only 2 studies previously analyzed peripheral frequency of CD28 null cells in subjects with acute ischemic stroke but, to our knowledge, peripheral frequency of CD28 null cells in each TOAST subtype of ischemic stroke has never been evaluated. We hypothesized that CD4+ cells and, in particular, the CD28 null cell subset could show a different degree of peripheral percentage in subjects with acute ischemic stroke in relation to clinical subtype and severity of ischemic stroke. The aim of our study was to analyze peripheral frequency of CD28 null cells in subjects with acute ischemic stroke in relation to TOAST diagnostic subtype, and to evaluate their relationship with scores of clinical severity of acute ischemic stroke, and their predictive role in the diagnosis of acute ischemic stroke and diagnostic subtype We enrolled 98 consecutive subjects admitted to our recruitment wards with a diagnosis of ischemic stroke. As controls we enrolled 66 hospitalized patients without a diagnosis of acute ischemic stroke. Peripheral frequency of CD4+ and CD28 null cells has been evaluated with a FACS Calibur flow cytometer. Subjects with acute ischemic stroke had a significantly higher peripheral frequency of CD4+ cells and CD28 null cells compared to control subjects without acute ischemic stroke. Subjects with cardioembolic stroke had a significantly higher peripheral frequency of CD4+ cells and CD28 null cells compared to subjects with other TOAST subtypes. We observed a significant relationship between CD28 null cells peripheral percentage and Scandinavian Stroke Scale and NIHSS scores. ROC curve analysis showed that CD28 null cell percentage may be useful to differentiate between stroke subtypes. These findings seem suggest a possible role for a T-cell component also in acute ischemic stroke clinical setting showing a different

HIV-Infected Individuals with Low CD4/CD8 Ratio despite Effective Antiretroviral Therapy Exhibit Altered T Cell Subsets, Heightened CD8+ T Cell Activation, and Increased Risk of Non-AIDS Morbidity and Mortality

PubMed Central

Serrano-Villar, Sergio; Sainz, Talia; Lee, Sulggi A.; Hunt, Peter W.; Sinclair, Elizabeth; Shacklett, Barbara L.; Ferre, April L.; Hayes, Timothy L.; Somsouk, Ma; Hsue, Priscilla Y.; Van Natta, Mark L.; Meinert, Curtis L.; Lederman, Michael M.; Hatano, Hiroyu; Jain, Vivek; Huang, Yong; Hecht, Frederick M.; Martin, Jeffrey N.; McCune, Joseph M.; Moreno, Santiago; Deeks, Steven G.

2014-01-01

A low CD4/CD8 ratio in elderly HIV-uninfected adults is associated with increased morbidity and mortality. A subset of HIV-infected adults receiving effective antiretroviral therapy (ART) fails to normalize this ratio, even after they achieve normal CD4+ T cell counts. The immunologic and clinical characteristics of this clinical phenotype remain undefined. Using data from four distinct clinical cohorts and three clinical trials, we show that a low CD4/CD8 ratio in HIV-infected adults during otherwise effective ART (after CD4 count recovery above 500 cells/mm3) is associated with a number of immunological abnormalities, including a skewed T cell phenotype from naïve toward terminally differentiated CD8+ T cells, higher levels of CD8+ T cell activation (HLADR+CD38+) and senescence (CD28− and CD57+CD28−), and higher kynurenine/tryptophan ratio. Changes in the peripheral CD4/CD8 ratio are also reflective of changes in gut mucosa, but not in lymph nodes. In a longitudinal study, individuals who initiated ART within six months of infection had greater CD4/CD8 ratio increase compared to later initiators (>2 years). After controlling for age, gender, ART duration, nadir and CD4 count, the CD4/CD8 ratio predicted increased risk of morbidity and mortality. Hence, a persistently low CD4/CD8 ratio during otherwise effective ART is associated with increased innate and adaptive immune activation, an immunosenescent phenotype, and higher risk of morbidity/mortality. This ratio may prove useful in monitoring response to ART and could identify a unique subset of individuals needed of novel therapeutic interventions. PMID:24831517

A Low Peripheral Blood CD4/CD8 Ratio Is Associated with Pulmonary Emphysema in HIV.

PubMed

Triplette, Matthew; Attia, Engi F; Akgün, Kathleen M; Soo Hoo, Guy W; Freiberg, Matthew S; Butt, Adeel A; Wongtrakool, Cherry; Goetz, Matthew Bidwell; Brown, Sheldon T; Graber, Christopher J; Huang, Laurence; Crothers, Kristina

2017-01-01

The prevalence of emphysema is higher among HIV-infected (HIV+) individuals compared to HIV-uninfected persons. While greater tobacco use contributes, HIV-related effects on immunity likely confer additional risk. Low peripheral blood CD4+ to CD8+ T-lymphocyte (CD4/CD8) ratio may reflect chronic inflammation in HIV and may be a marker of chronic lung disease in this population. Therefore, we sought to determine whether the CD4/CD8 ratio was associated with chronic obstructive pulmonary disease (COPD), particularly the emphysema subtype, in a cohort of HIV+ subjects. We performed a cross-sectional analysis of 190 HIV+ subjects enrolled in the Examinations of HIV Associated Lung Emphysema (EXHALE) study. Subjects underwent baseline laboratory assessments, pulmonary function testing and chest computed tomography (CT) analyzed for emphysema severity and distribution. We determined the association between CD4/CD8 ratio and emphysema, and the association between CD4/CD8 ratio and pulmonary function markers of COPD. Mild or greater emphysema (>10% lung involvement) was present in 31% of subjects. Low CD4/CD8 ratio was associated with >10% emphysema in multivariable models, adjusting for risk factors including smoking, current and nadir CD4 count and HIV RNA level. Those with CD4/CD8 ratio <0.4 had 6.3 (1.1-39) times the odds of >10% emphysema compared to those with a ratio >1.0 in fully adjusted models. A low CD4/CD8 ratio was also associated with reduced diffusion capacity (DLCO). A low CD4/CD8 ratio was associated with emphysema and low DLCO in HIV+ subjects, independent of other risk factors and clinical markers of HIV. The CD4/CD8 ratio may be a useful, clinically available, marker for risk of emphysema in HIV+ subjects in the antiretroviral therapy (ART) era.

A Low Peripheral Blood CD4/CD8 Ratio Is Associated with Pulmonary Emphysema in HIV

PubMed Central

Attia, Engi F.; Akgün, Kathleen M.; Soo Hoo, Guy W.; Freiberg, Matthew S.; Butt, Adeel A.; Wongtrakool, Cherry; Goetz, Matthew Bidwell; Brown, Sheldon T.; Graber, Christopher J.; Huang, Laurence; Crothers, Kristina

2017-01-01

Objectives The prevalence of emphysema is higher among HIV-infected (HIV+) individuals compared to HIV-uninfected persons. While greater tobacco use contributes, HIV-related effects on immunity likely confer additional risk. Low peripheral blood CD4+ to CD8+ T-lymphocyte (CD4/CD8) ratio may reflect chronic inflammation in HIV and may be a marker of chronic lung disease in this population. Therefore, we sought to determine whether the CD4/CD8 ratio was associated with chronic obstructive pulmonary disease (COPD), particularly the emphysema subtype, in a cohort of HIV+ subjects. Methods We performed a cross-sectional analysis of 190 HIV+ subjects enrolled in the Examinations of HIV Associated Lung Emphysema (EXHALE) study. Subjects underwent baseline laboratory assessments, pulmonary function testing and chest computed tomography (CT) analyzed for emphysema severity and distribution. We determined the association between CD4/CD8 ratio and emphysema, and the association between CD4/CD8 ratio and pulmonary function markers of COPD. Results Mild or greater emphysema (>10% lung involvement) was present in 31% of subjects. Low CD4/CD8 ratio was associated with >10% emphysema in multivariable models, adjusting for risk factors including smoking, current and nadir CD4 count and HIV RNA level. Those with CD4/CD8 ratio <0.4 had 6.3 (1.1–39) times the odds of >10% emphysema compared to those with a ratio >1.0 in fully adjusted models. A low CD4/CD8 ratio was also associated with reduced diffusion capacity (DLCO). Conclusions A low CD4/CD8 ratio was associated with emphysema and low DLCO in HIV+ subjects, independent of other risk factors and clinical markers of HIV. The CD4/CD8 ratio may be a useful, clinically available, marker for risk of emphysema in HIV+ subjects in the antiretroviral therapy (ART) era. PMID:28122034

Infant sex-specific placental cadmium and DNA methylation associations

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mohanty, April F., E-mail: april.mohanty@va.gov; Department of Epidemiology, School of Public Health, University of Washington, Seattle, WA; Farin, Fred M., E-mail: freddy@u.washington.edu

Background: Recent evidence suggests that maternal cadmium (Cd) burden and fetal growth associations may vary by fetal sex. However, mechanisms contributing to these differences are unknown. Objectives: Among 24 maternal-infant pairs, we investigated infant sex-specific associations between placental Cd and placental genome-wide DNA methylation. Methods: We used ANOVA models to examine sex-stratified associations of placental Cd (dichotomized into high/low Cd using sex-specific Cd median cutoffs) with DNA methylation at each cytosine-phosphate-guanine site or region. Statistical significance was defined using a false discovery rate cutoff (<0.10). Results: Medians of placental Cd among females and males were 5 and 2 ng/g, respectively.more » Among females, three sites (near ADP-ribosylation factor-like 9 (ARL9), siah E3 ubiquitin protein ligase family member 3 (SIAH3), and heparin sulfate (glucosamine) 3-O-sulfotransferase 4 (HS3ST4) and one region on chromosome 7 (including carnitine O-octanoyltransferase (CROT) and TP5S target 1 (TP53TG1)) were hypomethylated in high Cd placentas. Among males, high placental Cd was associated with methylation of three sites, two (hypomethylated) near MDS1 and EVI1 complex locus (MECOM) and one (hypermethylated) near spalt-like transcription factor 1 (SALL1), and two regions (both hypomethylated, one on chromosome 3 including MECOM and another on chromosome 8 including rho guanine nucleotide exchange factor (GEF) 10 (ARHGEF10). Differentially methylated sites were at or close to transcription start sites of genes involved in cell damage response (SIAH3, HS3ST4, TP53TG1) in females and cell differentiation, angiogenesis and organ development (MECOM, SALL1) in males. Conclusions: Our preliminary study supports infant sex-specific placental Cd-DNA methylation associations, possibly accounting for previously reported differences in Cd-fetal growth associations across fetal sex. Larger studies are needed to replicate and extend these

Effect of CMV and Aging on the Differential Expression of CD300a, CD161, T-bet, and Eomes on NK Cell Subsets.

PubMed

Lopez-Sejas, Nelson; Campos, Carmen; Hassouneh, Fakhri; Sanchez-Correa, Beatriz; Tarazona, Raquel; Pera, Alejandra; Solana, Rafael

2016-01-01

Natural killer (NK) cells are innate lymphoid cells involved in the defense against virus-infected cells and tumor cells. NK cell phenotype and function is affected with age and cytomegalovirus (CMV) latent infection. Aging affects the frequency and phenotype of NK cells, and CMV infection also contributes to these alterations. Thus, a reduction of CD56 bright NK cell subpopulation associated with age and an expansion of memory-like NK cells CD56 dim CD57 + NKG2C + probably related to CMV seropositivity have been described. NK cells express T-bet and Eomes transcription factors that are necessary for the development of NK cells. Here, we analyze the effect of age and CMV seropositivity on the expression of CD300a and CD161 inhibitory receptors, and T-bet and Eomes transcription factors in NK cell subsets defined by the expression of CD56 and CD57. CD300a is expressed by the majority of NK cells. CD56 bright NK cells express higher levels of CD300a than CD56 dim NK cells. An increase in the expression of CD300a was associated with age, whereas a decreased expression of CD161 in CD56 dim NK cells was associated with CMV seropositivity. In CD56 dim NK cells, an increased percentage of CD57 + CD300a + and a reduction in the percentage of CD161 + CD300a + cells were found to be associated with CMV seropositivity. Regarding T-bet and Eomes transcription factors, CMV seropositivity was associated with a decrease of T-bet hi in CD56 dim CD57 + NK cells from young individuals, whereas Eomes expression was increased with CMV seropositivity in both CD56 bright and CD56 dim CD57 +/- (from middle age and young individuals, respectively) and was decreased with aging in all NK subsets from the three group of age. In conclusion, CMV infection and age induce significant changes in the expression of CD300a and CD161 in NK cell subsets defined by the expression of CD56 and CD57. T-bet and Eomes are differentially expressed on NK cell subsets, and their expression is affected by CMV

CD3-T cell receptor modulation is selectively induced in CD8 but not CD4 lymphocytes cultured in agar.

PubMed Central

Oudrhiri, N; Farcet, J P; Gourdin, M F; M'Bemba, E; Gaulard, P; Katz, A; Divine, M; Galazka, A; Reyes, F

1990-01-01

The CD3-T cell receptor (TcR) complex is central to the immune response. Upon binding by specific ligands, internalized CD3-TcR molecules increase, and either T cell response or unresponsiveness may ensue depending on the triggering conditions. Using semi-solid agar culture, we have shown previously that quiescent CD4 but not CD8 lymphocytes generate clonal colonies under phytohaemagglutinin stimulation. Here we have demonstrated that the agar induces selective CD3-TcR modulation in the CD8 and not in the CD4 subset. CD8 lymphocytes preactivated in liquid culture and recultured in agar with exogenous recombinant interleukin-2 generate colonies with a modulated CD3-TcR surface expression. The peptides composing the CD3-TcR complex are synthesized in CD8 colonies as well as in CD4; however, the CD3 gamma chain is phosphorylated at a higher level in CD8 colonies. A component of the agar polymer, absent in agarose, appears to be the ligand that induces differential CD3-TcR modulation in the CD8 subset. In contrast to agar culture, CD8 colonies can be derived from quiescent CD8 lymphocytes in agarose. These CD8 colonies express unmodulated CD-TcR. CD3-TcR modulation with anti-CD3 monoclonal antibody prior to culturing in agarose inhibits the colony formation. We conclude that given triggering conditions can result in both CD3-TcR modulation and inhibition of the proliferative response selectively in the CD8 lymphocyte subset and not in the CD4. Images Fig. 3 Fig. 4 Fig. 5 PMID:2146997

CD137 is a Useful Marker for Identifying CD4+ T Cell Responses to Mycobacterium tuberculosis.

PubMed

Yan, Z-H; Zheng, X-F; Yi, L; Wang, J; Wang, X-J; Wei, P-J; Jia, H-Y; Zhou, L-J; Zhao, Y-L; Zhang, H-T

2017-05-01

Upregulation of CD137 on recently activated CD8 + T cells has been used to identify rare viral and tumour antigen-specific T cells from the peripheral blood. We aimed to evaluate the accuracy of CD137 for identifying Mycobacterium tuberculosis (Mtb)-reactive CD4 + T cells in the peripheral blood of infected individuals by flow cytometry and to investigate the characteristics of these CD137 + CD4 + T cells. We initially enrolled 31 active tuberculosis (TB) patients, 31 individuals with latent TB infection (LTBI) and 25 healthy donors. The intracellular CD137 and interferon-γ (IFN-γ) production by CD4 + T cells was simultaneously detected under unstimulated and CFP10-stimulated (culture filtrate protein 10, a Mtb-specific antigen) conditions. In unstimulated CD4 + T cells, we found that the CD137 expression in the TB group was significantly higher than that in the LTBI group. Stimulation with CFP10 largely increased the CD4 + T cell CD137 expression in both the TB and LTBI groups. After CFP10 stimulation, the frequency of CD137 + CD4 + T cells was higher than that of IFN-γ + CD4 + T cells in both the TB and LTBI groups. Most of the CFP10-activated IFN-γ-secreting cells were CD137-positive, but only a small fraction of the CD137-positive cells expressed IFN-γ. An additional 20 patients with TB were enrolled to characterize the CD45RO + CCR7 + , CD45RO + CCR7 - and CD45RO - subsets in the CD137 + CD4 + T cell populations. The Mtb-specific CD137 + CD4 + T cells were mainly identified as having an effector memory phenotype. In conclusion, CD137 is a useful marker that can be used for identifying Mtb-reactive CD4 + T cells by flow cytometry. © 2017 The Foundation for the Scandinavian Journal of Immunology.

Age-dependent changes of serum soluble CD30 concentration in children.

PubMed

Chrul, Slawomir; Polakowska, Ewa

2011-08-01

  CD30 was originally described as a marker on Reed-Sternberg cells in Hodgkin lymphoma. The extracellular portion of CD30 is proteolytically cleaved from CD30+ cells, to produce a soluble form of the molecule (sCD30) detectable in serum. Measurement of sCD30 concentration in serum has been suggested to be a potential tool in monitoring of inflammatory status in variety of diseases. Several investigators reported the relevance for sCD30 as a predictive marker for allograft rejection following organ transplantation. The aim of the study was to verify whether sCD30 serum concentrations may be affected by an age in healthy children. Heparinized venous blood was taken from 78 healthy children. For the analysis of sCD30 levels, the commercially available sCD30 ELISA was used. The sCD30 was detected in all serum samples and concentrations ranged from 6.75 to 68.07ng/mL. The statistical analysis of all individuals showed that sCD30 concentration was significantly age depended (r=-0.618, p<0.0001). When sCD30 concentrations were analyzed in regard to gender, no significant differences were identified in age subgroups. © 2011 John Wiley & Sons A/S.

CD4 cells can be more efficient at tumor rejection than CD8 cells.

PubMed

Perez-Diez, Ainhoa; Joncker, Nathalie T; Choi, Kyungho; Chan, William F N; Anderson, Colin C; Lantz, Olivier; Matzinger, Polly

2007-06-15

Researchers designing antitumor treatments have long focused on eliciting tumor-specific CD8 cytotoxic T lymphocytes (CTL) because of their potent killing activity and their ability to reject transplanted organs. The resulting treatments, however, have generally been surprisingly poor at inducing complete tumor rejection, both in experimental models and in the clinic. Although a few scattered studies suggested that CD4 T "helper" cells might also serve as antitumor effectors, they have generally been studied mostly for their ability to enhance the activity of CTL. In this mouse study, we compared monoclonal populations of tumor-specific CD4 and CD8 T cells as effectors against several different tumors, and found that CD4 T cells eliminated tumors that were resistant to CD8-mediated rejection, even in cases where the tumors expressed major histocompatibility complex (MHC) class I molecules but not MHC class II. MHC class II expression on host tissues was critical, suggesting that the CD4 T cells act indirectly. Indeed, the CD4 T cells partnered with NK cells to obtain the maximal antitumor effect. These findings suggest that CD4 T cells can be powerful antitumor effector cells that can, in some cases, outperform CD8 T cells, which are the current "gold standard" effector cell in tumor immunotherapy.

Bromelain treatment reduces CD25 expression on activated CD4+ T cells in vitro✩

PubMed Central

Secor, Eric R.; Singh, Anurag; Guernsey, Linda A.; McNamara, Jeff T.; Zhan, Lijun; Maulik, Nilanjana; Thrall, Roger S.

2009-01-01

Bromelain (Br), an extract from pineapple stem with cysteine protease activity, exerts anti-inflammatory effects in a number of inflammatory models. We have previously shown that Br treatment decreased activated CD4+ T cells and has a therapeutic role in an ovalbumin-induced murine model of allergic airway disease. The current study was designed to determine the effect of Br on CD4+ T cell activation, specifically the expression of CD25 in vitro. CD25 is up regulated upon T cell activation, found as a soluble fraction (sCD25) and is a therapeutic target in inflammation, autoimmunity and allergy. Br treatment of anti-CD3 stimulated CD4+ T cells reduced CD25 expression in a dose and time dependent manner. This reduction of CD25 was dependent on the proteolytic action of Br as the addition of E64 (a cysteine protease inhibitor) abrogated this response. The concentration of sCD25 was increased in supernatants of Br treated activated CD4+ T cells as compared to control cells, suggesting that Br proteolytically cleaved cell-surface CD25. This novel mechanism of action identifies how Br may exert its therapeutic benefits in inflammatory conditions. PMID:19162239

How do health and biological age influence chronological age and sex differences in cognitive aging: moderating, mediating, or both?

PubMed

Wahlin, Ake; MacDonald, Stuart W S; deFrias, Cindy M; Nilsson, Lars-Göran; Dixon, Roger A

2006-06-01

Much research on cognitive competence in normal older adults has documented age and sex differences. The authors used new cross-sectional data from the Victoria Longitudinal Study (VLS) (n=386; age 61 to 95 years) to examine how health and biological age influence age and sex differences in cognitive aging. The authors found evidence for both moderating and mediating influences. Age differences were moderated by health status, such that the negative effects of age were most pronounced among participants of relatively better health. Sex differences were moderated by health and were more pronounced among participants reporting comparatively poorer health. Although health mediated a notable amount of age-related cognitive variation, BioAge mediated considerably more variance, even after statistical control for differences in health. A complex pattern emerged for the mediation of sex differences: Although BioAge accounted for sex-related variation in cognitive performance, health operated to suppress these differences. Overall, both health and BioAge predicted cognitive variation independently of chronological age. Copyright (c) 2006 APA, all rights reserved.

Plasma n-6 Fatty Acid Levels Are Associated With CD4 Cell Counts, Hospitalization, and Mortality in HIV-Infected Patients.

PubMed

Kabagambe, Edmond K; Ezeamama, Amara E; Guwatudde, David; Campos, Hannia; Fawzi, Wafaie

2016-12-15

Fatty acids, including n-6 series, modulate immune function, but their effect on CD4 cell counts, death, or hospitalization in HIV-infected patients on antiretroviral therapy is unknown. In a randomized trial for effects of multivitamins in HIV-infected patients in Uganda, we used gas chromatography to measure plasma n-6 fatty acids at baseline; determined CD4 counts at baseline, 3, 6, 12, and 18 months; and recorded hospitalization or death events. The associations of fatty acids with CD4 counts and events were analyzed using repeated-measures analysis of variance and Cox regression, respectively. Among 297 patients with fatty acids measurements, 16 patients died and 69 were hospitalized within 18 months. Except for linoleic acid, n-6 fatty acids levels were positively associated with CD4 counts at baseline but not during follow-up. In models that included all 5 major n-6 fatty acids, age; sex; body mass index; anemia status; use of antiretroviral therapy, multivitamin supplements, and alcohol; and the risk of death or hospitalization decreased significantly with an increase in linoleic acid and gamma-linolenic acid levels, whereas associations for dihomo-gamma-linolenic acid, arachidonic acid, and aolrenic acid were null. The hazard ratios (95% confidence intervals) per 1 SD increase in linoleic acid and gamma-linolenic acid were 0.73 (0.56-0.94) and 0.51 (0.36-0.72), respectively. Gamma-linolenic acid remained significant (hazard ratio = 0.51; 95% confidence interval: 0.35 to 0.68) after further adjustment for other plasma fatty acids. Lower levels of gamma-linolenic acid are associated with lower CD4 counts and an increased risk of death or hospitalization. These results suggest a potential for using n-6 fatty acids to improve outcomes from antiretroviral therapy.

CD4+ T Cell Help Guides Formation of CD103+ Lung-Resident Memory CD8+ T Cells during Influenza Viral Infection

PubMed Central

Laidlaw, Brian J.; Zhang, Nianzhi; Marshall, Heather D.; Staron, Mathew M.; Guan, Tianxia; Hu, Yinghong; Cauley, Linda S.; Craft, Joe; Kaech, Susan M.

2014-01-01

SUMMARY Tissue-resident memory T (Trm) cells provide enhanced protection against infection at mucosal sites. Here we found that CD4+ T cells are important for the formation of functional lung-resident CD8+ T cells after influenza virus infection. In the absence of CD4+ T cells, CD8+ T cells displayed reduced expression of CD103 (Itgae), were mislocalized away from airway epithelia, and demonstrated an impaired ability to recruit CD8+ T cells to the lung air-ways upon heterosubtypic challenge. CD4+ T cell-derived interferon-γ was necessary for generating lung-resident CD103+ CD8+ Trm CD8 T cells. Furthermore, expression of the transcription factor T-bet was increased in “unhelped” lung Trm cells, and a reduction in T-bet rescued CD103 expression in the absence of CD4+ T cell help. Thus, CD4+ T cell-dependent signals are important to limit expression of T-bet and allow for the development of CD103+ CD8+ Trm cells in the lung airways following respiratory infection. PMID:25308332

Significant CD4, CD8, and CD19 lymphopenia in peripheral blood of sarcoidosis patients correlates with severe disease manifestations.

PubMed

Sweiss, Nadera J; Salloum, Rafah; Gandhi, Seema; Ghandi, Seema; Alegre, Maria-Luisa; Sawaqed, Ray; Badaracco, Maria; Pursell, Kenneth; Pitrak, David; Baughman, Robert P; Moller, David R; Garcia, Joe G N; Niewold, Timothy B

2010-02-05

Sarcoidosis is a poorly understood chronic inflammatory condition. Infiltration of affected organs by lymphocytes is characteristic of sarcoidosis, however previous reports suggest that circulating lymphocyte counts are low in some patients with the disease. The goal of this study was to evaluate lymphocyte subsets in peripheral blood in a cohort of sarcoidosis patients to determine the prevalence, severity, and clinical features associated with lymphopenia in major lymphocyte subsets. Lymphocyte subsets in 28 sarcoid patients were analyzed using flow cytometry to determine the percentage of CD4, CD8, and CD19 positive cells. Greater than 50% of patients had abnormally low CD4, CD8, or CD19 counts (p<4x10(-10)). Lymphopenia was profound in some cases, and five of the patients had absolute CD4 counts below 200. CD4, CD8, and CD19 lymphocyte subset counts were significantly correlated (Spearman's rho 0.57, p = 0.0017), and 10 patients had low counts in all three subsets. Patients with severe organ system involvement including neurologic, cardiac, ocular, and advanced pulmonary disease had lower lymphocyte subset counts as a group than those patients with less severe manifestations (CD4 p = 0.0043, CD8 p = 0.026, CD19 p = 0.033). No significant relationships were observed between various medical therapies and lymphocyte counts, and lymphopenia was present in patients who were not receiving any medical therapy. Significant lymphopenia involving CD4, CD8, and CD19 positive cells was common in sarcoidosis patients and correlated with disease severity. Our findings suggest that lymphopenia relates more to disease pathology than medical treatment.

Significant CD4, CD8, and CD19 Lymphopenia in Peripheral Blood of Sarcoidosis Patients Correlates with Severe Disease Manifestations

PubMed Central

Sweiss, Nadera J.; Salloum, Rafah; Ghandi, Seema; Alegre, Maria-Luisa; Sawaqed, Ray; Badaracco, Maria; Pursell, Kenneth; Pitrak, David; Baughman, Robert P.; Moller, David R.; Garcia, Joe G. N.; Niewold, Timothy B.

2010-01-01

Background Sarcoidosis is a poorly understood chronic inflammatory condition. Infiltration of affected organs by lymphocytes is characteristic of sarcoidosis, however previous reports suggest that circulating lymphocyte counts are low in some patients with the disease. The goal of this study was to evaluate lymphocyte subsets in peripheral blood in a cohort of sarcoidosis patients to determine the prevalence, severity, and clinical features associated with lymphopenia in major lymphocyte subsets. Methodology/Principal Findings Lymphocyte subsets in 28 sarcoid patients were analyzed using flow cytometry to determine the percentage of CD4, CD8, and CD19 positive cells. Greater than 50% of patients had abnormally low CD4, CD8, or CD19 counts (p<4×10−10). Lymphopenia was profound in some cases, and five of the patients had absolute CD4 counts below 200. CD4, CD8, and CD19 lymphocyte subset counts were significantly correlated (Spearman's rho 0.57, p = 0.0017), and 10 patients had low counts in all three subsets. Patients with severe organ system involvement including neurologic, cardiac, ocular, and advanced pulmonary disease had lower lymphocyte subset counts as a group than those patients with less severe manifestations (CD4 p = 0.0043, CD8 p = 0.026, CD19 p = 0.033). No significant relationships were observed between various medical therapies and lymphocyte counts, and lymphopenia was present in patients who were not receiving any medical therapy. Conclusions/Significance Significant lymphopenia involving CD4, CD8, and CD19 positive cells was common in sarcoidosis patients and correlated with disease severity. Our findings suggest that lymphopenia relates more to disease pathology than medical treatment. PMID:20140091

Increased Numbers of CD4+CD25+ and CD8+CD25+ T-Cells in Peripheral Blood of Patients with Rheumatoid Arthritis with Parvovirus B19 Infection.

PubMed

Naciute, Milda; Maciunaite, Gabriele; Mieliauskaite, Diana; Rugiene, Rita; Zinkeviciene, Aukse; Mauricas, Mykolas; Murovska, Modra; Girkontaite, Irute

2017-01-01

To investigate T-cell subpopulations in peripheral blood of human parvovirus B19 DNA-positive (B19 + ) and -negative (B19 - ) patients with rheumatoid arthritis (RA) and healthy persons. Blood samples were collected from 115 patients with RA and 47 healthy volunteers; 27 patients with RA and nine controls were B19 + Cluster of differentiation (CD) 4, 8, 25 and 45RA were analyzed on blood cells. CD25 expression on CD4 + CD45RA + , CD4 + CD45RA - , CD8 + CD45RA + , CD8 + CD45RA - subsets were analyzed by flow cytometry. The percentage of CD25 low and CD25 hi cells was increased on CD4 + CD45RA + , CD4 + CD45RA - T-cells and the percentage of CD25 + cells was increased on CD8 + CD45RA + , CD8 + CD45RA - T-cells of B19 + patients with RA in comparison with B19 - patients and controls. Raised levels of CD4 and CD8 regulatory T-cells in B19 + RA patients could cause down-regulation of antiviral clearance mechanisms and lead to activation of persistent human parvovirus B19 infection in patients with RA. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

Monitoring α4β7 integrin expression on circulating CD4+ T cells as a surrogate marker for tracking intestinal CD4+ T cell loss in SIV infection

PubMed Central

Wang, Xiaolei; Xu, Huanbin; Gill, Amy F.; Pahar, Bapi; Kempf, Doty; Rasmussen, Terri; Lackner, Andrew A.; Veazey, Ronald S.

2013-01-01

Intestinal CD4+ T cells are rapidly and profoundly depleted in HIV-infected patients and SIV-infected macaques. However, monitoring intestinal cells in humans is difficult, and identifying surrogate markers in the blood, which correlate with loss or restoration of intestinal CD4+ T cells could be helpful in monitoring the success of therapeutic strategies and vaccine candidates. Recent studies indicate HIV utilizes the intestinal homing molecule α4β7 for attachment and signaling of CD4+ T cells, suggesting this molecule may play a central role in HIV pathogenesis. Here we compared β7HIGH integrin expression on CD4+ T cells in blood with loss of CD4+ T cells in the intestine of macaques throughout SIV infection. The loss of β7HIGH CD4+ T cells in blood closely paralleled the loss of intestinal CD4+ T cells, and proved to be a more reliable marker of intestinal CD4+ T cell loss than monitoring CCR5+ memory CD4+ T cells. These data are consistent with a recent hypothesis that α4β7 plays a role in the selective depletion of intestinal CD4+ T cells, and indicate that monitoring β7HIGH expression on CD4+ T cells in the blood may be a useful surrogate for estimating intestinal CD4+ T cell loss and restoration in HIV-infected patients. PMID:19710637

Sex differences in normal age trajectories of functional brain networks.

PubMed

Scheinost, Dustin; Finn, Emily S; Tokoglu, Fuyuze; Shen, Xilin; Papademetris, Xenophon; Hampson, Michelle; Constable, R Todd

2015-04-01

Resting-state functional magnetic resonance image (rs-fMRI) is increasingly used to study functional brain networks. Nevertheless, variability in these networks due to factors such as sex and aging is not fully understood. This study explored sex differences in normal age trajectories of resting-state networks (RSNs) using a novel voxel-wise measure of functional connectivity, the intrinsic connectivity distribution (ICD). Males and females showed differential patterns of changing connectivity in large-scale RSNs during normal aging from early adulthood to late middle-age. In some networks, such as the default-mode network, males and females both showed decreases in connectivity with age, albeit at different rates. In other networks, such as the fronto-parietal network, males and females showed divergent connectivity trajectories with age. Main effects of sex and age were found in many of the same regions showing sex-related differences in aging. Finally, these sex differences in aging trajectories were robust to choice of preprocessing strategy, such as global signal regression. Our findings resolve some discrepancies in the literature, especially with respect to the trajectory of connectivity in the default mode, which can be explained by our observed interactions between sex and aging. Overall, results indicate that RSNs show different aging trajectories for males and females. Characterizing effects of sex and age on RSNs are critical first steps in understanding the functional organization of the human brain. © 2014 Wiley Periodicals, Inc.

CD40 ligand blockade induces CD4+ T cell tolerance and linked suppression.

PubMed

Honey, K; Cobbold, S P; Waldmann, H

1999-11-01

The CD40-CD40 ligand (CD40L) interaction is a key event in the initiation of an adaptive immune response, and as such the therapeutic value of CD40L blockade has been studied in many experimental models of tissue transplantation and autoimmune disease. In rodents, transplantation of allogeneic tissues under the cover of anti-CD40L Abs has resulted in prolonged graft survival but not tolerance. In this report, we show that failure to induce tolerance probably results from the inability of anti-CD40L Abs to prevent graft rejection elicited by the CD8+ T cell subset. When the CD8+ T cell population is controlled independently, using anti-CD8 Abs, then tolerance is possible. Transplantation tolerance induced by anti-CD4 mAbs can often be associated with dominant regulation, manifested as infectious tolerance and linked suppression, both of which are mediated by CD4+ T cells. We show here that CD4+ T cells rendered tolerant using anti-CD40L therapy exhibit the same regulatory property of linked suppression, as demonstrated by their ability to accept grafts expressing third party Ags only if they are expressed in conjunction with the tolerated Ags. This observation of linked suppression reveals a hitherto undocumented consequence of CD40L blockade that suggests the tolerant state is maintained by a dominant regulatory mechanism. Our results suggest that, although anti-CD40L Abs are attractive clinical immunotherapeutic agents, additional therapies to control aggressive CD8+ T cell responses may be required.

Increased Numbers of CD4+CD25+ and CD8+CD25+ T-Cells in Peripheral Blood of Patients with Rheumatoid Arthritis with Parvovirus B19 Infection

PubMed Central

NACIUTE, MILDA; MACIUNAITE, GABRIELE; MIELIAUSKAITE, DIANA; RUGIENE, RITA; ZINKEVICIENE, AUKSE; MAURICAS, MYKOLAS; MUROVSKA, MODRA; GIRKONTAITE, IRUTE

2017-01-01

Aim: To investigate T-cell subpopulations in peripheral blood of human parvovirus B19 DNA-positive (B19+) and -negative (B19−) patients with rheumatoid arthritis (RA) and healthy persons. Patients and Methods: Blood samples were collected from 115 patients with RA and 47 healthy volunteers; 27 patients with RA and nine controls were B19+. Cluster of differentiation (CD) 4, 8, 25 and 45RA were analyzed on blood cells. CD25 expression on CD4+CD45RA+, CD4+CD45RA−, CD8+CD45RA+, CD8+CD45RA− subsets were analyzed by flow cytometry. Results: The percentage of CD25low and CD25hi cells was increased on CD4+CD45RA+, CD4+CD45RA− T-cells and the percentage of CD25+ cells was increased on CD8+CD45RA+, CD8+CD45RA− T-cells of B19+ patients with RA in comparison with B19− patients and controls. Conclusion: Raised levels of CD4 and CD8 regulatory T-cells in B19+ RA patients could cause down-regulation of antiviral clearance mechanisms and lead to activation of persistent human parvovirus B19 infection in patients with RA PMID:28358698

CRTAM determines the CD4+ cytotoxic T lymphocyte lineage

PubMed Central

Takeuchi, Arata; Badr, Mohamed El Sherif Gadelhaq; Miyauchi, Kosuke; Ishihara, Chitose; Onishi, Reiko; Guo, Zijin; Sasaki, Yoshiteru; Ike, Hiroshi; Takumi, Akiko; Tsuji, Noriko M.; Murakami, Yoshinori; Katakai, Tomoya; Kubo, Masato

2016-01-01

Naive T cells differentiate into various effector T cells, including CD4+ helper T cell subsets and CD8+ cytotoxic T cells (CTL). Although cytotoxic CD4+ T cells (CD4+CTL) also develop from naive T cells, the mechanism of development is elusive. We found that a small fraction of CD4+ T cells that express class I–restricted T cell–associated molecule (CRTAM) upon activation possesses the characteristics of both CD4+ and CD8+ T cells. CRTAM+ CD4+ T cells secrete IFN-γ, express CTL-related genes, such as eomesodermin (Eomes), Granzyme B, and perforin, after cultivation, and exhibit cytotoxic function, suggesting that CRTAM+ T cells are the precursor of CD4+CTL. Indeed, ectopic expression of CRTAM in T cells induced the production of IFN-γ, expression of CTL-related genes, and cytotoxic activity. The induction of CD4+CTL and IFN-γ production requires CRTAM-mediated intracellular signaling. CRTAM+ T cells traffic to mucosal tissues and inflammatory sites and developed into CD4+CTL, which are involved in mediating protection against infection as well as inducing inflammatory response, depending on the circumstances, through IFN-γ secretion and cytotoxic activity. These results reveal that CRTAM is critical to instruct the differentiation of CD4+CTL through the induction of Eomes and CTL-related gene. PMID:26694968

Effects of age and sex on voice onset time: Evidence from Mandarin voiceless stops.

PubMed

Ma, Junzhou; Chen, Xiaoxiang; Wu, Yezhou; Zhang, Linjie

2018-07-01

Considerable studies have addressed effects of age and sex on voice onset time (VOT) in English. However, few studies have examined these effects on Mandarin stops. This study attempts to examine effects of age and sex on VOT in Mandarin. A total of 85 Mandarin-speaking children, aged 4-18 years old, and 13 adults as reference participated in a production experiment. Productions were elicited by reading target words in carrier phrases. Results showed that children aged 6-7 years old had longer VOTs than older ones for highly aspirated stops, and the same tendency was not observed for unaspirated stops. However, no linear developmental trend was observed for both highly aspirated and unaspirated stops. In addition, females displayed longer VOTs for highly aspirated stops and shorter for unaspirated stops, whereas significant sex differences in VOTs existed from 14 years old to adulthood for highly aspirated stops, and no significant sex differences in VOTs were found for unaspirated stops in each group, indicating that sex differences in VOTs varied with age and aspiration. The findings suggest that physiological changes in and differences between males and females provide account for some, but not all differences in VOTs across age and sex.

Humoral response to influenza vaccination in relation to pre-vaccination antibody titres, vaccination history, cytomegalovirus serostatus and CD4/CD8 ratio.

PubMed

Strindhall, Jan; Ernerudh, Jan; Mörner, Andreas; Waalen, Kristian; Löfgren, Sture; Matussek, Andreas; Bengner, Malin

2016-01-01

Annual vaccination against influenza virus is generally recommended to elderly and chronically ill, but the relative importance of factors influencing the outcome is not fully understood. In this study of 88 individuals all aged 69 years, the increase in haemagglutinin-inhibiting (HI) antibodies to trivalent inactivated influenza vaccine was correlated with HI titres before vaccination, prior vaccinations against influenza, cytomegalovirus serostatus and, as an estimate of immune risk profile, the ratio between CD4 + and CD8 + T cells. Vaccine responses were impaired by high pre-existing HI antibody titres. For influenza B repeated vaccinations and an inverse CD4/CD8 ratio had a negative impact on the vaccine response. Cytomegalovirus seropositivity had no apparent effect on HI titres before or after vaccination. It is concluded that both pre-existing HI antibodies and previous vaccinations to influenza may influence the humoral response to influenza vaccination and that a CD4/CD8 ratio < 1 may indicate an impaired ability to respond to repeated antigenic stimulation.

Cutaneous CD30+ cells in children with atopic dermatitis.

PubMed

Cavagni, G; Caffarelli, C; Facchetti, F; Brugnoni, D; Notarangelo, L D; Tosoni, C; Altobelli, R

2000-03-01

CD30 expression can be considered a marker of Th2 cells. We investigated the presence of CD30+ cells in the lesional skin of children with atopic dermatitis (AD). We also analyzed the possible relationship between CD30+ cells and serum soluble CD 30 (sCD30) levels, and IgE, soluble interleukin-2 (IL-2) receptor (sIL-2R) or soluble CD23 (sCD23) levels in the blood, and clinical score. Ten eczematous children (4 males, 6 females; median age: 4 years and 5 months; range: 11 months to 14 years), 9 sex- and age-matched control children and an adult control group were studied. A clinical score (SCORAD index), was given to eczematous lesions. Blood was taken for the determination of IgE, sCD30, sIL-2R and sCD23 levels. Punch biopsies of lesional skin were stained with hematoxylin and eosin or incubated with anti-CD30 monoclonal antibodies. Skin prick tests (SPTs) were also performed. In the biopsy specimens, CD30 expression was observed in high proportions of infiltrating cells. In children with AD, total serum IgE, sCD30, sIL-2R, sCD23 and eosinophils were significantly elevated compared to controls. CD30+ cells were not associated with serum IgE, sCD30, sIL-2R, sCD23, or SPT results, score of inflammatory cells in lesional skin or clinical score. Children with AD who had high total IgE and specific IgE antibodies did not differ from those with normal total IgE and negative specific IgE in respect of age, clinical score, number of CD30+ cells, sCD30, sIL-2R and sCD23 levels, score of inflammatory cells in skin or clinical score. Our results showed remarkable numbers of CD30+ cells in the lesional skin and high sCD30 in the serum of children with AD. CD30+ cells did not correlate with systemic markers of IgE reaction. Copyright 2000 S. Karger AG, Basel

The CD4/CD8 Ratio is Inversely Associated with Carotid Intima-Media Thickness Progression in Human Immunodeficiency Virus-Infected Patients on Antiretroviral Treatment.

PubMed

Bernal Morell, Enrique; Serrano Cabeza, José; Muñoz, Ángeles; Marín, Irene; Masiá, Mar; Gutiérrez, Félix; Cano, Alfredo

2016-07-01

Inversion of the CD4/CD8 ratio (<1) has been identified as a surrogate marker of immunosenescence and an independent predictor of AIDS events in HIV-infected patients and mortality in the general population. We aimed to assess the association between the CD4/CD8 ratio and carotid intima-media thickness (cIMT) progression in treated HIV-infected patients as a marker of coronary heart disease. A longitudinal study was conducted during 3 years in 96 virally suppressed HIV-infected patients receiving antiretroviral treatment (ART). We analyzed the associations between the CD4/CD8 ratio, cardiovascular risk factors, and antiretroviral treatment (ART) and progression of subclinical atherosclerosis assessed using cIMT at baseline and after 3 years. Finally, 96 patients completed the study. Seventy six (79.1%) patients were male, aged 44 ± 10 years; 39 (40.6%) were on treatment with protease inhibitors; 49 (51.04%) with nonnucleoside reverse transcriptase inhibitors, 6 (6.25%) with integrase inhibitors, 3 (3.12%) with maraviroc, and 2 (2.08%) just with nucleoside reverse transcriptase inhibitors. The mean of ART exposition was 6.9 ± 5.9 years. Twenty six (27%) patients had family history of ischemic heart disease, 51 (53.12%) were smokers, 12 (12.5%) were hypertensive, 4 (4.16%) had type 2 diabetes, 23 (23.9%) had dyslipidemia, and 31 (32.3%) were infected with hepatitis C virus. Baseline cIMT was significantly associated with age (rho = 0.497; p < .001), basal glucemia (rho = 0.323; p = .001), triglycerides (rho = 0.232; p = .023), Framingham risk score (rho = 0.324; p = .001), CD4/CD8 ratio (rho = -0.176; p = .05), and dyslipidemia (0.72 ± 0.16 mm vs. 0.63 ± 0.11 mm; p = .029). In multivariable analysis where cardiovascular risk factor and ART were included, cIMT progression was inversely associated with CD4/CD8 ratio [odds ratio (OR) = 0.283; confidence interval (95% CI) 0.099-0.809; p = .019

CD4 and CD8 T-Cell Responses to Mycobacterial Antigens in African Children

PubMed Central

Tena-Coki, Nontobeko G.; Scriba, Thomas J.; Peteni, Nomathemba; Eley, Brian; Wilkinson, Robert J.; Andersen, Peter; Hanekom, Willem A.; Kampmann, Beate

2010-01-01

Rationale: The current tuberculosis (TB) vaccine, bacille Calmette-Guérin (BCG), does not provide adequate protection against TB disease in children. Furthermore, more efficacious TB vaccines are needed for children with immunodeficiencies such as HIV infection, who are at highest risk of disease. Objectives: To characterize mycobacteria-specific T cells in children who might benefit from vaccination against TB, focusing on responses to antigens contained in novel TB vaccines. Methods: Whole blood was collected from three groups of BCG-vaccinated children: HIV-seronegative children receiving TB treatment (n = 30), HIV-infected children (n = 30), and HIV-unexposed healthy children (n = 30). Blood was stimulated with Ag85B and TB10.4, or purified protein derivative, and T-cell cytokine production by CD4 and CD8 was determined by flow cytometry. The memory phenotype of antigen-specific CD4 and CD8 T cells was also determined. Measurements and Main Results: Mycobacteria-specific CD4 and CD8 T-cell responses were detectable in all three groups of children. Children receiving TB treatment had significantly higher frequencies of antigen-specific CD4 T cells compared with HIV-infected children (P = 0.0176). No significant differences in magnitude, function, or phenotype of specific T cells were observed in HIV-infected children compared with healthy control subjects. CD4 T cells expressing IFN-γ, IL-2, or both expressed a CD45RA−CCR7−CD27+/− effector memory phenotype. Mycobacteria-specific CD8 T cells expressed mostly IFN-γ in all groups of children; these cells expressed CD45RA−CCR7−CD27+/− or CD45RA+CCR7−CD27+/− effector memory phenotypes. Conclusions: Mycobacteria-specific T-cell responses could be demonstrated in all groups of children, suggesting that the responses could be boosted by new TB vaccines currently in clinical trials. PMID:20224065

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.

Extensive CD4 and CD8 T-cell cross-reactivity between alphaherpesviruses1

PubMed Central

Dong, Lichun; Russell, Ronnie M.; Barlow, Russell S.; Haas, Juergen G.; Ramchandani, Meena S.; Johnston, Christine; Buus, Soren; Redwood, Alec J.; White, Katie D.; Mallal, Simon A.; Phillips, Elizabeth J.; Posavad, Christine M.; Wald, Anna; Koelle, David M.

2015-01-01

The alphaherpesvirinae subfamily includes HSV types 1 and 2 and the sequence-divergent pathogen varicella zoster virus (VZV). T cells, controlled by TCR and HLA molecules that tolerate limited epitope amino acid variation, might cross-react between these microbes. We show that memory PBMC expansion with either HSV or VZV enriches for CD4 T cell lines that recognize the other agent at the whole virus, protein, and peptide levels, consistent with bi-directional cross-reactivity. HSV-specific CD4 T cells recovered from HSV seronegative persons can be partially explained by such VZV cross-reactivity. HSV-1-reactive CD8 T cells also cross-react with VZV-infected cells, full-length VZV proteins, and VZV peptides, and kill VZV-infected dermal fibroblasts. Mono- and cross-reactive CD8 T cells use distinct TCRB CDR3 sequences. Cross-reactivity to VZV is reconstituted by cloning and expressing TCRA/TCRB receptors from T-cells that are initially isolated using HSV reagents. Overall, we define 13 novel CD4 and CD8 HSV-VZV cross-reactive epitopes and strongly imply additional cross-reactive peptide sets. Viral proteins can harbor both CD4 and CD8 HSV/VZV cross-reactive epitopes. Quantitative estimates of HSV/VZV cross-reactivity for both CD4 and CD8 T cells vary from 10-50%. Based on these findings, we hypothesize host herpesvirus immune history may influence the pathogenesis and clinical outcome of subsequent infections or vaccinations for related pathogens, and that cross-reactive epitopes and TCRs may be useful for multi-alphaherpesvirus vaccine design and adoptive cellular therapy. PMID:26810224

Identifying sex and age of akiapolaau

USGS Publications Warehouse

Pratt, T.K.; Fancy, S.G.; Harada, C.K.; Lindsey, G.D.; Jacobi, J.D.

1994-01-01

Methods for identifying the sex and age of the Akiapolaau (Hemignathus munroi), an endangered honeycreeper found only on the island of Hawaii, were developed by examination and measurement of 73 museum specimens and 24 live birds captured in mist nests. Akiapolaau probably undergo a single annual molt, with most birds molting between February and July. The mottled juvenal plumage is replaced by a first basic plumage characterized by yellowish-gray or yellowish-green underparts and often by retained wingbars. Male Akiapolaau may not attain adult plumage until their third molt. In adult females, only the throat and upper breast become yellow, whereas in adult males the superciliaries, cheeks, and entire underparts are yellow. Adult males have greater exposed culmen, gonys, wing chord, tail, and tarsus lengths than do females. Akiapolaau in first prebasic molt or older can be identified as to sex by culmen length, that of males being >23.4 mm.

Variance in age-specific sex composition of Pacific halibut catches, and comparison of statistical and genetic methods for reconstructing sex ratios

NASA Astrophysics Data System (ADS)

Loher, Timothy; Woods, Monica A.; Jimenez-Hidalgo, Isadora; Hauser, Lorenz

2016-01-01

Declines in size at age of Pacific halibut Hippoglossus stenolepis, in concert with sexually-dimorphic growth and a constant minimum commercial size limit, have led to the expectation that the sex composition of commercial catches should be increasingly female-biased. Sensitivity analyses suggest that variance in sex composition of landings may be the most influential source of uncertainty affecting current understanding of spawning stock biomass. However, there is no reliable way to determine sex at landing because all halibut are eviscerated at sea. In 2014, a statistical method based on survey data was developed to estimate the probability that fish of any given length at age (LAA) would be female, derived from the fundamental observation that large, young fish are likely female whereas small, old fish have a high probability of being male. Here, we examine variability in age-specific sex composition using at-sea commercial and closed-season survey catches, and compare the accuracy of the survey-based LAA technique to genetic markers for reconstructing the sex composition of catches. Sexing by LAA performed best for summer-collected samples, consistent with the hypothesis that the ability to characterize catches can be influenced by seasonal demographic shifts. Additionally, differences between survey and commercial selectivity that allow fishers to harvest larger fish within cohorts may generate important mismatch between survey and commercial datasets. Length-at-age-based estimates ranged from 4.7% underestimation of female proportion to 12.0% overestimation, with mean error of 5.8 ± 1.5%. Ratios determined by genetics were closer to true sample proportions and displayed less variability; estimation to within < 1% of true ratios was limited to genetics. Genetic estimation of female proportions ranged from 4.9% underestimation to 2.5% overestimation, with a mean absolute error of 1.2 ± 1.2%. Males were generally more difficult to assign than females: 6.7% of

AFM force measurements of the gp120-sCD4 and gp120 or CD4 antigen-antibody interactions

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chen, Yong, E-mail: dr_yongchen@hotmail.com; Department of Microbiology and Immunology, University of Illinois at Chicago, Chicago, IL 60612; Zeng, Gucheng

2011-04-08

Highlights: {yields} The unbinding force of sCD4-gp120 interaction was 25.45 {+-} 20.46 pN. {yields} The unbinding force of CD4 antigen-antibody interaction was 51.22 {+-} 34.64 pN. {yields} The unbinding force of gp120 antigen-antibody interaction was 89.87 {+-} 44.63 pN. {yields} The interaction forces between various HIV inhibitors and the target molecules are significantly different. {yields} Functionalizing on AFM tip or substrate of an interaction pair caused different results. -- Abstract: Soluble CD4 (sCD4), anti-CD4 antibody, and anti-gp120 antibody have long been regarded as entry inhibitors in human immunodeficiency virus (HIV) therapy. However, the interactions between these HIV entry inhibitors andmore » corresponding target molecules are still poorly understood. In this study, atomic force microscopy (AFM) was utilized to investigate the interaction forces among them. We found that the unbinding forces of sCD4-gp120 interaction, CD4 antigen-antibody interaction, and gp120 antigen-antibody interaction were 25.45 {+-} 20.46, 51.22 {+-} 34.64, and 89.87 {+-} 44.63 pN, respectively, which may provide important mechanical information for understanding the effects of viral entry inhibitors on HIV infection. Moreover, we found that the functionalization of an interaction pair on AFM tip or substrate significantly influenced the results, implying that we must perform AFM force measurement and analyze the data with more caution.« less

Impact of Age and Sex on Response to Asthma Therapy.

PubMed

Dunn, Ryan M; Lehman, Erik; Chinchilli, Vernon M; Martin, Richard J; Boushey, Homer A; Israel, Elliot; Kraft, Monica; Lazarus, Stephen C; Lemanske, Robert F; Lugogo, Njira L; Peters, Stephen P; Sorkness, Christine A; Szefler, Stanley; Wechsler, Michael E

2015-09-01

Age and sex are associated with differences in asthma prevalence and morbidity. To determine if age and sex associate with distinct phenotypes and a variable response to therapy in subjects with mild to moderate asthma. We used Asthma Clinical Research Network data to determine the impact of age and sex on phenotypes and treatment failures among subjects participating in 10 trials from 1993 to 2003. A total of 1,200 subjects were identified (median age, 30.4 yr; male, 520 [43.3%]; female, 680 [56.7%]) and analyzed. A higher proportion of subjects greater than or equal to 30 years old experienced treatment failures (17.3% vs. 10.3%; odds ratio [OR], 1.82; confidence interval [CI], 1.30-2.54; P < 0.001), and rates increased proportionally with increasing age older than 30 across the cohort (OR per yr, 1.02 [CI, 1.01-1.04]; OR per 5 yr, 1.13 [CI, 1.04-1.22]; P < 0.001). Lower lung function and longer duration of asthma were associated with a higher risk of treatment failures. A higher proportion of subjects greater than or equal to 30 years old receiving controller therapy experienced treatment failures. When stratified by specific therapy, treatment failures increased consistently for every year older than age 30 in subjects on inhaled corticosteroids (OR per year, 1.03; CI, 1.01-1.07). Females had a slightly higher FEV1 % predicted (84.5% vs. 81.1%; P < 0.001) but similar asthma control measures. There was not a statistically significant difference in treatment failures between females and males (15.2% vs. 11.7%; P = 0.088). Older age is associated with an increased risk of treatment failure, particularly in subjects taking inhaled corticosteroids. There was no significant difference in treatment failures between sexes.

Progressive CD4+ central–memory T cell decline results in CD4+ effector–memory insufficiency and overt disease in chronic SIV infection

PubMed Central

Okoye, Afam; Meier-Schellersheim, Martin; Brenchley, Jason M.; Hagen, Shoko I.; Walker, Joshua M.; Rohankhedkar, Mukta; Lum, Richard; Edgar, John B.; Planer, Shannon L.; Legasse, Alfred; Sylwester, Andrew W.; Piatak, Michael; Lifson, Jeffrey D.; Maino, Vernon C.; Sodora, Donald L.; Douek, Daniel C.; Axthelm, Michael K.; Grossman, Zvi; Picker, Louis J.

2007-01-01

Primary simian immunodeficiency virus (SIV) infections of rhesus macaques result in the dramatic depletion of CD4+ CCR5+ effector–memory T (TEM) cells from extra-lymphoid effector sites, but in most infections, an increased rate of CD4+ memory T cell proliferation appears to prevent collapse of effector site CD4+ TEM cell populations and acute-phase AIDS. Eventually, persistent SIV replication results in chronic-phase AIDS, but the responsible mechanisms remain controversial. Here, we demonstrate that in the chronic phase of progressive SIV infection, effector site CD4+ TEM cell populations manifest a slow, continuous decline, and that the degree of this depletion remains a highly significant correlate of late-onset AIDS. We further show that due to persistent immune activation, effector site CD4+ TEM cells are predominantly short-lived, and that their homeostasis is strikingly dependent on the production of new CD4+ TEM cells from central–memory T (TCM) cell precursors. The instability of effector site CD4+ TEM cell populations over time was not explained by increasing destruction of these cells, but rather was attributable to progressive reduction in their production, secondary to decreasing numbers of CCR5− CD4+ TCM cells. These data suggest that although CD4+ TEM cell depletion is a proximate mechanism of immunodeficiency, the tempo of this depletion and the timing of disease onset are largely determined by destruction, failing production, and gradual decline of CD4+ TCM cells. PMID:17724130

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

CD32-Expressing CD4 T Cells Are Phenotypically Diverse and Can Contain Proviral HIV DNA.

PubMed

Martin, Genevieve E; Pace, Matthew; Thornhill, John P; Phetsouphanh, Chansavath; Meyerowitz, Jodi; Gossez, Morgane; Brown, Helen; Olejniczak, Natalia; Lwanga, Julianne; Ramjee, Gita; Kaleebu, Pontiano; Porter, Kholoud; Willberg, Christian B; Klenerman, Paul; Nwokolo, Nneka; Fox, Julie; Fidler, Sarah; Frater, John

2018-01-01

Efforts to both characterize and eradicate the HIV reservoir have been limited by the rarity of latently infected cells and the absence of a specific denoting biomarker. CD32a (FcγRIIa) has been proposed to be a marker for an enriched CD4 T cell HIV reservoir, but this finding remains controversial. Here, we explore the expression of CD32 on CD3 + CD4 + cells in participants from two primary HIV infection studies and identify at least three distinct phenotypes (CD32 low , CD32 + CD14 + , and CD32 high ). Of note, CD4 negative enrichment kits remove the majority of CD4 + CD32 + T cells, potentially skewing subsequent analyses if used. CD32 high CD4 T cells had higher levels of HLA-DR and HIV co-receptor expression than other subsets, compatible with their being more susceptible to infection. Surprisingly, they also expressed high levels of CD20, TCRαβ, IgD, and IgM (but not IgG), markers for both T cells and naïve B cells. Compared with other populations, CD32 low cells had a more differentiated memory phenotype and high levels of immune checkpoint receptors, programmed death receptor-1 (PD-1), Tim-3, and TIGIT. Within all three CD3 + CD4 + CD32 + phenotypes, cells could be identified in infected participants, which contained HIV DNA. CD32 expression on CD4 T cells did not correlate with HIV DNA or cell-associated HIV RNA (both surrogate measures of overall reservoir size) or predict time to rebound viremia following treatment interruption, suggesting that it is not a dominant biomarker for HIV persistence. Our data suggest that while CD32 + T cells can be infected with HIV, CD32 is not a specific marker of the reservoir although it might identify a population of HIV enriched cells in certain situations.

A novel differentiation pathway from CD4+ T cells to CD4− T cells for maintaining immune system homeostasis

PubMed Central

Zhao, X; Sun, G; Sun, X; Tian, D; Liu, K; Liu, T; Cong, M; Xu, H; Li, X; Shi, W; Tian, Y; Yao, J; Guo, H; Zhang, D

2016-01-01

CD4+ T lymphocytes are key players in the adaptive immune system and can differentiate into a variety of effector and regulatory T cells. Here, we provide evidence that a novel differentiation pathway of CD4+ T cells shifts the balance from a destructive T-cell response to one that favors regulation in an immune-mediated liver injury model. Peripheral CD4−CD8−NK1.1− double-negative T cells (DNT) was increased following Concanavalin A administration in mice. Adoptive transfer of DNT led to significant protection from hepatocyte necrosis by direct inhibition on the activation of lymphocytes, a process that occurred primarily through the perforin-granzyme B route. These DNT converted from CD4+ rather than CD8+ T cells, a process primarily regulated by OX40. DNT migrated to the liver through the CXCR3-CXCL9/CXCL10 interaction. In conclusion, we elucidated a novel differentiation pathway from activated CD4+ T cells to regulatory DNT cells for maintaining homeostasis of the immune system in vivo, and provided key evidence that utilizing this novel differentiation pathway has potential application in the prevention and treatment of autoimmune diseases. PMID:27077809

Increased loss of CCR5+ CD45RA- CD4+ T cells in CD8+ lymphocyte-depleted Simian immunodeficiency virus-infected rhesus monkeys.

PubMed

Veazey, Ronald S; Acierno, Paula M; McEvers, Kimberly J; Baumeister, Susanne H C; Foster, Gabriel J; Rett, Melisa D; Newberg, Michael H; Kuroda, Marcelo J; Williams, Kenneth; Kim, Eun-Young; Wolinsky, Steven M; Rieber, E Peter; Piatak, Michael; Lifson, Jeffrey D; Montefiori, David C; Brown, Charles R; Hirsch, Vanessa M; Schmitz, Jörn E

2008-06-01

Previously we have shown that CD8(+) T cells are critical for containment of simian immunodeficiency virus (SIV) viremia and that rapid and profound depletion of CD4(+) T cells occurs in the intestinal tract of acutely infected macaques. To determine the impact of SIV-specific CD8(+) T-cell responses on the magnitude of the CD4(+) T-cell depletion, we investigated the effect of CD8(+) lymphocyte depletion during primary SIV infection on CD4(+) T-cell subsets and function in peripheral blood, lymph nodes, and intestinal tissues. In peripheral blood, CD8(+) lymphocyte-depletion changed the dynamics of CD4(+) T-cell loss, resulting in a more pronounced loss 2 weeks after infection, followed by a temporal rebound approximately 2 months after infection, when absolute numbers of CD4(+) T cells were restored to baseline levels. These CD4(+) T cells showed a markedly skewed phenotype, however, as there were decreased levels of memory cells in CD8(+) lymphocyte-depleted macaques compared to controls. In intestinal tissues and lymph nodes, we observed a significantly higher loss of CCR5(+) CD45RA(-) CD4(+) T cells in CD8(+) lymphocyte-depleted macaques than in controls, suggesting that these SIV-targeted CD4(+) T cells were eliminated more efficiently in CD8(+) lymphocyte-depleted animals. Also, CD8(+) lymphocyte depletion significantly affected the ability to generate SIV Gag-specific CD4(+) T-cell responses and neutralizing antibodies. These results reemphasize that SIV-specific CD8(+) T-cell responses are absolutely critical to initiate at least partial control of SIV infection.

Influence of LTB4 on CD4-, CD8- thymocytes. Evidence that LTB4 plus IL-2 generate CD8+ suppressor thymocytes involved in tolerance to self. Effect of LTB4 and IL-2 on double negative thymocytes.

PubMed

Gualde, N; Cogny van Weydevelt, F; Buffière, F; Jauberteau, M O; Daculsi, R; Vaillier, D

1991-09-01

Leukotriene B4 (LTB4) is produced by a large variety of cells involved in immune response and it has been demonstrated that this arachidonic acid metabolite acts as an immunomodulator. Because LTB4 and IL-2 both influence the physiology of immature cells we studied the effects of the leukotriene on double negative thymocytes. For that purpose C57 Bl/6 double negative thymocytes were treated by LTB4 plus IL-2 in the presence of either autologous or allogenic red blood cells (RBC). Then, preincubated CD4- CD8- thymocytes were cocultured with red blood cells stimulated fresh splenocytes. We observed that fresh splenocytes responding to autologous RBC were CD4+ cells and that the proliferative response of spleen lymphocytes driven by RBC was inhibited by preincubated double negative thymocytes. On the other hand a majority of double negative thymocytes overnight preincubated in vitro in the presence of both IL-2 and LTB4 give rise to CD8+ CD4- cells. Therefore we speculate that LTB4 plus IL-2 generate CD8+ suppressor thymocytes among double negative thymocytes and that these suppressive T cells are involved in tolerance to self.

Effect of age and latent CMV infection on CD8+ CD56+ T cells (NKT-like) frequency and functionality.

PubMed

Hassouneh, Fakhri; Campos, Carmen; López-Sejas, Nelson; Alonso, Corona; Tarazona, Raquel; Solana, Rafael; Pera, Alejandra

2016-09-01

Changes in the T cell pool caused by CMV infection have been proposed to contribute to immunosenescence, but it has been postulated that CMV can also have some beneficial effects in young individuals improving the immune response to other pathogens. T cells expressing CD56 (NKT-like cells) are cytotoxic effector cells with a significant role in the immune response against cancer. We have studied how age and latent CMV infection affect the frequency of NKT-like cells (CD8+ CD56+ T cells) and their response to Staphylococcal Enterotoxin B (SEB) in the context of CMV and ageing. NKT-like cell percentage increases with the combination of both CMV and age. The response to SEB and the polyfunctional index of NKT-like cells also increase with age in CMV-seropositive individuals. In young individuals, CMV infection induces a shift on the polyfunctional profile of CD8+ CD56- T cells not observed on the NKT-like cells response. NKT-like cells expressing CD57 are expanded in CMV-seropositive individuals and are more polyfunctional than their CD57-  counterpart. In addition CD57- NKT-like cells are more polyfunctional than CD8+ CD56- CD57- T cells. The results support that the expansion of polyfunctional NKT-cells may have a beneficial effect on the immune response against pathogens. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Progressive CD4+ central memory T cell decline results in CD4+ effector memory insufficiency and overt disease in chronic SIV infection.

PubMed

Okoye, Afam; Meier-Schellersheim, Martin; Brenchley, Jason M; Hagen, Shoko I; Walker, Joshua M; Rohankhedkar, Mukta; Lum, Richard; Edgar, John B; Planer, Shannon L; Legasse, Alfred; Sylwester, Andrew W; Piatak, Michael; Lifson, Jeffrey D; Maino, Vernon C; Sodora, Donald L; Douek, Daniel C; Axthelm, Michael K; Grossman, Zvi; Picker, Louis J

2007-09-03

Primary simian immunodeficiency virus (SIV) infections of rhesus macaques result in the dramatic depletion of CD4(+) CCR5(+) effector-memory T (T(EM)) cells from extra-lymphoid effector sites, but in most infections, an increased rate of CD4(+) memory T cell proliferation appears to prevent collapse of effector site CD4(+) T(EM) cell populations and acute-phase AIDS. Eventually, persistent SIV replication results in chronic-phase AIDS, but the responsible mechanisms remain controversial. Here, we demonstrate that in the chronic phase of progressive SIV infection, effector site CD4(+) T(EM) cell populations manifest a slow, continuous decline, and that the degree of this depletion remains a highly significant correlate of late-onset AIDS. We further show that due to persistent immune activation, effector site CD4(+) T(EM) cells are predominantly short-lived, and that their homeostasis is strikingly dependent on the production of new CD4(+) T(EM) cells from central-memory T (T(CM)) cell precursors. The instability of effector site CD4(+) T(EM) cell populations over time was not explained by increasing destruction of these cells, but rather was attributable to progressive reduction in their production, secondary to decreasing numbers of CCR5(-) CD4(+) T(CM) cells. These data suggest that although CD4(+) T(EM) cell depletion is a proximate mechanism of immunodeficiency, the tempo of this depletion and the timing of disease onset are largely determined by destruction, failing production, and gradual decline of CD4(+) T(CM) cells.

CD(+)(4)CD(+)(25) Treg cells in thrombotic thrombocytopenic purpura associated with systemic lupus erythematosus patients.

PubMed

Huang, Hongdong; Sun, Weiming; Liang, Yumei; Long, Xi-Dai; Peng, Youming; Liu, Zhihua; Wen, Xiaojun; Jia, Meng

2014-09-01

CD(+)(4)CD(+)(25) Treg cells are of critical importance for maintenance of tolerance. The purpose of the this study was to observe the number of CD(+)(4)CD(+)(25) Treg cells in the patients with thrombotic thrombocytopenic purpura (TTP) associated with systemic lupus erythematosus (SLE), and to study pathogenesis of TTP with SLE. Seven patients with TTP associated with SLE and seven healthy volunteers were studied. The CD(+)(4)CD(+)(25) Treg cells were examined by flow cytometry. Clinical and laboratory data, such as urinary protein, serum creatinine, endothelial markers and immunologic serologics, were obtained from each patient and healthy volunteer. Glomerular injury was assessed by histopathology. Serum IL-2, IL-4, IL-6 and anti-endothelial cell antibody were analyzed by ELISA and anti-ADAMTS13 antibody were detected by Western blotting. CD(+)(4)CD(+)(25) Treg cells significantly decreased in TTP with SLE patients compared with controls (p < 0.05). CD(+)(4)CD(+)(25) Treg cells are negatively correlated with blood urea nitrogen, serum uric acid, supernatant IL-4, and proteinuria, and positively with estimated glomerular filtration rate (eGFR) in TTP with SLE patients. [Formula: see text] Treg cells gradually decreased as the severity of renal histology increased. Serum IL-2, IL-6, supernatant IL-4, anti-endothelial cell antibody, and anti-ADAMTS13 antibody significantly increased in TTP with SLE patients compared to those of the control groups (all p < 0.05). In contrast, serum levels of C3 were significantly decreased in TTP with SLE patients compared to those of the control groups (p < 0.05). CD(+)(4)CD(+)(25) Treg cells are not only lower in TTP with SLE patients, but also are correlated with disease severity in TTP with SLE patients.CD(+)(4)CD(+)(25)Treg cells may play an important role in the pathogenesis of TTP with SLE.

Regulatory CD4 T cells inhibit HIV-1 expression of other CD4 T cell subsets via interactions with cell surface regulatory proteins.

PubMed

Zhang, Mingce; Robinson, Tanya O; Duverger, Alexandra; Kutsch, Olaf; Heath, Sonya L; Cron, Randy Q

2018-03-01

During chronic HIV-1 infection, regulatory CD4 T cells (Tregs) frequently represent the largest subpopulation of CD4 T cell subsets, implying relative resistant to HIV-1. When HIV-1 infection of CD4 T cells was explored in vitro and ex vivo from patient samples, Tregs possessed lower levels of HIV-1 DNA and RNA in comparison with conventional effector and memory CD4 T cells. Moreover, Tregs suppressed HIV-1 expression in other CD4 T cells in an in vitro co-culture system. This suppression was mediated in part via multiple inhibitory surface proteins expressed on Tregs. Antibody blockade of CTLA-4, PD-1, and GARP on Tregs resulted in increased HIV-1 DNA integration and mRNA expression in neighboring CD4 T cells. Moreover, antibody blockade of Tregs inhibitory proteins resulted in increased HIV-1 LTR transcription in co-cultured CD4 T cells. Thus, Tregs inhibit HIV-1 infection of other CD4 T cell subsets via interactions with inhibitory cell surface proteins. Copyright © 2018 Elsevier Inc. All rights reserved.

Intrinsic and extrinsic contributors to defective CD8+ T cell responses with aging.

PubMed

Jergović, Mladen; Smithey, Megan J; Nikolich-Žugich, Janko

2018-05-01

Aging has a profound effect on the immune system, and both innate and adaptive arms of the immune system show functional decline with age. In response to infection with intracellular microorganisms, old animals mobilize decreased numbers of antigen-specific CD8+ T cells with reduced production of effector molecules and impaired cytolytic activity. However, the CD8+ T cell-intrinsic contribution to, and molecular mechanisms behind, these defects remain unclear. In this review we will discuss the mechanistic contributions of age related changes in the CD8+ T cell pool and the relative roles of intrinsic functional defects in aged CD8+ T cells vs. defects in the aged environment initiating the CD8+ T cell response. Copyright © 2018 Elsevier Inc. All rights reserved.

IL-4 Is Required for Sex Differences in Vulnerability to Focal Ischemia in Mice.

PubMed

Xiong, Xiaoxing; Xu, Lijun; Wei, Liang; White, Robin E; Ouyang, Yi-Bing; Giffard, Rona G

2015-08-01

Interleukin (IL)-4 protects from middle cerebral artery occlusion in male mice. Females generally show less injury in response to the same ischemic challenge, but the underlying mechanisms are not fully understood. We tested the importance of IL-4 in female protection using IL-4 knockout (KO) mice. IL-4 KO and wild-type (WT) mice of both sexes were subjected to middle cerebral artery occlusion. Infarct volume was assessed by triphenyltetrazolium chloride staining and neurobehavioral outcome by neuroscore. T cell proliferation was assessed after Concanavalin A exposure. Ischemic brain immune cell populations were analyzed by fluorescence-activated cell sorting and immunostaining. Infarction in WT females during estrus and proestrus phases was significantly smaller than in males; neurological score was better. Infarction volume was larger and neurological score worse in IL-4 KO compared with WT in both sexes, with no sex difference. Proliferation of T cells was inhibited in WT females with higher proliferation and no sex difference in IL-4 KO. Macrophage numbers and total T cells in the ischemic hemisphere were lower in WT females, and monocytes increased markedly in IL-4 KOs with no sex difference. The reduced macrophage infiltration in WT-females was predominantly M2. Loss of IL-4 increased CD68+ and iNOS+ cells and reduced YM1+ and Arg1+ cells in both sexes. IL-4 is required for female neuroprotection during the estrus phase of the estrus cycle. Protected WT females show a predominance of M2-activated microglia/macrophages and reduced inflammatory infiltration. Increasing macrophage M2 polarization, with or without added inhibition of infiltration, may be a new approach to stroke treatment. © 2015 American Heart Association, Inc.

In vivo fluctuation of Tax, Foxp3, CTLA-4, and GITR mRNA expression in CD4(+)CD25(+) T cells of patients with human T-lymphotropic virus type 1-associated myelopathy.

PubMed

Ramirez, E; Cartier, L; Rodriguez, L; Alberti, C; Valenzuela, M A

2010-11-01

HTLV-1 Tax expression exerts an inhibitory effect on the Foxp3 transcription factor in CD4(+)CD25(+) T-regulatory cells (Treg). For a better understanding of the role of Tax mRNA in the gene expression of cellular markers we measured Tax, Foxp3, CTLA-4, GITR, TGF-β, and IL-10 mRNA in Treg cells of 50 patients with human T-lymphotropic virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP; 27 women and 23 men; mean age: 56.7 years). The control group consisted of 23 non-infected subjects (12 women and 11 men) with a mean age of 51.3 years. Real-time PCR was used to measure mRNA of Tax proteins and several cellular markers of Treg function. Determinations revealed a high level of Tax mRNA in HAM/TSP (124.35 copies/100 CD4(+)CD25(+) T cells). Foxp3, GITR, and CTLA-4 mRNA levels were lower in HAM/TSP patients (mean ± SD, 22.07 ± 0.78, 9.63 ± 0.36, and 4.54 ± 0.39, respectively) than in non-infected controls (47.15 ± 12.94, 22.14 ± 1.91, and 21.07 ± 2.31). Both groups had similar levels of TGF-β and IL-10. An inverse relationship was found between Tax levels and Foxp3, CTLA-4, and GITR levels. Conversely, there was a direct correlation between levels of Foxp3, GITR, and CTLA-4. Disease severity and evolution time did not correlate with Tax or Foxp3 levels. The present results suggest that Tax and Foxp3 mRNA vary with the same degree of disease severity in HAM/TSP patients. Tax fluctuations may affect CTLA-4 and GITR expression via the Foxp3 pathway, causing virus-induced dysfunction of CD4(+)CD25(+) T cells in HAM/TSP patients.

The number and function of circulating CD34+CD133+ progenitor cells decreased in stable coronary artery disease but not in acute myocardial infarction

PubMed Central

Kondo, Takahisa; Shintani, Satoshi; Maeda, Kengo; Hayashi, Mutsuharu; Inden, Yasuya; Numaguchi, Yasushi; Sugiura, Kaichiro; Morita, Yasuhiro; Kitamura, Tomoya; Kamiya, Haruo; Sone, Takahito; Ohno, Miyoshi; Murohara, Toyoaki

2010-01-01

Objective Circulating CD34+CD133+ cells are one of the main sources of circulating endothelial progenitor cells (EPCs). Age is inversely related to the number and function of CD34+CD133+ progenitor cells in stable coronary artery disease (CAD), but the relationship remains unclear in acute myocardial infarction (AMI). The authors aimed to clarify how ageing affects the number and function of mobilised CD34+CD133+ progenitor cells in AMI. Design and results Circulating CD34+CD133+ progenitor cells were measured by flow cytometry. Measurements were made at admission for CAD, or on day 7 after the onset of AMI. In stable CAD (n=131), circulating CD34+CD133+ cells decreased with age (r=−0.344, p<0.0001). In AMI, circulating CD34+CD133+ cells did not correlate with age (n=50), and multivariate analysis revealed that the decreased number of circulating CD34+CD133+ cells was associated with male sex and higher peak creatinine kinase. The ability to give rise to functional EPCs, which show good migratory and tube-forming capabilities, deteriorated among stable CAD subjects (n=10) compared with AMI subjects (N=6). Conclusions In stable CAD, the number and function of circulating CD34+CD133+ progenitor cells decreased with age, whereas those mobilised and circulating in AMI did not. PMID:27325937

Physical fitness in preschool children: association with sex, age and weight status.

PubMed

Latorre Román, P Á; Moreno Del Castillo, R; Lucena Zurita, M; Salas Sánchez, J; García-Pinillos, F; Mora López, D

2017-03-01

Because fitness level is a potent biomarker of health from an early age, the improvements of physical fitness performance through the promotion of physical activity could be important for the health of preschool children, particularly in obesity prevention. The purpose of this study is to determine the physical fitness in children aged 3-6 years, discriminating performance by sex, age and body mass index (BMI). A total of 3868 children from 3 to 6 years agreed voluntarily to participate. Demographic characteristics revealed that 1961 children were male (age: 55.71 ± 11.11 months old, BMI = 16.03 ± 1.93 kg/m 2 ), and 1907 were female (age 56.16 ± 0.97 months old, BMI = 15.85 ± 1.89 kg/m 2 ), and they were selected from 51 schools in southern Spain. Significant differences were found between sexes: boys showed a greater performance on cardio respiratory endurance, reaction time, strength and running speed. We found significant differences by sex in the different age groups (3, 4, 5 and 6 years old). Sex differences in physical fitness are evident at an early age; in addition, the relationship between physical fitness and BMI is inconsistent in preschool children. The improvements of physical fitness performance and its association with physical activity could be important for the health of children, particularly in obesity prevention. © 2016 John Wiley & Sons Ltd.

Cytokines affecting CD4+T regulatory cells in transplant tolerance. III. Interleukin-5 (IL-5) promotes survival of alloantigen-specific CD4+ T regulatory cells.

PubMed

Hall, Bruce M; Plain, Karren M; Tran, Giang T; Verma, Nirupama D; Robinson, Catherine M; Nomura, Masaru; Boyd, Rochelle; Hodgkinson, Suzanne J

2017-08-01

CD4 + T cells mediate antigen-specific allograft tolerance, but die in culture without activated lymphocyte derived cytokines. Supplementation of the media with cytokine rich supernatant, from ConA activated spleen cells, preserves the capacity of tolerant cells to transfer tolerance and suppress rejection. rIL-2 or rIL-4 alone are insufficient to maintain these cells, however. We observed that activation of naïve CD4 + CD25 + FOXP3 + Treg with alloantigen and the Th2 cytokine rIL-4 induces them to express interleukin-5 specific receptor alpha (IL-5Rα) suggesting that IL-5, a Th2 cytokine that is produced later in the immune response may promote tolerance mediating Treg. This study examined if recombinant IL-5(rIL-5) promoted survival of tolerant CD4 + , especially CD4 + CD25 + T cells. CD4 + T cells, from DA rats tolerant to fully allogeneic PVG heart allografts surviving over 100days without on-going immunosuppression, were cultured with PVG alloantigen and rIL-5. The ability of these cells to adoptively transfer tolerance to specific-donor allograft and suppress normal CD4 + T cell mediated rejection in adoptive DA hosts was examined. Tolerant CD4 + CD25 + T cells' response to rIL-5 and expression of IL-5Rα was also assessed. rIL-5 was sufficient to promote transplant tolerance mediating CD4 + T cells' survival in culture with specific-donor alloantigen. Tolerant CD4 + T cells cultured with rIL-5 retained the capacity to transfer alloantigen-specific tolerance and inhibited naïve CD4 + T cells' capacity to effect specific-donor graft rejection. rIL-5 promoted tolerant CD4 + CD25 + T cells' proliferation in vitro when stimulated with specific-donor but not third-party stimulator cells. Tolerant CD4 + CD25 + T cells expressed IL-5Rα. This study demonstrated that IL-5 promoted the survival of alloantigen-specific CD4 + CD25 + T cells that mediate transplant tolerance. Copyright © 2017 Elsevier B.V. All rights reserved.

Sex-based differences in neurocognitive functioning in HIV-infected young adults.

PubMed

Burlacu, Ruxandra; Umlauf, Anya; Luca, Anca; Gianella, Sara; Radoi, Roxana; Ruta, Simona M; Marcotte, Thomas D; Ene, Luminita; Achim, Cristian L

2018-01-14

Sex differences in cognition of HIV positive (HIV) patients are controversial. We aimed to investigate the relationship between cognition, HIV status, and sex, in a highly homogenous cohort of young Romanians parenterally infected during early childhood. In total, 250 HIV participants were compared with age-matched HIV negative (HIV) controls (n = 72) in a cross-sectional study. After standardized neurocognitive, psychological testing and medical evaluation, linear regression was used to assess the effect of sex and HIV on neurocognitive outcomes. Study participants were on average 23 years old with balanced sex distribution (% women = 52% vs. 43%). HIV were more educated (12.7 vs. 11.6 years, P = 0.002).HIV status was associated with a lower global performance (β = -0.22, P < 0.001), after controlling for age and education. HIV women had better previous and current HIV-associated markers. The effect of HIV on global cognition did not differ between sexes in most cognitive domains (β = 0.07, P = 0.14). An interaction between sex, HIV status, and cognitive functioning was found in the psychomotor domain. HIV women had worse motor skills than HIV women (β = -0.32, P < 0.001) suggesting a specific effect of HIV on motor functioning in women only. Moreover, current CD4 less than 200 cells/μl (P = 0.013) and longer time lived with CD4 less than 200 cells/μl (P = 0.023) were negatively correlated with the motor scaled score in women (β = -0.22, P = 0.034). Despite less advanced disease in women, long-term HIV infection has an equally detrimental effect on cognitive performances of both sexes, in all cognitive domains, except the psychomotor domain where women are preferentially affected.

Enhanced expression of PD-1 and other activation markers by CD4+ T cells of young but not old patients with metastatic melanoma.

PubMed

van den Brom, Rob R H; van der Geest, Kornelis S M; Brouwer, Elisabeth; Hospers, Geke A P; Boots, Annemieke M H

2018-06-01

The biological behavior of melanoma is unfavorable in the elderly when compared to young subjects. We hypothesized that differences in T-cell responses might underlie the distinct behavior of melanoma in young and old melanoma patients. Therefore, we investigated the circulating T-cell compartment of 34 patients with metastatic melanoma and 42 controls, which were classified as either young or old. Absolute numbers of CD4+ T cells were decreased in young and old melanoma patients when compared to the age-matched control groups. Percentages of naive and memory CD4+ T cells were not different when comparing old melanoma patients to age-matched controls. Percentages of memory CD4+ T cells tended to be increased in young melanoma patients compared to young controls. Proportions of naive CD4+ T cells were lower in young patients than in age-matched controls, and actually comparable to those in old patients and controls. This was accompanied with increased percentages of memory CD4+ T cells expressing HLA-DR, Ki-67, and PD-1 in young melanoma patients in comparison to the age-matched controls, but not in old patients. Proportions of CD45RA-FOXP3 high memory regulatory T cells were increased in young and old melanoma patients when compared to their age-matched controls, whereas those of CD45RA+FOXP3 low naive regulatory T cells were similar. We observed no clear modulation of the circulating CD8+ T-cell repertoire in melanoma patients. In conclusion, we show that CD4+ T cells of young melanoma patients show signs of activation, whereas these signs are less clear in CD4+ T cells of old patients.

Separation of human CD4+CD39+ T cells by magnetic beads reveals two phenotypically and functionally different subsets

PubMed Central

Schuler, Patrick J.; Harasymczuk, Malgorzata; Schilling, Bastian; Lang, Stephan; Whiteside, Theresa L.

2011-01-01

Objective The ectonucleotidase CD39 is an enzyme involved in adenosine production. Its surface expression on human regulatory T cells (Treg) allows for their flow-cytometry-based isolation from peripheral blood. To further develop and improve this method on a scale supporting translational studies, we introduced capture of CD39+ Treg on magnetic immunobeads. Methods Peripheral blood mononuclear cells (PBMC) obtained from healthy donors were used for negative selection of CD4+ T cells on AutoMACS using antibodies (Abs) specific for all lineage+ cells. CD4+CD39+ Treg were captured by biotin-conjugated anti-CD39 Abs and anti-biotin Ab-coated magnetic beads. Isolated CD4+CD39+ T cells were phenotyped by flow cytometry for Treg-associated markers: CD39, CD73, FOXP3, CD25, CTLA-4, CCR4, CD45RO and CD121a or for the absence of CD127 and CD49d. CFSE-based proliferation assays and ATP hydrolysis were used to measure Treg functions. Results The purity, recovery and viability of the separated CD4+CD39+ T cells were satisfactory. The isolated CD4+CD39+ T cell population consisted of FOXP3+CD25+ T cells which hydrolyzed exogenous ATP and suppressed autologous CD4+ T cell proliferation and of FOXP3negCD25neg T cells without suppressor function. The same two subsets were detectable by flow cytometry in normal PBMC, gating on CD4+CD39+, CD4+CD127neg, CD4+CD49dneg or CD4+CD25high Treg. Conclusion CD4+CD39+ Treg capture on immunobeads led to a discovery of two CD39+ subsets. Similar to CD39+ Treg in the peripheral blood, half of these cells are CD25+FOXP3+ active suppressor cells, while the other half are CD25negFOXP3neg and do not mediate suppression. PMID:21513715

Syphilis among middle-aged female sex workers in China: a three-site cross-sectional study.

PubMed

Liu, Hongjie; Dumenci, Levent; Morisky, Donald E; Xu, Yongfang; Li, Xiaojing; Jiang, Baofa

2016-05-10

This study addresses the lack of empirical studies about the epidemic of syphilis among middle-aged female sex workers (FSWs). The objectives of this study were to investigate prevalence of syphilis, and its potential risk factors among middle-aged FSWs in China. A cross-sectional study with respondent-driven sampling (RDS). A multisite study conducted at three Chinese cites (Nanning, Hefei, and Qingdao) with different levels of sexually transmitted diseases in 2014. 1245 middle-aged female sex workers who were over 35 years old (about 400 per study site). Unprotected commercial sex, and syphilis and HIV infection were biologically tested and measured. The RDS-adjusted prevalence of active syphilis was 17.3% in Hefei, 9.9% in Qingdao, and 5.4% in Nanning. The RDS-adjusted prevalence of prevalent syphilis was between 6.8% and 33.6% in the three cities. The proportion of unprotected sex in the past 48 h verified by the prostate-specific antigen test (PSA) was between 27.8% and 42.4%. Multiple log-binomial regression analyses indicate that middle-aged FSWs who had 5 or more clients in the past week prior to interviews and engaged in unprotected sex were more likely to be active syphilitic cases. Middle-aged FSWs who had rural residency were less likely to be active syphilitic cases. In contrast with previous studies that reported low prevalence of syphilis and high prevalence of protected sex among FSWs in China, both the prevalence of syphilis and unprotected sex were high among middle-aged FSWs. Evidence-based intervention programmes should be developed and evaluated among this vulnerable population in China and other countries with similar settings. 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/

Sex- and age-based variation in transfusion practices among patients undergoing major surgery.

PubMed

Valero-Elizondo, Javier; Spolverato, Gaya; Kim, Yuhree; Wagner, Doris; Ejaz, Aslam; Frank, Steven M; Pawlik, Timothy M

2015-11-01

Data on hemoglobin (Hb) threshold levels for "appropriate" packed red blood cell (PRBC) transfusions have not taken into account patient-specific variables such as sex and age. We sought to define differences in perioperative transfusion practices based on patient sex and age among patients undergoing complex gastrointestinal (GI) and cardiothoracic-vascular (CT-V) surgical procedures. All patients undergoing any major GI or CT-V procedures between January 2010 and April 2014 at the Johns Hopkins Hospital were identified. Data on sex, age, as well as other clinicopathologic and procedures were collected and analyzed relative to transfusion practices (restrictive: transfusion at blood Hb < 7 vs liberal transfusion at Hb ≥ 7 g/dL). Among the 10,772 patients included in the study cohort, 4,689 (44.0%) were transfused with ≥ 1 PRBC. Median preoperative Hb was lower among women (12.3 vs 13.4 g/dL in men) and the aged (<65 years, 13.1 vs ≥ 65 years, 12.7 g/dL) patients (both P < .05). On adjusted analysis, male sex (odds ratio [OR], 1.13; 95% CI, 1.02-1.26; P = .03) and age ≥ 65 (OR, 1.77; 95% CI, 1.35-2.33; P < .001) were associated independently with an increased odds of receipt of ≥ 1 PRBC. Although sex did not seem to impact transfusion strategy, patient age did impact the relative trigger used by providers for a transfusion. Specifically, patients 65-74 years (OR, 2.87; 95% CI, 1.93-4.26) and those ≥ 74 years (OR, 3.42; 95% CI, 2.28-5.14) were at a much greater odds of being transfused liberally compared with patients <65 years old (both P < .05). The proportion of patients who had a potentially avoidable transfusion (ie, both trigger ≥ 7 and target ≥ 9 g/dL) was greater among aged patients (50%) compared with nonaged patients (41%; P < .001). Of note, a restrictive transfusion strategy did not increase the risk of overall morbidity among women (OR, 0.76; 95% CI, 0.59-0.99; P = .04) or aged (OR, 1.13; 95% CI, 0.87-1.47; P = .37) patients. Sex and age

Sex-Role Inconstancy, Biology, and Successful Aging: A Dialectical Model

ERIC Educational Resources Information Center

Sinnott, Jan Dynda

1977-01-01

This paper examines sex-role inconstancy from a life-span point of view. New environmental realities and an increasing life-span may make traditional sex roles less functional in old age. Evidence is presented for more successful aging in persons manifesting convergent sex-role behavior. (Author)

Comparison of cytokine mRNA expression in peripheral CD4(+) , CD8(+) and γδ T cells between healthy Holstein and Japanese Black calves.

PubMed

Ohtsuka, Hiromichi; Kobayashi, Hiroki; Kinouchi, Kumi; Kiyono, Miki; Maeda, Yousuke

2014-05-01

Japanese Black (JB) calves are more susceptible to infectious diseases compared to Holstein (Hol) calves. To clarify the immunological differences between JB and Hol calves, expression of cytokine messenger RNA (mRNA) was examined using peripheral CD4(+) , CD8(+) and γδ T cells. Healthy calves, 24 from each species, were examined. Blood samples were obtained from calves at 1 week, 1 month and 3 months old, eight calves for each age of each species. Peripheral blood mononuclear cells were stimulated with phytohemagglutin (PHA), and T cell subsets were isolated by positive selection using magnetic cell sorting (MACS). Levels of interlekin (IL)-2, IL-4, IL-10 and interferon (IFN)-γ mRNA in three T cell subsets were analyzed. WC1-N1(+) γδ T cell percentages were significantly lower in JB calves at 1 week and 1 month of age compared to Hol calves. In addition JB calves had significantly lower IL-2, IL-10 and IFN-γ mRNA in WC1-N1(+) γδ T cells at 1 and 3 months of age, whereas there were no significant differences in cytokine mRNA of CD4(+) and CD8(+) cells between the two groups. Decreased cytokine mRNA and cell number of peripheral γδ T cells may affect negatively on the immune system of JB calves. © 2014 Japanese Society of Animal Science.

Neurovascular control of blood pressure is influenced by aging, sex, and sex hormones.

PubMed

Baker, Sarah E; Limberg, Jacqueline K; Ranadive, Sushant M; Joyner, Michael J

2016-12-01

In this review, we highlight that the relationship between muscle sympathetic nerve activity (MSNA) and mean arterial pressure is complex, differs by sex, and changes with age. In young men there is an inverse relationship between MSNA and cardiac output where high MSNA is compensated for by low cardiac output. This inverse relationship is not seen in older men. In young women sympathetic vasoconstriction is offset by β-adrenoreceptor mediated vasodilation, limiting the ability of young women to maintain blood pressure in response to orthostatic stress. However, β-mediated dilation in women is attenuated with age, leading to unopposed α-adrenergic vasoconstriction and a rise in the direct transduction of MSNA into increases in blood pressure. We propose that these changes with age and menopausal status are major contributing factors in the increased prevalence of hypertension in older women. In addition to aging, we highlight that changes in sex hormones in young women (across the menstrual cycle, with oral contraceptive use, or with pregnancy) influence MSNA and the transduction of MSNA into increases in blood pressure. It is likely that the β-adrenergic receptors and/or changes in baroreflex sensitivity play a large role in these sex differences and changes with alterations in sex hormones. Copyright © 2016 the American Physiological Society.

CD147 (Basigin/Emmprin) identifies FoxP3+CD45RO+CTLA4+-activated human regulatory T cells.

PubMed

Solstad, Therese; Bains, Simer Jit; Landskron, Johannes; Aandahl, Einar Martin; Thiede, Bernd; Taskén, Kjetil; Torgersen, Knut Martin

2011-11-10

Human CD4(+)FoxP3(+) T cells are functionally and phenotypically heterogeneous providing plasticity to immune activation and regulation. To better understand the functional dynamics within this subset, we first used a combined strategy of subcellular fractionation and proteomics to describe differences at the protein level between highly purified human CD4(+)CD25(+) and CD4(+)CD25(-) T-cell populations. This identified a set of membrane proteins highly expressed on the cell surface of human regulatory T cells (Tregs), including CD71, CD95, CD147, and CD148. CD147 (Basigin or Emmprin) divided CD4(+)CD25(+) cells into distinct subsets. Furthermore, CD147, CD25, FoxP3, and in particular CTLA-4 expression correlated. Phenotypical and functional analyses suggested that CD147 marks the switch between resting (CD45RA(+)) and activated (CD45RO(+)) subsets within the FoxP3(+) T-cell population. Sorting of regulatory T cells into CD147(-) and CD147(+) populations demonstrated that CD147 identifies an activated and highly suppressive CD45RO(+) Treg subset. When analyzing CD4(+) T cells for their cytokine producing potential, CD147 levels grouped the FoxP3(+) subset into 3 categories with different ability to produce IL-2, TNF-α, IFN-γ, and IL-17. Together, this suggests that CD147 is a direct marker for activated Tregs within the CD4(+)FoxP3(+) subset and may provide means to manipulate cells important for immune homeostasis.

Adoptive cell therapy for lymphoma with CD4 T cells depleted of CD137-expressing regulatory T cells.

PubMed

Goldstein, Matthew J; Kohrt, Holbrook E; Houot, Roch; Varghese, Bindu; Lin, Jack T; Swanson, Erica; Levy, Ronald

2012-03-01

Adoptive immunotherapy with antitumor T cells is a promising novel approach for the treatment of cancer. However, T-cell therapy may be limited by the cotransfer of regulatory T cells (T(reg)). Here, we explored this hypothesis by using 2 cell surface markers, CD44 and CD137, to isolate antitumor CD4 T cells while excluding T(regs). In a murine model of B-cell lymphoma, only CD137(neg)CD44(hi) CD4 T cells infiltrated tumor sites and provided protection. Conversely, the population of CD137(pos)CD44hi CD4 T cells consisted primarily of activated T(regs). Notably, this CD137(pos) T(reg) population persisted following adoptive transfer and maintained expression of FoxP3 as well as CD137. Moreover, in vitro these CD137(pos) cells suppressed the proliferation of effector cells in a contact-dependent manner, and in vivo adding the CD137(pos)CD44(hi) CD4 cells to CD137(neg)CD44(hi) CD4 cells suppressed the antitumor immune response. Thus, CD137 expression on CD4 T cells defined a population of activated T(regs) that greatly limited antitumor immune responses. Consistent with observations in the murine model, human lymphoma biopsies also contained a population of CD137(pos) CD4 T cells that were predominantly CD25(pos)FoxP3(pos) T(regs). In conclusion, our findings identify 2 surface markers that can be used to facilitate the enrichment of antitumor CD4 T cells while depleting an inhibitory T(reg) population.

Antibody induced CD4 down-modulation of T cells is site-specifically mediated by CD64+ cells

PubMed Central

Vogel, Stephanie; Grabski, Elena; Buschjäger, Daniela; Klawonn, Frank; Döring, Marius; Wang, Junxi; Fletcher, Erika; Bechmann, Ingo; Witte, Torsten; Durisin, Martin; Schraven, Burkhart; Mangsbo, Sara M.; Schönfeld, Kurt; Czeloth, Niklas; Kalinke, Ulrich

2015-01-01

Treatment of PBMC with the CD4-specific mAb BT-061 induces CD4 down-modulation of T cells. Here we report that addition of BT-061 to purified T cells did not confer this effect, whereas incubation of T cells in BT-061 coated wells restored CD4 down-modulation. These results implied that Fcγ receptor mediated cell-cell interactions played a role. In consistence with this hypothesis PBMC depleted of CD64+ monocytes did not confer CD4 down-modulation of BT-061 decorated T cells. Strikingly, CD4 down-modulation was observed in BT-061 treated synovial fluid punctuated from patients’ inflamed joints that comprised enhanced numbers of CD64+ cells. In contrast, in a circulating whole blood system injection of BT-061 did not induce CD4 down-modulation, due to CD64 saturation by serum IgG. Similarly, tonsil derived mononuclear cells devoid of CD64+ cells did not show CD4 down-modulation, whereas addition of blood derived monocytes restored the effect. Thus, the interaction of BT-061 decorated T cells with CD64+ cells is needed for CD4 down-modulation, implying that in patients BT-061 would primarily induce CD4 down-modulation at inflammatory sites. These results highlight the need not only to examine the interaction of a given mAb with single FcγR, but also the immunological environment that is appropriate to support such interactions. PMID:26670584

Regulatory T Cells in the Control of Autoimmunity: the Essential Role of  Transforming Growth Factor β and Interleukin 4 in the Prevention of Autoimmune Thyroiditis in Rats by Peripheral CD4+CD45RC− Cells and CD4+CD8− Thymocytes

PubMed Central

Seddon, Benedict; Mason, Don

1999-01-01

Previous studies have shown that induction of autoimmune diabetes by adult thymectomy and split dose irradiation of PVG.RT1u rats can be prevented by their reconstitution with peripheral CD4+CD45RC−TCR-α/β+RT6+ cells and CD4+CD8− thymocytes from normal syngeneic donors. These data provide evidence for the role of regulatory T cells in the prevention of a tissue-specific autoimmune disease but the mode of action of these cells has not been reported previously. In this study, autoimmune thyroiditis was induced in PVG.RT1c rats using a similar protocol of thymectomy and irradiation. Although a cell-mediated mechanism has been implicated in the pathogenesis of diabetes in PVG.RT1u rats, development of thyroiditis is independent of CD8+ T cells and is characterized by high titers of immunoglobulin (Ig)G1 antithyroglobulin antibodies, indicating a major humoral component in the pathogenesis of disease. As with autoimmune diabetes in PVG.RT1u rats, development of thyroiditis was prevented by the transfer of CD4+CD45RC− and CD4+CD8− thymocytes from normal donors but not by CD4+CD45RC+ peripheral T cells. We now show that transforming growth factor (TGF)-β and interleukin (IL)-4 both play essential roles in the mechanism of this protection since administration of monoclonal antibodies that block the biological activity of either of these cytokines abrogates the protective effect of the donor cells in the recipient rats. The prevention of both diabetes and thyroiditis by CD4+CD45RC− peripheral cells and CD4+CD8− thymocytes therefore does not support the view that the mechanism of regulation involves a switch from a T helper cell type 1 (Th1) to a Th2-like response, but rather relies upon a specific suppression of the autoimmune responses involving TGF-β and IL-4. The observation that the same two cytokines were implicated in the protective mechanism, whether thymocytes or peripheral cells were used to prevent autoimmunity, strongly suggests that the

Brief Report: CD14brightCD16- monocytes and sCD14 level negatively associate with CD4-memory T-cell frequency and predict HCV-decline on therapy.

PubMed

Judge, Chelsey J; Sandberg, Johan K; Funderburg, Nicholas T; Sherman, Kenneth E; Butt, Adeel A; Kang, Minhee; Landay, Alan L; Lederman, Michael M; Anthony, Donald D

2016-11-01

During HIV+ hepatitis C virus (HCV)+ coinfection CD14CD16 monocytes produce soluble immune-activation markers that predict disease progression and poor response to interferon (IFN)-α treatment. We evaluated relationships among immune activation, monocyte phenotype, CD4-memory T cells, and HCV-, cytomegalovirus-, and cytomegalovirus/Epstein-Barr virus/influenza-specific IFN-γ-response before and during IFN-α treatment. Effector-memory and central-memory CD4 T-cell frequencies were lower in HCV+ HIV+ donors than in uninfected donors and correlated negatively with HCV level, CD14CD16 monocytes, and plasma sCD14. sCD14 and CD14CD16 monocytes negatively correlated with IFN-α-dependent HCV decline. CD4 effector-memory T cells positively associated with cytomegalovirus/Epstein-Barr virus/influenza(CEF)-specific IFN-γ response, while sCD14 negatively associated with both CD4 effector-memory T cells and CEF-specific IFN-γ response. These data support a role for memory-CD4 T cells in HCV containment and link immune activation and CD14CD16-monocyte frequency to the failure of IFN-dependent HCV clearance.

CD19+CD21low B cells and CD4+CD45RA+CD31+ T cells correlate with first diagnosis of chronic graft-versus-host disease.

PubMed

Greinix, Hildegard T; Kuzmina, Zoya; Weigl, Roman; Körmoczi, Ulrike; Rottal, Arno; Wolff, Daniel; Kralj, Mateja; Kalhs, Peter; Mitterbauer, Margit; Rabitsch, Werner; Edinger, Matthias; Holler, Ernst; Pickl, Winfried F

2015-02-01

Chronic graft-versus-host disease (cGVHD) is a serious and frequent complication of allogeneic hematopoietic stem cell transplantation (HCT). Currently, no biomarkers for prediction and diagnosis of cGVHD are available. We performed a large prospective study focusing on noninvasive biomarkers for National Institutes of Health-defined cGVHD patients (n = 163) in comparison to time-matched HCT recipients who never experienced cGVHD (n = 64), analyzed from day 100 after HCT. In logistic regression analysis, CD19(+)CD21(low) B cells (P = .002; hazard ratio [HR], 3.31; 95% confidence interval [CI], 1.53 to 7.17) and CD4(+)CD45RA(+)CD31(+) T cells (P < .001; HR, 3.88; 95% CI, 1.88 to 7.99) assessed on day 100 after HCT were significantly associated with subsequent development of cGVHD, independent of clinical parameters. A significant association with diagnosis of cGVHD was only observed for CD19(+)CD21(low) B cells (P = .008; HR, 3.00; 95% CI, 1.33 to 6.75) and CD4(+)CD45RA(+)CD31(+) T cells (P = .017; HR, 2.80; 95% CI, 1.19 to 6.55). CD19(+)CD21(low) B cells were found to have the highest discriminatory value with an area under the receiver operating curve of .77 (95% CI, .64 to .90). Our results demonstrate that CD19(+)CD21(low) B cells and CD4(+)CD45RA(+)CD31(+) T cells are significantly elevated in patients with newly diagnosed cGVHD. Copyright © 2015 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

Sex-based memory advantages and cognitive aging: a challenge to the cognitive reserve construct?

PubMed

Caselli, Richard J; Dueck, Amylou C; Locke, Dona E C; Baxter, Leslie C; Woodruff, Bryan K; Geda, Yonas E

2015-02-01