Sample records for b-cell lymphoproliferative disorders

  1. Molecular Pathogenesis of B-Cell Posttransplant Lymphoproliferative Disorder: What Do We Know So Far?

    PubMed Central

    Morscio, J.; Dierickx, D.; Tousseyn, T.

    2013-01-01

    Posttransplant lymphoproliferative disorder (PTLD) is a potentially fatal disease that arises in 2%–10% of solid organ and hematopoietic stem cell transplants and is most frequently of B-cell origin. This very heterogeneous disorder ranges from benign lymphoproliferations to malignant lymphomas, and despite the clear association with Epstein-Barr Virus (EBV) infection, its etiology is still obscure. Although a number of risk factors have been identified (EBV serostatus, graft type, and immunosuppressive regimen), it is currently not possible to predict which transplant patient will eventually develop PTLD. Genetic studies have linked translocations (involving C-MYC, IGH, BCL-2), various copy number variations, DNA mutations (PIM1, PAX5, C-MYC, RhoH/TTF), and polymorphisms in both the host (IFN-gamma, IL-10, TGF-beta, HLA) and the EBV genome to B-cell PTLD development. Furthermore, the tumor microenvironment seems to play an important role in the course of disease representing a local niche that can allow antitumor immune responses even in an immunocompromised host. Taken together, B-cell PTLD pathogenesis is very complex due to the interplay of many different (patient-dependent) factors and requires thorough molecular analysis for the development of novel tailored therapies. This review aims at giving a global overview of the currently known parameters that contribute to the development of B-cell PTLD. PMID:23690819

  2. EBV-driven B-cell lymphoproliferative disorders: from biology, classification and differential diagnosis to clinical management.

    PubMed

    Ok, Chi Young; Li, Ling; Young, Ken H

    2015-01-01

    Epstein-Barr virus (EBV) is a ubiquitous herpesvirus, affecting >90% of the adult population. EBV targets B-lymphocytes and achieves latent infection in a circular episomal form. Different latency patterns are recognized based on latent gene expression pattern. Latent membrane protein-1 (LMP-1) mimics CD40 and, when self-aggregated, provides a proliferation signal via activating the nuclear factor-kappa B, Janus kinase/signal transducer and activator of transcription, phosphoinositide 3-kinase/Akt (PI3K/Akt) and mitogen-activated protein kinase pathways to promote cellular proliferation. LMP-1 also induces BCL-2 to escape from apoptosis and gives a signal for cell cycle progression by enhancing cyclin-dependent kinase 2 and phosphorylation of retinoblastoma (Rb) protein and by inhibiting p16 and p27. LMP-2A blocks the surface immunoglobulin-mediated lytic cycle reactivation. It also activates the Ras/PI3K/Akt pathway and induces Bcl-xL expression to promote B-cell survival. Recent studies have shown that ebv-microRNAs can provide extra signals for cellular proliferation, cell cycle progression and anti-apoptosis. EBV is well known for association with various types of B-lymphocyte, T-lymphocyte, epithelial cell and mesenchymal cell neoplasms. B-cell lymphoproliferative disorders encompass a broad spectrum of diseases, from benign to malignant. Here we review our current understanding of EBV-induced lymphomagenesis and focus on biology, diagnosis and management of EBV-associated B-cell lymphoproliferative disorders. PMID:25613729

  3. Overexpression of Activation-Induced Cytidine Deaminase in MTX- and Age-Related Epstein-Barr Virus-Associated B-Cell Lymphoproliferative Disorders of the Head and Neck.

    PubMed

    Kikuchi, Kentaro; Ishige, Toshiyuki; Ide, Fumio; Ito, Yumi; Saito, Ichiro; Hoshino, Miyako; Inoue, Harumi; Miyazaki, Yuji; Nozaki, Tadashige; Kojima, Masaru; Kusama, Kaoru

    2015-01-01

    Recent research has shown that activation-induced cytidine deaminase (AID) triggers somatic hypermutation and recombination, in turn contributing to lymphomagenesis. Such aberrant AID expression is seen in B-cell leukemia/lymphomas, including Burkitt lymphoma which is associated with c-myc translocation. Moreover, Epstein-Barr virus (EBV) latent membrane protein-1 (LMP-1) increases genomic instability through early growth transcription response-1 (Egr-1) mediated upregulation of AID in B-cell lymphoma. However, few clinicopathological studies have focused on AID expression in lymphoproliferative disorders (LPDs). Therefore, we conducted an immunohistochemical study to investigate the relationship between AID and LMP-1 expression in LPDs (MTX-/Age-related EBV-associated), including diffuse large B-cell lymphomas (DLBCLs). More intense AID expression was detected in LPDs (89.5%) than in DLBCLs (20.0%), and the expression of LMP-1 and EBER was more intense in LPDs (68.4% and 94.7%) than in DLBCLs (10.0% and 20.0%). Furthermore, stronger Egr-1 expression was found in MTX/Age-EBV-LPDs (83.3%) than in DLBCLs (30.0%). AID expression was significantly constitutively overexpressed in LPDs as compared with DLBCLs. These results suggest that increased AID expression in LPDs may be one of the processes involved in lymphomagenesis, thereby further increasing the survival of genetically destabilized B-cells. AID expression may be a useful indicator for differentiation between LPDs and DLBCLs. PMID:25834572

  4. Overexpression of Activation-Induced Cytidine Deaminase in MTX- and Age-Related Epstein-Barr Virus-Associated B-Cell Lymphoproliferative Disorders of the Head and Neck

    PubMed Central

    Kikuchi, Kentaro; Ishige, Toshiyuki; Ide, Fumio; Ito, Yumi; Saito, Ichiro; Hoshino, Miyako; Inoue, Harumi; Miyazaki, Yuji; Nozaki, Tadashige; Kojima, Masaru; Kusama, Kaoru

    2015-01-01

    Recent research has shown that activation-induced cytidine deaminase (AID) triggers somatic hypermutation and recombination, in turn contributing to lymphomagenesis. Such aberrant AID expression is seen in B-cell leukemia/lymphomas, including Burkitt lymphoma which is associated with c-myc translocation. Moreover, Epstein-Barr virus (EBV) latent membrane protein-1 (LMP-1) increases genomic instability through early growth transcription response-1 (Egr-1) mediated upregulation of AID in B-cell lymphoma. However, few clinicopathological studies have focused on AID expression in lymphoproliferative disorders (LPDs). Therefore, we conducted an immunohistochemical study to investigate the relationship between AID and LMP-1 expression in LPDs (MTX-/Age-related EBV-associated), including diffuse large B-cell lymphomas (DLBCLs). More intense AID expression was detected in LPDs (89.5%) than in DLBCLs (20.0%), and the expression of LMP-1 and EBER was more intense in LPDs (68.4% and 94.7%) than in DLBCLs (10.0% and 20.0%). Furthermore, stronger Egr-1 expression was found in MTX/Age-EBV-LPDs (83.3%) than in DLBCLs (30.0%). AID expression was significantly constitutively overexpressed in LPDs as compared with DLBCLs. These results suggest that increased AID expression in LPDs may be one of the processes involved in lymphomagenesis, thereby further increasing the survival of genetically destabilized B-cells. AID expression may be a useful indicator for differentiation between LPDs and DLBCLs. PMID:25834572

  5. Post-transplant lymphoproliferative disorders (PTLD) after solid organ transplantation

    Microsoft Academic Search

    Anna L. Taylor; Robert Marcus; J. Andrew Bradley

    2005-01-01

    Post-transplant lymphoproliferative disorders (PTLD) are a well-recognised and potentially fatal complication after solid organ transplantation. They include a spectrum of disorders ranging from benign hyperplasia to invasive malignant lymphoma. The majority of cases are associated with Epstein Barr virus (EBV)-driven tumour formation in B cells and are a consequence of the detrimental effect of immunosuppressive agents on the immune-control of

  6. Pediatric post-transplant lymphoproliferative disorder after cardiac transplantation

    Microsoft Academic Search

    Hideaki Ohta; Norihide Fukushima; Keiichi Ozono

    2009-01-01

    Post-transplant lymphoproliferative disorder (PTLD) is a well recognized and potentially fatal complication after pediatric\\u000a cardiac transplantation. PTLD encompasses a wide spectrum, ranging from benign hyperplasia to more aggressive lymphoma. Most\\u000a cases are Epstein-Barr virus (EBV)-related B-cell tumors resulting from impaired immunity due to immunosuppressive therapy.\\u000a Pediatric recipients, often seronegative for EBV at transplantation, have a greater risk for PTLD than

  7. Lymphoproliferative disorders in chronic hepatitis C.

    PubMed

    Idilman, R; Colantoni, A; De Maria, N; Alkan, S; Nand, S; Van Thiel, D H

    2004-07-01

    Chronic hepatitis C virus (HCV) infection is associated with the development of lymphoproliferative disorders (LPDs). The aim of this investigation was to determine the prevalence and characterization of monoclonal gammopathy and benign and malignant LPDs in individuals with chronic hepatitis C. A total of 233 subjects diagnosed with chronic hepatitis C (male/female ratio: 131/102, median age; 49 years) were studied. Serum and urine were examined for the presence of a monoclonal gammopathy. A bone marrow aspirate and biopsy was obtained in individuals with a monoclonal gammopathy. Thirty-two patients (13.7%, 32 of 233) had a monoclonal gammopathy; 75% of them were benign and were not associated with malignant disorders (24 of 32) while 25% were associated with malignant LPDs or a plasma cell disorder (eight of 32). Two additional subjects without monoclonal gammopathy were diagnosed as having a malignant LPDs. The prevalence of malignant LPDs/plasma cell disorder in individuals with HCV-induced chronic liver disease was 4.3%. No difference was found in terms of disease duration, HCV genotype, viral load, alanine aminotransferase level or histopathologic score between the subjects with or without a monoclonal gammopathy. The presence of mixed cryoglobulinaemia was strongly associated with the presence of an underlying malignant disorder. Hence a monoclonal gammopathy is found in 14% of patients with chronic hepatitis C and is associated with malignant B-cell LPD in more than a quarter of such patients. The prevalence of LPDs in individuals with HCV-induced chronic liver disease is greater than that of the normal healthy population. PMID:15230852

  8. Post liver transplantation lymphoproliferative disorder mimics recurrence of hepatocellular carcinoma.

    PubMed

    Poovorawan, Kittiyod; Linlawan, Sittikorn; Wisedopas, Naruemon; Komolmit, Piyawat

    2013-01-01

    We report a case of Epstein-Barr virus (EBV)-related postliver transplantation lymphoproliferative disorder (PTLD) in a patient with post liver transplant which initially presented in a CT scan image mimicking recurrence of hepatocellular carcinoma. Histopathology showed atypical plasma cell-like infiltration, and immunohistochemistry confirmed diagnosis of EBV-associated diffuse large B-cell lymphoma. Typical imaging from dynamic phases contrast CT scan might not accurately diagnose recurrent HCC in postorthotropic liver transplantation. Liver biopsy should be performed for accurate diagnosis and proper treatment. PMID:24351512

  9. Primary cold agglutinin-associated lymphoproliferative disease: a B-cell lymphoma of the bone marrow distinct from lymphoplasmacytic lymphoma.

    PubMed

    Randen, Ulla; Trřen, Gunhild; Tierens, Anne; Steen, Chloé; Warsame, Abdirashid; Beiske, Klaus; Tjřnnfjord, Geir E; Berentsen, Sigbjřrn; Delabie, Jan

    2014-03-01

    Primary chronic cold agglutinin disease is a rare hemolytic disease mediated by monoclonal IGHV4-34-encoded cold agglutinins with a predominant specificity for the blood group antigen I. Bone marrow from 54 patients was studied to type the underlying lymphoproliferative disorder better. Bone marrow biopsies showed circumscribed intra-parenchymatous nodules with small monotonous monoclonal B cells in 40/54 patients (median infiltration: 10% of marrow cells) with a CD20(+), IgMs(+), IgDs(+), CD27(+), CD5(-/+), CD11c(-), CD23(-), CD38(-) immunophenotype. Neither plasmacytoid cytological features nor expression of plasma cell differentiation-associated transcription factors MUM1, XBP1 and BLIMP1 were noted in these B cells. However, a limited number of mature monoclonal IgM(+), IgD(-) plasma cells were present outside the lymphoid nodules and were diffusely scattered throughout the marrow. Of interest, the MYD88 L265P mutation, typical of lymphoplasmacytic lymphoma, was not detected (17/17 cases). Somatically mutated monoclonal IGHV4-34 gene rearrangement was demonstrated in eight patients with frozen samples (mean sequence homology 95.4%). However, mutations of BCL6 intron 1 were not demonstrated, except in one patient, suggesting that the lymphoma cells had not matured in the germinal center. In conclusion, cold agglutinin-associated lymphoproliferative disease displays homogeneous histological and immunophenotypic features. The absence of plasmacytoid cells, the presence of plasma cells predominantly outside the nodular lymphoid infiltrates, IGHV4-34 restriction and absence of MYD88 L265P mutation strongly suggest that cold agglutinin-associated lymphoproliferative disease is a distinct entity that is different from lymphoplasmacytic lymphoma. PMID:24143001

  10. Rosette formation with mouse erythrocytes. III. Studies in patients with primary immunodeficiency and lymphoproliferative disorders.

    PubMed Central

    Gupta, S; Good, R A; Siegal, F P

    1976-01-01

    Rosette formation with mouse erythrocytes and other cell-surface markers were examined on lymphocytes from patients with a variety of primary immunodeficiency and lymphoproliferative disorders. Mouse erythrocyte rosette-forming cells and lymphocytes with surface immunoglobulins were regularly absent in patients with Bruton type agammaglobulinaemia, immunodeficiency and thymoma syndrome and severe combined immunodeficiency disease. However, they were present in normal or low numbers in patients with common variable immunodeficiency, selective IgA deficiency and ataxis telangiectasia. Lymphocytes from patients with acute lymphoblastic leukaemia Sezary syndrome and mycosis fungoides made no or few rosettes with mouse erythrocytes. Increased numbers of mouse erythrocyte rosette-forming cells were present in patients with chronic lymphocytic leukaemia and Waldenstrom's macroglobulinaemia. The significance of the mouse erythrocyte rosette as a B-cell marker in the analysis of primary immunodeficiency and lymphoproliferative disorders is discussed. PMID:1068759

  11. Pure Red Cell Aplasia and Lymphoproliferative Disorders: An Infrequent Association

    PubMed Central

    Vlachaki, Efthymia; Diamantidis, Michael D.; Klonizakis, Philippos; Haralambidou-Vranitsa, Styliani; Ioannidou-Papagiannaki, Elizabeth; Klonizakis, Ioannis

    2012-01-01

    Pure red cell aplasia (PRCA) is a rare bone marrow failure syndrome defined by a progressive normocytic anaemia and reticulocytopenia without leukocytopenia and thrombocytopenia. Secondary PRCA can be associated with various haematological disorders, such as chronic lymphocytic leukaemia (CLL) or non-Hodgkin lymphoma (NHL). The aim of the present review is to investigate the infrequent association between PRCA and lymphoproliferative disorders. PRCA might precede the appearance of lymphoma, may present simultaneously with the lymphoid neoplastic disease, or might appear following the lymphomatic disorder. Possible pathophysiological molecular mechanisms to explain the rare association between PRCA and lymphoproliferative disorders are reported. Most cases of PRCA are presumed to be autoimmune mediated by antibodies against either erythroblasts or erythropoietin, by T-cells secreting factors selectively inhibiting erythroid colonies in the bone marrow or by NK cells directly lysing erythroblasts. Finally, focus is given to the therapeutical approach, as several treatment regimens have failed for PRCA. Immunosuppressive therapy and/or chemotherapy are effective for improving anaemia in the majority of patients with lymphoma-associated PRCA. Further investigation is required to define the pathophysiology of PRCA at a molecular level and to provide convincing evidence why it might appear as a rare complication of lymphoproliferative disorders. PMID:22593689

  12. Posttransplantation lymphoproliferative disorders in pediatric thoracic organ recipients

    Microsoft Academic Search

    Gerard J. Boyle; Marian G. Michaels; Steven A. Webber; A. S. Knisely; Geoffrey Kurland; Lynne A. Cipriani; Bartley P. Griffith; Frederick J. Fricker

    1997-01-01

    Objective: To determine the frequency, predisposing factors, clinical presentation, and outcome of posttransplantation lymphoproliferative disorders (PTLDs) in pediatric thoracic organ transplant recipients.Methods: Retrospective review of the medical records of all 120 children who survived longer than 1 month after thoracic organ transplantation at our center.Results: PTLD was diagnosed in 14 patients (11.7%), including 7.7% of heart and 19.5% of heart-lung\\/lung

  13. Rituximab as Treatment of Posttransplant Lymphoproliferative Disorder in Patients Who Underwent Small Bowel\\/Multivisceral Transplantation: Report of Three Cases

    Microsoft Academic Search

    M. Codeluppi; S. Cocchi; G. Guaraldi; F. Di Benedetto; A. Bagni; M. Pecorari; W. Gennari; A. D. Pinna; G. E. Gerunda; R. Esposito

    2005-01-01

    This report describes three cases of posttransplant lymphoproliferative disorder (PTLD) in multivisceral\\/small bowel transplant patients treated with rituximab (anti-CD20 monoclonal antibodies). In two cases (one of which was a B-cell lymphoma) a good response to therapy was achieved. A third case (with polymorphic PTLD with low CD20 expression) developed a refractory rejection and PTLD was still documented on graftectomy. Rituximab

  14. Isolated Upper Extremity Posttransplant Lymphoproliferative Disorder in a Child

    PubMed Central

    Halula, Sarah E.; Leino, Daniel G.; Patel, Manish N.; Racadio, John M.; Lungren, Matthew P.

    2015-01-01

    Posttransplant lymphoproliferative disorder (PTLD) is a well-described complication of solid organ and bone marrow transplants. The most common presentation is intra-abdominal lymphadenopathy or single or multiple intraparenchymal masses involving the liver, spleen, or kidneys. Here we describe the imaging and pathology findings of an unusual case of PTLD appearing as an intramuscular forearm lesion in a pediatric male. The manifestation of PTLD as an isolated upper extremity mass in a pediatric patient has to our knowledge not been described. PMID:26167324

  15. Hematopoietic Neoplasias in Horses: Myeloproliferative and Lymphoproliferative Disorders

    PubMed Central

    MUŃOZ, Ana; RIBER, Cristina; TRIGO, Pablo; CASTEJÓN, Francisco

    2010-01-01

    Leukemia, i.e., the neoplasia of one or more cell lines of the bone marrow, although less common than in other species, it is also reported in horses. Leukemia can be classified according to the affected cells (myeloproliferative or lymphoproliferative disorders), evolution of clinical signs (acute or chronic) and the presence or lack of abnormal cells in peripheral blood (leukemic, subleukemic and aleukemic leukemia). The main myeloproliferative disorders in horses are malignant histiocytosis and myeloid leukemia, the latter being classified as monocytic and myelomonocytic, granulocytic, primary erythrocytosis or polycythemia vera and megakaryocytic leukemia. The most common lymphoproliferative disorders in horses are lymphoid leukemia, plasma cell or multiple myeloma and lymphoma. Lymphoma is the most common hematopoietic neoplasia in horses and usually involves lymphoid organs, without leukemia, although bone marrow may be affected after metastasis. Lymphoma could be classified according to the organs involved and four main clinical categories have been established: generalized-multicentric, alimentary-gastrointestinal, mediastinal-thymic-thoracic and cutaneous. The clinical signs, hematological and clinical pathological findings, results of bone marrow aspirates, involvement of other organs, prognosis and treatment, if applicable, are presented for each type of neoplasia. This paper aims to provide a guide for equine practitioners when approaching to clinical cases with suspicion of hematopoietic neoplasia. PMID:24833969

  16. Ptaquiloside-induced, B-cell lymphoproliferative and early-stage urothelial lesions in mice.

    PubMed

    Gil da Costa, Rui M; Oliveira, Paula A; Vilanova, Manuel; Bastos, Margarida M S M; Lopes, Célia C; Lopes, Carlos

    2011-11-01

    Bracken (Pteridium aquilinum) has long been known to cause cancer in farm and laboratory animals. Ptaquiloside, a norsesquiterpene glycoside found in bracken, is considered its main carcinogenic toxin and is capable of inducing tumours in a variety of organ systems, but especially in the urinary bladder, depending on the animal species, the administration route employed and the duration of exposure. In the present study, 12 male CD-1 mice were intraperitoneally administered with 0.5 mg ptaquiloside weekly for 15 weeks, followed by 15 weeks without any treatment. Twelve animals used as controls were administered the vehicle solution (phosphate buffered saline). Two exposed animals died during the experimental work. On necropsy, blood and tissue samples (brain, eyes, thymus, heart, lungs, liver, digestive system, spleen, bladder, kidney, adrenal gland, urinary bladder, sexual accessory glands, testes, muscle, skin and femur) were collected for histological analysis. Leukograms were prepared from blood smears and total WBC counts obtained with a Neubauer chamber. Flow cytometry was used to assess blood T-(CD3(+)) and B-(CD19(+))-lymphocytes, medullary granulocytic (CD11b(+)/Ly-6G(-), CD11b(+)/Ly-6G(+)) and lymphocytic (CD19(+)/IgM(-), CD19+/IgM(+)) populations and thymic lymphoid (CD4(+), CD8(+), CD4(+)/CD8(+)) populations. Lymphoproliferative lesions were analysed immunohistochemically using antibodies against CD45R and CD3. All of the 10 surviving mice developed a lymphoproliferative malignancy. Lymphoproliferative disease was characterized by multifocal B-(CD45(+)/CD3(-))-lymphocytic renal (10/10 animals) and hepatic (2/10 animals) invasion, splenic white pulp hyperplasia (10/10) together with a significant increase in circulating B-(CD19(+))-lymphocytes and the appearance of circulating dysplastic lymphoid cells. Eight out of 10 ptaquiloside-exposed animals developed urothelial dysplasia (six low-grade dysplasia and two high-grade dysplasia). No lesions were detected in control mice. These results show that ptaquiloside is capable of inducing malignant transformation in mice and provide an in-depth characterisation of lymphoproliferative lesions. Furthermore, the urinary bladder is shown to be a target organ for this toxin in mice as well as in other animal species. PMID:21907228

  17. Increased incidence of EBV-associated lymphoproliferative disorders after allogeneic stem cell transplantation from matched unrelated donors due to a change of T cell depletion technique

    Microsoft Academic Search

    E Meijer; ICM Slaper-Cortenbach; SFT Thijsen; AW Dekker; LF Verdonck

    2002-01-01

    Here, the influence of T vs T and B cell depletion on the incidence of EBV-associated lymphoproliferative disorder (EBV-LPD) after bone marrow transplantation (BMT) from a matched unrelated donor (MUD) is analyzed. From 1982 to 1997 the soy bean agglutinin\\/sheep red blood cell (SBA\\/SRBC) method was used for T cell depletion. This technique is well established, but the use of

  18. Epstein-Barr virus-associated lymphoproliferative disorders.

    PubMed

    Grywalska, Ewelina; Markowicz, Justyna; Grabarczyk, Piotr; Pasiarski, Marcin; Roli?ski, Jacek

    2013-01-01

    The Epstein-Barr virus (EBV) is one of the most common human viruses, infecting more than 90% of the world's adult population. In some individuals the interplay between EBV replication, latency and immune control can be disrupted and evokes prolonged proliferation of EBV-infected lymphocytes and their malignant transformation. Since its discovery as the first human tumor virus, EBV has been implicated in the development of a wide range of human cancers. The evidence for an association with EBV is the strongest for Burkitt's lymphoma, NK/T cell lymphoma, nasopharyngeal carcinoma, Hodgkin's lymphoma and for malignant lymphomas in immune incompetent patients. Additionally, certain epithelial cell tumors, such as gastric carcinoma and breast carcinoma, have been defined as EBV related. However, the virus may be encountered in other types of malignancies. The oncogenic potential of EBV is related to its ability to infect and transform B lymphocytes into continuously growing lymphoblastoid cell lines. EBV encodes a series of products mimicking several growth, transcription and anti-apoptotic factors, to usurp control of the pathways that regulate diverse homeostatic cellular functions. However, the exact mechanism by which EBV promotes oncogenesis remains unclear. The focus of this review is to summarize the current knowledge of oncogenic potential of the Epstein-Barr virus and its role in the pathogenesis of EBV-associated lymphoproliferative disorders. PMID:23752600

  19. Viral induction and targeted inhibition of galectin-1 in EBV+ posttransplant lymphoproliferative disorders.

    PubMed

    Ouyang, Jing; Juszczynski, Przemyslaw; Rodig, Scott J; Green, Michael R; O'Donnell, Evan; Currie, Treeve; Armant, Myriam; Takeyama, Kunihiko; Monti, Stefano; Rabinovich, Gabriel A; Ritz, Jerome; Kutok, Jeffery L; Shipp, Margaret A

    2011-04-21

    Posttransplant lymphoproliferative disorders (PTLDs) are potentially fatal, EBV-driven B-cell malignancies that develop in immunocompromised solid organ or hematopoietic stem cell recipients. In PTLD, the expression of EBV proteins, including latent membrane protein 1 (LMP1) and LMP2A, viral immune evasion strategies, and impaired host immune surveillance foster the proliferation of EBV-transformed B cells. Current PTLD treatment strategies include reduction of immunosuppression, which increases the risk of graft rejection, anti-CD20 treatment, combination chemotherapy, and administration of EBV-specific cytotoxic T cells. In the present study, we report that EBV-transformed lymphoblastoid B-cell lines (LCLs) and primary PTLDs overexpress galectin-1 (Gal1), a carbohydrate-binding lectin that induces tolerogenic dendritic cells and triggers the selective apoptosis of CD4(+) Th1 and Th17 cells and cytotoxic T cells. In transcriptional reporter assays, LMP2A and LMP1 each increased Gal1-driven luciferase expression, and the combination of LMP2A and LMP1 was additive. In addition, small interfering RNA (siRNA)-mediated depletion of LMP2A decreased Gal1 protein abundance in EBV-transformed LCLs. Gal1 expression in LCLs was dependent on both activating protein 1 (AP-1) and PI3K. A newly developed neutralizing Gal1 mAb selectively inhibited Gal1-mediated apoptosis of EBV-specific CD8(+) T cells. Given the tolerogenic and immunosuppressive function of Gal1, antibody-mediated Gal1 neutralization may represent a novel immunotherapeutic strategy for PTLD and other Gal1-expressing tumors. PMID:21300977

  20. Defective control of Epstein-Barr virus-infected B cell growth in patients with X-linked lymphoproliferative disease.

    PubMed Central

    Yasuda, N; Lai, P K; Rogers, J; Purtlo, D T

    1991-01-01

    We studied the cellular function and lymphokine production of T cells from patients with X-linked lymphoproliferative disease (XLP) when activated by the challenge with Epstein-Barr virus (EBV) infection. We used an assay system in which T cells were stimulated with membrane antigens of autologous EBV-infected B lymphoblastoid cell lines (B-LCL) and we examined cellular and humoral factors derived from the stimulated T cells which control the growth of EBV-infected B-LCL. Immunoglobulin secretion from the autologous B-LCL was suppressed with radiosensitive suppressor cells in the patients with XLP. The degree of suppression was correlated with the immunoglobulin levels in the serum of the patients with acquired hypogammaglobulinaemia (P less than 0.05). In addition, T cells from the patients with XLP failed to produce interferon-gamma (IFN-gamma) (P less than 0.001). Moreover, the T cell supernatants from the patients with XLP were less potent to inhibit the B-LCL growth. This diminished inhibition of the B-LCL growth was correlated well with the decreased concentration of IFN-gamma in the T cell supernatants. These findings suggest that suppressor cells may be activated in the patients with the hypogammaglobulinaemia phenotype of XLP, but the frequent development of B cell lymphoma in hypogammaglobulinaemia indicate that immunoglobulin suppression may not exert enough pressure on the in vivo growth of EBV-infected B cells. The defective secretion of IFN-gamma may be, at least partially, responsible for the abnormal cytotoxic T cell and natural killer activities found in the patients with XLP, and may indicate the clinical evaluation about the preventive injection of IFN-gamma against the development of malignant lymphoma. PMID:1846327

  1. Recognizing and treating secondary immune thrombocytopenic purpura associated with lymphoproliferative disorders.

    PubMed

    Liebman, Howard A

    2009-01-01

    Immune thrombocytopenic purpura (ITP), a condition of low platelets, can occur from primary causes, often referred to as idiopathic thrombocytopenic purpura, or secondary to an underlying disease, such as an autoimmune disorder or an infection. Secondary ITP can also occur with lymphoproliferative malignancies, such as chronic lymphocytic leukemia (CLL), Hodgkin's disease (HD), and non-Hodgkin's lymphomas (NHL). ITP associated with lymphoproliferative disorders has the same mechanism of platelet destruction as in idiopathic or primary ITP. The current treatment paradigm for secondary ITP varies according to the underlying condition. Standard treatments for primary ITP, which include corticosteroids, intravenous immunoglobulin (IVIg), anti-D, and splenectomy, are often successful in secondary ITP. However, in most situations with secondary ITP, treatment should focus on resolving the underlying disorder before treating the shortage of platelets, and, in the circumstances of ITP developing in patients with lymphoproliferative disorders, responses are frequently linked to remission of the primary malignancy. PMID:19245932

  2. Outcome of Rapamycin Therapy for Post-Transplant-Lymphoproliferative Disorder after Kidney Transplantation: Case Series

    PubMed Central

    Ashrafi, Farzaneh; Shahidi, Shahrzad; Mortazavi, Mojgan

    2015-01-01

    ABSTRACT Background Post-transplant lymphoproliferative disorders (PTLD) are a complication of chronic immunosuppressive therapy in solid organ transplantation with a high mortality rate. Alternative treatments such as rapamycin have been explored. Methods: A detailed retrospective analysis was performed according to data collected from 13 patients with PTLD. At the time of PTLD diagnosis, immunosuppressive therapy was decreased and rapamycin administered. Overall survival, disease-free survival of patients and graft survival were determined. Results: Among 590 kidney transplant recipients, 13 adult patients with PTLD were included in this study. The mean age of the patients was 42.15 (range: 25–58) years at the time of PTLD diagnosis, and 9 patients were male. Histology was distributed in 9 diffuse large B cell, 1 Malt lymphoma, 1 Burkitt lymphoma, 2 Hodgkin-like PTLD. The response rate to rapamycin alone was 30.8%. The mean overall survival period was 23.38 months and 11 patients are still alive. In total, 10 patients (76.9%) achieved a complete remission with functioning graft in 11 (84.6%) patients. Conclusion: Despite the retrospective focus and limited number of patients, this study provides promising results regarding the effectiveness of stopping calcineurin inhibitors and switching to rapamycin for patients with PTLD. PMID:25802698

  3. Occurrence and prognostic relevance of CD30 expression in post-transplant lymphoproliferative disorders.

    PubMed

    Vase, Maja Řlholm; Maksten, Eva Futtrup; Bendix, Knud; Hamilton-Dutoit, Stephen; Andersen, Claus; Mřller, Michael Boe; Sřrensen, Sřren Schwartz; Jespersen, Bente; Kampmann, Jan; Sřndergĺrd, Esben; Nielsen, Patricia Switten; D'amore, Francesco

    2015-06-01

    Post-transplant lymphoproliferative disorders (PTLDs) are potentially fatal, often Epstein-Barr virus (EBV)-driven neoplasias developing in immunocompromised hosts. Initial treatment usually consists of a reduction in immunosuppressive therapy and/or rituximab with or without chemotherapy. However, patients who relapse do poorly, and new treatment options are warranted. With the introduction of the immunoconjugate brentuximab vedotin, the CD30 antigen has become an effectively targetable molecule. Therefore, we investigated the frequency and level of CD30 expression in PTLDs. We identified 108 patients with PTLDs diagnosed during 1994-2011, of whom 62 had adequate paraffin-embedded tissue for tissue microarray construction. Immunohistochemical expression of CD30 was consistently detected in all types of PTLD (overall 85.25%), including the monomorphic subtypes, and was correlated with a more favorable outcome. For diffuse large B-cell lymphoma (DLBCL)-type PTLD this was regardless of EBV status, and remained significant in multivariate analysis. Cell-of-origin had no independent prognostic value in our series of DLBCL PTLD. PMID:25248878

  4. Anticipation in Families with Chronic Lymphocytic Leukemia and Other Lymphoproliferative Disorders

    PubMed Central

    Awan, Haneef; Jřnsson, Viggo; Johannesen, Tom B.; Ly, Bernt; Tjřnnfjord, Geir E.

    2010-01-01

    Fifty-one parent-offspring pairs with chronic lymphocytic leukemia (CLL) or other lymphoproliferative disorders (nonCLL) such as malignant lymphoma, multiple myeloma, or other types of lymphocytic leukemia than CLL were ascertained independently in 38 families. There were 30 CLL-CLL parent-offspring pairs and 21 pairs with nonCLL in parents and/or in offspring. The median age of onset of disease was 13 years lower in the offspring than in the parents when comparing all 51 pairs (P < 0.001). This difference was mainly caused by a significantly lower age at onset in offspring with parental nonCLL (P < 0.001) where paternal disease was transferred especially to sons, while affected offspring to parents with CLL have the same age at debut of disease than their parents (P = 0.130) and a nearly equal transfer to sons and daughters. The low-malignant follicular small B-cell lymphoma was the predominant diagnosis within nonCLL. Anticipation is pointed out as one likely mechanism behind the lower age at onset of disease in offspring than in parents, even if a part of this difference is ascribed to a generally earlier diagnosis with modern technology in offspring than in parents. PMID:21566766

  5. Subcutaneous immunoglobulin in lymphoproliferative disorders and rituximab-related secondary hypogammaglobulinemia: a single-center experience in 61 patients

    PubMed Central

    Compagno, Nicolň; Cinetto, Francesco; Semenzato, Gianpietro; Agostini, Carlo

    2014-01-01

    Intravenous immunoglobulin replacement therapy represents the standard treatment for hypogammaglobulinemia secondary to B-cell lymphoproliferative disorders. Subcutaneous immunoglobulin infusion is an effective, safe and well-tolerated treatment approach in primary immunodeficiencies but no extensive data are available on their use in secondary hypogammaglobulinemia, a frequent phenomenon occurring after treatment with anti-CD20 monoclonal antibodies in lymphoproliferative disorders. In this retrospective study we evaluated efficacy (serum IgG trough levels, incidence of infections per year, need for antibiotics) and safety (number of adverse events) of intravenous (300 mg/kg/4 weeks) versus subcutaneous (75 mg/kg/week) immunoglobulin replacement therapy in 61 patients. In addition, the impact of the infusion methods on quality of life was compared. All patients were treated with subcutaneous immunoglobulin, and 33 out of them had been previously treated with intravenous immunoglobulin. Both treatments appeared to be effective in replacing Ig production deficiency and in reducing the incidence of infectious events and the need for antibiotics. Subcutaneous immunoglobulin obtained a superior benefit when compared to intravenous immunoglobulin achieving higher IgG trough levels, lower incidence of overall infection and need for antibiotics. The incidence of serious bacterial infections was similar with both infusion ways. As expected, a lower number of adverse events was registered with subcutaneous immunoglobulin, compared to intravenous immunoglobulin, with no serious adverse events. Finally, we observed an improvement in health-related quality of life parameters after the switch to subcutaneous immunoglobulin. Our results suggest that subcutaneous immunoglobulin is safe and effective in patients with hypogammaglobulinemia associated to lymphoproliferative disorders. PMID:24682509

  6. Immunophenotypic characterization of acute leukemias and chronic lymphoproliferative disorders: practical recommendations and classifications

    Microsoft Academic Search

    R. Garand; N. Robillard

    1997-01-01

    Immunophenotypic characterization of leukemic cells has become essential for the diagnosis of acute leukemias (AL) and chronic lymphoproliferative disorders (CLPD). Immunophenotyping allows to classify AL according to (i) lineage assignement of the leukemic clone based on the degree of specificity (or “score”) of expressed markers, (ii) the différentiation level of the clone and (iii) the presence of irrelevant markers. In

  7. An epigenetic view of B-cell disorders.

    PubMed

    Alberghini, Federica; Petrocelli, Valentina; Rahmat, Mahshid; Casola, Stefano

    2015-03-01

    B-cell development is a multistep process sustained by a highly coordinated transcriptional network under the control of a limited set of transcription factors. Epigenetic mechanisms, including DNA methylation, histone posttranslational modifications and microRNAs act in concert with transcription factors to promote lineage commitment, define and sustain cell identity and establish heritable cell-type- and stage-specific gene expression profiles. Epigenetic modifiers have recently emerged as key regulators of B-cell development and activation. Central to B-cell-mediated immunity are germinal centers, transient structures formed in secondary lymphoid organs where antigen-specific B cells undergo intense proliferation, immunoglobulin somatic hypermutation and isotype switching, to generate ultimately long-lived memory B cells and terminally differentiated plasma cells expressing high-affinity antibodies. Deregulation of one or more epigenetic axes represents a common feature of several B-cell disorders arising from germinal center B cells, including autoimmunity and lymphoma. Moreover, the hijacking of epigenetic determinants is central to the ability of the B-lymphotropic Epstein-Barr virus (EBV) to establish, via the germinal center reaction, life-long latency and occasionally contribute to malignant B-cell transformation. In the light of recent findings, this review will discuss the relevance of epigenetic deregulation in the pathogenesis of B-cell diseases. Understanding how specific epigenetic alterations contribute to the development of lymphomas, autoimmunity and EBV-associated disorders is instrumental to develop novel therapeutic interventions for the cure of these often fatal pathologies. PMID:25601271

  8. Usefulness of IGH/TCR PCR studies in lymphoproliferative disorders with inconclusive clonality by flow cytometry.

    PubMed

    Ribera, Jordi; Zamora, Lurdes; Juncŕ, Jordi; Rodríguez, Inés; Marcé, Silvia; Cabezón, Marta; Millá, Fuensanta

    2014-01-01

    In up to 5-15% of studies of lymphoproliferative disorders (LPD), flow cytometry (FCM) or immunomorphologic methods cannot discriminate malignant from reactive processes. The aim of this work was to determine the usefulness of PCR for solving these diagnostic uncertainties. We analyzed IGH and TCR? genes by PCR in 106 samples with inconclusive FCM results. A clonal result was registered in 36/106 studies, with a LPD being confirmed in 27 (75%) of these cases. Specifically, 9/9 IGH clonal and 16/25 TCR? clonal results were finally diagnosed with LPD. Additionally, two clonal TCR? samples with suspicion of undefined LPD were finally diagnosed with T LPD. Although polyclonal results were obtained in 47 of the cases studied (38 IGH and nine TCR?), hematologic neoplasms were diagnosed in 4/38 IGH polyclonal and in 1/9 TCR? polyclonal studies. There were also 14 PCR polyclonal results (four IGH, 10 TCR?), albeit nonconclusive. Of these, 2/4 were eventually diagnosed with B-cell lymphoma and 3/10 with T-cell LPD. In eight IGH samples, the results of PCR techniques were noninformative but in 3/8 cases a B lymphoma was finally confirmed. We concluded that PCR is a useful technique to identify LPD when FCM is inconclusive. A PCR clonal B result is indicative of malignancy but IGH polyclonal and nonconclusive results do not exclude lymphoid neoplasms. Interpretation of T-cell clonality should be based on all the available clinical and analytical data. PMID:23943305

  9. Usefullness of IGH/TCR PCR studies in lymphoproliferative disorders with inconclusive clonality by flow cytometry.

    PubMed

    Ribera, Jordi; Zamora, Lurdes; Juncŕ, Jordi; Rodríguez, Inés; Marcé, Silvia; Cabezón, Marta; Millá, Fuensanta

    2013-07-25

    In up to 5-15% of studies of lymphoproliferative disorders (LPD) flow cytometry (FCM) or immunomorphologic methods cannot discriminate malignant from reactive processes. The aim of this work was to determine the usefulness of PCR for solving these diagnostic uncertainties. We analyzed IGH and TCR? genes by PCR in 106 samples with inconclusive FCM results. A clonal result was registered in 36/106 studies, with a LPD being confirmed in 27 (75%) of these cases. Specifically, 9/9 IGH clonal and 16/25 TCR? clonal results were finally diagnosed with LPD. Additionally, 2 clonal TCR? samples with suspicion of undefined LPD were finally diagnosed with T LPD. Although polyclonal results were obtained in 47 of the cases studied (38 IGH and 9 TCR?), hematologic neoplasms were diagnosed in 4/38 IGH polyclonal and in 1/9 TCR? polyclonal studies. There were also 14 PCR polyclonal results (4 IGH, 10 TCR?), albeit non-conclusive. Of these, 2/4 were eventually diagnosed with B-cell lymphoma and 3/10 with T-cell LPD. In 8 IGH samples the results of PCR techniques were non-informative but in 3/8 cases a B lymphoma was finally confirmed. We concluded that PCR is a useful technique to identify LPD when FCM is inconclusive. A PCR clonal B result is indicative of malignancy but IGH polyclonal and non-conclusive results do not exclude lymphoid neoplasms. Interpretation of T-cell clonality should be based on all the available clinical and analytical data. © 2013 Clinical Cytometry Society. PMID:23894019

  10. The role of molecular analysis of immunoglobulin and T cell receptor gene rearrangements in the diagnosis of lymphoproliferative disorders

    PubMed Central

    Langerak, A; van Krieken, J H J M; Wolvers-Tettero, I; Kerkhof, E; Mulder, A; Vrints, L; Coebergh, J; Schuuring, E; Kluin, P.; van Dongen, J J M

    2001-01-01

    Aims—To investigate whether the analysis of immunoglobulin (Ig)/T cell receptor (TCR) rearrangements is useful in the diagnosis of lymphoproliferative disorders. Methods—In a series of 107 consecutive cases with initial suspicion of non-Hodgkin's lymphoma (NHL), Southern blot (SB) analysis of Ig/TCR rearrangements was performed. Results—In 98 of 100 histopathologically conclusive cases, Ig/TCR gene results were concordant. In one presumed diffuse large B cell lymphoma (DLCL) and one follicular lymphoma (FL) case no clonality could be detected by SB analysis, or by polymerase chain reaction (PCR) at second stage. In the DLCL, sampling error might have occurred; the FL was revised after an initial diagnosis of reactivity. In many of the histopathologically inconclusive cases Ig/TCR gene SB analysis was helpful, giving support for the histopathological suspicion. However, because of a lack of (clinical) follow up data this could not be confirmed in a few cases. Conclusions—Experienced haematopathologists or a pathologist panel can diagnose malignant versus reactive lesions in most cases without the need for Ig/TCR gene analysis and can select the 5–10% of cases that might benefit from molecular clonality studies. Key Words: B cell lymphoma • immunoglobulin and T cell receptor genes • clonality analysis • Southern blotting PMID:11429433

  11. Epstein-Barr virus: dermatologic associations and implications: part II. Associated lymphoproliferative disorders and solid tumors.

    PubMed

    Eminger, Lindsay A; Hall, Lawrence David; Hesterman, Kathleen S; Heymann, Warren R

    2015-01-01

    Epstein-Barr virus (EBV) was the first human virus to be associated with oncogenesis. Over the past few decades, cumulative research has revealed that latent EBV infection may be implicated in the pathogenesis of a heterogeneous group of lymphoproliferative disorders and malignancies occurring in both immunocompetent and immunocompromised hosts. Many of these diseases have either primary or secondary cutaneous manifestations. Serologic studies and EBV-encoded RNA in situ hybridization stains have been used to show the association of EBV with disease; while these findings may imply a role, they do not equate with causation. In part II of this continuing medical education review, the salient features of EBV-associated lymphoproliferative disorders and solid tumors are detailed. PMID:25497918

  12. Multiple Clinical Presentations of Lymphoproliferative Disorders in Pediatric Liver Transplant Recipients: A Single-Center Experience

    Microsoft Academic Search

    M. L. Pinho-Apezzato; U. Tannuri; A. C. A. Tannuri; E. S. Mello; F. Lima; N. E. Gibelli; M. M. Santos; A. A. Ayoub; J. G. Maksoud-Filho; M. C. Velhote; M. M. Silva; W. C. Andrade; H. T. Miyatani

    2010-01-01

    Posttransplantation lymphoproliferative disorder (PTLD) is a serious complication following solid organ transplantation that has been linked to Epstein-Barr virus (EBV) infection. The aim of this article was to describe a single-center experience with the multiplicity of clinical presentations of PTLD. Among 350 liver transplantations performed in 303 children, 13 survivor children displayed a histological diagnosis of PTLD (13\\/242 survivors; 5.4%).

  13. Waldenström's macroglobulinemia harbors a unique proteome where Ku70 is severely underexpressed as compared with other B-lymphoproliferative disorders.

    PubMed

    Perrot, A; Pionneau, C; Azar, N; Baillou, C; Lemoine, F M; Leblond, V; Merle-Béral, H; Béné, M-C; Herbrecht, R; Bahram, S; Vallat, L

    2012-01-01

    Waldenström's macroglobulinemia (WM) is a clonal B-cell lymphoproliferative disorder (LPD) of post-germinal center nature. Despite the fact that the precise molecular pathway(s) leading to WM remain(s) to be elucidated, a hallmark of the disease is the absence of the immunoglobulin heavy chain class switch recombination. Using two-dimensional gel electrophoresis, we compared proteomic profiles of WM cells with that of other LPDs. We were able to demonstrate that WM constitutes a unique proteomic entity as compared with chronic lymphocytic leukemia and marginal zone lymphoma. Statistical comparisons of protein expression levels revealed that a few proteins are distinctly expressed in WM in comparison with other LPDs. In particular we observed a major downregulation of the double strand repair protein Ku70 (XRCC6); confirmed at both the protein and RNA levels in an independent cohort of patients. Hence, we define a distinctive proteomic profile for WM where the downregulation of Ku70-a component of the non homologous end-joining pathway-might be relevant in disease pathophysiology. PMID:22961060

  14. B7-H1 (PD-L1, CD274) suppresses host immunity in T-cell lymphoproliferative disorders

    PubMed Central

    Wilcox, Ryan A.; Feldman, Andrew L.; Wada, David A.; Yang, Zhi-Zhang; Comfere, Nneka I.; Dong, Haidong; Kwon, Eugene D.; Novak, Anne J.; Markovic, Svetomir N.; Pittelkow, Mark R.; Witzig, Thomas E.

    2009-01-01

    Stromal elements present within the tumor microenvironment may suppress host immunity and promote the growth of malignant lymphocytes in B cell–derived non-Hodgkin lymphoma (NHL). In contrast, little is known about the microenvironment's role in T cell–derived NHL. B7-H1 (PD-L1, CD274), a member of the B7 family of costimulatory/coinhibitory ligands expressed by both malignant cells and stromal cells within the tumor microenvironment, has emerged as an important immune modulator capable of suppressing host immunity. Therefore, B7-H1 expression and function were analyzed in cutaneous and peripheral T-cell NHL. B7-H1 was expressed by tumor cells, monocytes, and monocyte-derived cells within the tumor microenvironment in T-cell NHL and was found to inhibit T-cell proliferation and promote the induction of FoxP3+ regulatory T cells. Collectively, the data presented provide the first evidence implicating B7-H1 in the suppression of host immunity in T-cell lymphoproliferative disorders and suggest that the targeting of B7-H1 may represent a novel therapeutic approach. PMID:19597183

  15. Post-transplant lymphoproliferative disorder after kidney transplantation: time to adopt monitoring of Epstein-Barr virus?

    PubMed

    Biller, P; Michaux, L; Pauw, L De; Camboni, A; Mourad, M; Kanaan, N

    2015-06-01

    Although post-transplant lymphoproliferative disorder is a classical complication encountered after kidney transplantation, its diagnosis can still be challenging and its outcome life-threatening. Most cases are related to Epstein-Barr virus (EBV) infection and occur mainly in the first year post-transplant, favoured by the seronegative EBV status of the recipient transplanted with a kidney from a seropositive donor, and strong immunosuppression. We report the case of a young kidney-pancreas transplant recipient who developed post-transplant lymphoproliferative disorder (PTLD) early after transplantation, with a rapid fatal issue. We review the pathogenesis, clinical presentation, and management of PTLD with a focus on prevention. PMID:25541210

  16. [KHSV/EBV associated germinotropic lymphoproliferative disorder: a rare entity, case report and review of the literature].

    PubMed

    Taris, Michaël; de Mascarel, Antoine; Riols, Mercédčs; Delwail, Vincent; Milpied, Noël; Dubus, Pierre; Parrens, Marie

    2014-10-01

    We report a case of KSHV/EBV associated germinotropic lymphoproliferative disorder (LPG) in a 49-year-old African patient, without immunosuppression. LPG is a rare entity arising in immunocompetent patients in opposition to other lymphoproliferative disorders associated to Kaposi sarcoma-associated herpes virus (KSHV). The disease presents itself as localized lymphadenopathy with an infiltration of germinal centers by plasmablastic cells coinfected by KSHV and EBV (Epstein-Barr Virus). After treatment, the outcome is favorable. Differential diagnosis in our case, due to the presence of clusters of Hodgkin-like cells in the mantle zone, included lymphocyte rich classic Hodgkin lymphoma (LHCRL) and nodular lymphocyte predominant Hodgkin lymphoma (LHNPL). Finally, we highlight the differential diagnostic criteria of KSHV lymphoproliferative diseases. PMID:25439990

  17. Primary central nervous system posttransplantation lymphoproliferative disorder after heart and lung transplantation.

    PubMed

    Gifford, G; Fay, K; Jabbour, A; Ma, D D

    2015-05-01

    Primary central nervous system posttransplantation lymphoproliferative disorder (PCNS-PTLD) is uncommon, especially after heart or lung transplantation. Database analysis from a single heart and lung transplantation centre and a literature review pertaining to PCNS-PTLD was performed. In this study, the prevalence of PCNS-PTLD was 0.18% after heart and/or lung transplants. Of 1674 transplants, three cases of PCNS-PTLD developed 14 months, 9 years and 17 years posttransplant, and all were Epstein-Barr virus driven malignancies. Literature review of the topic revealed predominantly retrospective studies, with most reported cases after renal transplantation. The overall survival is poor, and it may be improved by early diagnosis and treatment. There are no published guidelines on the management of PCNS-PTLD; immune-chemotherapy in conjunction with reduction of immune suppression is preferred based on available evidence. PMID:25955465

  18. Residential exposure to electric power transmission lines and risk of lymphoproliferative and myeloproliferative disorders: a case?control study

    Microsoft Academic Search

    R. M. Lowenthal; D. M. Tuck; I. C. Bray

    2007-01-01

    Background: Studies have shown an association between electromagnetic fieldsandchildhoodleukaemia.Theaimofthisstudywastodeterminewhether there is an increased risk of lymphoproliferative disorders (LPD) or myelopro- liferative disorders (MPD) associated with residence 300 m from high-voltage power lines. Methods: Case-control study of 854 patients diagnosed with LPD or MPD (including leukaemia, lymphoma and related conditions) aged 0-94 years comprising all cases diagnosed in Tasmania between 1972

  19. Cutaneous B-Cell Lymphomas

    Microsoft Academic Search

    Antonio Subtil

    \\u000a Cutaneous lymphoproliferative disorders are a markedly heterogeneous group of diseases and ­represent one of the most challenging\\u000a areas in dermatopathology. Careful correlation of clinical, histopathological, immunophenotypic, and molecular findings is\\u000a essential for the accurate ­diagnosis and proper classification of these neoplasms [1]. There are several types of B-cell\\u000a ­lymphoma which may show skin involvement, either primarily or as a secondary

  20. Autoimmune Lymphoproliferative Syndrome (ALPS)

    MedlinePLUS

    ... Syndrome (ALPS) Top Banner Content Area Skip Content Marketing Share this: Main Content Area Autoimmune lymphoproliferative syndrome (ALPS) is a rare genetic disorder of the immune system that affects both children and adults. In ALPS, unusually high numbers of ...

  1. Increased Protection from Vaccinia Virus Infection in Mice Genetically Prone to Lymphoproliferative Disorders

    PubMed Central

    Seedhom, Mina O.; Mathurin, Keisha S.; Kim, Sung-Kwon

    2012-01-01

    Mutations in the genes that encode Fas or Fas ligand (FasL) can result in poor restraints on lymphocyte activation and in increased susceptibility to autoimmune disorders. Because these mutations portend a continuously activated immune state, we hypothesized that they might in some cases confer resistance to infection. To examine this possibility, the immune response to, morbidity caused by, and clearance of vaccinia virus (VACV) Western Reserve was examined in 5- to 7-week-old Fas mutant (lpr) mice, before an overt lymphoproliferative disorder was observable. On day 6 after VACV infection, C57BL/6-lpr (B6-lpr) mice had decreased morbidity, decreased viral titers, and an increased percentage and number of CD4+ and CD8+ T cells. As early as day 2 after infection, B6-lpr mice had decreased liver and spleen viral titers and increased numbers of and increased gamma interferon (IFN-?) production by several different effector cell populations. Depletion of individual effector cell subsets did not inhibit the resistance of B6-lpr mice. Uninfected B6-lpr mice also had increased numbers of NK cells, ??+ T cells, and CD44+ CD4+ and CD44+ CD8+ T cells compared to uninfected B6 mice. Antibody to IFN-? resulted in increased virus load in both B6 and B6-lpr mice and eliminated the differences in viral titers between them. These results suggest that IFN-? produced by multiple activated leukocyte populations in Fas-deficient hosts enhances resistance to some viral infections. PMID:22438562

  2. Notch-Deficient Skin Induces a Lethal Systemic B-Lymphoproliferative Disorder by Secreting TSLP, a Sentinel for Epidermal Integrity

    Microsoft Academic Search

    Shadmehr Demehri; Zhenyi Liu; Jonghyeob Lee; Meei-Hua Lin; Seth D Crosby; Christopher J Roberts; Perry W Grigsby; Jeffrey H Miner; Andrew G Farr; Raphael Kopan

    2008-01-01

    Epidermal keratinocytes form a highly organized stratified epithelium and sustain a competent barrier function together with dermal and hematopoietic cells. The Notch signaling pathway is a critical regulator of epidermal integrity. Here, we show that keratinocyte-specific deletion of total Notch signaling triggered a severe systemic B-lymphoproliferative disorder, causing death. RBP-j is the DNA binding partner of Notch, but both RBP-j–dependent

  3. A novel recurrent NPM1-TYK2 gene fusion in cutaneous CD30-positive lymphoproliferative disorders.

    PubMed

    Velusamy, Thirunavukkarasu; Kiel, Mark J; Sahasrabuddhe, Anagh A; Rolland, Delphine; Dixon, Catherine A; Bailey, Nathanael G; Betz, Bryan L; Brown, Noah A; Hristov, Alexandra C; Wilcox, Ryan A; Miranda, Roberto N; Medeiros, L Jeffrey; Jeon, Yoon K; Inamdar, Kedar V; Lim, Megan S; Elenitoba-Johnson, Kojo S J

    2014-12-11

    The spectrum of cutaneous CD30-positive lymphoproliferative disorders (LPDs) includes lymphomatoid papulosis and primary cutaneous anaplastic large cell lymphoma. Chromosomal translocations targeting tyrosine kinases in CD30-positive LPDs have not been described. Using whole-transcriptome sequencing, we identified a chimeric fusion involving NPM1 (5q35) and TYK2 (19p13) that encodes an NPM1-TYK2 protein containing the oligomerization domain of NPM1 and an intact catalytic domain in TYK2. Fluorescence in situ hybridization revealed NPM1-TYK2 fusions in 2 of 47 (4%) primary cases of CD30-positive LPDs and was absent in other mature T-cell neoplasms (n = 151). Functionally, NPM1-TYK2 induced constitutive TYK2, signal transducer and activator of transcription 1 (STAT1), STAT3, and STAT5 activation. Conversely, a kinase-defective NPM1-TYK2 mutant abrogated STAT1/3/5 signaling. Finally, short hairpin RNA-mediated silencing of TYK2 abrogated lymphoma cell growth. This is the first report of recurrent translocations involving TYK2, and it highlights the novel therapeutic opportunities in the treatment of CD30-positive LPDs with TYK2 translocations. PMID:25349176

  4. Maintaining calcineurin inhibition after the diagnosis of post-transplant lymphoproliferative disorder improves renal graft survival.

    PubMed

    Serre, Jean-Emmanuel; Michonneau, David; Bachy, Emmanuel; Noël, Laure-Hélčne; Dubois, Valérie; Suberbielle, Caroline; Kreis, Henri; Legendre, Christophe; Mamzer-Bruneel, Marie-France; Morelon, Emmanuel; Thaunat, Olivier

    2014-01-01

    Post-transplant lymphoproliferative disorder (PTLD) is an uncontrolled proliferation of transformed lymphocytes fostered by immunosuppression. In addition to chemotherapy, treatment of PTLD includes a reduction of maintenance immunosuppression. Patients with PTLD have an increased risk of graft loss, suggesting that reduced immunosuppression strategy needs to be optimized with regard to graft outcome. Here we retrospectively reviewed 101 cases involving PTLD to identify the risks associated with graft loss. During a median follow-up of 70 months, 39 patients died and 21 lost their graft. Multivariate analysis found that an eGFR under 30?ml/min per 1.73?m(2) at PTLD diagnosis, a biopsy-proven acute rejection episode following reduction of immunosuppression, and the absence of calcineurin inhibition in maintenance immunosuppression are independent risk factors for allograft loss. Neither the type of PTLD nor the chemotherapy regimen was predictive of allograft failure. Histological analysis of graft biopsies showed that maintaining calcineurin inhibition after the diagnosis of PTLD reduced the risk of developing de novo anti-HLA antibodies and humoral rejection. Remarkably, calcineurin inhibitor maintenance was neither associated with higher mortality nor with worse progression-free survival. Thus, maintaining calcineurin inhibition at a reduced dose after the diagnosis of PTLD seems safe and may improve renal graft outcome, possibly through better control of the recipient's humoral immune response. PMID:23802193

  5. Detection of BRAF mutations in patients with hairy cell leukemia and related lymphoproliferative disorders.

    PubMed

    Blombery, Piers A; Wong, Stephen Q; Hewitt, Chelsee A; Dobrovic, Alexander; Maxwell, Ellen L; Juneja, Surender; Grigoriadis, George; Westerman, David A

    2012-05-01

    Hairy cell leukemia has been shown to be strongly associated with the BRAF V600E mutation. We screened 59 unenriched archived bone marrow aspirate and peripheral blood samples from 51 patients with hairy cell leukemia using high resolution melting analysis and confirmatory Sanger sequencing. The BRAF V600E mutation was detected in 38 samples (from 36 patients). The BRAF V600E mutation was detected in all samples with disease involvement above the limit of sensitivity of the techniques used. Thirty-three of 34 samples from other hematologic malignancies were negative for BRAF mutations. A BRAF K601E mutation was detected in a patient with splenic marginal zone lymphoma. Our data support the recent finding of a disease defining point mutation in hairy cell leukemia. Furthermore, high resolution melting with confirmatory Sanger sequencing are useful methods that can be employed in routine diagnostic laboratories to detect BRAF mutations in patients with hairy cell leukemia and related lymphoproliferative disorders. PMID:22133769

  6. Detection of BRAF mutations in patients with hairy cell leukemia and related lymphoproliferative disorders

    PubMed Central

    Blombery, Piers A.; Wong, Stephen Q.; Hewitt, Chelsee A.; Dobrovic, Alexander; Maxwell, Ellen L.; Juneja, Surender; Grigoriadis, George; Westerman, David A.

    2012-01-01

    Hairy cell leukemia has been shown to be strongly associated with the BRAF V600E mutation. We screened 59 unenriched archived bone marrow aspirate and peripheral blood samples from 51 patients with hairy cell leukemia using high resolution melting analysis and confirmatory Sanger sequencing. The BRAF V600E mutation was detected in 38 samples (from 36 patients). The BRAF V600E mutation was detected in all samples with disease involvement above the limit of sensitivity of the techniques used. Thirty-three of 34 samples from other hematologic malignancies were negative for BRAF mutations. A BRAF K601E mutation was detected in a patient with splenic marginal zone lymphoma. Our data support the recent finding of a disease defining point mutation in hairy cell leukemia. Furthermore, high resolution melting with confirmatory Sanger sequencing are useful methods that can be employed in routine diagnostic laboratories to detect BRAF mutations in patients with hairy cell leukemia and related lymphoproliferative disorders. PMID:22133769

  7. Radioimmunotherapy ((90) Y-Ibritumomab Tiuxetan) for Posttransplant Lymphoproliferative Disorders After Prior Exposure to Rituximab.

    PubMed

    Rossignol, J; Terriou, L; Robu, D; Willekens, C; Hivert, B; Pascal, L; Guieze, R; Trappe, R; Baillet, C; Huglo, D; Morschhauser, F

    2015-07-01

    Posttransplantation lymphoproliferative disorders (PTLDs) are life-threatening complications after solid organ and hematopoietic stem cell transplantation. Only half of CD20-positive PTLDs respond to rituximab monotherapy, and outcomes remain poor for patients with relapsed/refractory disease, especially those who do not qualify for an anthracycline containing regimen due to frailty or comorbidities. Radioimmunotherapy (RIT) might be an option in this particular setting. We report a panel of eight patients with rituximab refractory/relapsed CD20-positive PTLDs including three ineligible for subsequent CHOP-like chemotherapy who received (90) Y-Ibritumomab tiuxetan as a single agent (n?=?7) or combined to chemotherapy (n?=?1). Five out of eight patients were kidney transplant recipients, while 2/8 had a liver transplant and 1/8 had a heart transplant. Patients received a median of two previous therapies. Overall response rate was 62.5%. Importantly, all responders achieved complete response. At a median follow-up of 37 months [5; 84], complete response was ongoing in four patients. Toxicity was predominantly hematological and easily manageable. No graft rejection was noticed concomitantly or following RIT administration despite immunosuppression reduction after diagnosis of PTLDs. This report emphasizes the potential efficiency of salvage RIT for early rituximab refractory PTLDs without any unexpected toxicity. PMID:25868706

  8. Peripheral T-cell and NK cell lymphoproliferative disorders: cell of origin, clinical and pathological implications.

    PubMed

    Inghirami, Giorgio; Chan, Wing C; Pileri, Stefano

    2015-01-01

    T-cell lymphoproliferative disorders are a heterogeneous group of neoplasms with distinct clinical-biological properties. The normal cellular counterpart of these processes has been postulated based on functional and immunophenotypic analyses. However, T lymphocytes have been proven to be remarkably capable of modulating their properties, adapting their function in relationship with multiple stimuli and to the microenvironment. This impressive plasticity is determined by the equilibrium among a pool of transcription factors and by DNA chromatin regulators. It is now proven that the acquisition of specific genomic defects leads to the enforcement/activation of distinct pathways, which ultimately alter the preferential activation of defined regulators, forcing the neoplastic cells to acquire features and phenotypes distant from their original fate. Thus, dissecting the landscape of the genetic defects and their functional consequences in T-cell neoplasms is critical not only to pinpoint the origin of these tumors but also to define innovative mechanisms to re-adjust an unbalanced state to which the tumor cells have become addicted and make them vulnerable to therapies and targetable by the immune system. In our review, we briefly describe the pathological and clinical aspects of the T-cell lymphoma subtypes as well as NK-cell lymphomas and then focus on the current understanding of their pathogenesis and the implications on diagnosis and treatment. PMID:25510275

  9. Posttransplant Lymphoproliferative Disease in Liver Transplant Patients

    Microsoft Academic Search

    Christina Hartmann; Marcus Schuchmann; Tim Zimmermann

    2011-01-01

    Posttransplant lymphoproliferative disorders (PTLD) are a life-threatening complication following solid organ transplantation.\\u000a Many posttransplant lymphomas develop from the uncontrolled proliferation of Epstein–Barr virus (EBV)-infected B-cells, whereas\\u000a EBV-negative PTLDs were increasingly recognized within the past decade. Major risk factors for the development of PTLDs after\\u000a liver transplantation are immunosuppressive therapy and the type of underlying disease: viral hepatitis, autoimmune liver\\u000a disease,

  10. Detection of Epstein-Barr Virus DNA in Sera from Transplant Recipients with Lymphoproliferative Disorders

    Microsoft Academic Search

    AJIT P. LIMAYE; MEEI-LI HUANG; EDERLYN E. ATIENZA; JAMES M. FERRENBERG; LAWRENCE COREY

    1999-01-01

    Early diagnosis of Epstein-Barr Virus (EBV)-associated posttransplant lymphoproliferative disease (PTLD) is important because many patients respond to reduction in immunosuppression, especially if PTLD is detect- ed at an early stage. Previous studies have found elevated EBV DNA levels in blood from patients with PTLD, but these assays required isolation of cellular blood fractions and quantitation. We evaluated the presence of

  11. Hepatitis C infection and lymphoproliferative disease: Accidental comorbidities?

    PubMed Central

    Khoury, Tawfik; Chen, Shmuel; Adar, Tomer; Jacob, E Ollech; Mizrahi, Meir

    2014-01-01

    Chronic hepatitis C virus (HCV) infection has been associated with liver cancer and cirrhosis, autoimmune disorders such as thyroiditis and mixed cryoglobulinema, and alterations in immune function and chronic inflammation, both implicated in B cell lymphoproliferative diseases that may progress to non-Hodgkin lymphoma (NHL). HCV bound to B cell surface receptors can induce lymphoproliferation, leading to DNA mutations and/or lower antigen response thresholds. These findings and epidemiological reports suggest an association between HCV infection and NHL. We performed a systematic review of the literature to clarify this potential relationship. We searched the English-language literature utilizing Medline, Embase, Paper First, Web of Science, Google Scholar, and the Cochrane Database of Systematic Reviews, with search terms broadly defined to capture discussions of HCV and its relationship with NHL and/or lymphoproliferative diseases. References were screened to further identify relevant studies and literature in the basic sciences. A total of 62 reports discussing the relationship between HCV, NHL, and lymphoproliferative diseases were identified. Epidemiological studies suggest that at least a portion of NHL may be etiologically attributable to HCV, particularly in areas with high HCV prevalence. Studies that showed a lack of association between HCV infection and lymphoma may have been influenced by small sample size, short follow-up periods, and database limitations. The association appears strongest with the B-cell lymphomas relative to other lymphoproliferative diseases. Mechanisms by which chronic HCV infection promotes lymphoproliferative disease remains unclear. Lymphomagenesis is a multifactorial process involving genetic, environmental, and infectious factors. HCV most probably have a role in the lymphomagenesis but further study to clarify the association and underlying mechanisms is warranted. PMID:25473174

  12. Age-related EBV-associated lymphoproliferative disorders in the Western population: a spectrum of reactive lymphoid hyperplasia and lymphoma

    PubMed Central

    Dojcinov, Stefan D.; Venkataraman, Girish; Pittaluga, Stefania; Wlodarska, Iwona; Schrager, Jeffrey A.; Raffeld, Mark; Hills, Robert K.

    2011-01-01

    We investigated age-related EBV+ B-cell lymphoproliferations in the Western population. The clinical features, histology, immunophenotype, EBV-encoded RNA in situ hybridization, and clonality by PCR of T-cell receptor gamma and immunoglobulin genes were categorized in 122 EBV+ lesions as follows: (1) reactive lymphoid hyperplasia; (2) polymorphic extranodal or (3) polymorphic nodal lymphoproliferative disease (LPD); and (4) diffuse large B-cell lymphoma (DLBCL). Interphase FISH for IG and PAX5 gene rearrangements was performed on 17 cases of DLBCL. The overall median age was 75 years (range, 45-101 years; 67 men, 55 women), and 67, 79, 73, and 77 years, respectively, for groups 1 through 4. Sixteen of 21 cases of polymorphic extranodal LPD were classified as EBV+ mucocutaneous ulcer. PCR for immunoglobulin genes was polyclonal in reactive lymphoid hyperplasia (84%) and monoclonal in 33%, 63%, and 56% of polymorphic extranodal and nodal LPD cases and DLBCL, respectively. All groups showed restricted/clonal T-cell receptor responses (27%-70%). By FISH, 19% of DLBCLs showed IGH@ rearrangements, but PAX5 was unaffected. Disease-specific 5-year survival was 100%, 93%, 57%, and 25% for groups 1-4, respectively, and 100% for patients with EBV+ mucocutaneous ulcer. Disease volume was predictive of therapy response (P = .0002), and pathologic subtype was predictive of overall outcome (P = .001). Age-related EBV+ B-cell LPD encompasses a wider disease spectrum than previously recognized and includes both reactive and neoplastic conditions. Reduction in the T-cell repertoire may contribute to decreased immune surveillance. PMID:21385849

  13. Primary Cutaneous Gamma-Delta T-Cell Lymphoproliferative Disorder in a 3-Year-Old Boy.

    PubMed

    Soon, Christopher W M; Link, Michael; Kim, Youn H; Kim, Jinah

    2015-07-01

    Primary cutaneous gamma-delta T-cell lymphoma (PCGD-TCL) is a rare disorder, constituting less than 1% of primary cutaneous lymphomas. Most cases occur in adults and may present as plaques or nodules with ulceration. Here we describe an unusual case of PCGD-TCL in a 3-year-old boy who presented with asymptomatic subcutaneous nodules. To our knowledge, this report represents one of the youngest reported patients with gamma-delta lymphoma/lymphoproliferative disorder. In addition, our patient has an indolent clinical presentation with greater than 1 year clinical follow-up. Because gamma-delta T-cell lymphomas are exceedingly rare in children, we acknowledge that the clinical course/outcome in young patients is still unclear. We hope to add to the recognition that PCGD-TCLs demonstrate a wide clinical spectrum of disease with relatively indolent presentations in some cases. PMID:25072685

  14. Immunophenotyping by flow cytometry of fine needle aspirates in the diagnosis of lymphoproliferative disorders: A retrospective study.

    PubMed

    Henrique, R M; Sousa, M E; Godinho, M I; Costa, I; Barbosa, I L; Lopes, C A

    1999-01-01

    In order to determine the value of flow cytometric (FCM) immunophenotyping of fine-needle aspirates (FNA) in the diagnosis and classification of lymphoproliferative diseases, 61 tissue samples were studied and compared with the cytologic/histological results. In vivo and ex vivo FNA biopsy yielded the material for FCM, which comprised an extensive number of lymphoid cell markers. In all but three cases sufficient cells were collected. Overall, malignancy was diagnosed in 33 cases from a total of 47 (70.2%), and in the remaining cases malignancy was not detected. Eleven cases were correctly diagnosed as reactive processes (11/11). There were no false positive cases of malignancy, as diagnosed by FCM-FNA. The best accuracy was achieved in the low-grade B-cell lymphomas and lymphoblastic lymphoma/leukemia. We conclude that in a significant number of cases, FCM-FNA permits the separation between lymphoid malignancies and reactive processes without false positive results. It was found to be particularly useful in the differential diagnosis of mantle-cell and small-lymphocytic lymphoma and in the identification of lymphoblastic lymphoma/leukemia. PMID:10494131

  15. Adoptive therapy for EBV-induced cancers: driving success with post-transplant lymphoproliferative disorder to other EBV-derived tumors.

    PubMed

    Smith, Corey; Khanna, Rajiv

    2015-06-01

    Epstein-Barr virus (EBV) infection is associated with a range of human malignancies of lymphocytic and epithelial cell origin. In addition to viral-mediated and genetic oncogenic events that lead to the establishment of EBV-associated malignancies, defects in the immune control of EBV likely play a significant role in promoting the survival of malignant cells. This breakdown in immune surveillance is most evident in immunocompromised transplant patients who are susceptible to the development of post-transplant lymphoproliferative disorders. Observations over the last two decades have shown that reconstitution of EBV-specific cellular immunity via adoptive cell therapy can have a dramatic effect on both preventing and treating post-transplant lymphoproliferative disorders, leading to hope that similar strategies could be effective in preventing more prevalent EBV-associated malignancies. PMID:26065480

  16. Molecular Cytogenetic Delineation of a Novel Critical Genomic Region in Chromosome Bands 11q22.3-923.1 in Lymphoproliferative Disorders

    Microsoft Academic Search

    Stephan Stilgenbauer; Peter Liebisch; Michael R. James; Martin Schroder; Brigitte Schlegelberger; Konstanze Fischer; Martin Bentz; Peter Lichter; Hartmut Dohner

    1996-01-01

    Aberrations of the long arm of chromosome 11 are among the most common chromosome abnormalities in lymphoproliferative disorders (LPD). Translocations involving BCL1 at 11q13 are strongly associated with mantle cell lymphoma. Other nonrandom aberrations, especially deletions and, less frequently, translocations, involving bands 11q21-923 have been identified by chromosome banding analysis. To date, the critical genomic segment and candidate genes involved

  17. Management of Febrile Neutropenia – a German Prospective Hospital Cost Analysis in Lymphoproliferative Disorders, Non-Small Cell Lung Cancer, and Primary Breast Cancer

    Microsoft Academic Search

    Angela Ihbe-Heffinger; Bernadette J. Paessens; Christoph von Schilling; Margarita Shlaen; Nina Gottschalk; Karin Berger; Rudolf Bernard; Marion Kiechle; Christian Peschel; Volker R. Jacobs

    2011-01-01

    SummaryBackground: Febrile neutropenia\\/leukopenia (FN\\/FL) is the most frequent dose-limiting toxicity of myelosuppressive chemotherapy, but German data on economic consequences are limited. Patients and Methods: A prospective, multicentre, longitudinal, observational study was carried out to evaluate the occurrence of FN\\/FL and its impact on health resource utilization and costs in non-small cell lung cancer (NSCLC), lymphoproliferative disorder (LPD), and primary breast

  18. Hodgkin lymphoma post-transplant lymphoproliferative disorder following pediatric renal transplant: serial imaging with F-18 FDG PET/CT.

    PubMed

    Makis, William; Lisbona, Robert; Derbekyan, Vilma

    2010-09-01

    Post-transplant lymphoproliferative disorder (PTLD) occurs in 1.2% of pediatric renal transplant patients, and is frequently Epstein-Barr Virus mediated. Hodgkin Lymphoma PTLD is the rarest of the 4 types of PTLDs recognized by the World Health Organization, with an incidence of <4% of all PTLD patients. It has a distinct clinical course and treatment from all other types of PTLD. This is a case of a 16-year-old girl who had a renal transplant in 2000 due to Moya Moya disease. Her first F-18 FDG PET/CT done in 2006 showed mildly FDG-avid mediastinal adenopathy (histologically nonspecific reactive nodes), however in 2009, after presenting with fevers, a repeat PET/CT showed extensive intensely FDG-avid disease. Biopsy of a supraclavicular node identified Hodgkin Lymphoma PTLD. The patient was treated with chemotherapy and reimaged, showing excellent response to therapy. In contrast, classic PTLD is treated by withdrawal of immunosuppression and administration of Rituximab. F-18 FDG PET/CT is known to be very useful in the staging and monitoring of response to therapy in the setting of classic PTLD. In this case, serial F-18 FDG PET/CT scans proved very useful in the evaluation and follow-up of the rare and distinct Hodgkin Lymphoma PTLD subtype. PMID:20706047

  19. Post-transplant lymphoproliferative disorder presenting as a tumor adjacent to the renal allograft: A case report and review of the literature

    PubMed Central

    GAO, CHEN; PENG, LONGKAI; PENG, FENGHUA; TUO, TING; LI, DAIQIANG

    2014-01-01

    Post-transplant lymphoproliferative disorder (PTLD) is a potentially fatal complication of solid organ transplantation. The current report presents the case of a 42-year-old male who developed PTLD within the first year following renal transplantation. The disorder manifested as a tumor adjacent to the lower pole of the renal allograft and resulted in urinary obstruction. Durable complete remission was achieved as a result of surgical resection followed by a reduction in immunosuppression and low-dose rituximab-based chemotherapy, indicating that this therapeutic strategy may be safe and effective for the treatment of specific cases of localized and resectable PTLD. PMID:25364435

  20. Cellular Immunotherapy Following Cyclophosphamide in Treating Patients With Recurrent Non-Hodgkin Lymphomas, Chronic Lymphocytic Leukemia or B-Cell Prolymphocytic Leukemia

    ClinicalTrials.gov

    2015-06-29

    Post-transplant Lymphoproliferative Disorder; B-Cell Prolymphocytic Leukemia; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Small Lymphocytic Lymphoma; Refractory Chronic Lymphocytic Leukemia; Refractory Hairy Cell Leukemia; Waldenström Macroglobulinemia; B-Cell Lymphoma, Unclassifiable, With Features Intermediate Between Diffuse Large B-Cell Lymphoma and Burkitt Lymphoma; B-Cell Lymphoma, Unclassifiable, With Features Intermediate Between Diffuse Large B-Cell Lymphoma and Classical Hodgkin Lymphoma; Recurrent Lymphoplasmacytic Lymphoma

  1. Chronic Epstein-Barr virus infection causing both benign and malignant lymphoproliferative disorders

    PubMed Central

    Kwun, Yoojin; Hong, Soo-Jong; Lee, Jin Seong; Son, Da Hye

    2014-01-01

    The Epstein-Barr virus (EBV) is oncogenic and can transform B cells from a benign to a malignant phenotype. EBV infection is also associated with lymphoid interstitial pneumonia (LIP). Here, we report the case of a 14-year-old boy who was diagnosed with a latent EBV infection and underlying LIP, without any associated immunodeficiency. He had been EBV-seropositive for 8 years. The first clinical presentations were chronic respiratory symptoms and recurrent pneumonia. The symptoms worsened in the following 2 years. The results of in situ hybridization were positive for EBV, which led to a diagnosis of LIP. The diagnosis was confirmed by the results of a thoracoscopic lung biopsy. The EBV titer of the bronchoalveolar lavage specimens obtained after acyclovir treatment was found to be fluctuating. The patient had latent EBV infection for 8 years, until presented at the hospital with intermittent abdominal pain and distension. Physical examination and pelvic computed tomography revealed a large mesenteric mass. A biopsy of the excised mass led to a diagnosis of Burkitt's lymphoma (BL). The patient received combination chemotherapy for 4 months, consisting of vincristine, methotrexate, cyclophosphamide, doxorubicin, and prednisolone. He is now tumor-free, with the LIP under control, and is being followed-up at the outpatient clinic. This is the first report of a Korean case of chronic latent EBV infection that developed into LIP and BL in a nonimmunocompromised child. PMID:25324869

  2. Hepatitis C virus syndrome: A constellation of organ- and non-organ specific autoimmune disorders, B-cell non-Hodgkin’s lymphoma, and cancer

    PubMed Central

    Ferri, Clodoveo; Sebastiani, Marco; Giuggioli, Dilia; Colaci, Michele; Fallahi, Poupak; Piluso, Alessia; Antonelli, Alessandro; Zignego, Anna Linda

    2015-01-01

    The clinical course of chronic hepatitis C virus (HCV) infection is characterized by possible development of both liver and extrahepatic disorders. The tropism of HCV for the lymphoid tissue is responsible for several immune-mediated disorders; a poly-oligoclonal B-lymphocyte expansion, commonly observed in a high proportion of patients with HCV infection, are responsible for the production of different autoantibodies and immune-complexes, such as mixed cryoglobulins. These serological alterations may characterize a variety of autoimmune or neoplastic diseases. Cryoglobulinemic vasculitis due to small-vessel deposition of circulating mixed cryoglobulins is the prototype of HCV-driven immune-mediated and lymphoproliferative disorders; interestingly, in some cases the disease may evolve to frank malignant lymphoma. In addition, HCV shows an oncogenic potential as suggested by several clinico-epidemiological and laboratory studies; in addition to hepatocellular carcinoma that represents the most frequent HCV-related malignancy, a causative role of HCV has been largely demonstrated in a significant percentage of patients with isolated B-cells non-Hodgkin’s lymphomas. The same virus may be also involved in the pathogenesis of papillary thyroid cancer, a rare neoplastic condition that may complicate HCV-related thyroid involvement. Patients with HCV infection are frequently asymptomatic or may develop only hepatic alteration, while a limited but clinically relevant number can develop one or more autoimmune and/or neoplastic disorders. Given the large variability of their prevalence among patients’ populations from different countries, it is possible to hypothesize a potential role of other co-factors, i.e., genetic and/or environmental, in the pathogenesis of HCV-related extra-hepatic diseases. PMID:25848462

  3. STAT3 mutations unify the pathogenesis of chronic lymphoproliferative disorders of NK cells and T-cell large granular lymphocyte leukemia

    PubMed Central

    Jerez, Andres; Clemente, Michael J.; Makishima, Hideki; Koskela, Hanna; LeBlanc, Francis; Peng Ng, Kwok; Olson, Thomas; Przychodzen, Bartlomiej; Afable, Manuel; Gomez-Segui, Ines; Guinta, Kathryn; Durkin, Lisa; Hsi, Eric D.; McGraw, Kathy; Zhang, Dan; Wlodarski, Marcin W.; Porkka, Kimmo; Sekeres, Mikkael A.; List, Alan; Mustjoki, Satu; Loughran, Thomas P.

    2012-01-01

    Chronic lymphoproliferative disorders of natural killer cells (CLPD-NKs) and T-cell large granular lymphocytic leukemias (T-LGLs) are clonal lymphoproliferations arising from either natural killer cells or cytotoxic T lymphocytes (CTLs). We have investigated for distribution and functional significance of mutations in 50 CLPD-NKs and 120 T-LGL patients by direct sequencing, allele-specific PCR, and microarray analysis. STAT3 gene mutations are present in both T and NK diseases: approximately one-third of patients with each type of disorder convey these mutations. Mutations were found in exons 21 and 20, encoding the Src homology 2 domain. Patients with mutations are characterized by symptomatic disease (75%), history of multiple treatments, and a specific pattern of STAT3 activation and gene deregulation, including increased expression of genes activated by STAT3. Many of these features are also found in patients with wild-type STAT3, indicating that other mechanisms of STAT3 activation can be operative in these chronic lymphoproliferative disorders. Treatment with STAT3 inhibitors, both in wild-type and mutant cases, resulted in accelerated apoptosis. STAT3 mutations are frequent in large granular lymphocytes suggesting a similar molecular dysregulation in malignant chronic expansions of NK and CTL origin. STAT3 mutations may distinguish truly malignant lymphoproliferations involving T and NK cells from reactive expansions. PMID:22859607

  4. High-Dose Y-90-Ibritumomab Tiuxetan Added to Reduced-Intensity Allogeneic Stem Cell Transplant Regimen for Relapsed or Refractory Aggressive B-Cell Lymphoma

    ClinicalTrials.gov

    2015-03-04

    B-cell Adult Acute Lymphoblastic Leukemia; Post-transplant Lymphoproliferative Disorder; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Grade III Lymphomatoid Granulomatosis; Recurrent Adult Immunoblastic Large Cell Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma

  5. Monocytes promote tumor cell survival in T-cell lymphoproliferative disorders and are impaired in their ability to differentiate into mature dendritic cells

    PubMed Central

    Wilcox, Ryan A.; Wada, David A.; Ziesmer, Steven C.; Elsawa, Sherine F.; Comfere, Nneka I.; Dietz, Allan B.; Novak, Anne J.; Witzig, Thomas E.; Feldman, Andrew L.; Pittelkow, Mark R.

    2009-01-01

    A variety of nonmalignant cells present in the tumor microenvironment promotes tumorigenesis by stimulating tumor cell growth and metastasis or suppressing host immunity. The role of such stromal cells in T-cell lymphoproliferative disorders is incompletely understood. Monocyte-derived cells (MDCs), including professional antigen-presenting cells such as dendritic cells (DCs), play a central role in T-cell biology. Here, we provide evidence that monocytes promote the survival of malignant T cells and demonstrate that MDCs are abundant within the tumor microenvironment of T cell–derived lymphomas. Malignant T cells were observed to remain viable during in vitro culture with autologous monocytes, but cell death was significantly increased after monocyte depletion. Furthermore, monocytes prevent the induction of cell death in T-cell lymphoma lines in response to either serum starvation or doxorubicin, and promote the engraftment of these cells in nonobese diabetic/severe combined immunodeficient mice. Monocytes are actively recruited to the tumor microenvironment by CCL5 (RANTES), where their differentiation into mature DCs is impaired by tumor-derived interleukin-10. Collectively, the data presented demonstrate a previously undescribed role for monocytes in T-cell lymphoproliferative disorders. PMID:19671921

  6. Improved PCR method for detecting monoclonal immunoglobulin heavy chain rearrangement in B cell neoplasms

    Microsoft Academic Search

    I Ramasamy; M Brisco; A Morley

    1992-01-01

    AIMS: To develop a simple, optimised, polymerase chain reaction (PCR) based method for detecting the rearranged immunoglobulin heavy chain (IgH). METHODS: Using as primers oligonucleotides (Fr2A, Fr2B) homologous to the conserved sequences to the framework II region and the joining (JH) region, 25 patients with B cell lymphoproliferative disorders, previously characterised by Southern blotting, and three patients with light chain

  7. Successful treatment of lymphoproliferative disease complicating primary immunodeficiency/immunodysregulatory disorders with reduced-intensity allogeneic stem-cell transplantation.

    PubMed

    Cohen, Jonathan M; Sebire, Neil J; Harvey, Julia; Gaspar, H Bobby; Cathy, Cale; Jones, Alison; Rao, Kanchan; Cubitt, David; Amrolia, Persis J; Davies, E Graham; Veys, Paul

    2007-09-15

    Lymphoproliferative disease (LPD) is a recognized complication of primary immunodeficiency (PID) and immunodysregulatory syndromes. Historically, it has a very poor outcome. For patients surviving LPD, myeloablative hematopoietic stem cell transplantation (SCT) was the only cure for the underlying PID, with a high risk of developing posttransplantation complications, including recurrent lymphoproliferative disease. We describe 8 patients with a range of PID and immunodysregulatory syndromes complicated by LPD. After initial treatment of the LPD (including the use of anti-CD20 monoclonal antibody, rituximab, in 6 of the patients), all patients underwent reduced-intensity conditioning (RIC) SCT with prospective monitoring for Epstein-Barr virus (EBV) viremia. After transplantation, 3 patients received rituximab, and 3 patients received prophylactic EBV-specific cytotoxic T-lymphocytes. Only 1 patient developed recurrent LPD posttransplantation, which responded to rituximab. All patients who underwent transplantation survive free of LPD and are cured of their PID at a median follow-up of 4 years (range, 1-7 years). With careful monitoring and pre-emptive therapy, we advocate this RIC SCT approach to patients with PID who have pre-existing EBV-LPD. PMID:17502458

  8. Induction and progression of human lymphoproliferative lesions by Epstein-Barr virus.

    PubMed Central

    Chappuis, B B; Müller-Hermelink, H K

    1990-01-01

    Epstein-Barr virus (EBV) is involved in numerous lymphoproliferative diseases. In addition to classical lesions such as endemic Burkitt's lymphoma and infectious mononucleosis, there are other disorders of the lymphoid system that are discussed in relation to EBV: B-cell lymphomas in immunosuppressed individuals. Hodgkin's disease and, to some extent, primary extranodal lymphomas. Studies of the EBV expression in classical and nonclassical lesions could lead to the better understanding of different EBV mechanisms in lymphomagenesis. Images FIGURE 1. FIGURE 2. PMID:2176977

  9. [Autoimmune and lymphoproliferative HCV-correlated manifestations: example of mixed cryoglobulinaemia (review)].

    PubMed

    Ghinoi, A; Mascia, M T; Puccini, R; Ferri, C

    2004-01-01

    Mixed cryoglobulinaemia (MC) is a systemic vasculitis involving small vessels (arterioles, capillaries, venules). The histological hallmark of the disease is the leukocytoclastic vasculitis secondary to the vascular deposition of circulating immune-complexes (CIC), mainly cryoglobulins and complement. The immune-mediated vasculitic lesions are responsible for different MC clinical features, including cutaneous and visceral organ involvement. Hepatitis C virus (HCV) represents the triggering factor in the large majority of MC patients (>90%). Moreover, several epidemiological, clinico-pathological and laboratory investigations suggested a possible role for HCV in a wide spectrum of immuno-lymphoproliferative disorders; namely, porphyria cutanea tarda, diabetes, polyarthritis, lung fibrosis, poly-dermatomyositis, thyroiditis, thyroid cancer, B-cell non-Hodgkin's lymphomas (B-NHL), etc. Renal involvement with or without MC syndrome can be observed in HCV-infected individuals. There is great geographical etherogeneity in the prevalence of HCV-related disorders. This epidemiological observation suggests a multifactorial and multistep process in the pathogenesis of these conditions, involving other unknown genetic and/or environmental factors. HCV lymphotropism may explain the mono-oligoclonal B-lymphocyte expansion observed in HCV-infected individuals, particularly in MC patients. The 'benign' lymphoproliferative disorder, classified as monotypic lymphoproliferative disorders of undetermined significance (MLDUS), may be responsible for the wide production of CIC, including cryoglobulins, rheumatoid factor and different organ and non-organ specific autoantibodies. The consequence is the appearance of various HCV-related autoimmune diseases, including MC syndrome. This latter may be complicated by B-NHL in 10% of the cases; moreover, HCV infection has been confirmed in a significant percentage of 'idiopathic B-NHL. For a correct therapeutic approach to cryoglobulinaemic vasculitis, as well as to other HCV-related disorders, we should deal with concomitant, conflicting conditions: HCV infection, autoimmune and lymphoproliferative alterations. In this scenario, we can treat the diseases at three different levels by means of etiologic, pathogenetic and/or symptomatic therapies. The eradication of HCV by combined interferon and ribavirin therapy can be achieved in only a minority of cases. On the contrary, severe complications such as glomerulonephritis, sensory-motor neuropathy or diffuse vasculitis can be effectively treated by a combination of corticosteroids, plasma exchange and cyclophosphamide. More recently, a pathogenetic treatment with rituximab, a monoclonal chimeric antibody that binds to the B-cell surface antigen CD20 with selective B-cell blockade, was proposed in patients with HCV-related MC syndrome. PMID:15285001

  10. SGN-35 in CD30-positive Lymphoproliferative Disorders (ALCL), Mycosis Fungoides (MF), and Extensive Lymphomatoid Papulosis (LyP)

    ClinicalTrials.gov

    2015-03-25

    CD-30 Positive Anaplastic Large T-cell Cutaneous Lymphoma; Lymphoma, Primary Cutaneous Anaplastic Large Cell; Lymphomatoid Papulosis; Mycosis Fungoides; Skin Lymphoma; Cutaneous Lymphomas; Lymphoma; Hematologic Disorder

  11. AUTOLOGOUS LYMPHOKINE-ACTIVATED KILLER CELL THERAPY OF EPSTEIN-BARR VIRUS-POSITIVE AND -NEGATIVE LYMPHOPROLIFERATIVE DISORDERS ARISING IN ORGAN TRANSPLANT RECIPIENTS1

    PubMed Central

    Nalesnik, Michael A.; Rao, Abdul S.; Furukawa, Hiro; Pham, Si; Zeevi, Adriana; Fung, John J.; Klein, George; Gritsch, H. Albin; Elder, Elaine; Whiteside, Theresa L.; Starzl, Thomas E.

    2010-01-01

    Lymphoreticular malignancies, collectively called posttransplant lymphoproliferative disorders (PTLD), eventually develop in 2–5% of organ transplant recipients. They frequently undergo regression when immunosuppression is reduced or stopped. This feature has been associated with a previous or de novo Epstein-Barr virus (EBV) infection. We herein describe immunotherapy with autologous lymphokine-activated killer (LAK) cells in seven patients with PTLD (four EBV-positive patients and three EBV-negative patients). Autologous peripheral blood mononuclear cells were obtained by leukapheresis, depleted of monocytes, and cultured in the presence of interleukin 2 for 10 to 11 days. A single dose of 5.2 × 109 to 5.6 × 1010 LAK cells was given intravenously. Systemic interleukin 2 was not administered. The four patients with EBV+ PTLD had complete tumor regression; two of them developed controllable rejection. Three patients are well 13–16 months after treatment; the fourth patient died of pneumonia 41 days after infusion. Three patients with EBV? lymphomas had no response despite prior evidence that their tumors also were subject to immune surveillance. Two of these three patients died after being given other treatment, and the third patient has persistent tumor. In conclusion, autologous LAK cell infusion was effective for treatment of four EBV+ organ transplant recipients. LAK cell efficacy for three patients with EBV? PTLD was not evaluable under the management circumstances in which this treatment was utilized. PMID:9142315

  12. EORTC, ISCL, and USCLC consensus recommendations for the treatment of primary cutaneous CD30-positive lymphoproliferative disorders: lymphomatoid papulosis and primary cutaneous anaplastic large-cell lymphoma*

    PubMed Central

    Pfaltz, Katrin; Vermeer, Maarten H.; Cozzio, Antonio; Ortiz-Romero, Pablo L.; Bagot, Martine; Olsen, Elise; Kim, Youn H.; Dummer, Reinhard; Pimpinelli, Nicola; Whittaker, Sean; Hodak, Emmilia; Cerroni, Lorenzo; Berti, Emilio; Horwitz, Steve; Prince, H. Miles; Guitart, Joan; Estrach, Teresa; Sanches, José A.; Duvic, Madeleine; Ranki, Annamari; Dreno, Brigitte; Ostheeren-Michaelis, Sonja; Knobler, Robert; Wood, Gary; Willemze, Rein

    2011-01-01

    Primary cutaneous CD30+ lymphoproliferative disorders (CD30+ LPDs) are the second most common form of cutaneous T-cell lymphomas and include lymphomatoid papulosis and primary cutaneous anaplastic large-cell lymphoma. Despite the anaplastic cytomorphology of tumor cells that suggest an aggressive course, CD30+ LPDs are characterized by an excellent prognosis. Although a broad spectrum of therapeutic strategies has been reported, these have been limited mostly to small retrospective cohort series or case reports, and only very few prospective controlled or multicenter studies have been performed, which results in a low level of evidence for most therapies. The response rates to treatment, recurrence rates, and outcome have not been analyzed in a systematic review. Moreover, international guidelines for staging and treatment of CD30+ LPDs have not yet been presented. Based on a literature analysis and discussions, recommendations were elaborated by a multidisciplinary expert panel of the Cutaneous Lymphoma Task Force of the European Organization for Research and Treatment of Cancer, the International Society for Cutaneous Lymphomas, and the United States Cutaneous Lymphoma Consortium. The recommendations represent the state-of-the-art management of CD30+ LPDs and include definitions for clinical endpoints as well as response criteria for future clinical trials in CD30+ LPDs. PMID:21841159

  13. CNI withdrawal for post-transplant lymphoproliferative disorders in kidney transplant is an independent risk factor for graft failure and mortality.

    PubMed

    Rabot, Nolwenn; Büchler, Matthias; Foucher, Yohann; Moreau, Anne; Debiais, Celine; Machet, Marie-Christine; Kessler, Michelle; Morelon, Emmanuel; Thierry, Antoine; Legendre, Christophe; Rivalan, Joseph; Kamar, Nassim; Dantal, Jacques

    2014-09-01

    Post-transplantation lymphoproliferative disorders (PTLD) are associated with poor patient and graft survival. The risk of rejection and subsequent graft loss are increased by the reduction of immunosuppression therapy, the cornerstone of PTLD treatment. This multicentre, retrospective, nonrandomized cohort study includes 104 adults who developed PTLD after renal or simultaneous renal/pancreatic transplantation between 1990 and 2007. It examines the effect of calcineurin inhibitor (CNI) withdrawal on long-term graft and patient survival. At 10 years postonset of PTLD, the Kaplan-Meier graft loss rate was 43.9% and graft loss or death with functioning graft was 64.4%. Cox multivariate analysis determined risk factors of graft loss as PTLD stage greater than I-II and CNI withdrawal, and for graft loss and mortality, these remained risk factors along with age over 60 years. Type and location of PTLD, year of diagnosis, and chemotherapy regime were not independent risk factors. Multivariate analysis determined CNI withdrawal as the most important risk factor for graft loss (HR = 3.07, CI 95%: 1.04-9.09; P = 0.04) and death (HR: 4.00, CI 95%: 1.77-9.04; P < 0.001). While long-term stable renal function after definitive CNI withdrawal for PTLD has been reported, this review determined that withdrawal is associated with reduced graft and patient survival. PMID:24964147

  14. Expansion of autoreactive unresponsive CD21-/low B cells in Sjögren's syndrome associated lymphoproliferation

    PubMed Central

    Saadoun, D; Terrier, B; Bannock, J; Vazquez, T; Massad, C; Kang, I; Joly, F; Rosenzwajg, M; Sene, D; Benech, P; Klatzmann, D; Meffre, E; Cacoub, P

    2014-01-01

    Background Primary Sjögren's syndrome (pSS) is the autoimmune disease associated with the higher risk of developing non-Hodgkin lymphoma. Objective To determine the nature of B cells driving lymphoproliferation in pSS. Methods B cell subsets and function were analyzed in peripheral blood from 66 adult patients with pSS [including 14 patients with B-cell lymphoproliferative disorder (LPD)] and 30 healthy donors, using flow cytometry, calcium mobilization, and gene array analysis. We tested by ELISA the reactivity of recombinant antibodies isolated from single B cells from pSS-LPD. Results We report here the expansion of an unusual CD21-/low B-cell population which correlates with lymphoproliferation in pSS patients. A majority of CD21–/low B cells from pSS patients expressed autoreactive antibodies, which recognized nuclear and cytoplasmic structures. These B cells belonged to the memory compartment because their immunoglobulin genes were mutated. They were unable to induce calcium flux, become activated, or proliferate in response to B-cell receptor and/or CD40 triggering, suggesting that these autoreactive B cells may be anergic. However, CD21–/low B cells from pSS remained responsive to TLR stimulation. Gene array analyses of CD21–/low B cells revealed molecules specifically expressed in these B cells and that are likely to induce their unresponsive stage. Conclusion pSS patients who display high frequencies of autoreactive and unresponsive CD21-/low B cells are susceptible for developing lymphoproliferation. These cells remain in peripheral blood controlled by functional anergy instead of being eliminated, and chronic antigenic stimulation through TLR stimulation may create a favorable environment for breaking tolerance and activating these cells. PMID:23279883

  15. Nodal and extranodal plasmacytomas expressing immunoglobulin A: an indolent lymphoproliferative disorder with a low risk of clinical progression

    PubMed Central

    Shao, Haipeng; Xi, Liqiang; Raffeld, Mark; Pittaluga, Stefania; Dunleavy, Kieron; Wilson, Wyndham; Spector, Nelson; Milito, Cristiane; Morais, Jose Carlos; Jaffe, Elaine S.

    2010-01-01

    Plasmacytomas expressing immunoglobulin A are rare and not well characterized. In this study, nine cases of IgA-positive plasmacytomas presenting in lymph node and three in extranodal sites were analyzed by morphology, immunohistochemistry, and PCR examination of immunoglobulin heavy and kappa light chain genes. Laboratory features were correlated with clinical findings. There were seven males and five females; age range was 10 to 66 years (median, 32 years). Six of the patients were younger than 30-years-old, five of whom had nodal disease. 67% (6/9) of the patients with nodal disease had evidence of immune system dysfunction, including human immunodeficiency virus (HIV) infection, T-cell deficiency, autoantibodies, arthritis, Sjögren’s syndrome, and decreased B-cells. An IgA M-spike was detected in 6/11 cases, and the M-protein was nearly always less than 30 g/L. All patients had an indolent clinical course without progression to plasma cell myeloma. Histologically, IgA plasmacytomas showed an interfollicular or diffuse pattern of plasma cell infiltration. The plasma cells were generally of mature Marschalko type with little or mild pleomorphism and exclusive expression of monotypic IgA. There was an equal expression of kappa and lambda light chains (ratio 6:6). Clonality was demonstrated in 9 of 12 cases: by PCR in 7 cases, by cytogenetic analysis in 1 case, and by immunofixation in 1 case. Clonality did not correlate with pattern of lymph node infiltration. Our results suggest that IgA plasmacytomas may represent a distinct form of extramedullary plasmacytoma characterized by younger age at presentation, frequent lymph node involvement and low risk of progression to plasma cell myeloma. PMID:20871216

  16. Epidemiology of posttransplant lymphoproliferative disorders in adult kidney and kidney pancreas recipients: report of the French registry and analysis of subgroups of lymphomas.

    PubMed

    Caillard, S; Lamy, F X; Quelen, C; Dantal, J; Lebranchu, Y; Lang, P; Velten, M; Moulin, B

    2012-03-01

    A registry of posttransplant lymphoproliferative disorders (PTLD) was set up for the entire population of adult kidney transplant recipients in France. Cases of PTLD were prospectively enrolled between January 1, 1998, and December 31, 2007. Ten-year cumulative incidence was analyzed in patients transplanted after January 1, 1989. PTLD risk factors were analyzed in patients transplanted after January 1, 1998 by Cox analysis. Cumulative incidence was 1% after 5 years, 2.1% after 10 years. Multivariate analysis showed that PTLD was significantly associated with: older age of the recipient 47-60 years and >60 years (vs. 33-46 years, adjusted hazard ratio (AHR) = 1.87, CI = 1.22-2.86 and AHR = 2.80, CI = 1.73-4.55, respectively, p < 0.0001), simultaneous kidney-pancreas transplantation (AHR = 2.52, CI = 1.27-5.01 p = 0.008), year of transplant 1998-1999 and 2000-2001 (vs. 2006-2007, AHR = 3.36, CI = 1.64-6.87 and AHR = 3.08, CI = 1.55-6.15, respectively, p = 0.003), EBV mismatch (HR = 5.31, CI = 3.36-8.39, p < 0.001), 5 or 6 HLA mismatches (vs. 0-4, AHR = 1.54, CI = 1.12-2.12, p = 0.008), and induction therapy (AHR = 1.42, CI = 1-2.02, p = 0.05). Analyses of subgroups of PTLD provided new information about PTLD risk factors for early, late, EBV positive and negative, polymorphic, monomorphic, graft and cerebral lymphomas. This nationwide study highlights the increased risk of PTLD as long as 10 years after transplantation and the role of cofactors in modifying PTLD risk, particularly in specific PTLD subgroups. PMID:22226336

  17. FCRL3 promotes TLR9-induced B-cell activation and suppresses plasma cell differentiation.

    PubMed

    Li, Fu Jun; Schreeder, Daniel M; Li, Ran; Wu, Jiongru; Davis, Randall S

    2013-11-01

    Fc receptor-like (FCRL) molecules are preferentially expressed by B lymphocytes and possess tyrosine-based immunoregulatory function. Although they generally inhibit B-cell receptor signaling, their influence on other activation pathways remains largely unexplored. In humans, FCRL3 encodes a type I transmembrane protein harboring both cytoplasmic ITAM and ITIM elements that can repress B-cell receptor activation. Despite this inhibitory property, mounting associations for FCRL3 with autoimmune and lympho-proliferative disorders imply a role for it in promoting B-cell pathogenesis. Here, we explore the influence of FCRL3 on B-cell responses to innate TLR9 stimulation. A detailed survey of blood B-cell populations found that FCRL3 expression increased as a function of differentiation and was higher among memory subsets with innate-like features. FCRL3 ligation augmented CpG oligodeoxynucleotide TLR9-mediated B-cell proliferation, activation, and survival, but surprisingly, abrogated plasma cell differentiation and antibody production. Although FCRL3 amplified the NF-?B and mitogen-activated protein kinase signaling cascades, it halted CpG triggered BLIMP1 induction in an ERK-dependent fashion. These findings indicate that FCRL3 differentially modulates innate signaling in B cells and provide new insight into the potential of this disease-associated receptor to counter-regulate adaptive and innate immunity. PMID:23857366

  18. The kinetics and apoptotic profile of circulating endothelial cells in autologous hematopoietic stem cell transplantation in patients with lymphoproliferative disorders.

    PubMed

    Szmigielska-Kaplon, Anna; Krawczynska, Anna; Czemerska, Magdalena; Pluta, Agnieszka; Cebula-Obrzut, Barbara; Grzybowska-Izydorczyk, Olga; Wolska, Anna; Szmigielska, Katarzyna; Smolewski, Piotr; Robak, Tadeusz; Wierzbowska, Agnieszka

    2013-09-01

    In neoplastic disorders, endothelial cells take part in tumor progression and also influence the recovery of hematopoiesis after high-dose chemotherapy. Measurements of circulating endothelial cells (CEC), their subsets and kinetics were taken in patients with lymphoid malignancies (37 multiple myeloma, ten lymphoma) during autologous hematopoietic stem cell transplantation (HSCT). CEC were evaluated by four-color flow cytometry at different time points. Additionally levels of angiopoietins 1 and 2 were evaluated by ELISA assay. The baseline number of CECs and their subsets in patients were higher than in the control group. The median CEC number dropped significantly after transplantation (from 9.5/?L to 6.2/?L, p < 0.001). Apoptosis of CECs 24 h after chemotherapy was enhanced in comparison to baseline values (median apoptotic CEC number 4.15/?L vs 3.1/?L; p < 0,001). The time for neutrophil engraftment was shorter for patients with a low apoptotic CEC count at baseline as compared to those with a high apoptotic CEC count (median time to engraftment 13 vs. 16 days respectively, p = 0.04). We observed an adverse correlation of progenitor CEC numbers measured 1 h after transplantation with the time to neutrophil engraftment (r = -0.49, p = 0.008). We also found a negative correlation between the number of CECs originating from microvessels measured 1 h after transplantation, and the time to neutrophil engraftment (r = -0.39, p = 0.04). Baseline angiopoietins 1 and 2 concentration did not influence the post-transplant regeneration time. CEC numbers significantly change during autologous HSCT. Our results suggest that progenitor CECs and CECs derived from microvessels both take part in successful engraftment. PMID:23636312

  19. Increased incidence of monoclonal B-cell infiltrate in chronic myeloproliferative disorders

    Microsoft Academic Search

    László Pajor; Ágnes Lacza; László Kereskai; Pál Jáksó; Miklós Egyed; János L Iványi; Gáspár Radványi; Péter Dombi; Katalin Pál; Hajna Losonczy

    2004-01-01

    A total of 106 trephine biopsy specimens with clinical, laboratory and pathology findings corresponding to chronic myeloproliferative disorders (CMPD) were analyzed to reveal the nature of the lymphoid infiltrate in the bone marrow. Histological investigation in 31 chronic myeloid leukemia (CML), 29 CMPDs not otherwise specified (CMPD-NOS), 28 essential thrombocytosis (ET), 15 polycythemia vera (PV) and three chronic eosinophilic leukemia\\/hypereosinophilic

  20. A comparison of flow cytometry, bone marrow biopsy, and bone marrow aspirates in the detection of lymphoid infiltration in B cell disorders

    Microsoft Academic Search

    S P Sah; E Matutes; A C Wotherspoon; R Morilla; D Catovsky

    2003-01-01

    Aims: To evaluate the diagnostic value of bone marrow aspirates, trephine biopsies (BMB), and flow cytometry (FC) in the assessment of bone marrow infiltration in chronic lymphoid disorders.Methods: Investigations were carried out in 110 diagnostic and follow up specimens from B cell disorders, namely: chronic lymphocytic leukaemia (CLL; 65), non-Hodgkin’s lymphoma (NHL; 39), and hairy cell leukaemia (HCL; 6). A

  1. Autoimmune Lymphoproliferative Syndrome Misdiagnosed as Hemophagocytic Lymphohistiocytosis

    PubMed Central

    Rudman Spergel, Amanda; Walkovich, Kelly; Price, Susan; Niemela, Julie E.; Wright, Dowain; Fleisher, Thomas A.

    2013-01-01

    Autoimmune lymphoproliferative syndrome (ALPS) is a rare inherited disorder of apoptosis, most commonly due to mutations in the FAS (TNFRSF6) gene. It presents with chronic lymphadenopathy, splenomegaly, and symptomatic multilineage cytopenias in an otherwise healthy child. Unfortunately, these clinical findings are also noted in other childhood lymphoproliferative conditions, such as leukemia, lymphoma, and hemophagocytic lymphohistiocytosis, which can confound the diagnosis. This report describes a 6-year-old girl with symptoms misdiagnosed as hemophagocytic lymphohistiocytosis and treated with chemotherapy before the recognition that her symptoms and laboratory values were consistent with a somatic FAS mutation leading to ALPS. This case should alert pediatricians to include ALPS in the differential diagnosis of a child with lymphadenopathy, splenomegaly, and cytopenias; obtain discriminating screening laboratory biomarkers, such as serum vitamin B-12 and ferritin levels; and, in the setting of a highly suspicious clinical scenario for ALPS, pursue testing for somatic FAS mutations when germ-line mutation testing is negative. PMID:24101757

  2. Lymphoproliferative Disease of the Orbit.

    PubMed

    Li, Emmy Y; Yuen, Hunter K; Cheuk, Wah

    2015-01-01

    Lymphoproliferative diseases of the orbit account for majority of orbital tumors. The pathologies range from reactive lymphoid hyperplasia to specific IgG4-related inflammation to malignant lymphomas. This review summarizes current concepts regarding pathology, clinical presentation, diagnosis, staging, and treatment strategies of major orbital lymphoproliferative diseases based on updated and relevant bibliography. PMID:26065355

  3. Intravascular large B-cell lymphoma complicated by invasive pulmonary aspergillosis: a rare presentation.

    PubMed

    Mahasneh, Tamadur; Harrington, Zinta; Williamson, Jonathan; Alkhawaja, Darweesh; Duflou, Jo; Shin, Joo-Shik

    2014-06-01

    We describe a patient with persisting fevers, a progressive pulmonary infiltrate, and high levels of serum lactate dehydrogenase. No underlying cause for these changes was found prior to her death despite extensive investigations. Postmortem tissue revealed invasive pulmonary aspergillosis and subsequent brain examination revealed vascular changes in keeping with intravascular large B-cell lymphoma (IVLBCL). On review, subtle yet extensive lymphomatous infiltrates involved the vasculature of multiple other organs, including the lungs. Aspergillosis is a relatively rare presenting feature of lymphoproliferative disorders, and IVLBCL is a rare subtype of diffuse large B-cell non-Hodgkin's lymphoma with, to our knowledge, very few case reports to date. Lymphoma should be considered in patients presenting with pneumonitis with bilateral lung infiltrates on imaging, with a high serum level of lactate dehydrogenase. PMID:25473570

  4. Intravascular large B-cell lymphoma complicated by invasive pulmonary aspergillosis: a rare presentation

    PubMed Central

    Mahasneh, Tamadur; Harrington, Zinta; Williamson, Jonathan; Alkhawaja, Darweesh; Duflou, Jo; Shin, Joo-Shik

    2014-01-01

    We describe a patient with persisting fevers, a progressive pulmonary infiltrate, and high levels of serum lactate dehydrogenase. No underlying cause for these changes was found prior to her death despite extensive investigations. Postmortem tissue revealed invasive pulmonary aspergillosis and subsequent brain examination revealed vascular changes in keeping with intravascular large B-cell lymphoma (IVLBCL). On review, subtle yet extensive lymphomatous infiltrates involved the vasculature of multiple other organs, including the lungs. Aspergillosis is a relatively rare presenting feature of lymphoproliferative disorders, and IVLBCL is a rare subtype of diffuse large B-cell non-Hodgkin's lymphoma with, to our knowledge, very few case reports to date. Lymphoma should be considered in patients presenting with pneumonitis with bilateral lung infiltrates on imaging, with a high serum level of lactate dehydrogenase. PMID:25473570

  5. Polyangiitis with Granulomatosis as a Paraneoplastic Syndrome of B-Cell Lymphoma of the Lacrimal Gland

    PubMed Central

    Wills Sanín, Beatriz; Bolivar, Yenny R. Cárdenas; Carvajal, Jose J.; Quintero, Guillermo E.; Andrade, Rafael

    2014-01-01

    Introduction. The clinical course of an autoimmune paraneoplastic syndrome parallels the natural history of the primary malignancy. In most cases, such paraneoplastic are syndromes hardly distinguishable from idiopathic autoimmune diseases. A case of polyangiitis with granulomatosis as a paraneoplastic syndrome in a patient with B-cell Lymphoma of the lacrimal gland has not yet been reported. Case Presentation. We present the case of a male patient with a B-cell Lymphoma of the lacrimal gland, who debuted with symptoms similar to rheumatoid arthritis and acute renal failure, secondary to polyangiitis with granulomatosis. The current pathophysiological hypotheses explaining the relationship between a lymphoproliferative disease and an autoimmune paraneoplastic disorder are discussed. Conclusion. Tumor-associated segmental necrotizing glomerulopathy is a very rare manifestation of glomerular diseases. Some atypical clinical features should increase the suspicion of an underlying tumor, in which case it is essential to treat the primary neoplasia, in order to control the autoimmune manifestations. PMID:25580314

  6. Efficient Infection of a Human B Cell Line with Cell-Free Kaposi's Sarcoma-Associated Herpesvirus

    PubMed Central

    Dollery, Stephen J.; Santiago-Crespo, Rey J.; Kardava, Lela; Moir, Susan

    2014-01-01

    ABSTRACT Kaposi's sarcoma-associated herpesvirus (KSHV) is causatively linked to two B cell lymphoproliferative disorders, multicentric Castleman's disease and primary effusion lymphoma. Latently infected B cells are a major KSHV reservoir, and virus activation from tonsillar B cells can result in salivary shedding and virus transmission. Paradoxically, human B cells (primary and continuous) are notoriously refractory to infection, thus posing a major obstacle to the study of KSHV in this cell type. By performing a strategic search of human B cell lymphoma lines, we found that MC116 cells were efficiently infected by cell-free KSHV. Upon exposure to recombinant KSHV.219, enhanced green fluorescent protein reporter expression was detected in 17 to 20% of MC116 cells. Latent-phase transcription and protein synthesis were detected by reverse transcription-PCR and detection of latency-associated nuclear antigen expression, respectively, in cell lysates and individual cells. Selection based on the puromycin resistance gene in KSHV.219 yielded cultures with all cells infected. After repeated passaging of the selected KSHV-infected cells without puromycin, latent KSHV was maintained in a small fraction of cells. Infected MC116 cells could be induced into lytic phase with histone deacetylase inhibitors, as is known for latently infected non-B cell lines, and also selectively by the B cell-specific pathway involving B cell receptor cross-linking. Lytic-phase transition was documented by red fluorescent protein reporter expression, late structural glycoprotein (K8.1A, gH) detection, and infectious KSHV production. MC116 cells were CD27?/CD10+, characteristic of transitional B cells. These findings represent an important step in the establishment of an efficient continuous B cell line model to study the biologically relevant steps of KSHV infection. IMPORTANCE PMID:24257608

  7. The B cell transcription program mediates hypomethylation and overexpression of key genes in Epstein-Barr virus-associated proliferative conversion

    PubMed Central

    2013-01-01

    Background Epstein-Barr virus (EBV) infection is a well characterized etiopathogenic factor for a variety of immune-related conditions, including lymphomas, lymphoproliferative disorders and autoimmune diseases. EBV-mediated transformation of resting B cells to proliferating lymphoblastoid cells occurs in early stages of infection and is an excellent model for investigating the mechanisms associated with acquisition of unlimited growth. Results We investigated the effects of experimental EBV infection of B cells on DNA methylation profiles by using high-throughput analysis. Remarkably, we observed hypomethylation of around 250 genes, but no hypermethylation. Hypomethylation did not occur at repetitive sequences, consistent with the absence of genomic instability in lymphoproliferative cells. Changes in methylation only occurred after cell divisions started, without the participation of the active demethylation machinery, and were concomitant with acquisition by B cells of the ability to proliferate. Gene Ontology analysis, expression profiling, and high-throughput analysis of the presence of transcription factor binding motifs and occupancy revealed that most genes undergoing hypomethylation are active and display the presence of NF-?B p65 and other B cell-specific transcription factors. Promoter hypomethylation was associated with upregulation of genes relevant for the phenotype of proliferating lymphoblasts. Interestingly, pharmacologically induced demethylation increased the efficiency of transformation of resting B cells to lymphoblastoid cells, consistent with productive cooperation between hypomethylation and lymphocyte proliferation. Conclusions Our data provide novel clues on the role of the B cell transcription program leading to DNA methylation changes, which we find to be key to the EBV-associated conversion of resting B cells to proliferating lymphoblasts. PMID:23320978

  8. PI3K? inhibition augments the efficacy of rapamycin in suppressing proliferation of Epstein-Barr virus (EBV)+ B cell lymphomas.

    PubMed

    Furukawa, S; Wei, L; Krams, S M; Esquivel, C O; Martinez, O M

    2013-08-01

    Posttransplant lymphoproliferative disorder (PTLD) continues to be a devastating and potentially life-threatening complication in organ transplant recipients. PTLD is associated with EBV infection and can result in malignant B cell lymphomas. Here we demonstrate that the PI3K/Akt/mTOR pathway is highly activated in EBV+ B cell lymphoma lines derived from patients with PTLD. Treatment with the mTORC1 inhibitor Rapamycin (RAPA) partially inhibited the proliferation of EBV+ B cell lines. Resistance to RAPA treatment correlated with high levels of Akt phosphorylation. An mTORC1/2 inhibitor and a PI3K/mTOR dual inhibitor suppressed Akt phosphorylation and showed a greater anti-proliferative effect on EBV+ B lymphoma lines compared to RAPA. EBV+ B cell lymphoma lines expressed high levels of PI3K?. We demonstrate that PI3K? is responsible for Akt activation in EBV+ B cell lymphomas, and that selective inhibition of PI3K? by either siRNA, or a small molecule inhibitor, augmented the anti-proliferative effect of RAPA on EBV+ B cell lymphomas. These results suggest that PI3K? is a novel, potential therapeutic target for the treatment of EBV-associated PTLD and that combined blockade of PI3K? and mTOR provides increased efficacy in inhibiting proliferation of EBV+ B cell lymphomas. PMID:23841834

  9. Cutaneous lymphomas: an update. Part 2: B-cell lymphomas and related conditions.

    PubMed

    Kempf, Werner; Kazakov, Dmitry V; Mitteldorf, Christina

    2014-03-01

    : Primary cutaneous B-cell lymphomas (PCBCL) are the second most common form of primary cutaneous lymphomas and account for approximately 25%-30% of all primary cutaneous lymphomas. Both forms of low-grade malignant PCBCL, primary cutaneous follicle center lymphoma (PCFCL) and primary cutaneous marginal zone lymphoma of mucosa-associated lymphoid tissue-type (MALT lymphoma) (PCMZL) represent the vast majority of PCBCL and show an indolent slowly progressive course and an excellent prognosis despite a high recurrence rate. Genetic analysis indicates that PCMZL differ from other forms of extranodal MALT lymphomas. The more common class-switched and the non-class-switched form of PCMZL can be distinguished as two distinctive subsets that differ in the cellular composition, IgM expression, and biological behavior with extracutaneous involvement found in the non-class-switched form. Recently, unusual clinical and histological forms of PCMZL and PCFCL manifesting with miliary or agminated lesions have been described that are diagnostically challenging. In contrast to PCMZL and PCFCL, primary cutaneous diffuse large B-cell lymphoma, leg type, and other rare forms of large B-cell lymphomas such as intravascular large B-cell lymphoma have an unfavorable prognosis. There is an emerging group of Epstein-Barr virus (EBV)-driven B-cell lymphoproliferations including posttransplant lymphoproliferative disorders and mucocutaneous ulcer occurring in immunocompromised patients and EBV-associated diffuse large B-cell lymphoma of the elderly arising in the setting of senescence-linked immunodeficiency. This review reports on recent findings expanding the spectrum of clinicopathological features, differential diagnostic aspects, and the pathogenesis of PCBCL and discusses the group of EBV-associated B-cell lymphoproliferations involving the skin. PMID:24658377

  10. Revised diagnostic criteria and classification for the autoimmune lymphoproliferative syndrome (ALPS): report from the 2009 NIH International Workshop

    PubMed Central

    Bleesing, Jack J.; Dianzani, Umberto; Fleisher, Thomas A.; Jaffe, Elaine S.; Lenardo, Michael J.; Rieux-Laucat, Frederic; Siegel, Richard M.; Su, Helen C.; Teachey, David T.

    2010-01-01

    Lymphadenopathy in children for which no infectious or malignant cause can be ascertained constitutes a challenging diagnostic dilemma. Autoimmune lymphoproliferative syndrome (ALPS) is a human genetic disorder of lymphocyte apoptosis resulting in an accumulation of lymphocytes and childhood onset chronic lymphadenopathy, splenomegaly, multilineage cytopenias, and an increased risk of B-cell lymphoma. In 1999, investigators at the National Institutes of Health (NIH) suggested criteria to establish the diagnosis of ALPS. Since then, with approximately 500 patients with ALPS studied worldwide, significant advances in our understanding of the disease have prompted the need for revisions to the existing diagnostic criteria and classification scheme. The rationale and recommendations outlined here stem from an international workshop held at NIH on September 21 and 22, 2009, attended by investigators from the United States, Europe, and Australia engaged in clinical and basic science research on ALPS and related disorders. It is hoped that harmonizing the diagnosis and classification of ALPS will foster collaborative research and better understanding of the pathogenesis of autoimmune cytopenias and B-cell lymphomas. PMID:20538792

  11. Paediatric nodal marginal zone B-cell lymphadenopathy of the neck: a Haemophilus influenzae-driven immune disorder?

    PubMed

    Kluin, Philip M; Langerak, Anton W; Beverdam-Vincent, Jannetta; Geurts-Giele, Willemina Rr; Visser, Lydia; Rutgers, Bea; Schuuring, Ed; Van Baarlen, Joop; Lam, King H; Seldenrijk, Kees; Kibbelaar, Robby E; de Wit, Peter; Diepstra, Arjan; Rosati, Stefano; van Noesel, Max M; Zwaan, C Michel; Hunting, Jarmo Cb; Hoogendoorn, Mels; van der Gaag, Ellen J; van Esser, Joost W J; de Bont, Eveline; Kluin-Nelemans, Hanneke C; Winter, Rik H; Lo Ten Foe, Jerome R; van der Zanden, Adri Gm

    2015-07-01

    Many hyperplasias and lymphomas of marginal zone B-cells are associated with infection. We identified six children and one adolescent with cervical lymphadenopathy showing prominent polyclonal nodal marginal zone hyperplasia (pNMZH) and four adolescents with monoclonal paediatric nodal marginal zone lymphoma (pNMZL). The clonality status was assessed using BIOMED-2-IG PCR analysis. Haemophilus influenzae was identified in all six cases of pNMZH that could be tested by direct culture (N = 3) or a very sensitive PCR for the H. influenzae gyrase gene in frozen materials (N = 5). H. influenzae was not detected in three pNMZLs and 28 non-specific reactive cervical lymph nodes of age-matched controls, except for a single control node that was obtained during oropharyngeal surgery for a cleft palate showing very low copy numbers of H. influenzae. pNMZH patients were younger than pNMZL patients (median age 12 versus 21 years). pNMZH showed a prominent nodular appearance with variable fibrosis without acute inflammation. Within the nodules, the expanded germinal centres and variably sized marginal zones were colonized by activated B-cells with weak expression of IgD and lack of CD10 and/or BCL6 expression. Some areas showed skewed light chain expression in plasma cells (4/5 cases lambda). In four cases tested, this was confirmed by flow cytometry for surface Ig (3/4 cases lambda). In contrast, pNMZL showed more extensive expansion of marginal zones by centrocytoid cells and often expression of BCL2 protein. Several H. influenzae strains are known to interact with the constant part of IgD on human B-cells, leading to their polyclonal proliferation and activation. We speculate that in vivo stimulation of IgD+ marginal zone B-cells by this bacterium may be implicated in this particular lymphadenopathy that should be distinguished from monoclonal pNMZL. Copyright © 2015 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. PMID:25722108

  12. How I treat autoimmune lymphoproliferative syndrome

    PubMed Central

    Oliveira, Joăo Bosco

    2011-01-01

    Autoimmune lymphoproliferative syndrome (ALPS) represents a failure of apoptotic mechanisms to maintain lymphocyte homeostasis, permitting accumulation of lymphoid mass and persistence of autoreactive cells that often manifest in childhood with chronic nonmalignant lymphadenopathy, hepatosplenomegaly, and recurring multilineage cytopenias. Cytopenias in these patients can be the result of splenic sequestration as well as autoimmune complications manifesting as autoimmune hemolytic anemia, immune-mediated thrombocytopenia, and autoimmune neutropenia. More than 300 families with hereditary ALPS have now been described; nearly 500 patients from these families have been studied and followed worldwide over the last 20 years by our colleagues and ourselves. Some of these patients with FAS mutations affecting the intracellular portion of the FAS protein also have an increased risk of B-cell lymphoma. The best approaches to diagnosis, follow-up, and management of ALPS, its associated cytopenias, and other complications resulting from infiltrative lymphoproliferation and autoimmunity are presented. This trial was registered at www.clinicaltrial.gov as #NCT00001350. PMID:21885601

  13. Antileukemic Activity of Sulforaphane in Primary Blasts from Patients Affected by Myelo- and Lympho-Proliferative Disorders and in Hypoxic Conditions

    PubMed Central

    Fimognari, Carmela; Turrini, Eleonora; Sestili, Piero; Calcabrini, Cinzia; Carulli, Giovanni; Fontanelli, Giulia; Rousseau, Martina; Cantelli-Forti, Giorgio; Hrelia, Patrizia

    2014-01-01

    Sulforaphane is a dietary isothiocyanate found in cruciferous vegetables showing antileukemic activity. With the purpose of extending the potential clinical impact of sulforaphane in the oncological field, we investigated the antileukemic effect of sulforaphane on blasts from patients affected by different types of leukemia and, taking into account the intrinsically hypoxic nature of bone marrow, on a leukemia cell line (REH) maintained in hypoxic conditions. In particular, we tested sulforaphane on patients with chronic lymphocytic leukemia, acute myeloid leukemia, T-cell acute lymphoblastic leukemia, B-cell acute lymphoblastic leukemia, and blastic NK cell leukemia. Sulforaphane caused a dose-dependent induction of apoptosis in blasts from patients diagnosed with acute lymphoblastic or myeloid leukemia. Moreover, it was able to cause apoptosis and to inhibit proliferation in hypoxic conditions on REH cells. As to its cytotoxic mechanism, we found that sulforaphane creates an oxidative cellular environment that induces DNA damage and Bax and p53 gene activation, which in turn helps trigger apoptosis. On the whole, our results raise hopes that sulforaphane might set the stage for a novel therapeutic principle complementing our growing armature against malignancies and advocate the exploration of sulforaphane in a broader population of leukemic patients. PMID:25019218

  14. Monoclonal B-cell lymphocytosis and early-stage chronic lymphocytic leukemia: diagnosis, natural history, and risk stratification.

    PubMed

    Strati, Paolo; Shanafelt, Tait D

    2015-07-23

    Monoclonal B lymphocytosis (MBL) is defined as the presence of a clonal B-cell population in the peripheral blood with fewer than 5 × 10(9)/L B-cells and no other signs of a lymphoproliferative disorder. The majority of cases of MBL have the immunophenotype of chronic lymphocytic leukemia (CLL). MBL can be categorized as either low count or high count based on whether the B-cell count is above or below 0.5 × 10(9)/L. Low-count MBL can be detected in ?5% of adults over the age of 40 years when assessed using standard-sensitivity flow cytometry assays. A number of biological and genetic characteristics distinguish low-count from high-count MBL. Whereas low-count MBL rarely progresses to CLL, high-count MBL progresses to CLL requiring therapy at a rate of 1% to 2% per year. High-count MBL is distinguished from Rai 0 CLL based on whether the B-cell count is above or below 5 × 10(9)/L. Although individuals with both high-count MBL and CLL Rai stage 0 are at increased risk of infections and second cancers, the risk of progression requiring treatment and the potential to shorten life expectancy are greater for CLL. This review highlights challenging questions regarding the classification, risk stratification, management, and supportive care of patients with MBL and CLL. PMID:26065657

  15. B-Cell Cutaneous Lymphoid Hyperplasia Representing Progressive Transformation of Germinal Center: A Report of 2 Cases

    Microsoft Academic Search

    Masaru Kojima; Shinji Sakurai; Ken Shimizu; Hideaki Itoh

    2010-01-01

    Cutaneous lymphoid hyperplasia (CLH) is a reactive polyclonal benign lymphoproliferative process predominantly composed of B cells or T cells, either localized or disseminated. The authors report histomorphologic, immunophenotypic, and genotypic findings of 2 cases of B-cell CLH demonstrating progressive transformation of germinal center (PTGC). Histologically, most of the lymphoid follicles were PTGCs with a few hyperplastic germinal centers. PTGC was

  16. Pre-B cell colony enhancing factor/NAMPT/visfatin in inflammation and obesity-related disorders.

    PubMed

    Moschen, Alexander R; Gerner, Romana R; Tilg, Herbert

    2010-06-01

    Whereas prototypic adipocytokines such as adiponectin or leptin are mainly derived from adipocytes, others such as pre-B cell colony enhancing factor (PBEF)/nicotinamide phosphoribosyl transferase (NAMPT)/visfatin or resistin are produced by various cell types throughout the body. Although first discovery of this molecule as PBEF suggested primarily a cytokine function, its rediscovery as the key enzyme in nicotinamide adenine dinucleotide (NAD) generation has considerably widened its biological perspective. Finally, the same molecule was introduced as visfatin claiming an insulin-mimetic effect which has been questioned. Both extracellular (cytokinelike) and intracellular (enzymatic) functions are responsible for its relevance in immune, metabolic and stress responses. Its cytokine functions are mainly pro-inflammatory as it induces potently various other pro-inflammatory cytokines such as tumor necrosis factor alpha (TNFa) or interleukin-6 (IL-6). Its intracellular functions concentrate on the regulation of the activity of NAD-consuming enzymes such as various sirtuins thereby also affecting (TNFa) biosynthesis, cell life-span and longevity. Biochemical neutralization of PBEF/NAMPT/visfatin has been proven effective in various models of inflammation including sepsis/arthritis and in various models of cancer. Patients with non-alcoholic fatty liver disease (NAFLD) exhibit increased serum concentrations of PBEF/Nampt/visfatin and weight loss is associated both with a decrease in serum levels and reduced liver expression. Many of the biological functions of this "cytokine-enzyme" have been characterized in the last years, however, its definite role in various metabolic, inflammatory and malignant diseases has yet to be defined. PMID:20370672

  17. XIAP deficiency in humans causes an X-linked lymphoproliferative syndrome

    Microsoft Academic Search

    Stéphanie Rigaud; Marie-Claude Fondančche; Nathalie Lambert; Benoit Pasquier; Véronique Mateo; Pauline Soulas; Lionel Galicier; Françoise Le Deist; Frédéric Rieux-Laucat; Patrick Revy; Alain Fischer; Genevičve de Saint Basile; Sylvain Latour

    2006-01-01

    The homeostasis of the immune response requires tight regulation of the proliferation and apoptosis of activated lymphocytes. In humans, defects in immune homeostasis result in lymphoproliferation disorders including autoimmunity, haemophagocytic lymphohystiocytosis and lymphomas. The X-linked lymphoproliferative syndrome (XLP) is a rare, inherited immunodeficiency that is characterized by lymphohystiocytosis, hypogammaglobulinaemia and lymphomas, and that usually develops in response to infection with

  18. New potential therapeutic approach for the treatment of B-Cell malignancies using chlorambucil/hydroxychloroquine-loaded anti-CD20 nanoparticles.

    PubMed

    Mezzaroba, Nelly; Zorzet, Sonia; Secco, Erika; Biffi, Stefania; Tripodo, Claudio; Calvaruso, Marco; Mendoza-Maldonado, Ramiro; Capolla, Sara; Granzotto, Marilena; Spretz, Ruben; Larsen, Gustavo; Noriega, Sandra; Lucafň, Marianna; Mansilla, Eduardo; Garrovo, Chiara; Marín, Gustavo H; Baj, Gabriele; Gattei, Valter; Pozzato, Gabriele; Núńez, Luis; Macor, Paolo

    2013-01-01

    Current B-cell disorder treatments take advantage of dose-intensive chemotherapy regimens and immunotherapy via use of monoclonal antibodies. Unfortunately, they may lead to insufficient tumor distribution of therapeutic agents, and often cause adverse effects on patients. In this contribution, we propose a novel therapeutic approach in which relatively high doses of Hydroxychloroquine and Chlorambucil were loaded into biodegradable nanoparticles coated with an anti-CD20 antibody. We demonstrate their ability to effectively target and internalize in tumor B-cells. Moreover, these nanoparticles were able to kill not only p53 mutated/deleted lymphoma cell lines expressing a low amount of CD20, but also circulating primary cells purified from chronic lymphocitic leukemia patients. Their safety was demonstrated in healthy mice, and their therapeutic effects in a new model of Burkitt's lymphoma. The latter serves as a prototype of an aggressive lympho-proliferative disease. In vitro and in vivo data showed the ability of anti-CD20 nanoparticles loaded with Hydroxychloroquine and Chlorambucil to increase tumor cell killing in comparison to free cytotoxic agents or Rituximab. These results shed light on the potential of anti-CD20 nanoparticles carrying Hydroxychloroquine and Chlorambucil for controlling a disseminated model of aggressive lymphoma, and lend credence to the idea of adopting this therapeutic approach for the treatment of B-cell disorders. PMID:24098639

  19. Epstein–Barr virus-associated lymphoproliferative disease in non-immunocompromised hosts: a status report and summary of an international meeting, 8–9 September 2008

    PubMed Central

    Cohen, J. I.; Kimura, H.; Nakamura, S.; Ko, Y.-H.; Jaffe, E. S.

    2009-01-01

    Background: Recently novel Epstein–Barr virus (EBV) lymphoproliferative diseases (LPDs) have been identified in non-immunocompromised hosts, both in Asia and Western countries. These include aggressive T-cell and NK-cell LPDs often subsumed under the heading of chronic active Epstein–Barr virus (CAEBV) infection and EBV-driven B-cell LPDs mainly affecting the elderly. Design: To better define the pathogenesis, classification, and treatment of these disorders, participants from Asia, The Americas, Europe, and Australia presented clinical and experimental data at an international meeting. Results: The term systemic EBV-positive T-cell LPD, as adopted by the WHO classification, is preferred as a pathological classification over CAEBV (the favored clinical term) for those cases that are clonal. The disease has an aggressive clinical course, but may arise in the background of CAEBV. Hydroa vacciniforme (HV) and HV-like lymphoma represent a spectrum of clonal EBV-positive T-cell LPDs, which have a more protracted clinical course; spontaneous regression may occur in adult life. Severe mosquito bite allergy is a related syndrome usually of NK cell origin. Immune senescence in the elderly is associated with both reactive and neoplastic EBV-driven LPDs, including EBV-positive diffuse large B-cell lymphomas. Conclusion: The participants proposed an international consortium to facilitate further clinical and biological studies of novel EBV-driven LPDs. PMID:19515747

  20. Persistent Polyclonal B Cell Lymphocytosis B Cells Can Be Activated through CD40-CD154 Interaction

    PubMed Central

    Néron, Sonia; Darveau, André; Delage, Robert

    2014-01-01

    Persistent polyclonal B cell lymphocytosis (PPBL) is a rare disorder, diagnosed primarily in adult female smokers and characterized by an expansion of CD19+CD27+IgM+ memory B cells, by the presence of binucleated lymphocytes, and by a moderate elevation of serum IgM. The clinical course is usually benign, but it is not known whether or not PPBL might be part of a process leading to the emergence of a malignant proliferative disorder. In this study we sought to investigate the functional response of B cells from patients with PPBL by use of an optimal memory B cell culture model based on the CD40-CD154 interaction. We found that the proliferation of PPBL B cells was almost as important as that of B cells from normal controls, resulting in high immunoglobulin secretion with in vitro isotypic switching. We conclude that the CD40-CD154 activation pathway is functional in the memory B cell population of PPBL patients, suggesting that the disorder may be due to either a dysfunction of other cells in the microenvironment or a possible defect in another B cell activation pathway. PMID:25580126

  1. Kaposi's sarcoma-associated herpesvirus oncoprotein K13 protects against B cell receptor-induced growth arrest and apoptosis through NF-?B activation.

    PubMed

    Graham, Ciaren; Matta, Hittu; Yang, Yanqiang; Yi, Han; Suo, Yulan; Tolani, Bhairavi; Chaudhary, Preet M

    2013-02-01

    Kaposi's sarcoma-associated herpesvirus (KSHV) has been linked to the development of Kaposi's sarcoma, primary effusion lymphoma, and multicentric Castleman's disease (MCD). We have characterized the role of KSHV-encoded viral FLICE inhibitory protein (vFLIP) K13 in the modulation of anti-IgM-induced growth arrest and apoptosis in B cells. We demonstrate that K13 protects WEHI 231, an immature B-cell line, against anti-IgM-induced growth arrest and apoptosis. The protective effect of K13 was associated with the activation of the NF-?B pathway and was deficient in a mutant K13 with three alanine substitutions at positions 58 to 60 (K13-58AAA) and a structural homolog, vFLIP E8, both of which lack NF-?B activity. K13 upregulated the expression of NF-?B subunit RelB and blocked the anti-IgM-induced decline in c-Myc and rise in p27(Kip1) that have been associated with growth arrest and apoptosis. K13 also upregulated the expression of Mcl-1, an antiapoptotic member of the Bcl2 family. Finally, K13 protected the mature B-cell line Ramos against anti-IgM-induced apoptosis through NF-?B activation. Inhibition of anti-IgM-induced apoptosis by K13 may contribute to the development of KSHV-associated lymphoproliferative disorders. PMID:23236068

  2. B cell therapies for rheumatoid arthritis: beyond B cell depletion.

    PubMed

    Calero, Ismael; Nieto, Jose Antonio; Sanz, Ińaki

    2010-05-01

    Initially suggested by the presence of rheumatoid factor autoantibodies, multiple pathogenic roles for B cells (both antibody-mediated and antibody-independent) in rheumatoid arthritis (RA) now are supported by a growing body of experimental observations and human studies. The pathogenic significance of B cells in this disease also has been established conclusively by the proven benefit of Rituximab-induced B cell depletion in RA patients refractory to tumor necrosis factor (TNF) blockade. This article reviews the rationale for the use of B cell-targeting therapies in RA and discusses the caveats and limitations of indiscriminate B cell depletion as currently applied, ncluding incomplete depletion of pathogenic B cells and elimination of protective B cells. Finally, it presents alternative therapeutic strategies that exploit current knowledge of B cell activation, survival, and differentiation to provide more selective B cell and plasma cell targeting. PMID:20510237

  3. Rapidly fatal myeloproliferative disorders in mice with deletion of Casitas B-cell lymphoma (Cbl) and Cbl-b in hematopoietic stem cells.

    PubMed

    Naramura, Mayumi; Nandwani, Neha; Gu, Hua; Band, Vimla; Band, Hamid

    2010-09-14

    Casitas B-cell lymphoma (Cbl)-family E3 ubiquitin ligases are negative regulators of tyrosine kinase signaling. Recent work has revealed a critical role of Cbl in the maintenance of hematopoietic stem cell (HSC) homeostasis, and mutations in CBL have been identified in myeloid malignancies. Here we show that, in contrast to Cbl or Cbl-b single-deficient mice, concurrent loss of Cbl and Cbl-b in the HSC compartment leads to an early-onset lethal myeloproliferative disease in mice. Cbl, Cbl-b double-deficient bone marrow cells are hypersensitive to cytokines, and show altered biochemical response to thrombopoietin. Thus, Cbl and Cbl-b play redundant but essential roles in HSC regulation, whose breakdown leads to hematological abnormalities that phenocopy crucial aspects of mutant Cbl-driven human myeloid malignancies. PMID:20805496

  4. Rapidly fatal myeloproliferative disorders in mice with deletion of Casitas B-cell lymphoma (Cbl) and Cbl-b in hematopoietic stem cells

    PubMed Central

    Naramura, Mayumi; Nandwani, Neha; Gu, Hua; Band, Vimla; Band, Hamid

    2010-01-01

    Casitas B-cell lymphoma (Cbl)-family E3 ubiquitin ligases are negative regulators of tyrosine kinase signaling. Recent work has revealed a critical role of Cbl in the maintenance of hematopoietic stem cell (HSC) homeostasis, and mutations in CBL have been identified in myeloid malignancies. Here we show that, in contrast to Cbl or Cbl-b single-deficient mice, concurrent loss of Cbl and Cbl-b in the HSC compartment leads to an early-onset lethal myeloproliferative disease in mice. Cbl, Cbl-b double-deficient bone marrow cells are hypersensitive to cytokines, and show altered biochemical response to thrombopoietin. Thus, Cbl and Cbl-b play redundant but essential roles in HSC regulation, whose breakdown leads to hematological abnormalities that phenocopy crucial aspects of mutant Cbl-driven human myeloid malignancies. PMID:20805496

  5. Prevalence of targetable oncogenic mutations and genomic alterations in Epstein-Barr virus-associated diffuse large B-cell lymphoma of the elderly.

    PubMed

    Gebauer, Niklas; Gebauer, Judith; Hardel, Tim Tristan; Bernard, Veronica; Biersack, Harald; Lehnert, Hendrik; Rades, Dirk; Feller, Alfred Christian; Thorns, Christoph

    2015-04-01

    Epstein-Barr virus (EBV)-associated diffuse large B-cell lymphoma (DLBCL) of the elderly constitutes a provisional clinicopathological entity in the current World Health Organization (WHO) classification and its genomic features remain sparsely characterized. We investigated a cohort of 26 cases of untreated de novo EBV-positive DLBCL of the elderly by high-resolution array-based comparative genomic profiling and fluorescence in situ hybridization (FISH). Moreover, we screened for activating mutations affecting nuclear factor (NF)-?B pathway signaling and chromatin remodeling (EZH2, CD79B, CARD11 and MYD88) due to their impact of gene expression signatures and postulated upcoming therapeutic targetability. We identified an overlap between genomic aberrations previously described to be exclusive features of plasmablastic lymphoma (PL), post-transplant lymphoproliferative disorder (PTLD) and DLBCL, respectively, indicating a close cytogenetic relationship between these entities. Few mutations affecting CD79B and CARD11 and no MYD88 mutations were detectable, hinting at EBV-mediated activation of NF-?B as an alternative to pathologically enforced B-cell receptor signaling in this rare entity. PMID:25030036

  6. B Cells in Autoimmune Diseases

    PubMed Central

    Hampe, Christiane S.

    2012-01-01

    The role of B cells in autoimmune diseases involves different cellular functions, including the well-established secretion of autoantibodies, autoantigen presentation and ensuing reciprocal interactions with T cells, secretion of inflammatory cytokines, and the generation of ectopic germinal centers. Through these mechanisms B cells are involved both in autoimmune diseases that are traditionally viewed as antibody mediated and also in autoimmune diseases that are commonly classified as T cell mediated. This new understanding of the role of B cells opened up novel therapeutic options for the treatment of autoimmune diseases. This paper includes an overview of the different functions of B cells in autoimmunity; the involvement of B cells in systemic lupus erythematosus, rheumatoid arthritis, and type 1 diabetes; and current B-cell-based therapeutic treatments. We conclude with a discussion of novel therapies aimed at the selective targeting of pathogenic B cells. PMID:23807906

  7. Germinal center B-cells.

    PubMed

    Hamel, Keith M; Liarski, Vladimir M; Clark, Marcus R

    2012-08-01

    Within the B-cell follicle of secondary lymphoid organs, germinal center (GC) reactions produce high affinity antibody-secreting plasma cells (PCs) and memory B-cells necessary for the host's defense against invading pathogens. This process of GC formation is reliant on the activation of antigen-specific B-cells by T-cells capable of recognizing epitopes of the same antigenic complex. The unique architecture of secondary lymphoid organs facilitates these initial GC events through the placement of large clonally-diverse B-cell follicles near equally diverse T-cell zones. Antigen-activated B-cells that receive proper differentiation signals at the T-cell border of the B-cell follicle initiate an early GC B-cell transcriptional profile and migrate to follicular dendritic cell (FDC) networks within the B-cell follicle to seed the GC reaction. Peripheral to FDCs, GC B-cells rapidly divide in dark zones of the GC, and undergo somatic hypermutation of their immunoglobulin (Ig) variable domain. Newly formed GC B-cell clones then migrate into the GC light zone where they compete for antigen and secondary signals presented by FDCs and a specialized subset of CD4(+) T-cells known as T-follicular helper (T(FH)) cells. Survival, proliferative and differentiation signals delivered by mature FDCs and T(FH) cells initiate transcriptional programs that determine if GC B-cells become memory B-cells or terminally differentiated PCs. To prevent oncogenic transformation and/or the escape of autoreactive clones, there are several regulatory mechanisms that restrict GC B-cell proliferation and survival. Here we will detail the recent advances in GC B-cell biology that relate to their generation and fate-determination as well as their pathogenic potential. PMID:22390182

  8. Lymphoproliferative disease virus in wild turkeys in southeast United States

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Previously, retroviral neoplasms reported in wild upland game birds in the United States of America have typically been associated with reticuloendotheliosis virus (REV) infection. The information presented herein described the first reports of lymphoproliferative disease virus (LPDV) infection in ...

  9. Marginal-zone B cells

    Microsoft Academic Search

    Flavius Martin; John F. Kearney

    2002-01-01

    Recent advances in genomics and proteomics, combined with the facilitated generation and analysis of transgenic and gene-knockout animals, have revealed new complexities in classical biological systems, including the B-cell compartment. Studies on an 'old', but poorly characterized, B-cell subset — the naive, marginal-zone (MZ) B-cell subset — over the past two years have spawned an avalanche of data that encompass

  10. B Cells and Immunological Tolerance

    Microsoft Academic Search

    Nataly Manjarrez-Orduńo; Tâm D Quách; Ińaki Sanz

    2009-01-01

    Work from multiple groups continues to provide additional evidence for the powerful and highly diverse roles, both protective and pathogenic, that B cells play in autoimmune diseases. Similarly, it has become abundantly clear that antibody-independent functions may account for the opposing influences that B cells exercise over other arms of the immune response and ultimately over autoimmunity itself. Finally, it

  11. Molecular programming of B cell memory

    Microsoft Academic Search

    Shinji Okitsu; Nathaniel Wang; Louise McHeyzer-Williams; Michael McHeyzer-Williams

    2011-01-01

    The development of high-affinity B cell memory is regulated through three separable phases, each involving antigen recognition by specific B cells and cognate T helper cells. Initially, antigen-primed B cells require cognate T cell help to gain entry into the germinal centre pathway to memory. Once in the germinal centre, B cells with variant B cell receptors must access antigens

  12. Post-transplant lymphoproliferative disease of donor origin, following haematopoietic stem cell transplantation in a patient with blastic plasmacytoid dendritic cell neoplasm.

    PubMed

    Piccin, Andrea; Morello, Enrico; Svaldi, Mirija; Haferlach, Torsten; Facchetti, Fabio; Negri, Giovanni; Vecchiato, Cinzia; Fisogni, Simona; Pusceddu, Irene; Cortelazzo, Sergio

    2012-12-01

    Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an extremely rare condition that originates from dendritic cells. We report on the first case of Epstein-Barr virus (EBV)-driven post-transplant lymphoproliferative disorder (PTLD) of donor origin in a BPDC patient post-allogeneic haematopoietic stem cell transplantation (HSCT). Flow cytometry study identified a cell population CD4+/CD56+/CD45RA+/CD123+/TCL1+ suggestive of BPDCN diagnosis, which was confirmed by a lymph node biopsy (cells positive for BCL11a, BDCA-2, CD2AP, CD123, TCL1 and S100). Cytogenetic analysis revealed a complex karyotype: (19 metaphase) 47,XX,t(1;6)(q21;q2?5),-13?+?2mar[11]/47, XX, +21 [3]/46,XX [5]. The patient was started on acute myeloid leukaemia (AML) induction schedule, and subsequently an allogeneic HSCT was performed. On day +36 post-HSCT, bone marrow biopsy/aspirate showed complete morphological remission, and chimerism study showed 100% donor chimera. However, on day +37, the patient was found to have enlarged cervical and supraclavicular lymphoadenopathy, splenomegaly and raised lactic dehydrogenase. EBV-DNA copies in blood were elevated, consistent with a lytic cycle. A lymph node biopsy showed EBV encoded RNA and large atypical B cells (CD45dim-, CD4+/CD56+, monoclonal for k-chain, CD19+/CD20+/CD21+/CD22+/CD38+/CD43+/CD79?-/CD5-/CD10-), consistent with PTLD monomorphic type. Chimerism study showed that PTLD was of donor origin. This case together with the recent literature findings on BPDCN and PTLD are discussed. PMID:22915052

  13. Identification of lymphoproliferative disease virus in wild turkeys (Meleagris gallopavo) in the United States

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Viral-associated lymphoproliferative neoplasia in domestic poultry is caused by infection with a herpesvirus (Marek’s disease virus) or three species of retroviruses [Reticuloendotheliosis virus (REV), Avian leukosis/sarcoma virus, lymphoproliferative disease virus (LPDV)]. Previously, retroviral n...

  14. Anti-B cell antibody therapies for inflammatory rheumatic diseases.

    PubMed

    Faurschou, Mikkel; Jayne, David R W

    2014-01-01

    Several monoclonal antibodies targeting B cells have been tested as therapeutics for inflammatory rheumatic diseases. We review important observations from randomized clinical trials regarding the efficacy and safety of anti-B cell antibody-based therapies for rheumatoid arthritis, systemic lupus erythematosus, antineutrophil cytoplasmic antibody-associated vasculitis, polymyositis/dermatomyositis, and primary Sjögren's syndrome. For some anti-B cell agents, clinical benefits have been convincingly demonstrated, while other B cell-targeted therapies failed to improve outcomes when added to standard-of-care treatment or were associated with increased rates of adverse events. Although the risk-benefit balance seems to be acceptable for currently licensed anti-B cell agents, additional studies are required to fully assess the safety of treatment regimens involving prolonged interference with B cell counts and functions in rheumatic disorders. Future studies should also evaluate how to maintain disease control by means of conventional and/or biologic immunosuppressants after remission-induction with anti-B cell antibodies. PMID:24160940

  15. Autoimmune lymphoproliferative syndrome-like disease in patients with LRBA mutation.

    PubMed

    Revel-Vilk, Shoshana; Fischer, Ute; Keller, Bärbel; Nabhani, Schafiq; Gámez-Díaz, Laura; Rensing-Ehl, Anne; Gombert, Michael; Hönscheid, Andrea; Saleh, Hani; Shaag, Avraham; Borkhardt, Arndt; Grimbacher, Bodo; Warnatz, Klaus; Elpeleg, Orly; Stepensky, Polina

    2015-07-01

    Mutations in LPS-responsive and beige-like anchor (LRBA) gene were recently described in patients with combined immunodeficiency, enteropathy and autoimmune cytopenia. Here, we extend the clinical and immunological phenotypic spectrum of LRBA associated disorders by reporting on three patients from two unrelated families who presented with splenomegaly and lymphadenopathy, cytopenia, elevated double negative T cells and raised serum Fas ligand levels resembling autoimmune lymphoproliferative syndrome (ALPS) and one asymptomatic patient. Homozygous loss of function mutations in LRBA were identified by whole exome analysis. Similar to ALPS patients, Fas mediated apoptosis was impaired in LRBA deficient patients, while apoptosis in response to stimuli of the intrinsic mitochondria mediated apoptotic pathway was even enhanced. This manuscript illustrates the phenotypic overlap of other primary immunodeficiencies with ALPS-like disorders and strongly underlines the necessity of genetic diagnosis in order to provide early correct diagnosis and subsequent care. PMID:25931386

  16. Signaling Lymphocyte Activated Molecule (SLAM)/SLAM-associated Protein (SAP) Pathway Regulates Human B-cell Tolerance

    PubMed Central

    Menard, Laurence; Cantaert, Tineke; Chamberlain, Nicolas; Tangye, Stuart G.; Riminton, Sean; Church, Joseph A.; Klion, Amy; Cunninham-Rundles, Charlotte; Nichols, Kim E.; Meffre, Eric

    2014-01-01

    Background SAP can mediate the function of SLAM molecules, which have been proposed to be involved in the development of autoimmunity in mice. Objective We sought to determine if the SLAM/SAP pathway regulates the establishment of human B-cell tolerance and what mechanisms of B-cell tolerance could be affected by SAP deficiency. Methods We tested the reactivity of antibodies isolated from single B cells from SAP-deficient X-linked lymphoproliferative disease (XLP) patients. The expressions of SAP and SLAM family members were assessed in human bone marrow developing B cells. We also analyzed regulatory T cell (Treg) function in XLP patients and healthy controls. Results We found that new emigrant/transitional B cells from XLP patients were enriched in autoreactive clones, revealing a defective central B-cell tolerance checkpoint in the absence of functional SAP. In agreement with a B-cell intrinsic regulation of central tolerance, we identified SAP expression in a discrete subset of bone marrow immature B cells. SAP colocalized with SLAMF6 only in association with clustered B-cell receptors (BCRs) likely recognizing self-antigens, suggesting that SLAM/SAP regulate BCR-mediated central tolerance. In addition, XLP patients displayed defective peripheral B-cell tolerance, which is normally controlled by Tregs. Tregs in XLP patients seem functional but SAP-deficient T cells were resistant to Treg-mediated suppression. Indeed, SAP-deficient T cells were hyper-responsive to TCR stimulation, which resulted in increased secretion of interleukin-2, IFN? and TNF?. Conclusions SAP expression is required for the counterselection of developing autoreactive B cells and prevents their T-cell dependent accumulation in the periphery. PMID:24373350

  17. Targeting neoplastic B cells and harnessing microenvironment: the "double face" of ibrutinib and idelalisib.

    PubMed

    Maffei, Rossana; Fiorcari, Stefania; Martinelli, Silvia; Potenza, Leonardo; Luppi, Mario; Marasca, Roberto

    2015-01-01

    Tyrosine kinase inhibitors (TKIs) targeting signaling molecules downstream B cell receptor (BCR) are powerfully spreading in the therapeutic landscape of B cell lymphoproliferative disease, due to a manageable toxicity profile and encouraging clinical effectiveness. In particular, ibrutinib, previously called PCI-32765, is a potent inhibitor of Bruton tyrosine kinase (Btk), recently approved for the treatment of relapsed mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL). Moreover, idelalisib (formerly GS-1101 and CAL-101) is a selective reversible inhibitor of the p110? isoform of phosphoinositol 3 kinase (PI3K) approved for the treatment of patients with relapsed follicular lymphoma (FL) and CLL. These agents directly affect the neoplastic clone, disrupting the supportive platform provided by BCR signaling cascade and by other microenvironmental mutualistic interactions, and also interfering with chemokine gradients and adhesive properties of neoplastic B cells. In the present review, we describe the clinical efficacy of ibrutinib and idelalisib in CLL and B cell non-Hodgkin lymphoma (B-NHL), then focusing on the mode of action (MOA) of these TKIs towards the neoplastic B cell compartment. At last, the review would further expand the view on potential additional targets of ibrutinib and idelalisib belonging to other microenvironmental cellular elements. PMID:26022368

  18. Kaposi sarcoma herpesvirus (KSHV) vFLIP oncoprotein induces B cell transdifferentiation and tumorigenesis in mice.

    PubMed

    Ballon, Gianna; Chen, Kang; Perez, Rocio; Tam, Wayne; Cesarman, Ethel

    2011-03-01

    Kaposi sarcoma herpesvirus (KSHV) is specifically associated with Kaposi sarcoma (KS) and 2 B cell lymphoproliferative diseases, namely primary effusion lymphoma (PEL) and multicentric Castleman disease (MCD). KS, PEL, and MCD are largely incurable and poorly understood diseases most common in HIV-infected individuals. Here, we have revealed the role of viral FLICE-inhibitory protein (vFLIP) in the initiation of PEL and MCD by specifically expressing vFLIP at different stages of B cell differentiation in vivo. Mice showed MCD-like abnormalities and immunological defects including lack of germinal centers (GCs), impaired Ig class switching, and affinity maturation. In addition, they showed increased numbers of cells expressing cytoplasmic IgM-?, a thus far enigmatic feature of the KSHV-infected cells in MCD. B cell-derived tumors arose at high incidence and displayed Ig gene rearrangement with downregulated expression of B cell-associated antigens, which are features of PEL. Interestingly, these tumors exhibited characteristics of transdifferentiation and acquired expression of histiocytic/dendritic cell markers. These results define immunological functions for vFLIP in vivo and reveal what we believe to be a novel viral-mediated tumorigenic mechanism involving B cell reprogramming. Additionally, the robust recapitulation of KSHV-associated diseases in mice provides a model to test inhibitors of vFLIP as potential anticancer agents. PMID:21339646

  19. A novel lymphoproliferative/autoimmune syndrome resembling murine lpr/gld disease.

    PubMed Central

    Sneller, M C; Straus, S E; Jaffe, E S; Jaffe, J S; Fleisher, T A; Stetler-Stevenson, M; Strober, W

    1992-01-01

    In mice, the two distinct autosomal recessive genes lpr and gld can induce a syndrome characterized by autoantibody formation and the progressive accumulation of an unusual CD4-CD8- T cell population in peripheral lymphoid tissue. This phenotype does not precisely mirror any human disease. In this report we describe two patients with a progressive lymphoproliferative disorder associated with autoimmunity. The peripheral blood and lymph nodes of these patients contained large numbers of an unusual CD4-CD8- T cell population. These CD4-CD8- T cells express surface markers characteristic of mature peripheral blood T cells (CD3, CD2, CD5), express the alpha/beta form of the T cell receptor, and do not express surface markers characteristic of immature thymocytes (CD1) or NK cells (CD16, CD56). Functionally, these cells exhibited deficient proliferation and lymphokine production upon stimulation with mitogenic antibodies to CD3 or CD2. Both proliferation and lymphokine production could be augmented by co-stimulation with an antibody directed at the CD28 determinant. The clinical and immunological features of this syndrome resemble the lymphoproliferative/autoimmune disease seen in lpr and gld mice. Images PMID:1386609

  20. Genetics Home Reference: Autoimmune lymphoproliferative syndrome

    MedlinePLUS

    ... Guillain-Barre syndrome), or the connective tissues (systemic lupus erythematosus) that provide strength and flexibility to structures ... involves lymphoproliferation and the tendency to develop systemic lupus erythematosus. Individuals with this form of the disorder ...

  1. B cells in Sjögren's syndrome: indications for disturbed selection and differentiation in ectopic lymphoid tissue

    Microsoft Academic Search

    Arne Hansen; Peter E Lipsky; Thomas Dörner

    2007-01-01

    Primary Sjögren's syndrome (pSS) is an autoimmune disorder characterized by specific pathological features. A hallmark of pSS is B-cell hyperactivity as manifested by the production of autoantibodies, hypergammaglobulinemia, formation of ectopic lymphoid structures within the inflamed tissues, and enhanced risk of B-cell lymphoma. Changes in the distribution of peripheral B-cell subsets and differences in post-recombination processes of immunoglobulin variable region

  2. B-cell targeting in rheumatoid arthritis and other autoimmune diseases

    Microsoft Academic Search

    Geraldine Cambridge; Jonathan C. W. Edwards

    2006-01-01

    B-cell-targeted therapy for autoimmune disease emerged from theoretical proposition to practical reality between 1997 and 1998, with the availability of the B-cell-depleting monoclonal antibody rituximab. Since then, a score of autoantibody-associated disorders have been treated, with most convincing evidence of efficacy seen in subjects with rheumatoid arthritis. Several classes of B-cell-targeted agent are now under investigation. From the outset, a

  3. The potential utility of B cell-directed biologic therapy in autoimmune diseases

    Microsoft Academic Search

    D. G. Arkfeld

    2008-01-01

    Increasing awareness of the importance of aberrant B cell regulation in autoimmunity has driven the clinical development of\\u000a novel B cell-directed biologic therapies with the potential to treat a range of autoimmune disorders. The first of these drugs—rituximab,\\u000a a chimeric monoclonal antibody against the B cell-specific surface marker CD20—was recently approved for treating rheumatoid\\u000a arthritis in patients with an inadequate

  4. In Vivo, Multimodal Imaging of B Cell Distribution and Response to Antibody Immunotherapy in Mice

    Microsoft Academic Search

    Daniel L. J. Thorek; Patricia Y. Tsao; Vaishali Arora; Lanlan Zhou; Robert A. Eisenberg; Andrew Tsourkas; Derya Unutmaz

    2010-01-01

    BackgroundB cell depletion immunotherapy has been successfully employed to treat non-Hodgkin's lymphoma. In recent years, increasing attention has been directed towards also using B-cell depletion therapy as a treatment option in autoimmune disorders. However, it appears that the further development of these approaches will depend on a methodology to determine the relation of B-cell depletion to clinical response and how

  5. Evolution of B Cell Immunity

    PubMed Central

    Sunyer, J. Oriol

    2013-01-01

    Two types of adaptive immune strategies are known to have evolved in vertebrates: the VLR-based system, which is present in jawless organisms and is mediated by VLRA and VLRB lymphocytes, and the BCR/TCR-based system, which is present in jawed species and is provided by B and T cell receptors expressed on B and T cells, respectively. Here we summarize features of B cells and their predecessors in the different animal phyla, focusing the review on B cells from jawed vertebrates. We point out the critical role of nonclassical species and comparative immunology studies in the understanding of B cell immunity. Because nonclassical models include species relevant to veterinary medicine, basic science research performed in these animals contributes to the knowledge required for the development of more efficacious vaccines against emerging pathogens. PMID:25340015

  6. The B-cell receptor orchestrates environment-mediated lymphoma survival and drug resistance in B-cell malignancies.

    PubMed

    Shain, K H; Tao, J

    2014-08-01

    Specific niches within the lymphoma tumor microenvironment (TME) provide sanctuary for subpopulations of tumor cells through stromal cell-tumor cell interactions. These interactions notably dictate growth, response to therapy and resistance of residual malignant B cells to therapeutic agents. This minimal residual disease (MRD) remains a major challenge in the treatment of B-cell malignancies and contributes to subsequent disease relapse. B-cell receptor (BCR) signaling has emerged as essential mediator of B-cell homing, survival and environment-mediated drug resistance (EMDR). Central to EMDR are chemokine- and integrin-mediated interactions between lymphoma and the TME. Further, stromal cell-B cell adhesion confers a sustained BCR signaling leading to chemokine and integrin activation. Recently, the inhibitors of BCR signaling have garnered a substantial clinical interest because of their effectiveness in B-cell disorders. The efficacy of these agents is, at least in part, attributed to attenuation of BCR-dependent lymphoma-TME interactions. In this review, we discuss the pivotal role of BCR signaling in the integration of intrinsic and extrinsic determinants of TME-mediated lymphoma survival and drug resistance. PMID:24037527

  7. Common Occurrence of Monoclonal B-cell Lymphocytosis Among Members of High-Risk CLL Families

    PubMed Central

    Goldin, Lynn R.; Lanasa, Mark C.; Slager, Susan L.; Cerhan, James R.; Vachon, Celine M.; Strom, Sara S.; Camp, Nicola J.; Spector, Logan G.; Leis, Jose F.; Morrison, Vicki A.; Glenn, Martha; Rabe, Kari G.; Achenbach, Sara J.; Algood, Sallie D.; Abbasi, Fatima; Fontaine, Laura; Yau, Michelle; Rassenti, Laura Z.; Kay, Neil E.; Call, Timothy G.; Hanson, Curtis A.; Weinberg, J. Brice; Marti, Gerald E.; Caporaso, Neil E.

    2010-01-01

    Summary Monoclonal B-cell lymphocytosis (MBL) is an asymptomatic haematological condition characterized by low absolute levels of B-cell clones with a surface immunophenotype similar to that of chronic lymphocytic leukaemia (CLL). In the general population, MBL increases with age with a prevalence of 5–9% in individuals over age 60 years. It has been reported to be higher among first-degree relatives from CLL families. We report results of multi-parameter flow cytometry among 505 first-degree relatives with no personal history of lymphoproliferative disease from 140 families having at least two cases of CLL. Seventeen percent of relatives had MBL. Age was the most important determinant where the probability for developing MBL by age 90 years was 61%. MBL clustered in certain families but clustering was independent of the number of known CLL cases in a family. As is the case with CLL, males had a significantly higher risk for MBL than did females (p=0.04). MBL patients had significantly higher mean absolute lymphocyte counts (2.4 × 109/l) and B-cell counts (0.53 × 109/l) than those with a normal B-cell immunophenotype. Our findings show that MBL occurs at a very high rate in high risk CLL families. Both the age and gender distribution of MBL are parallel to CLL, implying a shared inherited risk. PMID:20738309

  8. Natural history of autoimmune lymphoproliferative syndrome associated with FAS gene mutations

    PubMed Central

    Price, Susan; Shaw, Pamela A.; Seitz, Amy; Joshi, Gyan; Davis, Joie; Niemela, Julie E.; Perkins, Katie; Hornung, Ronald L.; Folio, Les; Rosenberg, Philip S.; Puck, Jennifer M.; Hsu, Amy P.; Lo, Bernice; Pittaluga, Stefania; Jaffe, Elaine S.; Fleisher, Thomas A.; Lenardo, Michael J.

    2014-01-01

    Autoimmune lymphoproliferative syndrome (ALPS) presents in childhood with nonmalignant lymphadenopathy and splenomegaly associated with a characteristic expansion of mature CD4 and CD8 negative or double negative T-cell receptor ??+ T lymphocytes. Patients often present with chronic multilineage cytopenias due to autoimmune peripheral destruction and/or splenic sequestration of blood cells and have an increased risk of B-cell lymphoma. Deleterious heterozygous mutations in the FAS gene are the most common cause of this condition, which is termed ALPS-FAS. We report the natural history and pathophysiology of 150 ALPS-FAS patients and 63 healthy mutation-positive relatives evaluated in our institution over the last 2 decades. Our principal findings are that FAS mutations have a clinical penetrance of <60%, elevated serum vitamin B12 is a reliable and accurate biomarker of ALPS-FAS, and the major causes of morbidity and mortality in these patients are the overwhelming postsplenectomy sepsis and development of lymphoma. With longer follow-up, we observed a significantly greater relative risk of lymphoma than previously reported. Avoiding splenectomy while controlling hypersplenism by using corticosteroid-sparing treatments improves the outcome in ALPS-FAS patients. This trial was registered at www.clinicaltrials.gov as #NCT00001350. PMID:24398331

  9. Expression of HSV-1 Receptors in EBV-Associated Lymphoproliferative Disease Determines Susceptibility to Oncolytic HSV

    PubMed Central

    Wang, Pin-Yi; Currier, Mark A; Hansford, Loen; Kaplan, David; Chiocca, E. Antonio; Uchida, Hiroaki; Goins, William F.; Cohen, Justus B.; Glorioso, Joseph C.; van Kuppevelt, Toin H.; Mo, Xiaokui; Cripe, Timothy P

    2012-01-01

    Epstein-Barr virus (EBV)-associated B cell lymphoproliferative disease (LPD) after hematopoietic stem cell or solid organ transplantation remains a life-threatening complication. Expression of the virus-encoded gene product, EBER, has been shown to prevent apoptosis via blockade of PKR activation. Because PKR is a major cellular defense against Herpes simplex virus, and oncolytic HSV-1 (oHSV) mutants have shown promising anti-tumor efficacy in preclinical models, we sought to determine whether EBV-LPD cells are susceptible to infection by oHSVs. We tested three primary EBV-infected lymphocyte cell cultures from neuroblastoma (NB) patients as models of naturally acquired EBV-LPD. NB12 was most susceptible, NB122R was intermediate, and NB88R2 was essentially resistant. Despite EBER expression, PKR was activated by oHSV infection. Susceptibility to oHSV correlated with the expression of the HSV receptor, nectin-1. The resistance of NB88R2 was reversed by exogenous nectin-1 expression, whereas down-regulation of nectin-1 on NB12 decreased viral entry. Xenografts derived from the EBV-LPDs exhibited only mild (NB12) or no (NB88R2) response to oHSV injection, compared with a neuroblastoma cell line that showed a significant response. We conclude that EBV-LPDs are relatively resistant to oHSV virotherapy, in some cases due to low virus receptor expression but also due to intact anti-viral PKR signaling. PMID:23254370

  10. The histomorphologic spectrum of primary cutaneous diffuse large B-cell lymphoma: a study of 79 cases.

    PubMed

    Plaza, Jose A; Kacerovska, Denisa; Stockman, David L; Buonaccorsi, J Noelle; Baillargeon, Paul; Suster, Saul; Kazakov, Dmitry V

    2011-10-01

    Primary cutaneous large B-cell lymphomas (PCLBCL) have historically been a matter of debate in the literature. The 2005 World Health Organization-European Organization for Research and Treatment of Cancer (WHO-EORTC) classification scheme segregated cutaneous B-cell lymphomas into 3 groups: primary cutaneous marginal zone B-cell lymphoma, primary cutaneous follicle center cell lymphoma, and primary cutaneous diffuse large B-cell lymphoma (PCDLBCL), "leg type" (PCDLBCL-LT). Additionally, the WHO-EORTC classification scheme utilized the term PCLBCL "other" not otherwise specified (NOS) type for rare cases of PCLBCL not belonging to either the "leg type" or the primary cutaneous follicle center cell lymphoma group. In this study, we retrospectively assessed the histomorphologic features of 79 cases of PCDLBCLs, including those of "leg type" and "other" NOS type, to further categorize the histologic spectrum of these unusual cutaneous neoplasms. The histologic diagnosis of PCLBCL usually poses little diagnostic difficulty; however, some cases may adopt unusual or unfamiliar appearances mimicking other lymphoproliferative disorders or other malignant neoplasms. Seventy-nine cases, occurring in 37 men and 42 women, aged 34-94 years, were analyzed. Fifty-three cases were classified as "leg type" and 26 cases were classified as "other" NOS type using the WHO-EORTC classification. Of the 53 cases classified as "leg type," 33 were women and 20 were men; of the 26 cases of "other" NOS type, 9 were women and 17 were men. In the "leg type" category, 31 cases were located on the lower extremities, 5 cases on the face, 5 cases on the arm, 3 cases on the chest, 2 cases on the shoulder, 2 cases on the back, 1 case on the trunk, 1 case on the buttock, 1 case on the supraclavicular area, 1 case on the head, and 1 case on the flank. Of the "other" NOS type category, 8 cases were located on the face, 5 cases on the shoulder, 3 cases on the head, 2 cases on the abdomen, 2 cases on the chest, 1 case on the trunk, 1 on the vulva, 1 on the axilla, 1 on the back, 1 on the neck, and 1 on the hip. Most cases assessed showed the classic morphologic appearance of PCDLBCL, but cases mimicking Burkitt lymphoma (starry-sky pattern), natural killer-cell (NK) lymphoma, mycosis fungoides (epidermotropism), low-grade B-cell lymphomas, epithelial malignancies, and Merkel cell carcinoma were encountered in this series. The high frequency of these rare histologic patterns can be explained by a bias associated with consultation practice. Careful histologic examination and immunohistochemical stains were used to establish the correct diagnosis. The differential diagnosis of PCDLBCL is broad and difficult to define histologically. Knowledge of these rare histologic variants is necessary to avoid misinterpretation of these cases as nonlymphoid malignancies. PMID:21937906

  11. [Advances in the knowledge and management of autoimmune lymphoproliferative syndrome].

    PubMed

    Garrido Colino, C

    2014-02-01

    Autoimmune lymphoproliferative syndrome (ALPS) represents a failure of apoptotic mechanisms to maintain lymphocyte homeostasis. ALPS often manifest in childhood with cytopenias, chronic non-malignant lymphoproliferation and autoimmune complications. A number of new insights have improved the understanding of the genetics and biology of ALPS. The treatment of the disease has changed and mycophenolate mofetil and sirolimus have been demonstrated to have marked activity against the disease, improving quality of life for many patients. These will be discussed in this review. PMID:24055319

  12. The Conserved Disulfide Bond within Domain II of Epstein-Barr Virus gH Has Divergent Roles in Membrane Fusion with Epithelial Cells and B Cells

    PubMed Central

    Möhl, Britta S.; Sathiyamoorthy, Karthik; Jardetzky, Theodore S.

    2014-01-01

    ABSTRACT Epstein-Barr virus (EBV) infects target cells via fusion with cellular membranes. For entry into epithelial cells, EBV requires the herpesvirus conserved core fusion machinery, composed of glycoprotein B (gB) and gH/gL. In contrast, for B cell fusion it requires gB and gH/gL with gp42 serving as a cell tropism switch. The available crystal structures for gH/gL allow the targeted analysis of structural determinants of gH to identify functional regions critical for membrane fusion. Domain II of EBV gH contains two disulfide bonds (DBs). The first is unique for EBV and closely related gammaherpesviruses. The second is conserved across the beta- and gammaherpesviruses and is positioned to stabilize a putative syntaxin-like bundle motif. To analyze the role of these DBs in membrane fusion, gH was mutated by amino acid substitution of the DB cysteines. Mutation of the EBV-specific DB resulted in diminished gH/gL cell surface expression that correlated with diminished B cell and epithelial cell fusion. In contrast, mutation of the conserved DB resulted in wild-type-like B cell fusion, whereas epithelial cell fusion was greatly reduced. The gH mutants bound well to gp42 but had diminished binding to epithelial cells. Tyrosine 336, located adjacent to cysteine 335 of the conserved DB, also was found to be important for DB stabilization and gH/gL function. We conclude that the conserved DB has a cell type-specific function, since it is important for the binding of gH to epithelial cells initiating epithelial cell fusion but not for fusion with B cells and gp42 binding. IMPORTANCE EBV predominantly infects epithelial and B cells in humans, which can result in EBV-associated cancers, such as Burkitt and Hodgkin lymphoma, as well as nasopharyngeal carcinoma. EBV is also associated with a variety of lymphoproliferative disorders, typically of B cell origin, observed in immunosuppressed individuals, such as posttransplant or HIV/AIDS patients. The gH/gL complex plays an essential but still poorly characterized role as an important determinant for EBV cell tropism. In the current studies, we found that mutants in the DB C278/C335 and the neighboring tyrosine 336 have cell type-specific functional deficits with selective decreases in epithelial cell, but not B cell, binding and fusion. The present study brings new insights into the gH function as a determinant for epithelial cell tropism during herpesvirus-induced membrane fusion and highlights a specific gH motif required for epithelial cell fusion. PMID:25231307

  13. Phagocytic B cells in a reptile.

    PubMed

    Zimmerman, Laura M; Vogel, Laura A; Edwards, Kevin A; Bowden, Rachel M

    2010-04-23

    Evidence for a developmental relationship between B cells and macrophages has led to the hypothesis that B cells evolved from a phagocytic predecessor. The recent identification of phagocytic IgM+ cells in fishes and amphibians supports this hypothesis, but raises the question of when, evolutionarily, was phagocytic capacity lost in B cells? To address this, leucocytes were isolated from red-eared sliders, Trachemys scripta, incubated with fluorescent beads and analysed using flow cytometry and confocal microscopy. Results indicate that red-eared slider B cells are able to ingest foreign particles and suggest that ectothermic vertebrates may use phagocytic B cells as part of a robust innate immune response. PMID:19846448

  14. Reduced numbers of switched memory B cells with high terminal differentiation potential in Down syndrome.

    PubMed

    Carsetti, Rita; Valentini, Diletta; Marcellini, Valentina; Scarsella, Marco; Marasco, Emiliano; Giustini, Ferruccio; Bartuli, Andrea; Villani, Alberto; Ugazio, Alberto G

    2015-03-01

    Children with Down syndrome (DS) have increased susceptibility to infections and a high frequency of leukemia and autoimmune disorders, suggesting that immunodeficiency and immune dysfunction are integral parts of the syndrome. A reduction in B-cell numbers has been reported, associated with moderate immunodeficiency and normal immunoglobulin levels. Here, we compared B-cell populations of 19 children with DS with those in healthy age-matched controls. We found that all steps of peripheral B-cell development are altered in DS, with a more severe defect during the later stages of B-cell development. Transitional and mature-naďve B-cell numbers are reduced by 50% whereas switched memory B cells represent 10-15% of the numbers in age-matched controls. Serum IgM levels were slightly reduced, but all other immunoglobulin isotypes were in the normal range. The frequency of switched memory B cells specific for vaccine antigens was significantly lower in affected children than in their equivalently vaccinated siblings. In vitro switched memory B cells of patients with DS have an increased ability to differentiate into antibody-forming cells in response to TLR9 signals. Tailored vaccination schedules increasing the number of switched memory B cells may improve protection and reduce the risk of death from infection in DS. PMID:25472482

  15. Rationale for B cell targeting in SLE

    PubMed Central

    Sanz, Ińaki

    2014-01-01

    B cells are central pathogenic players in Systemic Lupus Erythematosus and multiple other autoinmune diseases through antibody production as well as antibody independent functiona. At the same time, B cells are known to play important regulatory functions that may protect against autoimmune manifestations. Yet, the functional role of different B cell populations and their contribution to disease remain to be understood. The advent of agents that specifically target B cells, in particular anti-CD20 and ant-BLyS antibodies, have demonstrated the efficacy of this approach for the treatment of human autoimmunity. The analysis of patients treated with these and other B cell agents provide a unique opportunity to understand the correlates of clinical response and the significance of different B cell subsets. Here we discuss this information and how it could be used to better understand SLE and improve the rational design of B cell directed therapies in this disease. PMID:24763533

  16. Memory B cells in mouse models.

    PubMed

    Bergmann, B; Grimsholm, O; Thorarinsdottir, K; Ren, W; Jirholt, P; Gjertsson, I; Mĺrtensson, I-L

    2013-08-01

    One of the principles behind vaccination, as shown by Edward Jenner in 1796, and host protection is immunological memory, and one of the cells central to this is the antigen-experienced memory B cell that responds rapidly upon re-exposure to the initiating antigen. Classically, memory B cells have been defined as progenies of germinal centre (GC) B cells expressing isotype-switched and substantially mutated B cell receptors (BCRs), that is, membrane-bound antibodies. However, it has become apparent over the last decade that this is not the only pathway to B cell memory. Here, we will discuss memory B cells in mice, as defined by (1) cell surface markers; (2) multiple layers; (3) formation in a T cell-dependent and either GC-dependent or GC-independent manner; (4) formation in a T cell-independent fashion. Lastly, we will touch upon memory B cells in; (5) mouse models of autoimmune diseases. PMID:23679222

  17. SAP expression in T cells, not in B cells, is required for humoral immunity

    PubMed Central

    Veillette, André; Zhang, Shaohua; Shi, Xiaochu; Dong, Zhongjun; Davidson, Dominique; Zhong, Ming-Chao

    2008-01-01

    SAP (also named SH2D1A) is an intracellular adaptor molecule expressed in T cells, natural killer (NK) cells, and some B cells. The SAP gene is mutated in X-linked lymphoproliferative (XLP) disease, a human immunodeficiency characterized by a faulty immune response to Epstein–Barr virus infection. Previous reports documented severe defects in antibody production and germinal center (GC) formation in SAP-deficient humans and mice genetically engineered to lack SAP expression. However, in vitro studies and adoptive transfer experiments provided conflicting data as to whether this phenotype is caused by a functional defect resulting from SAP deficiency in T cells, B cells, or both. Here, we ascertained which cell types are responsible for this humoral immunity defect by using a conditional gene targeting approach. We also thoroughly examined the expression pattern of SAP in normal immune cells by using intracellular flow cytometry. The results showed that expression of SAP in T cells, but not in B cells or NK cells, is required and sufficient for SAP-dependent antibody production and GC formation. These data provide a critical insight into the mechanism by which SAP regulates humoral immunity. They also help elucidate the basis of a severe human immunodeficiency. PMID:18212118

  18. Autoantibody-dependent and autoantibody-independent roles for B cells in systemic lupus erythematosus: past, present, and future

    PubMed Central

    Jacob, Noam; Stohl, William

    2009-01-01

    It has long been known that B cells produce autoantibodies and, thereby, contribute to the pathogenesis of many autoimmune diseases. Systemic lupus erythematosus (SLE), a prototypic systemic autoimmune disorder, is characterized by high circulating autoantibody titers and immune-complex deposition that can trigger inflammatory damage in multiple organs/organ systems. Although the interest in B cells in SLE has historically focused on their autoantibody production, we now appreciate that B cells have multiple autoantibody-independent roles in SLE as well. B cells can efficiently present antigen and activate T cells, they can augment T cell activation through co-stimulatory interactions, and they can produce numerous cytokines which affect inflammation, lymphogenesis, and immune regulation. Not surprisingly, B cells have become attractive therapeutic targets in SLE. With these points in mind, this review will focus on the autoantibody-dependent and autoantibody-independent roles for B cells in SLE and on therapeutic approaches that target B cells. PMID:20014977

  19. B cell lymphoma and myeloma in murine Gaucher's disease.

    PubMed

    Pavlova, E V; Wang, S Z; Archer, J; Dekker, N; Aerts, J M F G; Karlsson, S; Cox, T M

    2013-09-01

    Multiple myeloma and B cell lymphoma are leading causes of death in Gaucher's disease but the nature of the stimulus driving the often noted clonal expansion of immunoglobulin-secreting B cells and cognate lymphoid malignancy is unknown. We investigated the long-term development of B cell malignancies in an authentic model of non-neuronopathic Gaucher's disease in mice: selective deficiency of ?-glucocerebrosidase in haematopoietic cells [Gba(tm1Karl/tm1Karl)Tg(Mx1-cre)1Cgn/0, with excision of exons 9-11 of the murine GBA1 gene, is induced by poly[I:C]. Mice with Gaucher's disease showed visceral storage of ?-glucosylceramide and greatly elevated plasma ?-glucosylsphingosine [median 57.9 (range 19.8-159) nm; n = 39] compared with control mice from the same strain [median 0.56 (range 0.04-1.38) nm; n = 29] (p < 0.0001). Sporadic fatal B cell lymphomas developed in 11 of 21 GD mice (6-24 months) but only two of eight control animals developed tumours by age 24 months. Unexpectedly, most mice with overt lymphoma had absent or few Gaucher cells but local inflammatory macrophages were present. Eleven of 39 of Gaucher mice developed monoclonal gammopathy, but in the control group only one animal of 25 had clonal immunoglobulin abnormalities. Seven of 10 of the B cell lymphomas were found to secrete a monoclonal paraprotein and the lymphomas stained intensely for pan-B cell markers; reactive T lymphocytes were also present in tumour tissue. In the Gaucher mouse strain, it was notable that, as in patients with this disease, CD138(+) plasma cells frequently surrounded splenic macrophages engorged with glycosphingolipid. Our strain of mice, with inducible deficiency of ?-glucocerebrosidase in haematopoietic cells and a high frequency of sporadic lethal B cell malignancies, faithfully recapitulates human Gaucher's disease: it serves as a tractable model to investigate the putative role of bioactive sphingolipids in the control of B cell proliferation and the pathogenesis of myelomatosis-the most prevalent human cancer associated with this disorder. PMID:23775597

  20. Binding of HLA-G to ITIM-bearing Ig-like transcript 2 receptor suppresses B cell responses.

    PubMed

    Naji, Abderrahim; Menier, Catherine; Morandi, Fabio; Agaugué, Sophie; Maki, Guitta; Ferretti, Elisa; Bruel, Sylvie; Pistoia, Vito; Carosella, Edgardo D; Rouas-Freiss, Nathalie

    2014-02-15

    Inhibition of B cells constitutes a rational approach for treating B cell-mediated disorders. We demonstrate in this article that the engagement of the surface Ig-like transcript 2 (ILT2) inhibitory receptor with its preferential ligand HLA-G is critical to inhibit B cell functions. Indeed, ILT2-HLA-G interaction impedes both naive and memory B cell functions in vitro and in vivo. Particularly, HLA-G inhibits B cell proliferation, differentiation, and Ig secretion in both T cell-dependent and -independent models of B cell activation. HLA-G mediates phenotypic and functional downregulation of CXCR4 and CXCR5 chemokine receptors on germinal center B cells. In-depth analysis of the molecular mechanisms mediated by ILT2-HLA-G interaction showed a G0/G1 cell cycle arrest through dephosphorylation of AKT, GSK-3?, c-Raf, and Foxo proteins. Crucially, we provide in vivo evidence that HLA-G acts as a negative B cell regulator in modulating B cell Ab secretion in a xenograft mouse model. This B cell regulatory mechanism involving ILT2-HLA-G interaction brings important insight to design future B cell-targeted therapies aimed at reducing inappropriate immune reaction in allotransplantation and autoimmune diseases. PMID:24453251

  1. Microbes and B cell development.

    PubMed

    Wesemann, Duane R

    2015-01-01

    Animals and many of their chronic microbial inhabitants form relationships of symbiotic mutualism, which occurs when coexisting life-forms derive mutual benefit from stable associations. While microorganisms receive a secure habitat and constant food source from vertebrate hosts, they are required for optimal immune system development and occupy niches otherwise abused by pathogens. Microbes have also been shown to provide vertebrate hosts with metabolic capabilities that enhance energy and nutrient uptake from the diet. The immune system plays a central role in the establishment and maintenance of host-microbe homeostasis, and B lineage cells play a key role in this regulation. Here, I reviewed the structure and function of the microbiota and the known mechanisms of how nonpathogenic microbes influence B cell biology and immunoglobulin repertoire development early in life. I also discuss what is known about how B lineage cells contribute to the process of shaping the composition of commensal/mutualistic microbe membership. PMID:25591467

  2. The Mucosal B-Cell System

    Microsoft Academic Search

    Per Brandtzaeg; Finn-Eirik Johansen

    The mucosal B-cell system forms the adaptive basis for humoral immune defense of the extensive mucosae. Such antibody protection\\u000a depends on a complex cooperation between local B cells and secretory epithelia. Mucosa-associated lymphoid tissue (MALT) gives\\u000a rise to activated B cells with striking J-chain expression that are seeded to local and distant secretory effector sites.\\u000a Such homing is the biological

  3. Filgrastim, lenograstim and pegfilgrastim in the mobilization of peripheral blood progenitor cells in patients with lymphoproliferative malignancies.

    PubMed

    Ria, Roberto; Reale, Antonia; Melaccio, Assunta; Racanelli, Vito; Dammacco, Franco; Vacca, Angelo

    2015-05-01

    Patients with lymphoproliferative disorders, candidate to autologous stem cell transplantation (ASCT), require mobilization with chemotherapy and granulocyte colony -stimulating factor (G-CSF). This study looked for differences in hematopoietic peripheral stem cells (HPSCs) mobilization in response to the three available G-CSFs, namely lenograstim, filgrastim, and pegfilgrastim. Between 2000 and 2012, 146 patients (66 M and 80 F) who underwent ASCT for multiple myeloma, non-Hodgkin's lymphoma or Hodgkin's lymphoma were studied. All patients received induction therapy and then a mobilization regimen with cyclophosphamide plus lenograstim, or filgrastim, or pegfilgrastim. From days 12 to 14, HPSCs were collected by two to three daily leukaphereses. Our results show that high-dose cyclophosphamide plus lenograstim achieved adequate mobilization and the collection target more quickly and with fewer leukaphereses as compared to filgrastim and pegfilgrastim. No differences between the three regimens were observed regarding toxicity and days to WBC and platelet recovery. Thus, lenograstim may represent the ideal G-CSF for PBSC mobilization in patients with lymphoproliferative diseases. Further studies are needed to confirm these results and better understand the biological bases of these differences. PMID:24722996

  4. B cells as therapeutic targets in SLE

    PubMed Central

    Sanz, Ińaki; Lee, F. Eun-Hyung

    2014-01-01

    The use of B-cell targeted therapies for the treatment of systemic lupus erythematosus (SLE) has generated great interest owing to the multiple pathogenic roles carried out by B cells in this disease. Strong support for targeting B cells is provided by genetic, immunological and clinical observations that place these cells at the center of SLE pathogenesis, as initiating, amplifying and effector cells. Interest in targeting B cells has also been fostered by the successful use of similar interventions to treat other autoimmune diseases such as rheumatoid arthritis, and by the initial promise shown by B-cell depletion to treat SLE in early studies. Although the initial high enthusiasm has been tempered by negative results from phase III trials of the B-cell-depleting agent rituximab in SLE, renewed vigor should be instilled in the field by the convergence of the latest results using agents that inhibit B-cell-activating factor (BAFF, also known as BLyS and tumor necrosis factor ligand superfamily, member 13b), further analysis of data from trials using rituximab and greatly improved understanding of B-cell biology. Combined, the available information identifies several new avenues for the therapeutic targeting of B cells in SLE. PMID:20520647

  5. B cell depletion therapy ameliorates autoimmune disease through ablation of IL-6-producing B cells.

    PubMed

    Barr, Tom A; Shen, Ping; Brown, Sheila; Lampropoulou, Vicky; Roch, Toralf; Lawrie, Sarah; Fan, Boli; O'Connor, Richard A; Anderton, Stephen M; Bar-Or, Amit; Fillatreau, Simon; Gray, David

    2012-05-01

    B cells have paradoxical roles in autoimmunity, exerting both pathogenic and protective effects. Pathogenesis may be antibody independent, as B cell depletion therapy (BCDT) leads to amelioration of disease irrespective of autoantibody ablation. However, the mechanisms of pathogenesis are poorly understood. We demonstrate that BCDT alleviates central nervous system autoimmunity through ablation of IL-6-secreting pathogenic B cells. B cells from mice with experimental autoimmune encephalomyelitis (EAE) secreted elevated levels of IL-6 compared with B cells from naive controls, and mice with a B cell-specific IL-6 deficiency showed less severe disease than mice with wild-type B cells. Moreover, BCDT ameliorated EAE only in mice with IL-6-sufficient B cells. This mechanism of pathogenesis may also operate in multiple sclerosis (MS) because B cells from MS patients produced more IL-6 than B cells from healthy controls, and this abnormality was normalized with B cell reconstitution after Rituximab treatment. This suggests that BCDT improved disease progression, at least partly, by eliminating IL-6-producing B cells in MS patients. Taking these data together, we conclude that IL-6 secretion is a major mechanism of B cell-driven pathogenesis in T cell-mediated autoimmune disease such as EAE and MS. PMID:22547654

  6. B cell depletion therapy ameliorates autoimmune disease through ablation of IL-6–producing B cells

    PubMed Central

    Shen, Ping; Brown, Sheila; Lampropoulou, Vicky; Roch, Toralf; Lawrie, Sarah; Fan, Boli; O’Connor, Richard A.; Anderton, Stephen M.; Bar-Or, Amit; Fillatreau, Simon; Gray, David

    2012-01-01

    B cells have paradoxical roles in autoimmunity, exerting both pathogenic and protective effects. Pathogenesis may be antibody independent, as B cell depletion therapy (BCDT) leads to amelioration of disease irrespective of autoantibody ablation. However, the mechanisms of pathogenesis are poorly understood. We demonstrate that BCDT alleviates central nervous system autoimmunity through ablation of IL-6–secreting pathogenic B cells. B cells from mice with experimental autoimmune encephalomyelitis (EAE) secreted elevated levels of IL-6 compared with B cells from naive controls, and mice with a B cell–specific IL-6 deficiency showed less severe disease than mice with wild-type B cells. Moreover, BCDT ameliorated EAE only in mice with IL-6–sufficient B cells. This mechanism of pathogenesis may also operate in multiple sclerosis (MS) because B cells from MS patients produced more IL-6 than B cells from healthy controls, and this abnormality was normalized with B cell reconstitution after Rituximab treatment. This suggests that BCDT improved disease progression, at least partly, by eliminating IL-6–producing B cells in MS patients. Taking these data together, we conclude that IL-6 secretion is a major mechanism of B cell–driven pathogenesis in T cell–mediated autoimmune disease such as EAE and MS. PMID:22547654

  7. KLF2--a negative regulator of pre-B cell clonal expansion and B cell activation.

    PubMed

    Winkelmann, Rebecca; Sandrock, Lena; Kirberg, Jörg; Jäck, Hans-Martin; Schuh, Wolfgang

    2014-01-01

    Maturation as well as antigen-dependent activation of B cells is accompanied by alternating phases of proliferation and quiescence. We and others have previously shown that Krüppel-like factor 2 (KLF2), a regulator of T cell quiescence and migration, is upregulated in small resting precursor (pre)-B cells after assembly of the immature pre-B cell receptor (pre-BCR) and is downregulated upon antigen-induced proliferation of mature B cells. These findings suggest that KLF2, besides its function in maintaining follicular B cell identity, peripheral B cell homeostasis and homing of antigen-specific plasma cells to the bone marrow, also controls clonal expansion phases in the B cell lineage. Here, we demonstrate that enforced expression of KLF2 in primary pre-B cells results in a severe block of pre-BCR-induced proliferation, upregulation of the cell cycle inhibitors p21 and p27 and downregulation of c-myc. Furthermore, retroviral KLF2 transduction of primary B cells impairs LPS-induced activation, favors apoptosis and results in reduced abundance of factors, such as AID, IRF4 and BLIMP1, that control the antigen-dependent phase of B cell activation and plasma cell differentiation. Hence, we conclude that KLF2 is not only a key player in terminating pre-B cell clonal expansion but also a potent suppressor of B cell activation. PMID:24874925

  8. Interleukin-5 Supports the Expansion of Fas Ligand-Expressing Killer B Cells that Induce Antigen-Specific Apoptosis of CD4+ T Cells and Secrete Interleukin-10

    PubMed Central

    Klinker, Matthew W.; Reed, Tamra J.; Fox, David A.; Lundy, Steven K.

    2013-01-01

    Beyond their critical role in humoral immunity, B lymphocytes can employ a variety of immunomodulatory mechanisms including expression of the apoptosis-inducing molecule Fas ligand (FasL; CD178). Here, we extensively characterized the surface phenotype of FasL+ killer B cells, showing they are enriched in the IgMhighCD5+CD1dhigh B cell subset previously reported to contain a higher frequency of B cells producing interleukin-10 (IL-10). A rare population of B cells expressing IL-10 was present among FasL+ B cells, but most FasL+ B cells did not produce IL-10. We also identify interleukin-5 (IL-5) as a novel inducer of killer B cell function. Constitutively FasL+ B cells expressed higher levels of the IL-5 receptor, and treating B cells with IL-5 and CD40L resulted in the expansion of a B cell population enriched for FasL+ cells. B cells stimulated with IL-5 and CD40L were potent inducers of apoptosis in activated primary CD4+ T cells, and this killing function was antigen-specific and dependent upon FasL. IL-5 also enhanced IL-10 secretion in B cells stimulated with CD40L. Taken together these findings elucidate the relationship of FasL+ B cells and IL-10-producing B cells and demonstrate that IL-5 can induce or enhance both killer B cell activity and IL-10 secretion in B cells. Finally, we found that the killer B cell activity induced by IL-5 was completely blocked by IL-4, suggesting the existence of a previously unknown antagonistic relationship between these type-2 cytokines in modulating the activity of killer B cells. Targeting this IL-5/IL-4 signaling axis may therefore represent a novel area of drug discovery in inflammatory disorders. PMID:23940537

  9. Intravascular B-cell lymphoma.

    PubMed

    Erös, Nóra; Károlyi, Zsuzsánna; Kovács, Anikó; Takács, István; Radványi, Gáspár; Kelényi, Gábor

    2002-11-01

    Intravascular (angiotropic) lymphoma is a unique and rare cutaneous lymphoma in which the malignant T or B lymphoid cells proliferate within the lumens of small blood vessels, primarily in the skin and central nervous system. Erythematous, tender nodules, tumors, and telangiectases are the most common skin symptoms in addition to various neurologic signs. Progression of the disease produces secondary organ involvement with variable symptoms and can be fatal. We describe a case of a 74-year-old woman with edematous, infiltrated, orange-like skin with multiple telangiectases, generalized edema, severe weakness, and extremely high values of lactate dehydrogenase. Skin biopsy specimens revealed atypical large cells filling up the lumens of dermal capillaries. Immunohistochemical investigation results identified them as B cells with CD20, CD45, CD79a, Ki-67, and HLA-DR positivity. After administration of diuretics, colchicine, and systemic PUVA therapy, the patient lost her edema, her skin became tender and free of telangiectases, and laboratory alterations normalized. Because of heavy neuralgia in her legs, oral monochemotherapy was introduced with chlorambucil, and now the patient is in remission. PMID:12399744

  10. Co-inherited mutations of Fas and caspase-10 in development of the autoimmune lymphoproliferative syndrome

    PubMed Central

    Cerutti, Elisa; Campagnoli, Maria F; Ferretti, Massimo; Garelli, Emanuela; Crescenzio, Nicoletta; Rosolen, Angelo; Chiocchetti, Annalisa; Lenardo, Michael J; Ramenghi, Ugo; Dianzani, Umberto

    2007-01-01

    Background Autoimmune lymphoproliferative syndrome (ALPS) is a rare inherited disorder characterized by defective function of Fas, autoimmune manifestations that predominantly involve blood cells, polyclonal accumulation of lymphocytes in the spleen and lymph nodes with lymphoadenomegaly and/or splenomegaly, and expansion of TCR??+ CD4/CD8 double-negative (DN) T cells in the peripheral blood. Most frequently, it is due to Fas gene mutations, causing ALPS type Ia (ALPS-Ia). However, other mutations, namely of the FasL gene (ALPS-Ib) and the caspase-10 gene (ALPS-II) are occasionally detected, whereas some patients do not present any known mutations (ALPS-III). Recently, mutations of the NRAS gene have been suggested to cause ALPS-IV. Results This work reports two patients that are combined heterozygous for single nucleotide substitutions in the Fas and caspase-10 genes. The first patient carried a splice site defect suppressing allele expression in the Fas gene and the P501L substitution in caspase-10. The second had a mutation causing a premature stop codon (Q47X) in the Fas gene and the Y446C substitution in caspase-10. Fas expression was reduced and caspase-10 activity was decreased in both patients. In both patients, the mutations were inherited from distinct healthy parents. Conclusion These data strongly suggest that co-transmission of these mutation was responsible for ALPS. PMID:17999750

  11. Unusual case of B cell lymphoma after immunosuppressive treatment for psoriasis

    PubMed Central

    Nosotti, Lorenzo; Baiocchini, Andrea; Bonifati, Claudio; Visco-Comandini, Ubaldo; Mirisola, Concetta; Del Nonno, Franca

    2015-01-01

    Lymphomas may be induced by the systemic immunosuppressive therapies used to treat psoriasis, such as ciclosporin, methotrexate and tumour necrosis factor (TNF)-? blockers. The biologic agents currently used in psoriasis include alefacept, efalizumab, and the TNF-? antagonists etanercept, infliximab, and adalimumab. Infections and cancer are the main possible consequences of intended or unexpected immunosuppression. We report a 59-year-old man with a history of severe psoriasis vulgaris treated with traditional immunosuppressant drugs followed by anti-TNF-? therapy; the patient was firstly hospitalized for an acute cholestatic toxic hepatitis, which we supposed to be related to adalimumab. The first liver biopsy showed active disease with severe hepatocellular damage caused by heavy lymphocytes infiltrate in portal tracts at in the interface with a not conclusive diagnosis of lymphoproliferative disease. The correct diagnosis of T cell/histiocyte- rich large B cell lymphoma (T/HRBCL) was only reached through a gastric biopsy and a second liver biopsy. T/HRBCL is an uncommon morphologic variant of diffuse large B-cell lymphoma not described until now in psoriatic patients receiving immunosuppressive biologic agents. In psoriatic patients, treated with biologic immunosuppressive agents, the suspect of abdominal lymphoma should always be included as differential diagnosis. Abdominal ultrasound evaluation need therefore to be included in the pre-treatment screening as in the follow-up surveillance. PMID:25914782

  12. Alterations in Peripheral Blood B Cell Subsets and Dynamics of B Cell Responses during Human Schistosomiasis

    PubMed Central

    Labuda, Lucja A.; Ateba-Ngoa, Ulysse; Feugap, Eliane Ngoune; Heeringa, Jorn J.; van der Vlugt, Luciën E. P. M.; Pires, Regina B. A.; Mewono, Ludovic; Kremsner, Peter G.; van Zelm, Menno C.; Adegnika, Ayola A.; Yazdanbakhsh, Maria; Smits, Hermelijn H.

    2013-01-01

    Antibody responses are thought to play an important role in control of Schistosoma infections, yet little is known about the phenotype and function of B cells in human schistosomiasis. We set out to characterize B cell subsets and B cell responses to B cell receptor and Toll-like receptor 9 stimulation in Gabonese schoolchildren with Schistosoma haematobium infection. Frequencies of memory B cell (MBC) subsets were increased, whereas naive B cell frequencies were reduced in the schistosome-infected group. At the functional level, isolated B cells from schistosome-infected children showed higher expression of the activation marker CD23 upon stimulation, but lower proliferation and TNF-? production. Importantly, 6-months after 3 rounds of praziquantel treatment, frequencies of naive B cells were increased, MBC frequencies were decreased and with the exception of TNF-? production, B cell responsiveness was restored to what was seen in uninfected children. These data show that S. haematobium infection leads to significant changes in the B cell compartment, both at the phenotypic and functional level. PMID:23505586

  13. B-cell waste classification sampling plan

    SciTech Connect

    HOBART, R.L.

    1999-11-20

    This report documents the methods used to collect samples and analyze data necessary to verify and/or determine the radionuclide content of the 324 Facility B-Cell decontamination and decommissioning waste stream.

  14. B Cell-Derived Interleukin 10 Does Not Regulate Spontaneous Systemic Autoimmunity in MRL.Faslpr mice

    PubMed Central

    Teichmann, Lino L.; Kashgarian, Michael; Weaver, Casey T.; Roers, Axel; Müller, Werner; Shlomchik, Mark J.

    2011-01-01

    B cells contribute to the pathogenesis of chronic autoimmune disorders like systemic lupus erythematosus (SLE) via multiple effector functions. However, B cells are also implicated in regulating SLE and other autoimmune syndromes via release of IL-10. B cells secreting IL-10 have been termed “Breg” and have been proposed as a separate subset of cells, a concept that remains controversial. The balance between pro- and anti-inflammatory effects could determine the success of B cell targeted therapies for autoimmune disorders and it is therefore pivotal to understand the significance of B cell-secreted IL-10 in spontaneous autoimmunity. By lineage specific deletion of Il10 from B cells we demonstrate that B cell-derived IL-10 is ineffective in suppressing the spontaneous activation of self-reactive B and T cells during lupus. Correspondingly, severity of organ disease and survival rates in mice harboring Il10 deficient B cells are unaltered. Genetic marking of cells that transcribe Il10 illustrates that the pool of IL-10 competent cells is dominated by CD4 T cells and macrophages. IL-10 competent cells of the B lineage are rare in vivo and among them short-lived plasmablasts have the highest frequency, suggesting an activation rather than lineage-driven phenotype. Putative Breg phenotypic subsets such as CD1dhiCD5+ and CD21hiCD23hi B cells are not enriched in Il10 transcription. These genetic studies demonstrate that in a spontaneous model of murine lupus, IL-10 dependent B cell regulation does not restrain disease and thus the pathogenic effects of B cells are not detectably counterbalanced by their IL-10 dependent regulatory functions. PMID:22156495

  15. Ageing of the B-cell repertoire.

    PubMed

    Martin, Victoria; Bryan Wu, Yu-Chang; Kipling, David; Dunn-Walters, Deborah

    2015-09-01

    Older people are more susceptible to infection, less responsive to vaccination and have a more inflammatory immune environment. Using spectratype analysis, we have previously shown that the B-cell repertoire of older people shows evidence of inappropriate clonal expansions in the absence of challenge, and that this loss of B-cell diversity correlates with poor health. Studies on response to vaccination, using both spectratyping and high-throughput sequencing of the repertoire, indicate that older responses to challenge are lacking in magnitude and/or delayed significantly. Also that some of the biologically significant differences may be in different classes of antibody. We have also previously shown that normal young B-cell repertoires can vary between different phenotypic subsets of B cells. In this paper, we present an analysis of immunoglobulin repertoire in different subclasses of antibody in five different populations of B cell, and show how the repertoire in these different groups changes with age. Although some age-related repertoire differences occur in naive cells, before exogenous antigen exposure, we see indications that there is a general dysregulation of the selective forces that shape memory B-cell populations in older people. PMID:26194751

  16. [Benign lymphoproliferative lesions of the parotid gland in HIV infection].

    PubMed

    Cecconi, L; Busi Rizzi, E; Schininŕ, V; Mazzuoli, G

    1996-01-01

    The authors investigated the role of ultrasonography (US) as the method of choice in diagnosing parotid lesions in HIV+ patients. Bilateral parotid gland enlargement associated with laterocervical lymph node enlargement is a sign of HIV infection. This pathologic condition is observed in 2-10% of seropositive patients. Histology demonstrates benign lymphoproliferative lesions referrable to immune system activation. Our series consisted of 37 HIV+ patients monitored with US for a year, all patients had cytologic confirmation of their disease, with needle biopsy in 9 patients and with MR studies in 4 patients. US showed focal solid lesions, with cystic and mixed appearance in the 26 adult subjects and gross parenchymal inhomogeneity in the 11 children; laterocervical lymph node enlargement was associated in 31 cases. In the only two cases with unilateral parotid involvement, an abscess and a lymphoma were diagnosed. To conclude, US findings in HIV+ patients, although aspecific, can help make the correct diagnosis, if they are integrated with the patient's history and clinical findings. PMID:8966280

  17. Effects of a biologic agent in a patient with rheumatoid arthritis after treatment for methotrexate-associated B-cell lymphoma: a case report

    PubMed Central

    2014-01-01

    Background Several studies have suggested an increased risk of malignant tumor in patients with rheumatoid arthritis. It has been also reported that rheumatoid arthritis patients have a high incidence of lymphoma compared with the general population, and that patients receiving methotrexate, which is the anchor drug for rheumatoid arthritis treatment, can develop lymphoproliferative disease. Nevertheless, management of rheumatoid arthritis after treatment for methotrexate-associated lymphoma has not been fully investigated. We here report a patient with rheumatoid arthritis who developed malignant lymphoma associated with methotrexate therapy. Moreover, we describe the use of a biologic agent for a rheumatoid arthritis patient after treatment for lymphoma associated with methotrexate. Case presentation A 60-year-old Japanese man with a 20-year history of rheumatoid arthritis was admitted to our hospital with a left inguinal tumor. Open biopsy was performed and a biopsy specimen revealed diffuse large B-cell lymphoma. As our patient had received methotrexate for 4 years, we diagnosed the lymphoproliferative disease as being methotrexate-related. This lymphoma was not associated with Epstein- Barr virus by Epstein-Barr virus-encoded ribonucleic acid in-situ hybridization, but this patient was an Epstein-Barr virus carrier, regarding serological testing. The lymphoma went into complete remission after 6 courses of rituximab plus cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone/prednisolone therapy. Two years later, however, rheumatoid arthritis activity gradually increased and was not controlled with salazosulfapyridine. Etanercept was administered in view of its possible effect on B-cells, and this reduced the level of disease activity without recurrence of lymphoma. Conclusion The management of rheumatoid arthritis after treatment for methotrexate-associated lymphoma has not been fully investigated yet. Etanercept appeared to be safe because of its B-cell effect, but further observation is necessary to make a firm conclusion. Further accumulation of cases is needed to clarify which biologics are safe and effective for treatment of methotrexate-associated B-cell lymphoma. PMID:24721419

  18. Regulatory B cells, helminths, and multiple sclerosis.

    PubMed

    Correale, Jorge; Equiza, Tomas Rivero

    2014-01-01

    Multiple sclerosis (MS) is an inflammatory demyelinating disease affecting the central nervous system. Autoimmunity appears to play a key role in both susceptibility to MS and development of disease, and pathogenesis has been linked to defects in distinct regulatory cell subsets. B cells are known for their capacity to produce antibodies. Recent advances in B cell biology, however, have demonstrated that regulatory B cells, a functional subset of B cells, contribute to tolerance development. Regulatory B cells were originally described in mouse autoimmunity and inflammation models where they dampen inflammation, but have also been found in several helminth infection models. We recently demonstrated that helminth-infected MS patients show a significantly lower clinical and radiological disease activity. Parasite-driven protection was associated with regulatory T cell induction and secretion of suppressive cytokines such as IL-10 and TGF-?. In addition, helminth infections in MS patients induced regulatory B cell populations producing high levels of IL-10, dampening harmful immune responses through a mechanism mediated, at least in part, by the ICOS-B/RP-1 pathway. More importantly, production of IL-10 by B cells in this study was restricted to helminth-infected individuals exclusively.The first part of this chapter will detail the criteria used in this study for selection of helminth-infected MS patients, MS patients without infection, and patients infected with Trypanosoma cruzi. Methods for isolation of peripheral blood CD19(+) cells and in particular for their stimulation with heat-inactivated Staphylococcus aureus Cowan strain, CDw32L cells, and CD40 antibody will also be described in detail. Finally, we will illustrate the procedures used to analyze phenotypic surface markers on these cells and characterize them in terms of IL-4, IL-6, IL-10, TNF-?, lymphotoxin, and TGF-? secretion. PMID:25015286

  19. Mycophenolic Acid Differentially Impacts B Cell Function Depending on the Stage of Differentiation

    PubMed Central

    Karnell, Jodi L.; Karnell, Fredrick G.; Stephens, Geoffrey L.; Rajan, Bhargavi; Morehouse, Chris; Li, Ying; Swerdlow, Bonnie; Wilson, Mildred; Goldbach-Mansky, Raphaela; Groves, Christopher; Coyle, Anthony J.; Herbst, Ronald; Ettinger, Rachel

    2014-01-01

    Production of pathogenic Abs contributes to disease progression in many autoimmune disorders. The immunosuppressant agent mycophenolic acid (MPA) has shown clinical efficacy for patients with autoimmunity. The goal of these studies was to elucidate the mechanisms of action of MPA on B cells isolated from healthy individuals and autoimmune patients. In this study, we show that MPA significantly inhibited both proliferation and differentiation of primary human B cells stimulated under various conditions. Importantly, MPA did not globally suppress B cell responsiveness or simply induce cell death, but rather selectively inhibited early activation events and arrested cells in the G0/G1 phase of the cell cycle. Furthermore, MPA blocked expansion of both naive and memory B cells and prevented plasma cell (PC) differentiation and Ab production from healthy controls and individuals with rheumatoid arthritis. Finally, whereas MPA potently suppressed Ig secretion from activated primary B cells, terminally differentiated PCs were not susceptible to inhibition by MPA. The target of MPA, IMPDH2, was found to be downregulated in PCs, likely explaining the resistance of these cells to MPA. These results suggest that MPA provides benefit in settings of autoimmunity by directly preventing activation and PC differentiation of B cells; however, MPA is unlikely to impact autoantibody production by preexisting, long-lived PCs. PMID:21873529

  20. Intravenous Immunoglobulin and Immunomodulation of B-Cell – in vitro and in vivo Effects

    PubMed Central

    Mitrevski, Milica; Marrapodi, Ramona; Camponeschi, Alessandro; Cavaliere, Filomena Monica; Lazzeri, Cristina; Todi, Laura; Visentini, Marcella

    2014-01-01

    Intravenous immunoglobulin (IVIG) is used as replacement therapy in patients with antibody deficiencies and at higher dosages in immune-mediated disorders. Although different mechanisms have been described in vitro, the in vivo immunomodulatory effects of IVIG are poorly understood. Different studies have suggested that IVIG modulates B-cell functions as activation, proliferation, and apoptosis. Recently, it was shown that IVIG induces in vitro B-cell unresponsiveness similar to anergy. In accord with this, we recently reported that IVIG therapy in patients affected by common variable immunodeficiency (CVID) interferes in vivo with the B-cell receptor (BCR) signaling by increasing constitutive ERK activation and by reducing the phosphorylated ERK increment induced by BCR cross-linking. Moreover, we observed that IVIG induces in CVID patients an increase of circulating CD21low B-cells, an unusual population of anergic-like B-cells prone to apoptosis. Therefore, IVIG at replacement dose in vivo could prime B-cells to an anergic, apoptotic program. Here, we discuss these recent findings, which may improve our understanding of the immunomodulatory effects of IVIG, individualizing single involved molecules for more specific treatments. PMID:25657650

  1. Type II NKT-TFH cells against Gaucher lipids regulate B-cell immunity and inflammation

    PubMed Central

    Nair, Shiny; Boddupalli, Chandra Sekhar; Verma, Rakesh; Liu, Jun; Yang, Ruhua; Pastores, Gregory M.; Mistry, Pramod K.

    2015-01-01

    Chronic inflammation including B-cell activation is commonly observed in both inherited (Gaucher disease [GD]) and acquired disorders of lipid metabolism. However, the cellular mechanisms underlying B-cell activation in these settings remain to be elucidated. Here, we report that ?-glucosylceramide 22:0 (?GL1-22) and glucosylsphingosine (LGL1), 2 major sphingolipids accumulated in GD, can be recognized by a distinct subset of CD1d-restricted human and murine type II natural killer T (NKT) cells. Human ?GL1-22– and LGL1-reactive CD1d tetramer–positive T cells have a distinct T-cell receptor usage and genomic and cytokine profiles compared with the classical type I NKT cells. In contrast to type I NKT cells, ?GL1-22– and LGL1-specific NKT cells constitutively express T-follicular helper (TFH) phenotype. Injection of these lipids leads to an increase in respective lipid-specific type II NKT cells in vivo and downstream induction of germinal center B cells, hypergammaglobulinemia, and production of antilipid antibodies. Human ?GL1-22– and LGL1-specific NKT cells can provide efficient cognate help to B cells in vitro. Frequency of LGL1-specific T cells in GD mouse models and patients correlates with disease activity and therapeutic response. Our studies identify a novel type II NKT-mediated pathway for glucosphingolipid-mediated dysregulation of humoral immunity and increased risk of B-cell malignancy observed in metabolic lipid disorders. PMID:25499455

  2. Inhibitors of B-cell receptor signaling for patients with B-cell malignancies.

    PubMed

    Choi, Michael Y; Kipps, Thomas J

    2012-01-01

    The B-cell receptor (BCR) complex and its associated protein tyrosine kinases play a critical role in the development, proliferation, and survival of normal or malignant B cells. Regulated activity of the BCR complex promotes the expansion of selected B cells and the deletion of unwanted or self-reactive ones. Compounds that inhibit various components of this pathway, including spleen tyrosine kinase, Bruton's tyrosine kinase, and phosphoinositol-3 kinase, have been developed. We summarize the rationale for use of agents that can inhibit BCR signaling to treat patients with either indolent or aggressive B-cell lymphomas, highlight early clinical results, and speculate on the future application of such agents in the treatment of patients with various B-cell lymphomas. PMID:23006944

  3. Inhibitors of B-cell Receptor Signaling for patients with B-cell malignancies

    PubMed Central

    Choi, Michael Y.; Kipps, Thomas J.

    2012-01-01

    The B-cell receptor (BCR) complex and its associated protein-tyrosine kinases play a critical role in the development, proliferation, and survival of normal or malignant B cells. Regulated activity of the BCR complex promotes the expansion of selected B cells and the deletion of unwanted or self-reactive ones. Compounds that inhibit various components of this pathway, including spleen tyrosine kinase (Syk), Bruton’s tyrosine kinase (Btk), and phosphoinositol-3 kinase (PI3K), have been developed. Herein we summarize the rationale for use of agents that can inhibit BCR-signaling to treat patients with either indolent or aggressive B-cell lymphomas, highlight early clinical results, and speculate on the future application of such agents in the treatment of patients with various B-cell lymphomas. PMID:23006944

  4. The role of B cells in multiple sclerosis: rationale for B-cell-targeted therapies.

    PubMed

    Racke, Michael K

    2008-04-01

    Multiple sclerosis is an inflammatory demyelinating disease of the central nervous system with no clear etiology. Until recently, most studies have emphasized the role of T cells in the pathogenesis of multiple sclerosis. Data suggesting that B cells play a role in the pathogenesis of multiple sclerosis have been accumulating for the past five decades, demonstrating that the cerebrospinal fluid and central nervous system tissues of multiple sclerosis patients contain B cells, plasma cells, antibodies, and immunoglobulins. Data suggest that B cells are involved in antigen capture and presentation to T cells, cytokine production, antibody secretion, demyelination, tissue damage, and remyelination in multiple sclerosis. These advances in the understanding of B-cell and antibody roles in the pathophysiology of multiple sclerosis provide a strong rationale for B-cell-targeted therapies. PMID:18388801

  5. Neutropenia and G-CSF in lymphoproliferative diseases

    PubMed Central

    Ria, Roberto; Reale, Antonia; Moschetta, Michele; Dammacco, Franco; Vacca, Angelo

    2013-01-01

    Background Chemotherapy-induced neutropenia is a major cause of morbidity and mortality. It frequently causes dose reductions or treatment delay, which can be prevented or treated by the administration of granulocyte-colony-stimulating factor (G-CSF). However, a better knowledge of the incidence, day of onset after therapy, and duration of neutropenia is essential to optimize the use of G-CSF. Design and methods Six hundred and ninety-four patients from a single institution, affected by lympho-proliferative diseases, were retrospectively reviewed for the occurrence of grade 4 neutropenia and febrile neutropenia (FN). Duration of neutropenia and time of neutrophil nadir were also retrieved. The diagnoses included non-Hodgkin's lymphoma, Hodgkin's lymphoma, and multiple myeloma. Chemotherapy regimens were obviously different according to the diagnosis, disease stage, and first or subsequent lines of therapy. Results No patient received G-CSF as primary prophylaxis. Median nadir did not significantly differ among patients treated with first or successive lines of therapy. The incidence of grade 4 neutropenia and FN ranged from 0 to 94%, depending on the chemotherapy regimen. Patients receiving a first-line chemotherapy regimen had a significantly lower incidence of febrile grade 4 neutropenia compared to patients treated with a second or subsequent line of therapy. The duration of grade 4 neutropenia was significantly longer in patients given second or subsequent lines. Conclusion The results of this study could be useful to define the nadir onset in the hematologic setting in order to correctly tailor timing and duration of G-CSF prophylaxis and to assess the lowest fully effective dose. PMID:23321273

  6. Interleukin-12 stimulation of lymphoproliferative responses in Trypanosoma cruzi infection

    PubMed Central

    Galvăo da Silva, Ana Paula; de Almeida Abrahamsohn, Ises

    2001-01-01

    The cytokine interleukin-12 (IL-12) is essential for resistance to Trypanosoma cruzi infection because it stimulates the synthesis of interferon-? (IFN-?), a major activator of the parasiticidal effect of macrophages. A less studied property of IL-12 is its ability to amplify the proliferation of T or natural killer (NK) lymphocytes. We investigated the role of endogenously produced IL-12 in the maintenance of parasite antigen (T-Ag)-specific lymphoproliferative responses during the acute phase of T. cruzi infection. We also studied whether treatment with recombinant IL-12 (rIL-12) would stimulate T-Ag-specific or concanavalin A (Con A)-stimulated lymphoproliferation and abrogate the suppression that is characteristic of the acute phase of infection. Production of IL-12 by spleen-cell cultures during T. cruzi infection increased in the first days of infection (days 3–5) and decreased as infection progressed beyond day 7. The growth-promoting activity of endogenous IL-12 on T-Ag-specific proliferation was observed on day 5 of infection. Treatment of cultures with rIL-12 promoted a significant increase in Con A-stimulated proliferation by spleen cells from normal or infected mice. Enhanced T-Ag-specific proliferation by rIL-12 was seen in spleen cell cultures from infected mice providing that nitric oxide production was inhibited by treatment with the competitive inhibitor NG-monomethyl-l-arginine (NMMA). Enhancement of proliferation promoted by IL-12 occurred in the presence of neutralizing anti-interleukin-2 (IL-2) antibody, suggesting that this activity of IL-12 was partly independent of endogenous IL-2. Thymidine incorporation levels achieved with rIL-12 treatment of the cultures were ? 50% of those stimulated by rIL-2 in the same cultures. PMID:11722650

  7. B cell lymphoma in hiv transgenic mice

    PubMed Central

    2013-01-01

    Background Human Immunodeficiency Virus Type I (HIV-1) infection is associated with a high incidence of B-cell lymphomas. The role of HIV in these lymphomas is unclear and currently there are no valid in vivo models for better understanding HIV-related lymphomagenesis. Transgenic (Tg) 26 mice have a 7.4-kb pNL4-3 HIV-1 provirus lacking a 3.1-kb sequence encompassing parts of the gag-pol region. Approximately 15% of these HIV Tg mice spontaneously develop lymphoma with hallmark pre-diagnostic markers including skin lesions, diffuse lymphadenopathy and an increase in pro-inflammatory serum cytokines. Here we describe the phenotypic and molecular characteristics of the B cell leukemia/lymphoma in the Tg mice. Results The transformed B cell population consists of CD19+pre-BCR+CD127+CD43+CD93+ precursor B cells. The tumor cells are clonal and characterized by an increased expression of several cellular oncogenes. Expression of B cell-stimulatory cytokines IL-1?, IL-6, IL-10, IL-12p40, IL-13 and TNF? and HIV proteins p17, gp120 and nef were elevated in the Tg mice with lymphoma. Conclusions Increased expression of HIV proteins and the B-cell stimulatory factors is consistent with the interpretation that one or more of these factors play a role in lymphoma development. The lymphomas share many similarities with those occurring in HIV/AIDS+ patients and may provide a valuable model for understanding AIDS-related lymphomagenesis and elucidating the role played by HIV-1. PMID:23985023

  8. Human blood IgM "memory" B cells are circulating splenic marginal zone B cells harboring a prediversified immunoglobulin repertoire

    E-print Network

    Boyer, Edmond

    Human blood IgM "memory" B cells are circulating splenic marginal zone B cells harboring authorship Abstract The human peripheral B cell compartment displays a large population of IgM IgD CD27 The human peripheral B cell compartment displays, in contrast to the mouse, a large population of CD27

  9. Long-Lived Plasma Cells and Memory B Cells Produce Pathogenic Anti-GAD65 Autoantibodies in Stiff Person Syndrome

    Microsoft Academic Search

    Marta Rizzi; Rolf Knoth; Christiane S. Hampe; Peter Lorenz; Marie-Lise Gougeon; Brigitte Lemercier; Nils Venhoff; Francesca Ferrera; Ulrich Salzer; Hans-Jürgen Thiesen; Hans-Hartmut Peter; Ulrich A. Walker; Hermann Eibel; Jacques Zimmer

    2010-01-01

    Stiff person syndrome (SPS) is a rare, neurological disorder characterized by sudden cramps and spasms. High titers of enzyme-inhibiting IgG autoantibodies against the 65 kD isoform of glutamic acid decarboxylase (GAD65) are a hallmark of SPS, implicating an autoimmune component in the pathology of the syndrome. Studying the B cell compartment and the anti-GAD65 B cell response in two monozygotic

  10. Anti B cell therapy (rituximab) in the treatment of autoimmune diseases.

    PubMed

    Kazkaz, Hanadi; Isenberg, David

    2004-08-01

    B cells play an important role in the pathogenesis of many autoimmune diseases. Selective targeting of these cells has been recently achieved using a chimeric monoclonal antibody against the pan B cell surface marker CD20 (rituximab). This antibody was originally developed for the treatment of non-Hodgkin's lymphoma. It was found to be effective, well tolerated and had a very good safety profile. Recent studies have demonstrated the efficacy of rituximab in several refractory autoimmune disorders including rheumatoid arthritis, systemic lupus erythematosus, immune thrombocytopenic purpura, chronic cold agglutinin disease, IgM-mediated neuropathies and mixed cryoglobulinemia. PMID:15251135

  11. B Cell-Intrinsic CD84 and Ly108 Maintain Germinal Center B Cell Tolerance.

    PubMed

    Wong, Eric B; Soni, Chetna; Chan, Alice Y; Domeier, Phillip P; Shwetank; Abraham, Thomas; Limaye, Nisha; Khan, Tahsin N; Elias, Melinda J; Chodisetti, Sathi Babu; Wakeland, Edward K; Rahman, Ziaur S M

    2015-05-01

    Signaling lymphocyte activation molecules (SLAMs) play an integral role in immune regulation. Polymorphisms in the SLAM family receptors are implicated in human and mouse model of lupus disease. The lupus-associated, somatically mutated, and class-switched pathogenic autoantibodies are generated in spontaneously developed germinal centers (GCs) in secondary lymphoid organs. The role and mechanism of B cell-intrinsic expression of polymorphic SLAM receptors that affect B cell tolerance at the GC checkpoint are not clear. In this study, we generated several bacterial artificial chromosome-transgenic mice that overexpress C57BL/6 (B6) alleles of different SLAM family genes on an autoimmune-prone B6.Sle1b background. B6.Sle1b mice overexpressing B6-derived Ly108 and CD84 exhibit a significant reduction in the spontaneously developed GC response and autoantibody production compared with B6.Sle1b mice. These data suggest a prominent role for Sle1b-derived Ly108 and CD84 in altering the GC checkpoint. We further confirm that expression of lupus-associated CD84 and Ly108 specifically on GC B cells in B6.Sle1b mice is sufficient to break B cell tolerance, leading to an increase in autoantibody production. In addition, we observe that B6.Sle1b B cells have reduced BCR signaling and a lower frequency of B cell-T cell conjugates; the reverse is seen in B6.Sle1b mice overexpressing B6 alleles of CD84 and Ly108. Finally, we find a significant decrease in apoptotic GC B cells in B6.Sle1b mice compared with B6 controls. Our study establishes a central role for GC B cell-specific CD84 and Ly108 expression in maintaining B cell tolerance in GCs and in preventing autoimmunity. PMID:25801429

  12. Somatic hypermutation and B-cell lymphoma.

    PubMed Central

    Dunn-Walters, D; Thiede, C; Alpen, B; Spencer, J

    2001-01-01

    During the B-cell response to T-cell-dependent antigens, the B cells undergo a rapid proliferative phase in the germinal centre. This is accompanied by the introduction of mutations into the immunoglobulin (Ig) variable region (V) genes. The B cells are then selected according to the affinity of the encoded immunoglobulin for antigen, resulting in affinity maturation of the response. Analysis of mutations in IgV genes has given insight into the history of individual B cells and their malignancies. In most cases, analysis of mutations confirms classifications of B-cell lineage designated by studies of cellular morphology and surface antigen expression. However, of particular interest is the subdivision of groups of malignancies by analysis of somatic hypermutation. It is now apparent that there are two subsets of chronic lymphocytic leukaemia (CLL), one with a low load of mutations and poor prognosis. and one with a heavy load of mutations with a much more favourable prognosis. In addition, in Burkitt's lymphoma, sporadic and endemic subtypes are now considered possibly to have a different pathogenesis, reflected in differences in the numbers of mutations. Hodgkin's disease, which was a mystery for many years, has now been shown to be a B-cell tumour. Although in many cases the Ig genes are crippled by somatic hypermutation, it is thought that failure to express Ig is more likely to be associated with problems of transcription. It has been proposed that the distribution of mutations in a B-cell lymphoma can be used to determine whether a lymphoma is selected. We have investigated the load and distribution of mutations in one group of lymphomas--marginal zone B-cell lymphomas of mucosa-associated lymphoid tissues (MALT-type lymphoma), which are dependent on Helicobacter pylori for disease progression, to investigate the limits of information that can be derived from such studies. Comparison of the load of mutations demonstrates that these tumours have approximately the same load of mutations as normal mucosal marginal zone B cells from the Peyer's patches and mucosal plasma cells. This is consistent with the origin of these cells from mucosal marginal zone B cells with plasma cell differentiation. To investigate selection in MALT lymphomas we compared a region of the framework region three in ten MALT lymphomas which use the V(H4) family, with the same codons in groups of V(H4) genes that are out of frame between V and J. The latter accumulate mutations but are not used and are not selected. A group of V(H4) genes are in-frame between V and J were also included for comparison. There were no obvious differences in the distribution of mutations between the groups of genes; the same hot spots and cold spots were apparent in each. In the MALT lymphomas, selection was apparent in the framework regions only and the tendency was to conserve. We therefore feel that there is selection to conserve antibody structure and that this does not reflect selection for antigen. We do not believe that antigen selection can be deduced reliably from sequence information alone. It is possible that somatic hypermutation could be a cause of malignancy since it has been shown that the process may generate DNA strand breaks and is known to be able to generate insertions and deletions. Such events may mediate the translocation of genes--a process that is pivotal in the evolution of many lymphomas. PMID:11205334

  13. Monoclonal antibodies for B-cell lymphomas: rituximab and beyond.

    PubMed

    Bello, Celeste; Sotomayor, Eduardo M

    2007-01-01

    The year 2007 marks the 10th anniversary of approval by the U.S. Food and Drug Adminstration of the first monoclonal antibody for the treatment of cancer. Rituximab, an anti-CD20 chimeric monoclonal antibody, was approved for the treatment of patients with relapsed/refractory low-grade B-cell non-Hodgkin lymphomas. From an immunologic perspective, this therapeutic indication provided the long-elusive validation of immunotherapy as the fourth modality of treatment for patients with cancer. From a clinical perspective, it was hard to imagine then that this nonchemotherapeutic approach would dramatically impact the management of patients with almost every type of B-cell malignancy and that it would even find a place as a therapeutic option for patients with non-malignant disorders. Although thousands of patients have been treated worldwide with rituximab, there is still debate regarding its mechanism(s) of action. The demonstration that a number of patients do not benefit with this treatment and that no cures have been achieved with single-agent rituximab prompted several investigators to identify those barriers limiting the efficacy of this monoclonal antibody. Here, we summarize what we have learned in the past 10 years about rituximab efficacy and its mechanisms of action and resistance. We also discuss the new generation of monoclonal antibodies, the development of which has been spurred by the widespread success of anti-CD20 MAb therapy. PMID:18024635

  14. Insight into B cell development and differentiation.

    PubMed

    Moschese, V; Orlandi, P; Di Matteo, G; Chini, L; Carsetti, R; Di Cesare, S; Rossi, P

    2004-05-01

    The main topic of this article is B cell development and differentiation, with a special focus on the mechanisms and molecules that regulate the expression of humoral immunity. Molecular epidemiological analysis was performed on the genes responsible for the X-linked agammaglobulinemia (XLA) phenotype of the majority of Italian patients and their distinct mutations were characterized. Mutations in Bruton's tyrosine kinase (BTK), a member of Tec Family of protein tyrosine kinases, have been found to be mainly responsible for XLA disease. The exact function of BTK in signal transduction is not yet known; thus, the specific role of BTK in receptor-dependent calcium signaling and the pro-antiapoptotic regulatory activity was addressed by transfecting RAMOS-1, a BTK-deficient human Burkitt's/B cell leukemia line with wild-type and mutant constructs. This work may provide clues about critical sites in the molecule and give support for gene therapy as a potential successful approach to XLA. Another aspect of this research is the identification and dissection of the molecular events that are likely to be directly related to the ability to express various isotypes of immunoglobulin with differing function and certain B cell immunodeficiency, mainly common variable disease and non-X-linked hyperIgM. B cell development and maturation steps in different compartments of the immune system are tracked by the analysis of cell-surface molecules and components of the signal transduction pathways, i.e. CD40, CD30, CD27, CD38, CD22 and CD24. A few components involved in B cell development, maturation and differentiation and their specific functional role are at least partially known, but these are far from fitting into an understandable pathway at present. PMID:15176720

  15. New insights in the regulation of human B cell differentiation

    PubMed Central

    Schmidlin, Heike; Diehl, Sean A.; Blom, Bianca

    2009-01-01

    B lymphocytes provide the cellular basis of the humoral immune response. All stages of this process, from B cell activation to formation of germinal centers and differentiation into memory B cells or plasma cells, are influenced by extrinsic signals and controlled by transcriptional regulation. Compared to naďve B cells, memory B cells display a distinct expression profile, which allows for their rapid secondary responses. Indisputably, many B cell malignancies result from aberrations in the circuitry controlling B cell function, particularly during the GC reaction. Here we review new insights into memory B cell subtypes, recent literature on transcription factors regulating human B cell differentiation, and further evidence for B cell lymphomagenesis emanating from errors during the GC cell reactions. PMID:19447676

  16. Signal transduction through the B cell antigen receptor is normal in ataxia-telangiectasia B lymphocytes.

    PubMed

    Speck, Peter; Ikeda, Masato; Ikeda, Akiko; Lederman, Howard M; Longnecker, Richard

    2002-02-01

    The rare human genetic disorder ataxia-telangiectasia (A-T) has multiple consequences including a variable degree of immunodeficiency. Khanna and co-workers (Khanna, K. K., Yan, J., Watters, D., Hobson, K., Beamish, H., Spring, K., Shiloh, Y., Gatti, R. A., and Lavin, M. F. (1997) J. Biol. Chem. 272, 9489-9495) evaluated signaling in Epstein-Barr virus (EBV) immortalized A-T lymphoblastoid cell lines (LCLs), derived from the B cells of A-T patients. They showed that A-T lymphoblastoid cells lack signaling through the B cell antigen receptor and concluded that the fault in A-T encompasses intracellular signaling in B cells. However, it is established that EBV latent membrane protein 2A (LMP2A) blocks signaling in EBV-bearing cells by interaction with cellular tyrosine kinases. To test whether the reported fault in A-T B cells was not inherent in A-T but the result of influence of wild-type EBV, we derived A-T LCLs with wild-type or LMP2A-deleted EBV and studied signaling in these cells in response to cross-linking the B cell antigen receptor. We report that intracellular calcium mobilization and tyrosine phosphorylation in LMP2A-depleted LCLs derived from A-T patients is indistinguishable from that in LMP2A-depleted LCLs derived from normal controls. Further, signaling is blocked similarly in A-T and normal lymphoblastoid cells bearing wild-type EBV. In conclusion there is no evidence of any defect in B cell receptor signal transduction in A-T B cells. PMID:11733529

  17. Congenital B cell lymphocytosis explained by novel germline CARD11 mutations

    PubMed Central

    Xiao, Wenming; Stinson, Jeffrey R.; Lu, Wei; Chaigne-Delalande, Benjamin; Zheng, Lixin; Pittaluga, Stefania; Matthews, Helen F.; Schmitz, Roland; Jhavar, Sameer; Kuchen, Stefan; Kardava, Lela; Wang, Wei; Lamborn, Ian T.; Jing, Huie; Raffeld, Mark; Moir, Susan; Fleisher, Thomas A.; Staudt, Louis M.; Su, Helen C.

    2012-01-01

    Nuclear factor-?B (NF-?B) controls genes involved in normal lymphocyte functions, but constitutive NF-?B activation is often associated with B cell malignancy. Using high-throughput whole transcriptome sequencing, we investigated a unique family with hereditary polyclonal B cell lymphocytosis. We found a novel germline heterozygous missense mutation (E127G) in affected patients in the gene encoding CARD11, a scaffolding protein required for antigen receptor (AgR)–induced NF-?B activation in both B and T lymphocytes. We subsequently identified a second germline mutation (G116S) in an unrelated, phenotypically similar patient, confirming mutations in CARD11 drive disease. Like somatic, gain-of-function CARD11 mutations described in B cell lymphoma, these germline CARD11 mutants spontaneously aggregate and drive constitutive NF-?B activation. However, these CARD11 mutants rendered patient T cells less responsive to AgR-induced activation. By reexamining this rare genetic disorder first reported four decades ago, our findings provide new insight into why activating CARD11 mutations may induce B cell expansion and preferentially predispose to B cell malignancy without dramatically perturbing T cell homeostasis. PMID:23129749

  18. Specific Depletion of Myelin-Reactive B Cells via BCR-Targeting

    PubMed Central

    Stepanov, A. V.; Belogurov Jr., A. A.; Kothapalli, P.; Shamborant, O. G.; Knorre, V. D.; Telegin, G. B.; Ovsepyan, A. A.; Ponomarenko, N. A.; Deyev, S. M.; Kaveri, S. V.; Gabibov, A. G.

    2015-01-01

    B cells play a crucial role in the development and pathogenesis of systemic and organ-specific autoimmune diseases. Autoreactive B cells not only produce antibodies, but also secrete pro-inflammatory cytokines and present specific autoantigens to T cells. The treatment of autoimmune diseases via the elimination of the majority of B cells using the monoclonal anti-CD19/20 antibody (Rituximab) causes systemic side effects and, thus, requires a major revision. Therapeutic intervention directed towards selective elimination of pathogenic autoreactive B cells has the potential to become a universal approach to the treatment of various autoimmune abnormalities. Here, we developed a recombinant immunotoxin based on the immunodominant peptide of the myelin basic protein (MBP), fused to the antibody Fc domain. We showed that the obtained immunotoxin provides selective in vivo elimination of autoreactive B cells in mice with experimental autoimmune encephalomyelitis. The proposed conception may be further used for the development of new therapeutics for a targeted treatment of multiple sclerosis and other autoimmune disorders. PMID:26085947

  19. Avian oncogenesis induced by lymphoproliferative disease virus: a neglected or emerging retroviral pathogen?

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Lymphoproliferative disease virus (LPDV) is an exogenous oncogenic retrovirus that induces lymphoid tumors in some galliform species of birds. Historically, outbreaks of LPDV have been reported from Europe and Israel. Although the virus has previously never been detected in North America, herein we ...

  20. Advances in Human B Cell Phenotypic Profiling

    PubMed Central

    Kaminski, Denise A.; Wei, Chungwen; Qian, Yu; Rosenberg, Alexander F.; Sanz, Ignacio

    2012-01-01

    To advance our understanding and treatment of disease, research immunologists have been called-upon to place more centralized emphasis on impactful human studies. Such endeavors will inevitably require large-scale study execution and data management regulation (“Big Biology”), necessitating standardized and reliable metrics of immune status and function. A well-known example setting this large-scale effort in-motion is identifying correlations between eventual disease outcome and T lymphocyte phenotype in large HIV-patient cohorts using multiparameter flow cytometry. However, infection, immunodeficiency, and autoimmunity are also characterized by correlative and functional contributions of B lymphocytes, which to-date have received much less attention in the human Big Biology enterprise. Here, we review progress in human B cell phenotyping, analysis, and bioinformatics tools that constitute valuable resources for the B cell research community to effectively join in this effort. PMID:23087687

  1. Treatment recommendations for patients with Waldenström macroglobulinemia (WM) and related disorders: IWWM-7 consensus.

    PubMed

    Dimopoulos, Meletios A; Kastritis, Efstathios; Owen, Roger G; Kyle, Robert A; Landgren, Ola; Morra, Enrica; Leleu, Xavier; García-Sanz, Ramón; Munshi, Nikhil; Anderson, Kenneth C; Terpos, Evangelos; Ghobrial, Irene M; Morel, Pierre; Maloney, David; Rummel, Mathias; Leblond, Véronique; Advani, Ranjana H; Gertz, Morie A; Kyriakou, Charalampia; Thomas, Sheeba K; Barlogie, Bart; Gregory, Stephanie A; Kimby, Eva; Merlini, Giampaolo; Treon, Steven P

    2014-08-28

    Waldenström macroglobulinemia (WM) is a distinct B-cell lymphoproliferative disorder for which clearly defined criteria for the diagnosis, initiation of therapy, and treatment strategy have been proposed as part of the consensus panels of International Workshops on WM (IWWM). As part of the IWWM-7 and based on recently published and ongoing clinical trials, the panels updated treatment recommendations. Therapeutic strategy in WM should be based on individual patient and disease characteristics (age, comorbidities, need for rapid disease control, candidacy for autologous transplantation, cytopenias, IgM-related complications, hyperviscosity, and neuropathy). Mature data show that rituximab combinations with cyclophosphamide/dexamethasone, bendamustine, or bortezomib/dexamethasone provided durable responses and are indicated for most patients. New monoclonal antibodies (ofatumumab), second-generation proteasome inhibitors (carfilzomib), mammalian target of rapamycin inhibitors, and Bruton's tyrosine kinase inhibitors are promising and may expand future treatment options. A different regimen is typically recommended for relapsed or refractory disease. In selected patients with relapsed disease after long-lasting remission, reuse of a prior effective regimen may be appropriate. Autologous stem cell transplantation may be considered in young patients with chemosensitive disease and in newly diagnosed patients with very-high-risk features. Active enrollment of patients with WM in clinical trials is encouraged. PMID:25027391

  2. Treatment recommendations for patients with Waldenström macroglobulinemia (WM) and related disorders: IWWM-7 consensus

    PubMed Central

    Kastritis, Efstathios; Owen, Roger G.; Kyle, Robert A.; Landgren, Ola; Morra, Enrica; Leleu, Xavier; García-Sanz, Ramón; Munshi, Nikhil; Anderson, Kenneth C.; Terpos, Evangelos; Ghobrial, Irene M.; Morel, Pierre; Maloney, David; Rummel, Mathias; Leblond, Véronique; Advani, Ranjana H.; Gertz, Morie A.; Kyriakou, Charalampia; Thomas, Sheeba K.; Barlogie, Bart; Gregory, Stephanie A.; Kimby, Eva; Merlini, Giampaolo; Treon, Steven P.

    2014-01-01

    Waldenström macroglobulinemia (WM) is a distinct B-cell lymphoproliferative disorder for which clearly defined criteria for the diagnosis, initiation of therapy, and treatment strategy have been proposed as part of the consensus panels of International Workshops on WM (IWWM). As part of the IWWM-7 and based on recently published and ongoing clinical trials, the panels updated treatment recommendations. Therapeutic strategy in WM should be based on individual patient and disease characteristics (age, comorbidities, need for rapid disease control, candidacy for autologous transplantation, cytopenias, IgM-related complications, hyperviscosity, and neuropathy). Mature data show that rituximab combinations with cyclophosphamide/dexamethasone, bendamustine, or bortezomib/dexamethasone provided durable responses and are indicated for most patients. New monoclonal antibodies (ofatumumab), second-generation proteasome inhibitors (carfilzomib), mammalian target of rapamycin inhibitors, and Bruton's tyrosine kinase inhibitors are promising and may expand future treatment options. A different regimen is typically recommended for relapsed or refractory disease. In selected patients with relapsed disease after long-lasting remission, reuse of a prior effective regimen may be appropriate. Autologous stem cell transplantation may be considered in young patients with chemosensitive disease and in newly diagnosed patients with very-high-risk features. Active enrollment of patients with WM in clinical trials is encouraged. PMID:25027391

  3. Toward a B-cell signature of tolerance?

    PubMed

    Cugini, Daniela; Noris, Marina

    2010-09-01

    Operational tolerance is a rare and still unexplained phenomenon in organ transplantation. Pallier et al. analyzed the peripheral B-cell compartment of 12 renal transplant patients with drug-free long-term graft function and found a peculiar blood B-cell phenotype, with an expansion of memory activated B cells and increased expression of inhibitory molecules, suggesting a role of B cells in maintaining graft tolerance. PMID:20706216

  4. Permissive environment for B-cell maturation in myositis muscle in the absence of B-cell follicles.

    PubMed

    Salajegheh, Mohammad; Pinkus, Jack L; Amato, Anthony A; Morehouse, Chris; Jallal, Bahija; Yao, Yihong; Greenberg, Steven A

    2010-10-01

    Myositis muscle contains antigen-matured B-cells and plasma cells. Myositis muscle biopsy specimens were examined for nodular collections of T-cells, B-cells, myeloid dendritic cells, plasma cells, and follicular dendritic cells. Immunoglobulin and B-cell-activating factor (BAFF) transcripts were quantitated. Laser-capture microdissection was used to isolate single plasma cells, and their immunoglobulin transcripts were sequenced. Dense inflammatory infiltrates contained histological elements of ectopic lymphoid tissue but not B-cell follicles. Immunoglobulin transcript sequence analysis demonstrated spatially distributed, clonally related B-cells and plasma cells, suggesting local maturation of B-cells into plasma cells in myositis muscle. Regions of dense cellular infiltrates in myositis muscle are sometimes areas of B-cell maturation into antibody-producing plasma cells. An atypical lymphoid histology, lacking concentrated collections of germinal-center-like B-cell follicles, is capable of antigen-stimulated clonal maturation of antibody-producing plasma cells. PMID:20740627

  5. Analyzing actin dynamics during the activation of the B cell receptor in live B cells

    PubMed Central

    Liu, Chaohong; Miller, Heather; Sharma, Shruti; Beaven, Amy; Upadhyaya, Arpita; Song, Wenxia

    2012-01-01

    Actin reorganization has been shown to be important for lymphocyte activation in response to antigenic stimulation. However, methods for quantitative analysis of actin dynamics in live lymphocytes are still underdeveloped. In this study, we describe new methods to examine the actin dynamics in B cells induced by antigenic stimulation. Using the A20 B cell line expressing GFP–actin, we analyzed in real time the redistribution of F-actin and the lateral mobility of actin flow in the surface of B cells in response to soluble and/or membrane associated antigens. Using fluorescently labeled G-actin, we identified the subcellular location and quantified the level of de novo actin polymerization sites in primary B cells. Using A20 B cells expressing G-actin fused with the photoconvertible protein mEos, we examined the kinetics of actin polymerization and depolymerization at the same time. Our studies present a set of methods that are capable of quantitatively analyzing the role of actin dynamics in lymphocyte activation. PMID:22995298

  6. The J6JFH1 strain of hepatitis C virus infects human B-cells with low replication efficacy.

    PubMed

    Nakai, Masato; Seya, Tsukasa; Matsumoto, Misako; Shimotohno, Kunitada; Sakamoto, Naoya; Aly, Hussein H

    2014-08-01

    Abstract Hepatitis C virus (HCV) infection is a serious health problem worldwide that can lead to hepatocellular carcinoma or end-stage liver disease. Current treatment with pegylated interferon, ribavirin, and NS3/4A protease inhibitor would lead to a good prognosis in a large population of patients, but there is still no effective vaccine for HCV. HCV robustly infects hepatocytes in the liver. However, extrahepatic manifestations such as mixed cryoglobulinemia, a systemic immune complex-mediated disorder characterized by B-cell proliferation, which may evolve into overt B-cell non-Hodgkin's lymphoma, have been demonstrated. HCV-RNA is often found to be associated with peripheral blood lymphocytes, suggesting a possible interaction with peripheral blood mononuclear cells (PBMCs), especially B-cells with HCV. B-cell HCV infection was a matter of debate for a long time, and the new advance in HCV in vitro infectious systems suggest that exosome can transmit HCV genome to support "infection." We aimed to clarify the susceptibility of primary B-cells to HCV infection, and to study its functional effect. In this article, we found that the recombinant HCV J6JFH1 strain could infect human B-cells isolated from the peripheral blood of normal volunteers by the detection of both HCV-negative-strand RNA by reverse transcription polymerase chain reaction, and NS5A protein. We also show the blocking of HCV replication by type I interferon after B-cell HCV infection. Although HCV replication in B-lymphocytes showed lower efficiency, in comparison with hepatocyte line (Huh7) cells, our results clearly demonstrate that human B-lymphocytes without other non-B-cells can actually be infected with HCV, and that this interaction leads to the induction of B-cells' innate immune response, and change the response of these cells to apoptosis. PMID:24853207

  7. Immunobiology Human blood IgM "memory" B cells are circulating splenic marginal zone B cells harboring

    E-print Network

    Paris-Sud XI, Université de

    1 Immunobiology Human blood IgM "memory" B cells are circulating splenic marginal zone B cells des Hopitaux de Paris, Kremlin- Bicętre (France) 10 Institute of Anatomy and Cell Biology, University compartment displays a large population of IgM+ IgD+ CD27+ "memory" B cell carrying a mutated Ig receptor. We

  8. Plasma markers of B-cell activation and clonality in pediatric liver and hematopoietic stem cell transplant recipients

    PubMed Central

    Engels, Eric A.; Savoldo, Barbara; Pfeiffer, Ruth M.; Costello, Rene; Zingone, Adriana; Heslop, Helen E.; Landgren, Ola

    2012-01-01

    Introduction Transplant recipients are at risk of post-transplant lymphoproliferative disease (PTLD). Methods: Thirty-six pediatric transplant recipients were evaluated (18 hematopoietic stem cell and 18 liver recipients; 12 had PTLD). We studied 207 longitudinal plasma samples from these recipients for three markers of B-cell activation or clonality: immunoglobulin free light chains (FLCs), soluble CD30 (sCD30), and monoclonal immunoglobulins (M-proteins). Results Kappa FLCs, lambda FLCs, and sCD30 were elevated in 20.8%, 28.0%, and 94.2% of plasma specimens, respectively. FLC and sCD30 levels increased significantly 1.18–1.82 fold per log10 Epstein Barr virus (EBV) load in peripheral blood. Five PTLD cases manifested elevated FLCs with an abnormal kappa/lambda ratio, suggesting monoclonal FLC production. M-proteins were present in 91% of PTLD cases, vs. 50–67% of other recipients with high or low EBV loads (p=0.13). Concordance of FLCs, M-proteins, and PTLD tumor light chain restriction was imperfect. For example, one PTLD case with an IgG lambda M-protein had a tumor that was kappa restricted, and another case with an M-protein had a T-cell PTLD. In an additional case, an IgM kappa M-protein and excess kappa FLCs were both detected in plasma at PTLD diagnosis; while the tumor was not restricted at diagnosis, kappa restriction was present 5 years later when the PTLD relapsed. Discussion Plasma markers of B-cell dysfunction are frequent following transplantation and associated with poor EBV control. These abnormal markers may be produced by oligoclonal B-cell populations or PTLD tumor cells, and could potentially help identify recipients at high risk of PTLD. PMID:23222884

  9. Gene Expression Profiling of the Response to Interferon Beta in Epstein-Barr-Transformed and Primary B Cells of Patients with Multiple Sclerosis

    PubMed Central

    Khsheibun, Rana; Paperna, Tamar; Volkowich, Anat; Lejbkowicz, Izabella; Avidan, Nili; Miller, Ariel

    2014-01-01

    The effects of interferon-beta (IFN-?), one of the key immunotherapies used in multiple sclerosis (MS), on peripheral blood leukocytes and T cells have been extensively studied. B cells are a less abundant leukocyte type, and accordingly less is known about the B cell-specific response to IFN-?. To identify gene expression changes and pathways induced by IFN-? in B cells, we studied the in vitro response of human Epstein Barr-transformed B cells (lymphoblast cell lines-LCLs), and validated our results in primary B cells. LCLs were derived from an MS patient repository. Whole genome expression analysis identified 115 genes that were more than two-fold differentially up-regulated following IFN-? exposure, with over 50 previously unrecognized as IFN-? response genes. Pathways analysis demonstrated that IFN-? affected LCLs in a similar manner to other cell types by activating known IFN-? canonical pathways. Additionally, IFN-? increased the expression of innate immune response genes, while down-regulating many B cell receptor pathway genes and genes involved in adaptive immune responses. Novel response genes identified herein, NEXN, DDX60L, IGFBP4, and HAPLN3, B cell receptor pathway genes, CD79B and SYK, and lymphocyte activation genes, LAG3 and IL27RA, were validated as IFN-? response genes in primary B cells. In this study new IFN-? response genes were identified in B cells, with possible implications to B cell-specific functions. The study's results emphasize the applicability of LCLs for studies of human B cell drug response. The usage of LCLs from patient-based repositories may facilitate future studies of drug response in MS and other immune-mediated disorders with a B cell component. PMID:25025430

  10. Autoimmune lymphoproliferative syndrome-like syndrome presented as lupus-like syndrome with mycobacterial joint infection evolved into the lymphoma

    Microsoft Academic Search

    Young Hoon Hong; Choong Ki Lee

    2009-01-01

    The autoimmune lymphoproliferative syndrome (ALPS) and ALPS-like syndrome are variable clinical conditions characterized by\\u000a lymphoproliferative disease, autoimmune cytopenias and susceptibility to malignancy. A 59-year-old woman was admitted to the\\u000a hospital for intractable generalized pain and stiffness with multiple swollen joints for 2 weeks. A low-grade fever, intermittent\\u000a hypotension and confusion were associated with the pain. The evaluation revealed multiple joint bony

  11. A critical role of Rap1b in B-cell trafficking and marginal zone B-cell development

    PubMed Central

    Chen, Yuhong; Yu, Mei; Podd, Andrew; Wen, Renren; Chrzanowska-Wodnicka, Magdalena; White, Gilbert C.

    2008-01-01

    B-cell development is orchestrated by complex signaling networks. Rap1 is a member of the Ras superfamily of small GTP-binding proteins and has 2 isoforms, Rap1a and Rap1b. Although Rap1 has been suggested to have an important role in a variety of cellular processes, no direct evidence demonstrates a role for Rap1 in B-cell biology. In this study, we found that Rap1b was the dominant isoform of Rap1 in B cells. We discovered that Rap1b deficiency in mice barely affected early development of B cells but markedly reduced marginal zone (MZ) B cells in the spleen and mature B cells in peripheral and mucosal lymph nodes. Rap1b-deficient B cells displayed normal survival and proliferation in vivo and in vitro. However, Rap1b-deficient B cells had impaired adhesion and reduced chemotaxis in vitro, and lessened homing to lymph nodes in vivo. Furthermore, we found that Rap1b deficiency had no marked effect on LPS-, BCR-, or SDF-1–induced activation of mitogen-activated protein kinases and AKT but clearly impaired SDF-1–mediated activation of Pyk-2, a key regulator of SDF-1–mediated B-cell migration. Thus, we have discovered a critical and distinct role of Rap1b in mature B-cell trafficking and development of MZ B cells. PMID:18319399

  12. PRODUCTION OF TUMOR NECROSIS FACTOR\\/CACHECTIN BY HUMAN B CELL LINES AND TONSILLAR B CELLS

    Microsoft Academic Search

    SUN-SANG J. SUNG; L. JUNG; JAY A. WALTERS; WEI CHEN; CHANG YI WANG; SHU MAN FU

    TNF\\/cachectin has diverse physiological functions and is produced by a wide va- riety ofcell types (reviewed in reference 1). Recently, evidence has accumulated that TNF may play regulatory roles in T and B lymphocyte activation, proliferation, anddifferentiation (2, 3) . ActivatedT cellshave been shown to produce aconsider- able amount of TNF (4-6) . However, the capacity of B cells to

  13. A Case of Isolated Cardiac Hydatid Cyst that Mimics Lymphoproliferative Malignancy.

    PubMed

    Yildiz, Cenk Eray; Sinan, Ümit Ya?ar; Yildiz, Ahmet; Çetin, Gürkan; Küçüko?lu, Serdar

    2015-06-01

    Cardiac cystic echinococcosis is a rare parasitic infestation caused by Echinococcus granulosus larvae and it composes 0.5-2% of all human cystic echinococcosis cases. The left ventricle is the most common affected area followed by right ventricle, interventricular septum, left atrium, right atrium, and interatrial septum. The diagnosis is difficult because of nonspecific clinical and radiographic findings. We present a case of isolated apical cardiac cystic echinococcosis mimicking lymphoproliferative disease. PMID:25470654

  14. The SAP and SLAM families in immune responses and X-linked lymphoproliferative disease

    Microsoft Academic Search

    Michael J. Eck; Cox Terhorst; Pablo Engel

    2003-01-01

    SAP (signalling lymphocytic activation molecule (SLAM)-associated protein) is a T- and natural killer (NK)-cell-specific protein containing a single SH2 domain encoded by a gene that is defective or absent in patients with X-linked lymphoproliferative syndrome (XLP). The SH2 domain of SAP binds with high affinity to the cytoplasmic tail of the haematopoietic cell-surface glycoprotein SLAM and five related receptors. SAP

  15. Lymphoproliferative Disorders with Early Lethality in Mice Deficient in Ctla-4

    Microsoft Academic Search

    Paul Waterhouse; Josef M. Penninger; Emma Timms; Andrew Wakeham; Arda Shahinian; Kelvin P. Lee; Craig B. Thompson; Henrik Griesser; Tak W. Mak

    1995-01-01

    The role of the cell-surface molecule CTLA-4 in the regulation of T cell activation has been controversial. Here, lymph nodes and spleens of CTLA-4-deficient mice accumulated T cell blasts with up-regulated activation markers. These blast cells also infiltrated liver, heart, lung, and pancreas tissue, and amounts of serum immunoglobulin were elevated. The mice invariably became moribund by 3 to 4

  16. Entry of Francisella tularensis into Murine B Cells: The Role of B Cell Receptors and Complement Receptors

    PubMed Central

    Plzakova, Lenka; Krocova, Zuzana; Kubelkova, Klara; Macela, Ales

    2015-01-01

    Francisella tularensis, the etiological agent of tularemia, is an intracellular pathogen that dominantly infects and proliferates inside phagocytic cells but can be seen also in non-phagocytic cells, including B cells. Although protective immunity is known to be almost exclusively associated with the type 1 pathway of cellular immunity, a significant role of B cells in immune responses already has been demonstrated. Whether their role is associated with antibody-dependent or antibody-independent B cell functions is not yet fully understood. The character of early events during B cell–pathogen interaction may determine the type of B cell response regulating the induction of adaptive immunity. We used fluorescence microscopy and flow cytometry to identify the basic requirements for the entry of F. tularensis into B cells within in vivo and in vitro infection models. Here, we present data showing that Francisella tularensis subsp. holarctica strain LVS significantly infects individual subsets of murine peritoneal B cells early after infection. Depending on a given B cell subset, uptake of Francisella into B cells is mediated by B cell receptors (BCRs) with or without complement receptor CR1/2. However, F. tularensis strain FSC200 ?iglC and ?ftdsbA deletion mutants are defective in the ability to enter B cells. Once internalized into B cells, F. tularensis LVS intracellular trafficking occurs along the endosomal pathway, albeit without significant multiplication. The results strongly suggest that BCRs alone within the B-1a subset can ensure the internalization process while the BCRs on B-1b and B-2 cells need co-signaling from the co receptor containing CR1/2 to initiate F. tularensis engulfment. In this case, fluidity of the surface cell membrane is a prerequisite for the bacteria’s internalization. The results substantially underline the functional heterogeneity of B cell subsets in relation to F. tularensis. PMID:26161475

  17. Antibody Therapy of Pediatric B-Cell Lymphoma

    PubMed Central

    Meyer-Wentrup, Friederike; de Zwart, Verena; Bierings, Marc

    2013-01-01

    B-cell lymphoma in children accounts for about 10% of all pediatric malignancies. Chemotherapy has been very successful leading to an over-all 5-year survival between 80 and 90% depending on lymphoma type and extent of disease. Therapeutic toxicity remains high calling for better targeted and thus less toxic therapies. Therapeutic antibodies have become a standard element of B-cell lymphoma therapy in adults. Clinical experience in pediatric lymphoma patients is still very limited. This review outlines the rationale for antibody treatment of B-cell lymphomas in children and describes potential target structures on B-cell lymphoma cells. It summarizes the clinical experience of antibody therapy of B-cell lymphoma in children and gives an outlook on new developments and challenges for antibody therapy of pediatric B-cell lymphoma. PMID:23565504

  18. Negative signaling in B cells: SHIP Grbs Shc

    Microsoft Academic Search

    Susheela Tridandapani; Todd Kelley; Damon Cooney; Madhura Pradhan; K. Mark Coggeshall

    1997-01-01

    Negative signaling in B cells is initiated by co-crosslinking of the antigen receptor and the Fcy receptor, resulting in cessation of B-cell signaling events and, in turn, inhibiting B-cell proliferation and antibody secretion. Here, a competitive role is proposed for SHIP in blocking the interaction of Shc with the Grb2-Sos complex of proteins that lead to Ras activation in B

  19. Transcriptional networks in developing and mature B cells

    Microsoft Academic Search

    Antonius G. Rolink; Patrick Matthias

    2005-01-01

    The development of B cells from haematopoietic stem cells proceeds along a highly ordered, yet flexible, pathway. At multiple steps along this pathway, cells are instructed by transcription factors on how to further differentiate, and several check-points have been identified. These check-points are initial commitment to lymphocytic progenitors, specification of pre-B cells, entry to the peripheral B-cell pool, maturation of

  20. Is Hodgkin lymphoma just another B-cell lymphoma?

    Microsoft Academic Search

    Harald Stein; Roshanak Bob

    2009-01-01

    Hodgkin disease was the first defined lymphoid neoplasm. For many decades it was regarded as a disease separate from non-Hodgkin\\u000a lymphoma. However, recent studies have shown that the dysplastic cells of Hodgkin lymphoma (HL) are monoclonal B cells. This\\u000a finding raised again the question “Is HL just another B-cell lymphoma?” This article reviews the different aspects of HL and\\u000a B-cell

  1. Primary B-cell lymphoblastic lymphoma of the testis.

    PubMed

    Tombolini, Flavia; Lacetera, Vito; Gini, Guido; Capelli, Debora; Leoni, Pietro; Montironi, Rodolfo; Galosi, Andrea Benedetto; Muzzonigro, Giovanni

    2014-12-01

    We present a rare case of primary lymphoblastic B-cell lymphoma of the testis focusing on ultrasonographic and pathological features and clinical implications. Pathological examination revealed primary testicular lymphoblastic B-cell lymphoma which was treated with adjuvant chemotherapy, including rachicentesis with administration of chemotherapy and with radiotherapy of contralateral testis. Primary testicular lymphoblastic B cell lymphoma is an aggressive disease and it is necessary a multimodal therapy (surgery, chemotherapy and radiotherapy) to prevent metastasis. PMID:25641484

  2. Modulation of murine bone marrow-derived dendritic cells and B-cells by MCS-18 a natural product isolated from Helleborus purpurascens.

    PubMed

    Littmann, Leonie; Rössner, Susanne; Kerek, Franz; Steinkasserer, Alexander; Zinser, Elisabeth

    2008-01-01

    MCS-18, a natural product isolated from Helleborus purpurascens has been shown to have several beneficial effects in inflammatory and autoimmune disorders. However, very little is known regarding the immuno-modulatory capacity of MCS-18 in respect to murine bone marrow-derived dendritic cells (BM-DC) and B-cells. Thus, in the present study we examined the effect of MCS-18 on murine BM-DC and B-cells. Interestingly MCS-18 inhibited the expression of important DC-specific molecules and lead to an impaired T-cell stimulation capacity. In addition, MCS-18 also reduced B-cell proliferation and immunoglobulin production. PMID:18926301

  3. The development and function of thymic B cells.

    PubMed

    Perera, Jason; Huang, Haochu

    2015-07-01

    Thymic B cells are a unique population of B lymphocytes that reside at the cortico-medullary junction of the thymus, an organ that is specialized for the development and selection of T cells. These B cells are distinct from peripheral B cells both in terms of their origin and phenotype. Multiple lines of evidence suggest that they develop within the thymus from B lineage-committed progenitors and are not recirculating peripheral B cells. Furthermore, thymic B cells have a highly activated phenotype. Because of their location in the thymic medulla, they have been thought to play a role in T cell negative selection. Thymic B cells are capable of inducing negative selection in a number of model antigen systems, including viral super antigen, peptides from immunoglobulin, and cognate self antigen presented by B cell receptor-mediated uptake. These findings establish thymic B cells as a novel and important population to study; however, much work remains to be done to understand how all of these unique aspects of thymic B cell biology inform their function. PMID:25837998

  4. Attenuated liver fibrosis in the absence of B cells

    PubMed Central

    Novobrantseva, Tatiana I.; Majeau, Gerard R.; Amatucci, Aldo; Kogan, Sophia; Brenner, Ian; Casola, Stefano; Shlomchik, Mark J.; Koteliansky, Victor; Hochman, Paula S.; Ibraghimov, Alexander

    2005-01-01

    Analysis of mononuclear cells in the adult mouse liver revealed that B cells represent as much as half of the intrahepatic lymphocyte population. Intrahepatic B cells (IHB cells) are phenotypically similar to splenic B2 cells but express lower levels of CD23 and CD21 and higher levels of CD5. IHB cells proliferate as well as splenic B cells in response to anti-IgM and LPS stimulation in vitro. VDJ gene rearrangements in IHB cells contain insertions of N,P region nucleotides characteristic of B cells maturing in the adult bone marrow rather than in the fetal liver. To evaluate whether B cells can have an impact on liver pathology, we compared CCl4-induced fibrosis development in B cell–deficient and wild-type mice. CCl4 caused similar acute liver injury in mutant and wild-type mice. However, following 6 weeks of CCl4 treatment, histochemical analyses showed markedly reduced collagen deposition in B cell–deficient as compared with wild-type mice. By analyzing mice that have normal numbers of B cells but lack either T cells or immunoglobulin in the serum, we established that B cells have an impact on fibrosis in an antibody- and T cell–independent manner. PMID:16276416

  5. IFN-? treatment requires B cells for efficacy in neuroautoimmunity.

    PubMed

    Schubert, Ryan D; Hu, Yang; Kumar, Gaurav; Szeto, Spencer; Abraham, Peter; Winderl, Johannes; Guthridge, Joel M; Pardo, Gabriel; Dunn, Jeffrey; Steinman, Lawrence; Axtell, Robert C

    2015-03-01

    IFN-? remains the most widely prescribed treatment for relapsing remitting multiple sclerosis. Despite widespread use of IFN-?, the therapeutic mechanism is still partially understood. Particularly, the clinical relevance of increased B cell activity during IFN-? treatment is unclear. In this article, we show that IFN-? pushes some B cells into a transitional, regulatory population that is a critical mechanism for therapy. IFN-? treatment increases the absolute number of regulatory CD19(+)CD24(++)CD38(++) transitional B cells in peripheral blood relative to treatment-naive and Copaxone-treated patients. In addition, we found that transitional B cells from both healthy controls and IFN-?-treated MS patients are potent producers of IL-10, and that the capability of IFN-? to induce IL-10 is amplified when B cells are stimulated. Similar changes are seen in mice with experimental autoimmune encephalomyelitis. IFN-? treatment increases transitional and regulatory B cell populations, as well as IL-10 secretion in the spleen. Furthermore, we found that IFN-? increases autoantibody production, implicating humoral immune activation in B cell regulatory responses. Finally, we demonstrate that IFN-? therapy requires immune-regulatory B cells by showing that B cell-deficient mice do not benefit clinically or histopathologically from IFN-? treatment. These results have significant implications for the diagnosis and treatment of relapsing remitting multiple sclerosis. PMID:25646307

  6. B-cell-activating factor inhibits CD20-mediated and B-cell receptor-mediated apoptosis in human B cells

    PubMed Central

    Saito, Yohei; Miyagawa, Yoshitaka; Onda, Keiko; Nakajima, Hideki; Sato, Ban; Horiuchi, Yasuomi; Okita, Hajime; Katagiri, Yohko U; Saito, Masahiro; Shimizu, Toshiaki; Fujimoto, Junichiro; Kiyokawa, Nobutaka

    2008-01-01

    B-cell-activating factor (BAFF) is a survival and maturation factor for B cells belonging to the tumour necrosis factor superfamily. Among three identified functional receptors, the BAFF receptor (BAFF-R) is thought to be responsible for the effect of BAFF on B cells though details of how remain unclear. We determined that a hairy-cell leukaemia line, MLMA, expressed a relatively high level of BAFF-R and was susceptible to apoptosis mediated by either CD20 or B-cell antigen receptor (BCR). Using MLMA cells as an in vitro model of mature B cells, we found that treatment with BAFF could inhibit apoptosis mediated by both CD20 and BCR. We also observed, using immunoblot analysis and microarray analysis, that BAFF treatment induced activation of nuclear factor-?B2 following elevation of the expression level of Bcl-2, which may be involved in the molecular mechanism of BAFF-mediated inhibition of apoptosis. Interestingly, BAFF treatment was also found to induce the expression of a series of genes, such as that for CD40, related to cell survival, suggesting the involvement of a multiple mechanism in the BAFF-mediated anti-apoptotic effect. MLMA cells should provide a model for investigating the molecular basis of the effect of BAFF on B cells in vitro and will help to elucidate how B cells survive in the immune system in which BAFF-mediated signalling is involved. PMID:18540961

  7. Nodular lymphocyte-predominant Hodgkin's lymphoma and T-cell\\/histiocyte-rich large B-cell lymphoma: near neighbours or distant cousins?

    Microsoft Academic Search

    R. Achten; C. De Wolf-Peeters

    2004-01-01

    The clinicopathological distinctiveness of nodular lymphocyte-predominant Hodgkin's lymphoma (NLPHL) is now unanimously recognized. Occasionally, NLPHL lesions are difficult to distinguish from T-cell\\/histiocyte-rich large B-cell lymphoma (THR-BCL), a morphological variant of diffuse large B-cell lymphoma. It has been suggested that THR-BCL represents a phenotypically peculiar expression or an evolutionary stage of NLPHL. Here, we present a review of both disorders, integrating

  8. Identification of bovine B cell reactive and B cell specific monoclonal antibodies.

    PubMed

    Mukwedeya, D T; Takamatsu, H; Parkhouse, R M

    1993-11-01

    All monoclonal antibodies (mAbs) submitted to the workshop panel were screened for reactivity with bovine surface immunoglobulin (sIg)+ cells (gated small dense lymphocytes from peripheral blood) by fluorescence activated cell sorter (FACS) analysis. Eighteen temporary clusters--TCs 1-12, 15, 16, 18, 19, 25 and 26--contained mAbs reactive with sIg+ cells. mAb BAS21A (unclustered) and CC92 (TC25) were also reactive with sIg+ cells. Further FACS analysis with B cells from peripheral blood lymphocytes and mesenteric lymph nodes, and B and T lymphoma cell lines, indicated that the majority of mAbs within TCs 2, 4, 15, 18 and 26 reacted specifically with bovine B cells. Bovine B cell specific mAbs within these clusters were TH14B, IL-A55, CACT101A, MUC76A from TC4, VPM30, GC65A, CACT65A from TC15, IL-A58, CC56, CC70, IL-A65 from TC18, and CC57 and 26A9 from TC26. Three mAbs--IL-A65, CC70, and BAQ15A--within TC18 defined WC3; mAbs TD9 and CC56 may also be related to WC3. PMID:8310643

  9. How B Cells Influence Bone Biology in Health and Disease

    PubMed Central

    Horowitz, Mark C.; Fretz, Jackie A.; Lorenzo, Joseph A.

    2010-01-01

    It is now well established that important regulatory interactions occur between the cells in the hematopoietic, immune and skeletal systems (osteoimmunology). B lymphocytes (B cells) are responsible for the generation and production of antibodies or immunoglobulins in the body. Together with T cells these lymphocytes comprise the adaptive immune system, which allows an individual to develop specific responses to an infection and retain memory of that infection, allowing for a faster and more robust response if that same infection occurs again. In addition to this immune function, B cells have a close and multifaceted relationship with bone cells. B cells differentiate from hematopoietic stem cells (HSCs) in supportive niches found on endosteal bone surfaces. Cells in the osteoblast lineage support HSC and B cell differentiation in these niches. B cell differentiation is regulated, at least in part, by a series of transcription factors that function in a temporal manner. While these transcription factors are required for B cell differentiation, their loss causes profound changes in the bone phenotype. This is due, in part, to the close relationship between macrophage/osteoclast and B cell differentiation. Cross talk between B cells and bone cells is reciprocal with defects in the RANKL-RANK, OPG signaling axis resulting in altered bone phenotypes. While the role of B cells during normal bone remodeling appears minimal, activated B cells play an important role in many inflammatory diseases with associated bony changes. This review examines the relationship between B cells and bone cells and how that relationship affects the skeleton and hematopoiesis during health and disease. PMID:20601290

  10. Epigenetic ontogeny of the Igk locus during B cell development

    Microsoft Academic Search

    Maya Goldmit; Yanhong Ji; Jane Skok; Esther Roldan; Steffen Jung; Howard Cedar; Yehudit Bergman

    2004-01-01

    To become accessible for rearrangement, the immunoglobulin ? locus must undergo a series of epigenetic changes. This begins in pro–B cells with the relocation of both immunoglobulin ? alleles from the periphery to the center of the nucleus. In pre–B cells, one allele became preferentially packaged into an active chromatin structure characterized by histone acetylation and methylation of histone H3

  11. RESEARCH Open Access B cells as biomarkers and

    E-print Network

    Paris-Sud XI, Université de

    RESEARCH Open Access CD80+ and CD86+ B cells as biomarkers and possible therapeutic targets in HTLV-modifying therapies with long-term clinical benefits or validated biomarkers for clinical follow-up in HAM clinically useful biomarkers in HAM/TSP. Results: Ex vivo expression of CD80 and CD86 in T and B cells

  12. Differentiation of normal human pre-B cells in vitro

    PubMed Central

    1990-01-01

    The differentiation of surface Ig- pre-B cells into surface Ig+ B cells is a critical transition in mammalian B cell ontogeny. Elucidation of the growth factor requirements and differentiative potential of human pre-B cells has been hampered by the absence of a reproducible culture system that supports differentiation. Fluorescence-activated cell sorting and magnetic bead depletion were used to purify fetal bone marrow CD10+/surface mu- cells, which contain 60-70% cytoplasmic mu+ pre-B cells. CD10+/surface mu- cells cultured for 2 d were observed to differentiate into surface mu+ cells. Analysis by Southern blotting provided direct evidence that rearrangement of kappa light chain genes occurs in culture, and flow cytometric analysis revealed the appearance of surface Ig+ B cells expressing mu/kappa or mu/lambda. Unexpectedly, the kappa/lambda ratio in differentiated cells was the inverse of what is normally observed in adult peripheral blood. Differentiation occurs in the absence of exogenous growth factors or cytokines, suggesting that a stimulus-independent differentiative inertia might characterize pre-B cells in vivo. Future use of this model will facilitate our understanding of normal and abnormal human pre-B cell differentiation. PMID:2141629

  13. Murid Herpesvirus-4 Exploits Dendritic Cells to Infect B Cells

    PubMed Central

    Frederico, Bruno; Gill, Michael B.; Smith, Christopher M.; Belz, Gabrielle T.; Stevenson, Philip G.

    2011-01-01

    Dendritic cells (DCs) play a central role in initiating immune responses. Some persistent viruses infect DCs and can disrupt their functions in vitro. However, these viruses remain strongly immunogenic in vivo. Thus what role DC infection plays in the pathogenesis of persistent infections is unclear. Here we show that a persistent, B cell-tropic gamma-herpesvirus, Murid Herpesvirus-4 (MuHV-4), infects DCs early after host entry, before it establishes a substantial infection of B cells. DC-specific virus marking by cre-lox recombination revealed that a significant fraction of the virus latent in B cells had passed through a DC, and a virus attenuated for replication in DCs was impaired in B cell colonization. In vitro MuHV-4 dramatically altered the DC cytoskeleton, suggesting that it manipulates DC migration and shape in order to spread. MuHV-4 therefore uses DCs to colonize B cells. PMID:22102809

  14. Plasma Cell Disorders

    MedlinePLUS

    ... cell disorders are uncommon. They begin when a single plasma cell multiplies excessively. The resulting group of genetically identical ... a clone) produces a large quantity of a single type of antibody (immunoglobulin). Plasma cells develop from B cells (B lymphocytes), a type ...

  15. Methotrexate-associated Lymphoproliferative Disease with Multiple Pulmonary Nodules in a Patient with Rheumatoid Arthritis.

    PubMed

    Suemori, Koichiro; Hasegawa, Hitoshi; Ishizaki, Jun; Matsumoto, Takuya; Onishi, Sachiko; Sada, Eiji; Sugita, Atsuro; Yasukawa, Masaki

    2015-01-01

    Patients with rheumatoid arthritis (RA) treated with methotrexate (MTX) sometimes develop lymphoproliferative disease (LPD). MTX-associated LPD can affect nodal or extranodal sites, including the gastrointestinal tract, skin, lungs, kidneys and soft tissues, at almost equal frequency. However, it is very rare for MTX-associated LPD to manifest as multiple nodules in the lungs. We herein report the case of a RA patient who developed MTX-associated LPD with multiple pulmonary nodules during a 5-year course of MTX therapy. PMID:26028000

  16. ZNF385B is characteristically expressed in germinal center B cells and involved in B-cell apoptosis.

    PubMed

    Iijima, Kazutoshi; Yamada, Hiroyuki; Miharu, Masashi; Imadome, Ken-Ichi; Miyagawa, Yoshitaka; Akimoto, Shingo; Kobayashi, Kenichiro; Okita, Hajime; Nakazawa, Atsuko; Fujiwara, Shigeyoshi; Fujimoto, Junichiro; Kiyokawa, Nobutaka

    2012-12-01

    We previously identified zinc finger (ZF) protein ZNF385B as a molecule specifically expressed in Burkitt's lymphoma (BL) among hematologic malignancies. Here, we investigated ZNF385B expression in healthy B cells in a variety of hematological tissues by RT-PCR and immunohistochemistry. ZNF385B expression was found to be limited to a subset of GC B cells, the healthy counterpart to BL B cells. To elucidate the function of ZNF385B in healthy B cells, we established a tetracycline-controlled protein-inducible system in B-cell lines and observed that ectopic expression of the longest transcript variant of ZNF385B, possessing four ZF domains, induced upregulation of PERP and FAS/CD95, a downstream target of p53, and activation of caspase, resulting in apoptosis induction. However, a ZNF385B deletion mutant with three ZF domains corresponding to shorter isoforms, did not induce upregulation; rather it inhibited apoptosis induced by CD20 cross-linking and BCR stimulation. The direct binding of ZNF385B with p53 has suggested the involvement of ZNF385B in B-cell apoptosis via modulation of p53 transactivation; our data indicate that ZNF385B characteristically expressed in GC B cells has both proapoptotic and antiapoptotic activities depending on the type of isoform and should be a novel player in GC B-cell selection. PMID:22945289

  17. Integrin-mediated interactions between B cells and follicular dendritic cells influence germinal center B cell fitness.

    PubMed

    Wang, Xiaoming; Rodda, Lauren B; Bannard, Oliver; Cyster, Jason G

    2014-05-15

    Integrin-ligand interactions between germinal center (GC) B cells and Ag-presenting follicular dendritic cells (FDCs) have been suggested to play central roles during GC responses, but their in vivo requirement has not been directly tested. In this study, we show that, whereas integrins ?L?2 and ?4?1 are highly expressed and functional on mouse GC B cells, removal of single integrins or their ligands had little effect on B cell participation in the GC response. Combined ?2 integrin deficiency and ?4 integrin blockade also did not affect the GC response against a particulate Ag. However, the combined integrin deficiency did cause B cells to be outcompeted in splenic GC responses against a soluble protein Ag and in mesenteric lymph node GC responses against gut-derived Ags. Similar findings were made for ?2-deficient B cells in mice lacking VCAM1 on FDCs. The reduced fitness of the GC B cells did not appear to be due to decreased Ag acquisition, proliferation rates, or pAKT levels. In summary, our findings provide evidence that ?L?2 and ?4?1 play overlapping and context-dependent roles in supporting interactions with FDCs that can augment the fitness of responding GC B cells. We also find that mouse GC B cells upregulate ?v?3 and adhere to vitronectin and milk-fat globule epidermal growth factor VIII protein. Integrin ?3-deficient B cells contributed in a slightly exaggerated manner to GC responses, suggesting this integrin has a regulatory function in GC B cells. PMID:24740506

  18. Integrin-mediated interactions between B cells and follicular dendritic cells influence germinal center B cell fitness1

    PubMed Central

    Wang, Xiaoming; Rodda, Lauren; Bannard, Oliver; Cyster, Jason G.

    2014-01-01

    Integrin-ligand interactions between germinal center (GC) B cells and antigen-presenting follicular dendritic cells (FDCs) have been suggested to play central roles during GC responses but their in vivo requirement has not been directly tested. Here we show that while integrins ?L?2 and ?4?1 are highly expressed and functional on mouse GC B cells, removal of single integrins or their ligands had little effect on B cell participation in the GC response. Combined ?2-integrin deficiency and ?4-integrin blockade also did not affect the GC response against a particulate antigen. However, the combined integrin deficiency did cause B cells to be outcompeted in splenic GC responses against a soluble protein antigen and in mesenteric lymph node GC responses against gut-derived antigens. Similar findings were made for ?2-deficient B cells in mice lacking VCAM1 on FDCs. The reduced fitness of the GC B cells did not appear to be due to decreased antigen acquisition, proliferation rates or pAKT levels. In summary, our findings provide evidence that ?L?2 and ?4?1 play overlapping and context-dependent roles in supporting interactions with FDCs that can augment the fitness of responding GC B cells. We also find that mouse GC B cells upregulate ?v?3 and adhere to vitronectin and milk fat globule EGF-factor-8 protein. Integrin ?3-deficient B cells contributed in a slightly exaggerated manner to GC responses suggesting this integrin has a regulatory function in GC B cells. PMID:24740506

  19. Exploiting Human Memory B Cell Heterogeneity for Improved Vaccine Efficacy

    PubMed Central

    Pauli, Noel T.; Henry Dunand, Carole J.; Wilson, Patrick C.

    2011-01-01

    The major goal in vaccination is establishment of long-term, prophylactic humoral memory to a pathogen. Two major components to long-lived humoral memory are plasma cells for the production of specific immunoglobulin and memory B cells that survey for their specific antigen in the periphery for later affinity maturation, proliferation, and differentiation. The study of human B cell memory has been aided by the discovery of a general marker for B cell memory, expression of CD27; however, new data suggests the existence of CD27? memory B cells as well. These recently described non-canonical memory populations have increasingly pointed to the heterogeneity of the memory compartment. The novel B memory subsets in humans appear to have unique origins, localization, and functions compared to what was considered to be a “classical” memory B cell. In this article, we review the known B cell memory subsets, the establishment of B cell memory in vaccination and infection, and how understanding these newly described subsets can inform vaccine design and disease treatment. PMID:22566866

  20. Construction of a YAC contig and STS map spanning 2.5 Mbp in Xq25, the critical region for the X-linked lymphoproliferative (XLP) gene

    SciTech Connect

    Lanyi, A.; Li, B.F.; Li, S. [Univ. of Nebraska Medical Center, Omaha, NE (United States)] [and others

    1994-09-01

    X-linked lymphoproliferative disease (XLP) is characterized by a marked vulnerability in Epstein-Barr virus (EBV) infection. Infection of XLP patients with EBV invariably results in fatal mononucleosis, agammaglobulinemia or B-cell lymphoma. The XLP gene lies within a 10 cM region in Xq25 between DXS42 and DXS10. Initial chromosome studies revealed an interstitial, cytogenetically visible deletion in Xq25 in one XLP family (43-004). We estimated the size of the Xq25 deletion by dual laser flow karyotyping to involve 2% of the X chromosome, or approximately 3 Mbp of DNA sequences. To further delineate the deletion we performed a series of pulsed field gel electrophoresis (PFGE) analyses which showed that DXS6 and DXS100, two Xq25-specific markers, are missing from 45-004 DNA. Five yeast artificial chromosomes (YACs) from a chromosome X specific YAC library containing sequences deleted in patient`s 43-004 DNA were isolated. These five YACs did not overlap, and their end fragments were used to screen the CEPH MegaYAC library. Seven YACs were isolated from the CEPH MegaYAC library. They could be arranged into a contig which spans between DXS6 and DXS100. The contig contains a minimum of 2.5 Mbp of human DNA. A total of 12 YAC end clone, lambda subclones and STS probes have been used to order clones within the contig. These reagents were also used in Southern blot and patients showed interstitial deletions in Xq25. The size of these deletions range between 0.5 and 2.5 Mbp. The shortest deletion probably represents the critical region for the XLP gene.

  1. PDK1 regulates B cell differentiation and homeostasis

    PubMed Central

    Baracho, Gisele V.; Cato, Matthew H.; Zhu, Zilu; Jaren, Olav R.; Hobeika, Elias; Reth, Michael; Rickert, Robert C.

    2014-01-01

    Successful B cell differentiation and prevention of cell transformation depends on balanced and fine-tuned activation of cellular signaling pathways. The phosphatidyl inositol-3 kinase (PI3K) signaling pathway has emerged as a major regulator of B lymphocyte homeostasis and function. Phosphoinositide-dependent protein kinase-1 (PDK1) is the pivotal node in the PI3K pathway, regulating the stability and activity of downstream AGC kinases (including Akt, RSK, S6K, SGK, and PKC). Although the importance of PI3K activity in B cell differentiation is well documented, the role of PDK1 and other downstream effectors is underexplored. Here we used inducible and stage-specific gene targeting approaches to elucidate the role of PDK1 in early and peripheral B cell differentiation. PDK1 ablation enhanced cell cycle entry and apoptosis of IL-7–dependent pro-B cells, blocking Ig synthesis and B cell maturation. PDK1 also was essential for the survival and activation of peripheral B cells via regulation of PKC and Akt-dependent downstream effectors, such as GSK3?/? and Foxo1. We found that PDK1 deletion strongly impaired B cell receptor (BCR) signaling, but IL-4 costimulation was sufficient to restore BCR-induced proliferation. IL-4 also normalized PKC? activation and hexokinase II expression in BCR-stimulated cells, suggesting that this signaling pathway can act independent of PDK1 to support B cell growth. In summary, our results demonstrate that PDK1 is indispensable for B cell survival, proliferation, and growth regulation. PMID:24979759

  2. In vitro tolerance induction of neonatal murine B cells

    PubMed Central

    1976-01-01

    The susceptibility of neonatal and adult B lymphocytes to tolerance induction was analyzed by a modification of the in vitro splenic focus technique. This technique permits stimulation of individual hapten- specific clonal precursor cells from both neonatal and adult donors. Neonatal or adult BALB/c spleen cells were adoptively transferred into irradiated, syngeneic, adult recipients which had been carrier-primed to hemocyanin (Hy), thus maximizing stimulation to the hapten 2,4- dinitrophenyl coupled by Hy (DNP-Hy). Cultures were initially treated with DNP on several heterologous (non-Hy) carriers and subsequently stimulated with DNP-Hy. Whereas the responsiveness of adult B cells was not diminished by pretreatment with any DNP conjugate, the majority of the neonatal B-cell response was abolished by in vitro culture with all of the DNP-protein conjugates. During the 1st wk of life, the ability to tolerize neonatal splenic B cells progressively decreased. Thus, tolerance in this system is: (a) restricted to B cells early in development; (b) established by both tolerogens and immunogens; (c) achieved at low (10(-9) M determinant) antigen concentrations; and (d) highly specific, discriminating between DNP- and TNP-specific B cells. We conclude that: (a) B lymphocytes, during their development, mature through a stage in which they are extremely susceptible to tolerogenesis; (b) the specific interaction of B-cell antigen receptors with multivalent antigens, while irrelevant to mature B cells, is tolerogenic to neonatal (immature) B cells unless antigen is concomitantly recognized by primed T cells; and (c) differences in the susceptibility of immature and mature B lymphocytes to tolerance induction suggest intrinsic differences between neonatal and adult B cells and may provide a physiologically relevant model for the study of tolerance to self-antigens. PMID:58052

  3. Macromolecular assembly of the adaptor SLP-65 at intracellular vesicles in resting B cells.

    PubMed

    Engelke, Michael; Pirkuliyeva, Sona; Kühn, Julius; Wong, Leo; Boyken, Janina; Herrmann, Nadine; Becker, Stefan; Griesinger, Christian; Wienands, Jürgen

    2014-08-19

    The traditional view of how intracellular effector proteins are recruited to the B cell antigen receptor (BCR) complex at the plasma membrane is based on the occurrence of direct protein-protein interactions, as exemplified by the recruitment of the tyrosine kinase Syk (spleen tyrosine kinase) to phosphorylated motifs in BCR signaling subunits. By contrast, the subcellular targeting of the cytosolic adaptor protein SLP-65 (Src homology 2 domain-containing leukocyte adaptor protein of 65 kD), which serves as a proximal Syk substrate, is unclear. We showed that SLP-65 activation required its association at vesicular compartments in resting B cells. A module of ~50 amino acid residues located at the amino terminus of SLP-65 anchored SLP-65 to the vesicles. Nuclear magnetic resonance spectroscopy showed that the SLP-65 amino terminus was structurally disordered in solution but could bind in a structured manner to noncharged lipid components of cellular membranes. Our finding that preformed vesicular signaling scaffolds are required for B cell activation indicates that vesicles may deliver preassembled signaling cargo to sites of BCR activation. PMID:25140054

  4. B Cell Receptor Signaling: Picky About PI3Ks

    NSDL National Science Digital Library

    Jose J. Limon (University of California; Department of Molecular Biology and Biochemistry and Center for Immunology REV)

    2010-08-10

    The B cell receptor (BCR) and the pre-BCR control cell fate at many stages of B cell development, survival, and antigen response. Most of these processes require the activation of phosphatidylinositol 3-kinase (PI3K). Previous work has pointed to p110? as the key catalytic isoform of PI3K for many B cell responses. A study of mice with different combinations of PI3K mutations confirms the central role of p110? in agonist-mediated signaling, while identifying an unexpected function for the p110? isoform in tonic signaling by the pre-BCR and mature BCR.

  5. A Novel VHH Antibody Targeting the B Cell-Activating Factor for B-Cell Lymphoma

    PubMed Central

    Wu, Wen; Li, Shenghua; Zhang, Weijing; Sun, Jian; Ren, Guangda; Dong, Quanchao

    2014-01-01

    Objective: To construct an immune alpaca phage display library, in order to obtain a single domain anti-BAFF (B cell-activating factor) antibody. Methods: Using phage display technology, we constructed an immune alpaca phage display library, selected anti-BAFF single domain antibodies (sdAbs), cloned three anti-BAFF single-domain antibody genes into expression vector pSJF2, and expressed them efficiently in Escherichia coli. The affinity of different anti-BAFF sdAbs were measured by Bio layer interferometry. The in vitro biological function of three sdAbs was investigated by cell counting kit-8 (CCK-8) assay and a competitive enzyme-linked immunosorbent assay (ELISA). Results: We obtained three anti-BAFF single domain antibodies (anti-BAFF64, anti-BAFF52 and anti-BAFFG3), which were produced in high yield in Escherichia coli and inhibited tumor cell proliferation in vitro. Conclusion: The selected anti-BAFF antibodies could be candidates for B-cell lymphoma therapies. PMID:24879522

  6. Variations of the UNC13D Gene in Patients with Autoimmune Lymphoproliferative Syndrome

    PubMed Central

    Aricň, Maurizio; Boggio, Elena; Cetica, Valentina; Melensi, Matteo; Orilieri, Elisabetta; Clemente, Nausicaa; Cappellano, Giuseppe; Buttini, Sara; Soluri, Maria Felicia; Comi, Cristoforo; Dufour, Carlo; Pende, Daniela; Dianzani, Irma; Ellis, Steven R.; Pagliano, Sara; Marcenaro, Stefania; Ramenghi, Ugo; Chiocchetti, Annalisa; Dianzani, Umberto

    2013-01-01

    Autoimmune lymphoproliferative syndrome (ALPS) is caused by genetic defects decreasing Fas function and is characterized by lymphadenopathy/splenomegaly and expansion of CD4/CD8 double-negative T cells. This latter expansion is absent in the ALPS variant named Dianzani Autoimmune/lymphoproliferative Disease (DALD). In addition to the causative mutations, the genetic background influences ALPS and DALD development. We previously suggested a disease-modifying role for the perforin gene involved in familial hemophagocytic lymphohistiocytosis (FHL). The UNC13D gene codes for Munc13-4, which is involved in perforin secretion and FHL development, and thus, another candidate for a disease-modifying role in ALPS and DALD. In this work, we sequenced UNC13D in 21 ALPS and 20 DALD patients and compared these results with sequences obtained from 61 healthy subjects and 38 multiple sclerosis (MS) patients. We detected four rare missense variations in three heterozygous ALPS patients carrying p.Cys112Ser, p.Val781Ile, and a haplotype comprising both p.Ile848Leu and p.Ala995Pro. Transfection of the mutant cDNAs into HMC-1 cells showed that they decreased granule exocytosis, compared to the wild-type construct. An additional rare missense variation, p.Pro271Ser, was detected in a healthy subject, but this variation did not decrease Munc13-4 function. These data suggest that rare loss-of-function variations of UND13D are risk factors for ALPS development. PMID:23840885

  7. Insights into B cells and HIV-specific B-cell responses in HIV-infected individuals.

    PubMed

    Moir, Susan; Fauci, Anthony S

    2013-07-01

    Human immunodeficiency virus (HIV) disease is associated with dysregulation and dysfunction involving all major lymphocyte populations, including B cells. Such perturbations occur early in the course of infection and are driven in large part by immune activation resulting from ongoing HIV replication leading to bystander effects on B cells. While most of the knowledge regarding immune cell abnormalities in HIV-infected individuals has been gained from studies conducted on the peripheral blood, it is clear that the virus is most active and most damaging in lymphoid tissues. Here, we discuss B-cell perturbations in HIV-infected individuals, focusing on the skewing of B-cell subsets that circulate in the peripheral blood and their counterparts that reside in lymphoid tissues. This review also highlights recent advances in evaluating HIV-specific B-cell responses both in the memory B-cell compartment, as well as in circulating antibody-secreting plasmablasts and the more differentiated plasma cells residing in tissues. Finally, we consider how knowledge gained by investigating B cells in HIV-infected individuals may help inform the development of an effective antibody-based HIV vaccine. PMID:23772622

  8. Establishment and operation of a Good Manufacturing Practice-compliant allogeneic Epstein-Barr virus (EBV)-specific cytotoxic cell bank for the treatment of EBV-associated lymphoproliferative disease.

    PubMed

    Vickers, Mark A; Wilkie, Gwen M; Robinson, Nicolas; Rivera, Nadja; Haque, Tanzina; Crawford, Dorothy H; Barry, Jacqueline; Fraser, Neil; Turner, David M; Robertson, Victoria; Dyer, Phil; Flanagan, Peter; Newlands, Helen R; Campbell, John; Turner, Marc L

    2014-11-01

    Epstein-Barr virus (EBV) is associated with several malignancies, including post-transplant lymphoproliferative disorder (PTLD). Conventional treatments for PTLD are often successful, but risk organ rejection and cause significant side effects. EBV-specific cytotoxic T lymphocytes (CTLs) generated in vitro from peripheral blood lymphocytes provide an alternative treatment modality with few side effects, but autologous CTLs are difficult to use in clinical practice. Here we report the establishment and operation of a bank of EBV-specific CTLs derived from 25 blood donors with human leucocyte antigen (HLA) types found at high frequency in European populations. Since licensure, there have been enquiries about 37 patients, who shared a median of three class I and two class II HLA types with these donors. Cells have been infused into ten patients with lymphoproliferative disease, eight of whom achieved complete remission. Neither patient with refractory disease was matched for HLA class II. Both cases of EBV-associated non-haematopoietic sarcoma receiving cells failed to achieve complete remission. Thirteen patients died before any cells could be issued, emphasizing that the bank should be contacted before patients become pre-terminal. Thus, this third party donor-derived EBV-specific CTL cell bank can supply most patients with appropriately matched cells and most recipients have good outcomes. PMID:25066775

  9. Monovalent engagement of the BCR activates ovalbumin-specific transnuclear B cells

    E-print Network

    Avalos, Ana M.

    Valency requirements for B cell activation upon antigen encounter are poorly understood. OB1 transnuclear B cells express an IgG1 B cell receptor (BCR) specific for ovalbumin (OVA), the epitope of which can be mimicked ...

  10. B-Cell waste classification sampling and analysis plan

    SciTech Connect

    HOBART, R.L.

    1999-09-22

    This report documents the methods used to collect and analyze samples to obtain data necessary to verify and/or determine the radionuclide content of the 324 Facility B-Cell decontamination and decommissioning waste stream.

  11. COMPUTATION MODELING OF TCDD DISRUPTION OF B CELL TERMINAL DIFFERENTIATION

    EPA Science Inventory

    In this study, we established a computational model describing the molecular circuit underlying B cell terminal differentiation and how TCDD may affect this process by impinging upon various molecular targets....

  12. Inhibitory signaling by B cell Fc?RIIb

    Microsoft Academic Search

    K Mark Coggeshall

    1998-01-01

    The fact that B cells undergo feedback suppression, or negative signaling, through the interaction of secreted antibody with specific antigen has been extensively documented but the mechanisms involved in the process have been elusive. Experiments over the past year using B cell deletion mutants and dominant-negative enzymes have firmly established an important role for SH2-domain-containing inositol 5-phosphatase (SHIP) in negative

  13. Early Events of B Cell Activation by Antigen

    NSDL National Science Digital Library

    David Depoil (Cancer Research UK London Research Institute; Lymphocyte Interaction Laboratory REV)

    2009-03-24

    The activation of B cells confers long-lasting protection from a plethora of infectious diseases through the generation of plasma cells that produce high-affinity antibodies and memory cells. Engagement of the B cell receptor (BCR) with cognate antigen initiates intracellular signaling and subsequent internalization of antigen. Membrane-bound antigens are now considered the predominant forms that initiate B cell activation in vivo. We have shown that upon recognition of antigen on the surface of a presenting cell, the B cell undergoes a dramatic change in morphology characterized by rapid spreading followed by more prolonged contraction along the presenting surface. This two-phase response increases the amount of antigen that the B cell accumulates, internalizes, and subsequently presents to T cells. Thus, the spreading and contraction response shapes the outcome of B cell activation. We used a combination of planar lipid bilayers and total internal reflection fluorescence microscopy to investigate the early events that occur after engagement of the BCR and before B cell spreading. We observed the rapid formation of BCR-antigen microclusters, which we redefine as “microsignalosomes” because they mediate the coordinated recruitment of intracellular effectors, such as the kinases Lyn and Syk, the adaptor Vav, and phospholipase C–?2 (PLC-?2). We identified an essential role for the co-receptor CD19 in mediating spreading, and thus B cell activation, in response to membrane-bound antigen. Preliminary evidence suggests that the cellular morphology changes described in vitro are likely to occur upon recognition of antigen presented on the surface of macrophages in lymph nodes in vivo.

  14. Malaria-associated atypical memory B cells exhibit markedly reduced B cell receptor signaling and effector function.

    PubMed

    Portugal, Silvia; Tipton, Christopher M; Sohn, Haewon; Kone, Younoussou; Wang, Jing; Li, Shanping; Skinner, Jeff; Virtaneva, Kimmo; Sturdevant, Daniel E; Porcella, Stephen F; Doumbo, Ogobara K; Doumbo, Safiatou; Kayentao, Kassoum; Ongoiba, Aissata; Traore, Boubacar; Sanz, Inaki; Pierce, Susan K; Crompton, Peter D

    2015-01-01

    Protective antibodies in Plasmodium falciparum malaria are only acquired after years of repeated infections. Chronic malaria exposure is associated with a large increase in atypical memory B cells (MBCs) that resemble B cells expanded in a variety of persistent viral infections. Understanding the function of atypical MBCs and their relationship to classical MBCs will be critical to developing effective vaccines for malaria and other chronic infections. We show that VH gene repertoires and somatic hypermutation rates of atypical and classical MBCs are indistinguishable indicating a common developmental history. Atypical MBCs express an array of inhibitory receptors and B cell receptor (BCR) signaling is stunted in atypical MBCs resulting in impaired B cell responses including proliferation, cytokine production and antibody secretion. Thus, in response to chronic malaria exposure, atypical MBCs appear to differentiate from classical MBCs becoming refractory to BCR-mediated activation and potentially interfering with the acquisition of malaria immunity. PMID:25955968

  15. B Cell Selection and Affinity Maturation During an Antibody Response in the Mouse with Limited B Cell Diversity1

    Microsoft Academic Search

    Naoki Kanayama; Takafumi Kimoto; Kagefumi Todo; Yumiko Nishikawa; Masaki Hikida; Masaki Magari; Marilia Cascalho; Hitoshi Ohmori

    2002-01-01

    The quasi-monoclonal mouse has limited B cell diversity, whose major (80%) B cell Ag receptors are comprised of the knockin VH 17.2.25 (VHT)-encoded H chain and the 1o r2 L chain, thereby being specific for 4-hydroxy-3-nitrophenylacetyl. The p-nitrophenylacetyl (pNP) was found to be a low affinity analog of nitrophenylacetyl. We examined affinity maturation of anti-pNP IgG by analyzing mAbs obtained

  16. Activation of the B cell antigen receptor triggers reactivation of latent Kaposi's sarcoma-associated herpesvirus in B cells.

    PubMed

    Kati, Semra; Tsao, Edward H; Günther, Thomas; Weidner-Glunde, Magdalena; Rothämel, Thomas; Grundhoff, Adam; Kellam, Paul; Schulz, Thomas F

    2013-07-01

    Kaposi's sarcoma-associated herpesvirus (KSHV) is an oncogenic herpesvirus and the cause of Kaposi's sarcoma, primary effusion lymphoma (PEL) and multicentric Castleman's disease. Latently infected B cells are the main reservoir of this virus in vivo, but the nature of the stimuli that lead to its reactivation in B cells is only partially understood. We established stable BJAB cell lines harboring latent KSHV by cell-free infection with recombinant virus carrying a puromycin resistance marker. Our latently infected B cell lines, termed BrK.219, can be reactivated by triggering the B cell receptor (BCR) with antibodies to surface IgM, a stimulus imitating antigen recognition. Using this B cell model system we studied the mechanisms that mediate the reactivation of KSHV in B cells following the stimulation of the BCR and could identify phosphatidylinositol 3-kinase (PI3K) and X-box binding protein 1 (XBP-1) as proteins that play an important role in the BCR-mediated reactivation of latent KSHV. PMID:23678173

  17. Activation of the B Cell Antigen Receptor Triggers Reactivation of Latent Kaposi's Sarcoma-Associated Herpesvirus in B Cells

    PubMed Central

    Kati, Semra; Tsao, Edward H.; Günther, Thomas; Weidner-Glunde, Magdalena; Rothämel, Thomas; Grundhoff, Adam; Kellam, Paul

    2013-01-01

    Kaposi's sarcoma-associated herpesvirus (KSHV) is an oncogenic herpesvirus and the cause of Kaposi's sarcoma, primary effusion lymphoma (PEL) and multicentric Castleman's disease. Latently infected B cells are the main reservoir of this virus in vivo, but the nature of the stimuli that lead to its reactivation in B cells is only partially understood. We established stable BJAB cell lines harboring latent KSHV by cell-free infection with recombinant virus carrying a puromycin resistance marker. Our latently infected B cell lines, termed BrK.219, can be reactivated by triggering the B cell receptor (BCR) with antibodies to surface IgM, a stimulus imitating antigen recognition. Using this B cell model system we studied the mechanisms that mediate the reactivation of KSHV in B cells following the stimulation of the BCR and could identify phosphatidylinositol 3-kinase (PI3K) and X-box binding protein 1 (XBP-1) as proteins that play an important role in the BCR-mediated reactivation of latent KSHV. PMID:23678173

  18. TIM-1 signaling in B cells regulates antibody production

    SciTech Connect

    Ma, Juan [Department of Immunology, Juntendo University, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421 (Japan)] [Department of Immunology, Juntendo University, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421 (Japan); Usui, Yoshihiko [Department of Immunology, Juntendo University, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421 (Japan) [Department of Immunology, Juntendo University, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421 (Japan); Department of Ophthalmology, Tokyo Medical University, 6-7-1 Nishi-shinjuku-ku, Tokyo 160-0023 (Japan); Takeda, Kazuyoshi [Department of Immunology, Juntendo University, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421 (Japan)] [Department of Immunology, Juntendo University, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421 (Japan); Harada, Norihiro [Department of Immunology, Juntendo University, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421 (Japan) [Department of Immunology, Juntendo University, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421 (Japan); Department of Respiratory Medicine, Juntendo University, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421 (Japan); Research Institute for Diseases of Old Ages, Juntendo University, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421 (Japan); Yagita, Hideo; Okumura, Ko [Department of Immunology, Juntendo University, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421 (Japan)] [Department of Immunology, Juntendo University, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421 (Japan); Akiba, Hisaya, E-mail: hisaya@juntendo.ac.jp [Department of Immunology, Juntendo University, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421 (Japan)] [Department of Immunology, Juntendo University, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421 (Japan)

    2011-03-11

    Highlights: {yields} TIM-1 is highly expressed on anti-IgM + anti-CD40-stimulated B cells. {yields} Anti-TIM-1 mAb enhanced proliferation and Ig production on activated B cell in vitro. {yields} TIM-1 signaling regulates Ab production by response to TI-2 and TD antigens in vivo. -- Abstract: Members of the T cell Ig and mucin (TIM) family have recently been implicated in the control of T cell-mediated immune responses. In this study, we found TIM-1 expression on anti-IgM- or anti-CD40-stimulated splenic B cells, which was further up-regulated by the combination of anti-IgM and anti-CD40 Abs. On the other hand, TIM-1 ligand was constitutively expressed on B cells and inducible on anti-CD3{sup +} anti-CD28-stimulated CD4{sup +} T cells. In vitro stimulation of activated B cells by anti-TIM-1 mAb enhanced proliferation and expression of a plasma cell marker syndecan-1 (CD138). We further examined the effect of TIM-1 signaling on antibody production in vitro and in vivo. Higher levels of IgG2b and IgG3 secretion were detected in the culture supernatants of the anti-TIM-1-stimulated B cells as compared with the control IgG-stimulated B cells. When immunized with T-independent antigen TNP-Ficoll, TNP-specific IgG1, IgG2b, and IgG3 Abs were slightly increased in the anti-TIM-1-treated mice. When immunized with T-dependent antigen OVA, serum levels of OVA-specific IgG2b, IgG3, and IgE Abs were significantly increased in the anti-TIM-1-treated mice as compared with the control IgG-treated mice. These results suggest that TIM-1 signaling in B cells augments antibody production by enhancing B cell proliferation and differentiation.

  19. Dual mechanisms by which miR-125b represses IRF4 to induce myeloid and B-cell leukemias.

    PubMed

    So, Alex Yick-Lun; Sookram, Reeshelle; Chaudhuri, Aadel A; Minisandram, Aarathi; Cheng, David; Xie, Catherine; Lim, Ee Lyn; Flores, Yvette Garcia; Jiang, Shuai; Kim, Jocelyn Tammy; Keown, Christopher; Ramakrishnan, Parameswaran; Baltimore, David

    2014-08-28

    The oncomir microRNA-125b (miR-125b) is upregulated in a variety of human neoplastic blood disorders and constitutive upregulation of miR-125b in mice can promote myeloid and B-cell leukemia. We found that miR-125b promotes myeloid and B-cell neoplasm by inducing tumorigenesis in hematopoietic progenitor cells. Our study demonstrates that miR-125b induces myeloid leukemia by enhancing myeloid progenitor output from stem cells as well as inducing immortality, self-renewal, and tumorigenesis in myeloid progenitors. Through functional and genetic analyses, we demonstrated that miR-125b induces myeloid and B-cell leukemia by inhibiting interferon regulatory factor 4 (IRF4) but through distinct mechanisms; it induces myeloid leukemia through repressing IRF4 at the messenger RNA (mRNA) level without altering the genomic DNA and induces B-cell leukemia via genetic deletion of the gene encoding IRF4. PMID:25006123

  20. Monozygotic twins discordant for common variable immunodeficiency reveal impaired DNA demethylation during naďve-to-memory B-cell transition.

    PubMed

    Rodríguez-Cortez, Virginia C; Del Pino-Molina, Lucia; Rodríguez-Ubreva, Javier; Ciudad, Laura; Gómez-Cabrero, David; Company, Carlos; Urquiza, José M; Tegnér, Jesper; Rodríguez-Gallego, Carlos; López-Granados, Eduardo; Ballestar, Esteban

    2015-01-01

    Common variable immunodeficiency (CVID), the most frequent primary immunodeficiency characterized by loss of B-cell function, depends partly on genetic defects, and epigenetic changes are thought to contribute to its aetiology. Here we perform a high-throughput DNA methylation analysis of this disorder using a pair of CVID-discordant MZ twins and show predominant gain of DNA methylation in CVID B cells with respect to those from the healthy sibling in critical B lymphocyte genes, such as PIK3CD, BCL2L1, RPS6KB2, TCF3 and KCNN4. Individual analysis confirms hypermethylation of these genes. Analysis in naive, unswitched and switched memory B cells in a CVID patient cohort shows impaired ability to demethylate and upregulate these genes in transitioning from naive to memory cells in CVID. Our results not only indicate a role for epigenetic alterations in CVID but also identify relevant DNA methylation changes in B cells that could explain the clinical manifestations of CVID individuals. PMID:26081581

  1. Lipoxin A4 decreases human memory B cell antibody production via an ALX/FPR2-dependent mechanism: A link between resolution signals and adaptive immunity

    PubMed Central

    Ramon, Sesquile; Bancos, Simona; Serhan, Charles N.; Phipps, Richard P.

    2013-01-01

    Summary Specialized proresolving mediators (SPMs) are endogenous bioactive lipid molecules that play a fundamental role in the regulation of inflammation and its resolution. SPMs are classified into lipoxins, resolvins, protectins and maresins. Lipoxins and other SPMs have been identified in important immunological tissues including bone marrow, spleen and blood. Lipoxins regulate functions of the innate immune system including the promotion of monocyte recruitment and increase macrophage phagocytosis of apoptotic neutrophils. A major knowledge gap is whether lipoxins influence adaptive immune cells. Here, we analyzed the actions of lipoxin A4 (LXA4) and its receptor ALX/FPR2 on human B cells. LXA4 decreased IgM and IgG production on activated B cells through ALX/FPR2-dependent signaling, which downregulated NF-?B p65 nuclear translocation. LXA4 also inhibited human memory B cell antibody production and proliferation, but not naďve B cell function. Lastly, LXA4 decreased antigen-specific antibody production in vivo. To our knowledge, this is the first description of the actions of lipoxins on human B cells, which shows a link between resolution signals and adaptive immunity. Regulating antibody production is crucial to prevent unwanted inflammation. Harnessing the ability of lipoxins to decrease memory B cell antibody production can be beneficial to threat inflammatory and autoimmune disorders. PMID:24166736

  2. Perinatal immunotoxicity of benzene toward mouse B cell development

    SciTech Connect

    Wierda, D.; King, A.; Luebke, R.; Reasor, M.; Smialowicz, R.J.

    1989-01-01

    Benzene is widely used by chemical industries and exposure to benzene has been shown experimentally to be immunotoxic in adult animals. The present study addressed whether exposure of fetuses in utero to benzene compromises the development of fetal B lymphopoiesis and whether B-lymphocyte development recovers postnatally. Pregnant BALB/C dams were given intraperitoneal injections of benzene (100 mg/kg, twice daily) from day 12.5 of gestation through day 19.5 of gestation. Phenotypic analysis revealed that fetal liver cell suspensions from embryos exposed in utero contained fewer pre-B cells and B cells than corresponding controls. Fetal liver cell cultures established from these embryos also produced fewer B cells. In contrast, pre-B cells were elevated in the livers of 8-day-old neonates that had been exposed to benzene in utero. Moreover, responsiveness to the B-cell mitogen, LPS, was significantly decreased in spleen cell cultures derived from these neonates. The results indicate that in utero exposure to high concentrations of benzene alters fetal B lymphopoiesis and may compromise immune responsiveness postnatally.

  3. Cerebrospinal fluid B cells from multiple sclerosis patients are subject to normal germinal center selection

    Microsoft Academic Search

    Christopher Harp; Jane Lee; Doris Lambracht-Washington; Elizabeth Cameron; Gregory Olsen; Elliot Frohman; Michael Racke; Nancy Monson

    2007-01-01

    Previous findings from our laboratory demonstrated that some clonally expanded cerebrospinal fluid (CSF) B cells from MS patients exhibit diminished mutation targeting patterns in comparison to typical B cells selected in the context of germinal centers (GCs). In order to determine whether the overall CSF B cell repertoires adhered to mutation patterns typical of GC-selected B cells, we analyzed the

  4. Novel Therapies for Aggressive B-Cell Lymphoma

    PubMed Central

    Foon, Kenneth A.; Takeshita, Kenichi; Zinzani, Pier L.

    2012-01-01

    Aggressive B-cell lymphoma (BCL) comprises a heterogeneous group of malignancies, including diffuse large B-cell lymphoma (DLBCL), Burkitt lymphoma, and mantle cell lymphoma (MCL). DLBCL, with its 3 subtypes, is the most common type of lymphoma. Advances in chemoimmunotherapy have substantially improved disease control. However, depending on the subtype, patients with DLBCL still exhibit substantially different survival rates. In MCL, a mature B-cell lymphoma, the addition of rituximab to conventional chemotherapy regimens has increased response rates, but not survival. Burkitt lymphoma, the most aggressive BCL, is characterized by a high proliferative index and requires more intensive chemotherapy regimens than DLBCL. Hence, there is a need for more effective therapies for all three diseases. Increased understanding of the molecular features of aggressive BCL has led to the development of a range of novel therapies, many of which target the tumor in a tailored manner and are summarized in this paper. PMID:22536253

  5. Inferring processes underlying B-cell repertoire diversity.

    PubMed

    Elhanati, Yuval; Sethna, Zachary; Marcou, Quentin; Callan, Curtis G; Mora, Thierry; Walczak, Aleksandra M

    2015-09-01

    We quantify the VDJ recombination and somatic hypermutation processes in human B cells using probabilistic inference methods on high-throughput DNA sequence repertoires of human B-cell receptor heavy chains. Our analysis captures the statistical properties of the naive repertoire, first after its initial generation via VDJ recombination and then after selection for functionality. We also infer statistical properties of the somatic hypermutation machinery (exclusive of subsequent effects of selection). Our main results are the following: the B-cell repertoire is substantially more diverse than T-cell repertoires, owing to longer junctional insertions; sequences that pass initial selection are distinguished by having a higher probability of being generated in a VDJ recombination event; somatic hypermutations have a non-uniform distribution along the V gene that is well explained by an independent site model for the sequence context around the hypermutation site. PMID:26194757

  6. Transcriptional Control of Early T and B Cell Developmental Choices

    PubMed Central

    Rothenberg, Ellen V.

    2014-01-01

    T and B cells share a common somatic gene rearrangement mechanism for assembling the genes that code for their antigen receptors and developmental pathways with many parallels. Shared usage of basic helix-loop-helix E proteins as transcriptional drivers underlies these common features. However, the transcription factor networks in which these E proteins are embedded are different both in membership and in architecture for T and B cell gene regulatory programs. These differences permit lineage commitment decisions to be made in different hierarchical orders. Furthermore, in a contrast to B-cell gene networks, the T-cell gene network architecture for effector differentiation is sufficiently modular so that E protein inputs can be removed. Complete “T-cell-like” effector differentiation can proceed without T-cell receptor rearrangement or selection when E proteins are neutralized, yielding natural killer and other innate lymphoid cells. PMID:24471430

  7. Generation and identification of tumor-evoked regulatory B cells

    PubMed Central

    Biragyn, Arya; Lee-Chang, Catalina; Bodogai, Monica

    2014-01-01

    The involvement of Bregs in cancer remains poorly understood despite their well-documented regulation of responses to the self and protection from harmful autoimmunity. We recently discovered a unique regulatory B cell subset evoked by breast cancer to mediate protection of metastasizing cancer cells. These results together with the wealth of findings of the last 40 years on B cells in tumorigenesis suggest the existence of additional cancer Bregs modulating anticancer responses. To facilitate the search for them, here we provide our detailed protocol for the characterization and generation of tumor-evoked regulatory B cells. Wherever applicable, we also discuss nuances and uniqueness of a Breg study in cancer to warn potential pitfalls. PMID:25015287

  8. B cell receptor signaling in chronic lymphocytic leukemia

    PubMed Central

    Burger, Jan A.; Chiorazzi, Nicholas

    2013-01-01

    BCR signaling plays an important pathogenic role in chronic lymphocytic leukemia (CLL) and B cell lymphomas, based on structural restrictions of the BCR, and BCR-dependent survival and growth of the malignant B cells. In CLL and lymphoma subtypes, ligand-independent (“tonic”) and ligand-dependent BCR signaling have been characterized, which can involve mutations of BCR pathway components or be triggered by (auto-) antigens present in the tissue microenvironment. In CLL, based on high response rates and durable remissions in early-stage clinical trials, there is rapid clinical development of inhibitors targeting BCR-associated kinases (BTK, PI3K?), which will change treatment paradigms in CLL and other B cell malignancies. Here, we discuss the evolution of this field, from BCR-related prognostic markers, to mechanisms of BCR activation, and targeting of BCR-associated kinases, the emerging Achilles’ heel in CLL pathogenesis. PMID:23928062

  9. CD5-positive B-cell acute lymphoblastic leukemia.

    PubMed

    Peterson, Michael R; Noskoviak, Kyle J; Newbury, Robert

    2007-01-01

    CD5-positive B-cell acute lymphoblastic leukemia (ALL) is an exceedingly rare entity, with only a single case report in the literature. We report 2 additional cases of CD5-positive B-cell ALL in a 16-year-old male and a 15-year-old female. The 1st case was initially misdiagnosed as Ewing sarcoma due to a lack of CD45 expression and weak expression of CD99. Cytogenetic analysis of the 2nd case revealed trisomy 22, the 1st time this finding has been reported in ALL. Both patients had poor outcomes, as did the patient in the previously published case report. We conclude that CD5-positive B-cell ALL is a rare, aggressive malignancy with a poor prognosis that presents in adolescence. Pathologists and clinicians should be aware of this entity to avoid confusion with other small blue-cell tumors. PMID:17378623

  10. The epigenetic basis of diffuse large B-cell lymphoma.

    PubMed

    Jiang, Yanwen; Melnick, Ari

    2015-04-01

    The pathogenesis of diffuse large B-cell lymphoma (DLBCL) is strongly linked to perturbation of epigenetic mechanisms. The germinal center (GC) B cells from which DLBCLs arise are prone to instability in their cytosine methylation patterns. DLBCLs inherit this epigenetic instability and display variable degrees of epigenetic heterogeneity. Greater epigenetic heterogeneity is linked with poor clinical outcome. Somatic mutations of histone-modifying proteins have also emerged as a hallmark of DLBCL. The effect of these somatic mutations may be to disrupt epigenetic switches that control the GC phenotype and "lock in" certain oncogenic features of GC B cells, resulting in malignant transformation. DNA methyltransferase and histone methyltransferase inhibitors are emerging as viable therapeutic approaches to erase aberrant epigenetic programming, suppress DLBCL growth, and overcome chemotherapy resistance. This review will discuss these recent advances and their therapeutic implications. PMID:25805588

  11. Roles of B Cell-Intrinsic TLR Signals in Systemic Lupus Erythematosus

    PubMed Central

    Ma, Kongyang; Li, Jingyi; Fang, Yongfei; Lu, Liwei

    2015-01-01

    Toll-like receptors (TLRs) are a large family of pattern recognition receptors. TLR signals are involved in the pathogenesis of systemic lupus erythematosus. Mouse and human B cells constitutively express most TLRs. Many B cell subpopulations are highly responsive to certain TLR ligation, including B-1 B cells, transitional B cells, marginal zone B cells, germinal center B cell and memory B cells. The B cell-intrinsic TLR signals play critical roles during lupus process. In this review, roles of B cell-intrinsic TLR2, 4, 7, 8 and 9 signals are discussed during lupus pathogenesis in both mouse model and patients. Moreover, mechanisms underlying TLR ligation-triggered B cell activation and signaling pathways are highlighted. PMID:26068236

  12. Expression of AID transgene is regulated in activated B cells but not in resting B cells and kidney

    PubMed Central

    Shen, Hong Ming; Bozek, Grazyna; Pinkert, Carl A.; McBride, Kevin; Wang, Lilly; Kenter, Amy; Storb, Ursula

    2008-01-01

    Activation-induced DNA cytosine deaminase (AID) is required for somatic hypermutation (SHM) and efficient class switch recombination (CSR) of immunoglobulin (Ig) genes. We created AID-transgenic mice that express AID ubiquitously under the control of a ?–actin promoter. When crossed with AID?/? mice, the AID-transgenic, AID?/? mice carried out SHM and CSR, showing that the AID transgenes were functional. However, the frequencies of SHM in V- and switch-regions, and CSR were reduced compared to those in a wildtype AID background. Several criteria suggested that the inefficiency of SHM was due to reduced AID activity, rather than lack of recruiting error-prone DNA repair. High levels of AID mRNA were produced in resting B cells and kidney, cells that do not express AID in wildtype mice. Compared with these cells, activated B cells expressed about an order of magnitude less AID mRNA suggesting that there may be a post-transcriptional mechanism that regulates AID mRNA levels in professional AID producers but not other cells. The AID protein expressed in resting B cells and kidney was phosphorylated at serine-38. Despite this modification, known to enhance AID activity, resting B cells did not undergo SHM. Apparently, the large amounts of AID in resting B cells are not targeted to Ig genes in vivo, in contrast to findings in vitro. PMID:18067961

  13. Control of Viremia Enables Acquisition of Resting Memory B Cells with Age and Normalization of Activated B Cell Phenotypes in HIV-Infected Children.

    PubMed

    Muema, Daniel M; Macharia, Gladys N; Hassan, Amin S; Mwaringa, Shalton M; Fegan, Greg W; Berkley, James A; Nduati, Eunice W; Urban, Britta C

    2015-08-01

    HIV affects the function of all lymphocyte populations, including B cells. Phenotypic and functional defects of B cells in HIV-infected adults have been well characterized, but defects in children have not been studied to the same extent. We determined the proportion of B cell subsets and frequencies of Ag-specific memory B cells in peripheral blood from HIV-infected children and healthy controls, using flow cytometry and B cell ELISPOT, respectively. In addition, we measured the quantities and avidities of plasma Abs against various Ags by ELISA. We also determined plasma levels of BAFF and expression of BAFF receptors on B cells. Children with high HIV viremia had increased proportions of activated mature B cells, tissue-like memory B cells and plasmablasts, and low proportions of naive B cells when compared with community controls and children with low HIV viremia, similar to adults infected with HIV. HIV-infected groups had lower proportions of resting memory B cells than did community controls. Notably, high HIV viremia prevented the age-dependent accumulation of class-switched resting memory B cells. HIV-infected children, regardless of the level of viremia, showed lower quantities and avidities of IgG and lower frequencies of memory B cells against Expanded Program on Immunization vaccines. The HIV-infected children had an altered BAFF profile that could have affected their B cell compartment. Therefore, B cell defects in HIV-infected children are similar to those seen in HIV-infected adults. However, control of HIV viremia is associated with normalization of activated B cell subsets and allows age-dependent accumulation of resting memory B cells. PMID:26116511

  14. Activation of B cells by non-canonical helper signals.

    PubMed

    Cerutti, Andrea; Cols, Montserrat; Puga, Irene

    2012-09-01

    Cognate interaction between T and B lymphocytes of the adaptive immune system is essential for the production of high-affinity antibodies against microbes, and for the establishment of long-term immunological memory. Growing evidence shows that--in addition to presenting antigens to T and B cells--macrophages, dendritic cells and other cells of the innate immune system provide activating signals to B cells, as well as survival signals to antibody-secreting plasma cells. Here, we discuss how these innate immune cells contribute to the induction of highly diversified and temporally sustained antibody responses, both systemically and at mucosal sites of antigen entry. PMID:22868664

  15. Diffuse large B-cell lymphomas with plasmablastic differentiation

    Microsoft Academic Search

    Julie Teruya-Feldstein

    2005-01-01

    Recent evidence suggests that diffuse large B-cell lymphoma (DLBCL) with plasmablastic differentiation represents a clinically\\u000a heterogeneous spectrum with different clinicopathologic characteristics representing distinct entities. Subtypes of DLBCL\\u000a with plasmablastic features and terminal B-cell differentiation include plasmablastic lymphoma (PBL) of oral mucosa type;\\u000a PBL with plasmacytic differentiation; primary effusion lymphoma (PEL); KSHV-positive solid lymphoma\\/extracavitary PEL\\/HHV-8\\u000a associated DLBCL; and DLBCL expressing ALK.

  16. On the Meaning of Affinity Limits in B-Cell Epitope Prediction for Antipeptide Antibody-Mediated Immunity

    PubMed Central

    Caoili, Salvador Eugenio C.

    2012-01-01

    B-cell epitope prediction aims to aid the design of peptide-based immunogens (e.g., vaccines) for eliciting antipeptide antibodies that protect against disease, but such antibodies fail to confer protection and even promote disease if they bind with low affinity. Hence, the Immune Epitope Database (IEDB) was searched to obtain published thermodynamic and kinetic data on binding interactions of antipeptide antibodies. The data suggest that the affinity of the antibodies for their immunizing peptides appears to be limited in a manner consistent with previously proposed kinetic constraints on affinity maturation in vivo and that cross-reaction of the antibodies with proteins tends to occur with lower affinity than the corresponding reaction of the antibodies with their immunizing peptides. These observations better inform B-cell epitope prediction to avoid overestimating the affinity for both active and passive immunization; whereas active immunization is subject to limitations of affinity maturation in vivo and of the capacity to accumulate endogenous antibodies, passive immunization may transcend such limitations, possibly with the aid of artificial affinity-selection processes and of protein engineering. Additionally, protein disorder warrants further investigation as a possible supplementary criterion for B-cell epitope prediction, where such disorder obviates thermodynamically unfavorable protein structural adjustments in cross-reactions between antipeptide antibodies and proteins. PMID:23209458

  17. Monoclonal gammopathies and associated skin disorders

    Microsoft Academic Search

    Mazen S. Daoud; John A. Lust; Robert A. Kyle; Mark R. Pittelkow

    1999-01-01

    The monoclonal gammopathies are characterized by clonal proliferation of plasma cells and other clonally related cells in the B-cell lineage. These disorders include monoclonal gammopathy of undetermined significance, multiple myeloma, Waldenström macroglobulinemia, heavy chain diseases, plasmacytoma, and primary amyloidosis. Many skin disorders have been described in association with monoclonal gammopathies. This article provides an introduction to the definition, detection, natural

  18. Does B Cell Receptor Signaling in Chronic Lymphocytic Leukaemia Cells Differ from That in Other B Cell Types?

    PubMed Central

    Slupsky, Joseph R.

    2014-01-01

    Chronic lymphocytic leukaemia (CLL) is an incurable malignancy of mature B cells. CLL is important clinically in Western countries because of its commonality and because of the significant morbidity and mortality associated with the progressive form of this incurable disease. The B cell receptor (BCR) expressed on the malignant cells in CLL contributes to disease pathogenesis by providing signals for survival and proliferation, and the signal transduction pathway initiated by engagement of this receptor is now the target of several therapeutic strategies. The purpose of this review is to outline current understanding of the BCR signal cascade in normal B cells and then question whether this understanding applies to CLL cells. In particular, this review studies the phenomenon of anergy in CLL cells, and whether certain adaptations allow the cells to overcome anergy and allow full BCR signaling to take place. Finally, this review analyzes how BCR signals can be therapeutically targeted for the treatment of CLL. PMID:25101192

  19. Toxic effects of various pollutants in 11B7501 lymphoma B cell line from harbour seal (Phoca vitulina).

    PubMed

    Frouin, Héloďse; Fortier, Marlčne; Fournier, Michel

    2010-04-11

    Although, heavy metals and polycyclic aromatic hydrocarbons (PAHs) have been reported at high levels in marine mammals, little is known about the toxic effects of some of these contaminants. In this study, we assessed the immunotoxic and genotoxic effects of seven heavy metals (arsenic, vanadium, selenium, iron, zinc, silver and chromium) and one PAH (benzo[a]pyrene or B[a]P) on a lymphoma B cell line from harbour seal (Phoca vitulina). A significant reduction in lymphocyte proliferation was registered following an exposure to 0.05 microM of B[a]P, 5 microM of arsenic or selenium, 50 microM of vanadium, 100 microM of silver and 200 microM of iron. On the contrary, zinc increased the lymphoproliferative response at 200 microM. Decreased phagocytosis was observed at 20 microM of arsenic, 50 microM of B[a]P or selenium, 200 microM of zinc and 500 microM of vanadium. Micronuclei induction occurred with 0.2 microM of B[a]P, 100 microM of vanadium and with 200muM of arsenic or selenium. Exposure to 50muM of arsenic decreased G(2)/M phase of the cell cycle. Chromium did not induce any effects at the concentrations tested. Concentrations of heavy metals (except silver and vanadium) and B[a]P inducing an toxic effect are within the environmental ranges reported in the blood tissue of pinnipeds. The reduction of some functional activities of the harbour seal immune system may cause a significant weakness capable of altering host resistance to disease in free-ranging pinnipeds. PMID:20116412

  20. BEAM-alemtuzumab reduced-intensity allogeneic stem cell transplantation for lymphoproliferative diseases: GVHD, toxicity, and survival in 65 patients

    Microsoft Academic Search

    Rowena D. Faulkner; Charles Craddock; Jennifer L. Byrne; Prem Mahendra; Andrew P. Haynes; Hugh G. Prentice; Michael Potter; Antonio Pagliuca; Aloysius Ho; Stephen Devereux; Grant McQuaker; Ghulam Mufti; John Liu; Nigel H. Russell

    2003-01-01

    We report the outcomes of reduced-inten- sity allogeneic stem cell transplantation us- ing BEAM-alemtuzumab conditioning (carmustine, etoposide, cytosine arabino- side, melphalan, and alemtuzumab 10 mg\\/d on days 5t o1) in 6 United Kingdom transplant centers. Sixty-five pa- tients with lymphoproliferative diseases underwent sibling (n 57) or matched unrelated donor (n 8) transplantation. Sustained donor engraftment occurred in 60 (97%) of

  1. Expansion of Activated Peripheral Blood Memory B Cells in Rheumatoid Arthritis, Impact of B Cell Depletion Therapy, and Biomarkers of Response

    PubMed Central

    Adlowitz, Diana G.; Barnard, Jennifer; Biear, Jamie N.; Cistrone, Christopher; Owen, Teresa; Wang, Wensheng; Palanichamy, Arumugam; Ezealah, Ezinma; Campbell, Debbie; Wei, Chungwen; Looney, R. John; Sanz, Inaki; Anolik, Jennifer H.

    2015-01-01

    Although B cell depletion therapy (BCDT) is effective in a subset of rheumatoid arthritis (RA) patients, both mechanisms and biomarkers of response are poorly defined. Here we characterized abnormalities in B cell populations in RA and the impact of BCDT in order to elucidate B cell roles in the disease and response biomarkers. In active RA patients both CD27+IgD- switched memory (SM) and CD27-IgD- double negative memory (DN) peripheral blood B cells contained significantly higher fractions of CD95+ and CD21- activated cells compared to healthy controls. After BCD the predominant B cell populations were memory, and residual memory B cells displayed a high fraction of CD21- and CD95+ compared to pre-depletion indicating some resistance of these activated populations to anti-CD20. The residual memory populations also expressed more Ki-67 compared to pre-treatment, suggesting homeostatic proliferation in the B cell depleted state. Biomarkers of clinical response included lower CD95+ activated memory B cells at depletion time points and a higher ratio of transitional B cells to memory at reconstitution. B cell function in terms of cytokine secretion was dependent on B cell subset and changed with BCD. Thus, SM B cells produced pro-inflammatory (TNF) over regulatory (IL10) cytokines as compared to naďve/transitional. Notably, B cell TNF production decreased after BCDT and reconstitution compared to untreated RA. Our results support the hypothesis that the clinical and immunological outcome of BCDT depends on the relative balance of protective and pathogenic B cell subsets established after B cell depletion and repopulation. PMID:26047509

  2. Human CD43+ B cells are closely related not only to memory B cells phenotypically but also to plasmablasts developmentally in healthy individuals.

    PubMed

    Inui, Masanori; Hirota, Saeko; Hirano, Kumiko; Fujii, Hiroshi; Sugahara-Tobinai, Akiko; Ishii, Tomonori; Harigae, Hideo; Takai, Toshiyuki

    2015-07-01

    CD20(+)CD27(+)CD43(+) B (CD43(+) B) cells have been newly defined among PBMCs and proposed to be human B1 cells. However, it is controversial as to whether they are orthologs of murine B1 cells and how they are related to other B-cell populations, particularly CD20(+)CD27(+)CD43(-) memory B cells and CD20(low)CD27(high)CD43(high) plasmablasts. Our objective is to identify phenotypically the position of CD43(+) B cells among peripheral B-lineage cell compartments in healthy donors, with reference to B-cell subsets from patients with systemic lupus erythematosus (SLE). We found that CD43(+) B cells among PBMCs from healthy subjects were indistinguishable phenotypically from memory B cells in terms of surface markers, and spontaneous in vitro Ig and IL-10 secretion capability, but quite different from plasmablasts. However, a moderate correlation was found in the frequency of CD43(+) B cells with that of plasmablasts in healthy donors but not in SLE patients. An in vitro differentiation experiment indicated that CD43(+) B cells give rise to plasmablasts more efficiently than do memory B cells, suggesting that they are more closely related to plasmablasts developmentally than are memory B cells, which is also supported by quantitative PCR analysis of mRNA expression of B-cell and plasma cell signature genes. Thus, we conclude that, in healthy individuals, CD43(+) B cells are closely related not only to memory B cells phenotypically but also to plasmablasts developmentally, although the developmental origin of CD43(+) B cells is not necessarily the same as that of plasmablasts. PMID:25744616

  3. B cell follicles and antigen encounters of the third kind

    Microsoft Academic Search

    Jason G Cyster

    2010-01-01

    Defining where and in what form lymphocytes encounter antigen is fundamental to understanding how immune responses occur. Although knowledge of the recognition of antigen by CD4+ and CD8+ T cells has advanced greatly, understanding of the dynamics of B cell–antigen encounters has lagged. With the application of advanced imaging approaches, encounters of this third kind are now being brought into

  4. Tn polyagglutinability occurring in a patient with B cell lymphoma

    Microsoft Academic Search

    M. Wallner; R. Waldner

    1985-01-01

    A case of polymorphic immunocytoma (B cell lymphoma) coinciding with expression of Tn antigen on a population of erythrocytes is presented. Tn activation was found incidentally by screening blood samples of patients suffering from hematologic malignancies with a Tn specific lectin from Salvia sclarea. So far, Tn activation has been reported only in apparently healthy subjects or in subjects suffering

  5. Generation of Functional Human Pancreatic b Cells In Vitro

    E-print Network

    Blackwell, Keith

    Resource Generation of Functional Human Pancreatic b Cells In Vitro Felicia W. Pagliuca,1,3 Jeffrey in diabetes. However, insu- lin-producing cells previously generated from human pluripotent stem cells (h, and transplantation of these cells ame- liorates hyperglycemia in diabetic mice. INTRODUCTION The discovery of human

  6. Antigen-specific B cell responses of vaccinated, neonatal calves

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Responses of newborn calves to vaccination are variable and often characterized by marginal humoral (i.e., antibody) responses. The immune cell population pivotal in the production of antibody is the B cell. The composition and functional capacity of this population in the newborn calf is not well...

  7. [Ibrutinib: A new drug of B-cell malignancies].

    PubMed

    Thieblemont, Catherine

    2015-06-01

    Ibrutinib (Imbruvica(®)) is a first-in-class, orally administered once-daily, that inhibits B-cell antigen receptor signaling downstream of Bruton's tyrosine kinase (BTK). Ibrutinib has been approved in USA in February 2014 and in France in October 2014 for the treatment of patients with relapsed/refractory mantle cell lymphoma (MCL) or chronic lymphocytic leukaemia (CLL) and for the treatment of patients with CLL and a chromosome 17 deletion (del 17p) or TP53 mutation. In clinical studies, ibrutinib induced an impressive overall response rate (68%) in patients with relapsed/refractory MCL (phase II study). In CLL, ibrutinib has shown to significantly improve progression-free survival, response rate and overall survival in patients with relapsed/refractory CLL, including in those with del 17p. Ibrutinib had an acceptable tolerability profile. Less than 10% of patients discontinuited their treatment because of adverse events. Results are pending in other B-cell lymphomas subtypes such as in diffuse large B-cell lymphoma and in follicular lymphoma. An approval extension has already been enregistered for Waldenström disease in USA in January 2015. Given its efficacy and tolerability, ibrutinib is an emerging treatment option for patients with B-cell malignancies. PMID:26118882

  8. [Small cell B-cell lymphomas: guidelines for differential diagnosis].

    PubMed

    Coupland, S E; Dallenbach, F E; Stein, H

    2000-03-01

    Similar to the R.E.A.L-System, the small cell B-cell lymphomas of the new WHO classification consist of chronic lymphocytic leukaemia of B cell type, mantle cell lymphoma, follicular lymphoma, lymphoplasmocytic lymphoma/immunocytoma, hairy cell leukaemia, as well as plasmacytoma. The only major difference between the WHO- and the REAL-classification is the consideration of prolymphocytic leukaemia as a single disease entity in the former system. All the above-mentioned lymphomas arise from B cells of varying stages of differentiation and, therefore, often demonstrate architectural, cytological and immunophenotypic characteristics of their normal physiological counterparts. Consideration of tumour cell growth pattern, -cytology, -immunophenotype and -growth fraction, together with the presence and consistency of the reactive cell infiltrate, usually leads to categorisation of a lymphoma in the majority of cases. The molecular biological characteristics of follicular lymphoma and mantle cell lymphoma are the best defined of the small cell B-cell lymphomas. Chromosomal translocations involving the immunoglobulin heavy chain genes and the bcl-2 gene or Cyclin D1 gene, respectively, probably belong to the initial changes in a cell, which, together with several subsequent unidentified genetic alterations, lead to the development of these tumours. Although nodal small cell B-cell lymphomas are usually diagnosed at an advanced stage of the disease, the progression of the disease--with the exception of mantle cell lymphomas--is often indolent. As a result, the small cell B-cell lymphomas were previously considered as "low-grade" Non-Hodgkin lymphomas in the Kiel classification. However, since the progress of a lymphoma subtype can be heterogeneous and since mantle cell lymphomas cannot really be considered as "low-grade" tumours, "umbrella grading" of lymphomas has been discarded in the WHO classification, with emphasis being placed on grading within a lymphoma disease entity. In the following pages, the characteristics important for the diagnosis and categorisation of the small cell B-cell lymphomas will be summarised. Further, we present information regarding the molecular biological and clinical characteristics of these lymphomas. PMID:10840820

  9. Redirection of B cell responsiveness by transforming growth factor ? receptor

    PubMed Central

    Roes, Jürgen; Choi, B. Ken; Cazac, Balthazar B.

    2003-01-01

    The multifunctional transforming growth factor ? receptor (T?R) ligand pair plays a central role in the regulation of lymphocyte homeostasis and prevention of autoimmunity. Although the mechanisms underlying the induction of transcriptional modulators by T?R have been studied in considerable detail, relatively little is known about the regulatory pathways targeted. To shed light on the mechanisms involved in negative regulation of B cell responses we identified T?R-dependent transcriptome changes by comparative gene expression profiling of normal and T?R-deficient primary B cells. The data reveal T?R-mediated induction of inhibitors of antigen receptor signaling (Ship-1, CD72) as well as inhibitors of the Jak/Stat pathway and signaling by means of Toll-like receptors (SOCS1,3). These inhibitory effects are complemented by induction of antiproliferative transcription factors. In contrast to this inhibition, G protein-coupled receptors such as CXCR4 and agonists mediating Ca2+ flux (inositol trisphosphate receptor subtype 2) are induced by T?R, indicating enhancement of the Ca2+ storage/ release system and chemotactic responses. Suppression of proapoptotic genes suggests support of cell survival. Confirming the shift in B cell responsiveness, antigen-receptor-mediated activation of Syk and phospholipase C-?2, as well as Stat6 phosphorylation, is inhibited, whereas chemotaxis, Ca2+ release, and cell survival are enhanced in transforming growth factor-?-sensitive B cells. The data provide a molecular basis for T?R-mediated inhibition of B cell responsiveness and indicate that T?R maintains homeostasis not only through inhibition of the cell cycle but also by delivering a coherent instructive signal that redirects responsiveness to microenvironmental cues. PMID:12773615

  10. Essential role of EBF1 in the generation and function of distinct mature B cell types

    PubMed Central

    Vilagos, Bojan; Hoffmann, Mareike; Souabni, Abdallah; Sun, Qiong; Werner, Barbara; Medvedovic, Jasna; Bilic, Ivan; Minnich, Martina; Axelsson, Elin; Jaritz, Markus

    2012-01-01

    The transcription factor EBF1 is essential for lineage specification in early B cell development. In this study, we demonstrate by conditional mutagenesis that EBF1 is required for B cell commitment, pro–B cell development, and subsequent transition to the pre–B cell stage. Later in B cell development, EBF1 was essential for the generation and maintenance of several mature B cell types. Marginal zone and B-1 B cells were lost, whereas follicular (FO) and germinal center (GC) B cells were reduced in the absence of EBF1. Activation of the B cell receptor resulted in impaired intracellular signaling, proliferation and survival of EBF1-deficient FO B cells. Immune responses were severely reduced upon Ebf1 inactivation, as GCs were formed but not maintained. ChIP- and RNA-sequencing of FO B cells identified EBF1-activated genes that encode receptors, signal transducers, and transcriptional regulators implicated in B cell signaling. Notably, ectopic expression of EBF1 efficiently induced the development of B-1 cells at the expense of conventional B cells. These gain- and loss-of-function analyses uncovered novel important functions of EBF1 in controlling B cell immunity. PMID:22473956

  11. B-cell activating factor (BAFF) and BAFF-R levels correlate with B-cell subset activation and redistribution in controlled human malaria infection

    PubMed Central

    Scholzen, Anja; Teirlinck, Anne C.; Bijker, Else M.; Roestenberg, Meta; Hermsen, Cornelus C.; Hoffman, Stephen L.; Sauerwein, Robert W.

    2014-01-01

    Characteristic features of Plasmodium falciparum malaria are polyclonal B-cell activation and an altered composition of the blood B-cell compartment, including expansion of CD21?CD27? atypical memory B-cells. B-cell activating factor (BAFF) is a key cytokine in B-cell homeostasis, but its potential contribution to the modulation of the blood B-cell pool during malaria remains elusive. In the controlled human malaria model (CHMI) in malaria-naďve Dutch volunteers, we therefore examined the dynamics of BAFF induction and B-cell subset activation and composition, to investigate whether these changes are linked to malaria-induced immune activation and in particular induction of BAFF. Alterations in B-cell composition after CHMI closely resembled those observed in endemic areas. We further found distinct kinetics of proliferation for individual B-cell subsets across all developmental stages. Proliferation peaked either immediately after blood-stage infection or at convalescence, and for most subsets was directly associated with the peak parasitemia. Concomitantly, plasma BAFF levels during CHMI were increased and correlated with membrane-expressed BAFF on monocytes and dendritic cells, as well as blood-stage parasitemia and parasite-induced IFN?. Correlating with elevated plasma BAFF and IFN? levels, IgD?CD38lowCD21?CD27? atypical B-cells showed the strongest proliferative response of all memory B-cell subsets. This provides unique evidence for a link between malaria-induced immune activation and temporary expansion of this B-cell subset. Finally, baseline BAFF-receptor levels prior to CHMI were predictive of subsequent changes in proportions of individual B-cell subsets. These findings suggest an important role of BAFF in facilitating B-cell subset proliferation and redistribution as a consequence of malaria-induced immune activation. PMID:24646735

  12. Epstein-Barr virus associated diffuse large B-cell lymphoma complicated by autoimmune hemolytic anemia and pure red cell aplasia.

    PubMed

    Katayama, H; Takeuchi, M; Yoshino, T; Munemasa, M; Tada, A; Soda, R; Takahashi, K

    2001-07-01

    A 53-year old man with systemic lymphadenopathy and hepatosplenomegaly was diagnosed with diffuse large B cell-lymphoma after inguinal lymph node biopsy. Anemia was noted, direct and indirect Coombs tests were positive, and the haptoglobin level was low. However, the bone marrow aspirate revealed erythroid aplasia. Co-existing autoimmune haemolytic anemia (AIHA) and pure red cell aplasia (PRCA) were diagnosed. In situ hybridization with Epstein-Barr virus (EBV) encoded small RNA (EBER) showed positive findings in lymphoma cells. Southern blot hybridization revealed immunoglobulin heavy chain gene rearrangement and a clonal EBV terminal repeat, indicating monoclonal proliferation of EBV in infected B cells. The patient was treated with CHOP, resulting in a complete remission (CR). AIHA and PRCA subsided after 3 courses of chemotherapy. In conclusion, this case demonstrates not only the association of B-cell lymphoma with autoimmune disorders but also the involvement of EBV in these conditions. PMID:11699422

  13. Simultaneous presentation of Kaposi sarcoma and HHV8-associated large B-cell lymphoma in the same lymph node: A rare diagnosis in an HIV-negative patient

    PubMed Central

    Fernandes, Fabíola; Eloy, Catarina; Carimo, Awa; Pinto, Paula; Graves, Susannah; Simőes, Joana; Carrilho, Carla; Lopes, José Manuel

    2013-01-01

    Patient: Female, 18 Final Diagnosis: Simultanous presentation of Kaposi Sarcoma and Lymphoma Symptoms: — Medication: — Clinical Procedure: — Specialty: Oncology Objective Rare disease Background: KSHV/HHV-8 is associated with Kaposi’s sarcoma (KS) as well as with a few categories of lymphoproliferative diseases, mostly occurring in patients with HIV infection/AIDS. Although the association between lymphomas and Kaposi’s sarcoma has been described, the simultaneous presence of the 2 entities within the same organ is rare and mainly associated with HIV/ AIDS. Case Report: We report a case of simultaneous occurrence of Kaposi‘s sarcoma and large B-cell lymphoma in the same lymph node in a 18-year-old African woman who was HIV-negative. We found concurrent infection with Kaposi’s sarcoma herpes virus (KSHV) and Epstein-Barr virus (EBV), confirmed by PCR amplification of DNA obtained from distinct tumor areas selected in the paraffin block. Conclusions: The possibility of occurrence of 2 lesions with distinct features in the same organ may be unexpected for pathologists performing fine-needle aspiration cytology (FNAC) evaluation but must be considered, even in HIV-negative individuals, despite its rare occurrence, as was demonstrated by this case. PMID:23885287

  14. Follicular Lymphoma Presenting with Leptomeningeal Disease

    PubMed Central

    Costa, Ricardo; Costa, Renata

    2014-01-01

    Follicular lymphoma is generally an indolent B cell lymphoproliferative disorder of transformed follicular center B cells. Central nervous system metastasis is a very rare complication portending a very poor prognosis. We report a rare case of follicular lymphoma presenting with leptomeningeal involvement achieving a complete remission after initial therapy. PMID:25544910

  15. High TNF-? levels in resting B cells negatively correlate with their response.

    PubMed

    Frasca, Daniela; Diaz, Alain; Romero, Maria; Landin, Ana Marie; Blomberg, Bonnie B

    2014-06-01

    Aging significantly decreases the influenza vaccine-specific response as we and others have previously shown. Based on our previous data in aged mice, we hypothesize that the inflammatory status of the individual and of B cells themselves would impact B cell function. We here show that the ability to generate a vaccine-specific antibody response is negatively correlated with levels of serum TNF-?. Moreover, human unstimulated B cells from elderly make higher levels of TNF-? than those from young individuals, and these positively correlate with serum TNF-? levels. These all negatively correlate with B cell function, measured by activation-induced cytidine deaminase, the enzyme of class switch recombination and somatic hypermutation. Only memory B cells (either IgM or switched), but not naďve B cells, make appreciable levels of TNF-? and more in elderly as compared to young individuals. Finally, an anti-TNF-? antibody can increase the response in cultured B cells from the elderly, suggesting that TNF-? secreted by memory B cells affects IgM memory B cells and naďve B cells in an autocrine and/or paracrine manner. Our results show an additional mechanism for reduced B cell function in the elderly and propose B cell-derived TNF-? as another predictive biomarker of in vivo and in vitro B cell responses. PMID:24440385

  16. Latest advances in connective tissue disorders.

    PubMed

    Rao, Vijay; Bowman, Simon

    2013-08-01

    The connective tissue disorders comprise a number of related conditions that include systemic lupus erythematosus (SLE) and the antiphospholipid (Hughes) syndrome, scleroderma, myositis and Sjögren's syndrome. They are characterized by autoantibody production and other immune-mediated dysfunction. There are common clinical and serological features with some patients having multiple overlapping connective tissue disorders. The latest advances include new approaches to therapy, including more focused utilization of existing therapies and the introduction of biological therapies in SLE, more precise protocols for assessment of severe disease manifestations such as in interstitial lung disease and pulmonary artery hypertension in scleroderma, new antibodies for disease characterization in myositis and new approaches to patient assessment in Sjögren's syndrome. B cells have a critical role in most, if not all of these disorders such that B-cell depletion or suppression of B-cell activating cytokines improves disease in many patients. In particular, the introduction of rituximab, a monoclonal antibody targeting the CD20 molecule on B cells, into clinical practice for rheumatoid arthritis and B-cell lymphoma has been a key driver of experimental approaches to therapy in connective tissue disorders. Genetic studies also suggest a role for the innate immune system in disease pathogenesis, suggesting further future targets for biological therapies over the next few years. PMID:23904866

  17. Latest advances in connective tissue disorders

    PubMed Central

    Rao, Vijay

    2013-01-01

    The connective tissue disorders comprise a number of related conditions that include systemic lupus erythematosus (SLE) and the antiphospholipid (Hughes) syndrome, scleroderma, myositis and Sjögren’s syndrome. They are characterized by autoantibody production and other immune-mediated dysfunction. There are common clinical and serological features with some patients having multiple overlapping connective tissue disorders. The latest advances include new approaches to therapy, including more focused utilization of existing therapies and the introduction of biological therapies in SLE, more precise protocols for assessment of severe disease manifestations such as in interstitial lung disease and pulmonary artery hypertension in scleroderma, new antibodies for disease characterization in myositis and new approaches to patient assessment in Sjögren’s syndrome. B cells have a critical role in most, if not all of these disorders such that B-cell depletion or suppression of B-cell activating cytokines improves disease in many patients. In particular, the introduction of rituximab, a monoclonal antibody targeting the CD20 molecule on B cells, into clinical practice for rheumatoid arthritis and B-cell lymphoma has been a key driver of experimental approaches to therapy in connective tissue disorders. Genetic studies also suggest a role for the innate immune system in disease pathogenesis, suggesting further future targets for biological therapies over the next few years. PMID:23904866

  18. Progression and Transformation of Clonally Heterogeneous B-cell Lymphoma

    PubMed Central

    Weiss, Robert F.; Smith, Mitchell R.; Miller, Merlin G.; Cronin, John F.

    2015-01-01

    Indolent B- cell non-Hodgkin lymphoma can transform into aggressive lymphoma. We extend our prior mathematical model to analyze and predict transformation. To provide additional confidence in our model, we compare it with SCID mouse data for combination therapy of Diffuse Large B-cell Lymphoma, an aggressive form of the disease. We develop a two cell model that includes indolent and aggressive clones but no immune response and use it to predict transformation. An approximate model for the time to transformation is derived that provides insight regarding scaling effects. We then add an immune response and therapeutic measures, and illustrate the complex interactions among the various processes, with a focus on transformation. The implications for initial diagnosis and treatment of non-Hodgkin lymphoma are discussed. PMID:26068800

  19. Bisphosphonates target B cells to enhance humoral immune responses

    PubMed Central

    Tonti, Elena; Jiménez de Oya, Nereida; Galliverti, Gabriele; Moseman, E. Ashley; Di Lucia, Pietro; Amabile, Angelo; Sammicheli, Stefano; De Giovanni, Marco; Sironi, Laura; Chevrier, Nicolas; Sitia, Giovanni; Gennari, Luigi; Guidotti, Luca G.; von Andrian, Ulrich H.; Iannacone, Matteo

    2013-01-01

    Summary Bisphosphonates are a class of drugs that are widely used to inhibit loss of bone mass in patients. We show here that the administration of clinically relevant doses of bisphosphonates in mice increases antibody responses to live and inactive viruses, proteins, haptens and existing commercial vaccine formulations. Bisphosphonates exert this adjuvant-like activity in the absence of CD4+ and ?? T cells, neutrophils or dendritic cells and their effect does not rely on local macrophage depletion nor does it depend upon Toll-like receptor signaling or the inflammasome. Rather, bisphosphonates target directly B cells and enhance B cell expansion and antibody production upon antigen encounter. These data establish bisphosphonates as a novel class of adjuvants that boost humoral immune responses. PMID:24120862

  20. Cutaneous B cell lymphomas: Report of two interesting cases.

    PubMed

    Gurumurthy, Ravichandran; Mohapatra, Ranjan Kumar; Easow, Jose M; Mohan, Subhashini

    2015-01-01

    Cutaneous B cell lymphomas can arise primarily from the skin or may occur due to secondary spread from nodal lymphomas. Primary lymphomas are confined to the skin without systemic spread and they differ from secondary lymphomas in their clinical behavior, treatment and prognosis. Cutaneous lymphomas being relatively rare, lack of precise definition and understanding of their clinical behavior diseases leads to pitfalls in the diagnosis. We report two cases of cutaneous B cell lymphomas who presented with fever of unknown origin initially and later found to have skin lesions. Hence, skin can be a potential diagnostic clue in the evaluation of patients with fever of unknown origin. The distinctions between the primary and the secondary lymphomas become important in choosing the treatment and assessing the prognosis. PMID:25814707

  1. Tn polyagglutinability occurring in a patient with B cell lymphoma.

    PubMed

    Wallner, M; Waldner, R

    1985-11-01

    A case of polymorphic immunocytoma (B cell lymphoma) coinciding with expression of Tn antigen on a population of erythrocytes is presented. Tn activation was found incidentally by screening blood samples of patients suffering from hematologic malignancies with a Tn specific lectin from Salvia sclarea. So far, Tn activation has been reported only in apparently healthy subjects or in subjects suffering from or developing myeloid leukemia. PMID:3933597

  2. TSPAN33 is a novel marker of activated and malignant B cells.

    PubMed

    Luu, Van Phi; Hevezi, Peter; Vences-Catalan, Felipe; Maravillas-Montero, José Luis; White, Clayton Alexander; Casali, Paolo; Llorente, Luis; Jakez-Ocampo, Juan; Lima, Guadalupe; Vilches-Cisneros, Natalia; Flores-Gutiérrez, Juan Pablo; Santos-Argumedo, Leopoldo; Zlotnik, Albert

    2013-12-01

    We have identified Tspan33 as a gene encoding a transmembrane protein exhibiting a restricted expression pattern including expression in activated B cells. TSPAN33 is a member of the tetraspanin family. TSPAN33 is not expressed in resting B cells, but is strongly induced in primary human B cells following activation. Human 2E2 cells, a Burkitt's lymphoma-derived B cell model of activation and differentiation, also upregulate TSPAN33 upon activation. TSPAN33 is expressed in several lymphomas including Hodgkin's and Diffuse large B cell lymphoma. TSPAN33 is also expressed in some autoimmune diseases where B cells participate in the pathology, including rheumatoid arthritis patients, systemic lupus erythematosus (SLE), and in spleen B cells from MRL/Fas(lpr/lpr) mice (a mouse model of SLE). We conclude that TSPAN33 may be used as a diagnostic biomarker or as a target for therapeutic antibodies for treatment of certain B cell lymphomas or autoimmune diseases. PMID:24211713

  3. Innate and cognate roles of B cells in T cell differentiation and memory 

    E-print Network

    Morrison, Vicky L.

    2011-01-01

    B cells recognise antigens on micro-organisms through their B cell receptor (BCR) and via Toll-like receptors (TLRs), and thus respond in both innate and adaptive manners during the subsequent immune response. Innate ...

  4. APOBEC3 enzymes restrict marginal zone B cells.

    PubMed

    Beck-Engeser, Gabriele B; Winkelmann, Rebecca; Wheeler, Matthew L; Shansab, Maryam; Yu, Philipp; Wünsche, Sarah; Walchhütter, Anja; Metzner, Mirjam; Vettermann, Christian; Eilat, Dan; DeFranco, Anthony; Jäck, Hans-Martin; Wabl, Matthias

    2015-03-01

    In general, a long-lasting immune response to viruses is achieved when they are infectious and replication competent. In the mouse, the neutralizing antibody response to Friend murine leukemia virus is contributed by an allelic form of the enzyme Apobec3 (abbreviated A3). This is counterintuitive because A3 directly controls viremia before the onset of adaptive antiviral immune responses. It suggests that A3 also affects the antibody response directly. Here, we studied the relative size of cell populations of the adaptive immune system as a function of A3 activity. We created a transgenic mouse that expresses all seven human A3 enzymes and compared it to WT and mouse A3-deficient mice. A3 enzymes decreased the number of marginal zone B cells, but not the number of follicular B or T cells. When mouse A3 was knocked out, the retroelement hitchhiker-1 and sialyl transferases encoded by genes close to it were overexpressed three and two orders of magnitude, respectively. We suggest that A3 shifts the balance, from the fast antibody response mediated by marginal zone B cells with little affinity maturation, to a more sustained germinal center B-cell response, which drives affinity maturation and, thereby, a better neutralizing response. PMID:25501566

  5. Biphenotypic B-cell lymphoma in 2 cats.

    PubMed

    Granum, Liana; Gorman, Elena; Ruaux, Craig; Vernau, William

    2015-06-01

    The clinical and pathologic features of biphenotypic B-cell lymphoma in 2 cats are reported. Clinical presentation varied from multiple cutaneous masses identified on the thigh in one cat to signs of lethargy from acute hemorrhage due to neoplastic infiltration of one kidney in the other. Cytology and histopathology confirmed round cell neoplasia in both cats and immunochemical staining demonstrated expression of both B- and T-lymphocyte markers by the neoplastic cells in both animals. In PCR analysis of antigen receptor gene rearrangement, clonal rearrangement of B-cell receptor genes and polyclonal T-cell receptor gene rearrangement were demonstrated in both lymphomas. These findings were consistent with a diagnosis of B-cell lymphoma with aberrant CD3 expression in both cases. Clinical progression of disease post diagnosis was rapid in both cats, suggesting a poor prognosis for this lymphoma type. Although bigenotypic receptor rearrangement of lymphoma cells appears relatively common, this is the first known report of actual biphenotypic lymphoma in cats. PMID:25867846

  6. Artesunate Abolishes Germinal Center B Cells and Inhibits Autoimmune Arthritis

    PubMed Central

    Huang, Haochu

    2014-01-01

    The antimalarial drug artemisinin and its derivatives exhibit potent immunosuppressive activity in several autoimmune disease models, however the mechanisms are not well-understood. This study was designed to investigate the therapeutic effects and the underlying mechanisms of the artemisinin analog artesunate using the K/BxN mouse model of rheumatoid arthritis. The well-studied disease mechanisms of K/BxN model allowed us to pinpoint the effect of artesunate on disease. Artesunate treatment prevented arthritis development in young K/BxN mice by inhibiting germinal center (GC) formation and production of autoantibodies. In adult K/BxN mice with established arthritis, artesunate diminished GC B cells in a few days. However, artesunate did not affect the follicular helper T cells (Tfh). In contrast to the spontaneous K/BxN model, artesunate treatment exerted minor influence on K/BxN serum transfer induced arthritis suggesting that artesunate has minimal effect on inflammatory responses downstream of antibody production. Finally, we showed that artesunate preferentially inhibits proliferating GC B cells. These results identify GC B cells as a target of artesunate and provide a new rationale for using artemisinin analogues to treat autoimmune diseases mediated by autoantibodies. PMID:25116436

  7. Interleukin 7 independent development of human B cells.

    PubMed Central

    Prieyl, J A; LeBien, T W

    1996-01-01

    Mammalian hematopoietic stem cell (HSC) commitment and differentiation into lymphoid lineage cells proceed through a series of developmentally restricted progenitor compartments. A complete understanding of this process, and how it differs from HSC commitment and differentiation into cells of the myeloid/erythroid lineages, requires the development of model systems that support HSC commitment to the lymphoid lineages. We now describe a human bone marrow stromal cell culture that preferentially supports commitment and differentiation of human HSC to CD19+ B-lineage cells. Fluorescence activated cell sorterpurified CD34++/lineage-cells were isolated from fetal bone marrow and cultured on human fetal bone marrow stromal cells in serum-free conditions containing no exogenous cytokines. Over a period of 3 weeks, CD34++/lineage- cells underwent commitment, differentiation, and expansion into the B lineage. Progressive changes included: loss of CD34, acquisition of and graded increases in the level of cell surface CD19, and appearance of immature B cells expressing mu/kappa or mu/lambda cell surface Ig receptors. The tempo and phenotype of B-cell development was not influenced by the addition of IL-7 (10 ng/ml), or by the addition of goat anti-IL-7 neutralizing antibody. These results indicate a profound difference between mouse and human in the requirement for IL-7 in normal B-cell development, and provide an experimental system to identify and characterize human bone marrow stromal cell-derived molecules crucial for human B lymphopoiesis. PMID:8816803

  8. Bcipep: A database of B-cell epitopes

    PubMed Central

    Saha, Sudipto; Bhasin, Manoj; Raghava, Gajendra PS

    2005-01-01

    Background Bcipep is a database of experimentally determined linear B-cell epitopes of varying immunogenicity collected from literature and other publicly available databases. Results The current version of Bcipep database contains 3031 entries that include 763 immunodominant, 1797 immunogenic and 471 null-immunogenic epitopes. It covers a wide range of pathogenic organisms like viruses, bacteria, protozoa, and fungi. The database provides a set of tools for the analysis and extraction of data that includes keyword search, peptide mapping and BLAST search. It also provides hyperlinks to various databases such as GenBank, PDB, SWISS-PROT and MHCBN. Conclusion A comprehensive database of B-cell epitopes called Bcipep has been developed that covers information on epitopes from a wide range of pathogens. The Bcipep will be source of information for investigators involved in peptide-based vaccine design, disease diagnosis and research in allergy. It should also be a promising data source for the development and evaluation of methods for prediction of B-cell epitopes. The database is available at . PMID:15921533

  9. CD3-Positive B Cells: A Storage-Dependent Phenomenon

    PubMed Central

    Nagel, Angela; Möbs, Christian; Raifer, Hartmann; Wiendl, Heinz; Hertl, Michael; Eming, Rüdiger

    2014-01-01

    The majority of clinical studies requires extensive management of human specimen including e.g. overnight shipping of blood samples in order to convey the samples in a central laboratory or to simultaneously analyze large numbers of patients. Storage of blood samples for periods of time before in vitro/ex vivo testing is known to influence the antigen expression on the surface of lymphocytes. In this context, the present results show for the first time that the T cell antigen CD3 can be substantially detected on the surface of human B cells after ex vivo storage and that the degree of this phenomenon critically depends on temperature and duration after blood withdrawal. The appearance of CD3 on the B cell surface seems to be a result of contact-dependent antigen exchange between T and B lymphocytes and is not attributed to endogenous production by B cells. Since cellular subsets are often classified by phenotypic analyses, our results indicate that ex vivo cellular classification in peripheral blood might result in misleading interpretations. Therefore, in order to obtain results reflecting the in vivo situation, it is suggested to minimize times of ex vivo blood storage after isolation of PBMC. Moreover, to enable reproducibility of results between different research groups and multicenter studies, we would emphasize the necessity to specify and standardize the storage conditions, which might be the basis of particular findings. PMID:25329048

  10. B Cells Modulate Mucosal Associated Invariant T Cell Immune Responses

    PubMed Central

    Salerno-Goncalves, Rosangela; Rezwan, Tasmia; Sztein, Marcelo B.

    2014-01-01

    A common finding when measuring?T cell immunity to enteric bacterial vaccines in humans is the presence of background responses among individuals before immunization. Yet the nature of these background responses remains largely unknown. Recent findings show the presence in uninfected individuals of mucosal associated invariant?T (MAIT) cells that mount broad spectrum immune responses against a variety of microorganisms including Mycobacterium tuberculosis and enteric bacteria such as Escherichia coli and Salmonella. Therefore, we investigated whether MAIT immune responses to intestinal bacteria might account for the background responses observed before immunization. Here we measured MAIT immune responses to commensal and enteric pathogenic bacteria in healthy individuals with no history of oral immunization with enteric bacteria. We found that MAIT cells were activated by B cells infected with various bacteria strains (commensals and pathogens from the Enterobacteriaceae family), but not by uninfected cells. These responses were restricted by the non-classical MHC-related molecule 1 (MR1) and involved the endocytic pathway. The quality of these responses (i.e., cytokine profile) was dependent on bacterial load but not on the level expression of MR1 or bacterial antigen on B cell surface, suggesting that a threshold level of MR1 expression is required to trigger MAIT activation. These results provide important insights into the role of B cells as a source of antigen-presenting cells to MAIT cells and the gut immune surveillance of commensal microbiota. PMID:24432025

  11. Fanca deficiency reduces A/T transitions in somatic hypermutation and alters class switch recombination junctions in mouse B cells

    PubMed Central

    Nguyen, Thuy Vy; Riou, Lydia

    2014-01-01

    Fanconi anemia is a rare genetic disorder that can lead to bone marrow failure, congenital abnormalities, and increased risk for leukemia and cancer. Cells with loss-of-function mutations in the FANC pathway are characterized by chromosome fragility, altered mutability, and abnormal regulation of the nonhomologous end-joining (NHEJ) pathway. Somatic hypermutation (SHM) and immunoglobulin (Ig) class switch recombination (CSR) enable B cells to produce high-affinity antibodies of various isotypes. Both processes are initiated after the generation of dG:dU mismatches by activation-induced cytidine deaminase. Whereas SHM involves an error-prone repair process that introduces novel point mutations into the Ig gene, the mismatches generated during CSR are processed to create double-stranded breaks (DSBs) in DNA, which are then repaired by the NHEJ pathway. As several lines of evidence suggest a possible role for the FANC pathway in SHM and CSR, we analyzed both processes in B cells derived from Fanca?/? mice. Here we show that Fanca is required for the induction of transition mutations at A/T residues during SHM and that despite globally normal CSR function in splenic B cells, Fanca is required during CSR to stabilize duplexes between pairs of short microhomology regions, thereby impeding short-range recombination downstream of DSB formation. PMID:24799500

  12. Splenectomy in haemophagocytic lymphohistiocytosis: report of histopathological changes with CD19+ B-cell depletion and therapeutic results.

    PubMed

    Imashuku, S; Obayashi, M; Hosoi, G; Sako, M; Chen, J; Mugishima, H; Tsunamoto, K; Hibi, S; Todo, S

    2000-03-01

    The pathogenesis of haemophagocytic lymphohistiocytosis (HLH) in children without a known familial pattern of inheritance is often difficult to establish. Splenic enlargement, one of the main clinical findings in this disorder, has led to the use of splenectomy for uncontrollable coagulopathy, persistent cytopenia or both. This procedure is also thought to be a useful tool in making a differential diagnosis in cases of the immunochemotherapy-resistant HLH. We report here five cases of splenectomized childhood HLH, in which subsets of mononuclear spleen cells were analysed either by flow cytometry or immunohistochemistry, and the results were compared with those from cases of hereditary spherocytosis (controls). There was a statistically significant depletion of CD19+ B cells in the HLH cases (3.8 +/- 3.2% vs. 52.6 +/- 4.5%, P < 0. 0001) associated with an increase of T cells in three cases and of natural killer cells in another. The histopathological findings included atrophic white pulps, B-cell depletion with fibrosis and haemosiderosis in all five cases. Despite temporary therapeutic benefits, three of the HLH patients had a rapidly deteriorating post-splenectomy course and all three eventually died. These results demonstrate striking depletion of B cells in the enlarged spleens of children with HLH, which may be an intrinsic feature of HLH pathogenesis. Further study is needed to establish the therapeutic value of splenectomy in this disease. PMID:10759706

  13. A case of human B cell leukemia that implicates an autocrine mechanism in the abnormal growth of Leu 1 B cells.

    PubMed Central

    Kawamura, N; Muraguchi, A; Hori, A; Horii, Y; Mutsuura, S; Hardy, R R; Kikutani, H; Kishimoto, T

    1986-01-01

    Production of B cell growth factor (BCGF) from B-chronic lymphocytic leukemia (B-CLL) cells was demonstrated. Freshly isolated monoclonal B-CLL cells expressed surface mu, delta, B1, and Leu 1, but not Ba (an antigen expressed only on activated B cells). Upon stimulation with anti-IgM, they secreted BCGF, which could act on anti-IgM-stimulated autologous leukemic cells as well as anti-IgM-stimulated normal B cells. Cell lines established from these leukemic cells also constitutively secreted BCGF. The BCGF from B-CLL cells or established cell lines induced neither proliferation nor enhanced HLA-DR expression in resting B cells. These results show the presence of B cell-derived BCGF, which is distinct from BSF-1 and effective only on activated B cells. They also suggest that an autocrine mechanism may operate in the growth of B-CLL cells. Images PMID:3490495

  14. Isolation and characterization of a novel B cell activation gene

    SciTech Connect

    Hong, J.X.; Wilson, G.L.; Fox, C.H.; Kehrl, J.H. (National Institutes of Health, Bethesda, MA (United States))

    1993-05-01

    Using subtractive cDNA cloning, the authors have isolated a series of cDNA clones that are differentially expressed between B and T lymphocytes. Whereas some of the isolated cDNA are from known B cell-specific genes, many of them represent previously uncharacterized genes. One of these unknown genes was denoted as BL34. Northern blot analysis performed with the BL34 cDNA revealed a 1.6-kb mRNA transcript that was present at low levels in RNA extracted from resting B lymphocytes, but whose expression was markedly increased in RNA prepared from mitogen-activated B cells. Similarly, RNA prepared from several B cell lines treated with phorbol myristate acetate (PMA) contained high levels of BL34 mRNA. In contrast, RNA from purified T cells treated with phytohemagglutinin and PMA had undetectable amounts of BL34 mRNA. In addition, high levels of BL34 mRNA were detected in RNA purified from PBMC of a patient with B cell acute lymphocytic leukemia. Southern blot analysis of human DNA from various tissues and cells lines demonstrated that BL34 is a single-copy gene without evidence of rearrangement. Two full length BL34 cDNA were sequenced, and an open reading frame of 588 bp was identified that was predicted to encode for a 196 amino acid protein. Searches of several protein data bases failed to find any homologous proteins. To directly analyze the expression of BL34 mRNA in lymphoid tissues in situ, hybridization studies with human tonsil tissue sections were performed. BL34 mRNA was detected in a portion of the cells in the germinal center region and adjacent to the mantle region. Further characterization of the BL34 gene and its protein should lead to insights to its role in B cell function and the consequences of its over-expression in acute lymphocytic leukemia. 26 refs., 6 figs., 1 tab.

  15. A Rapid Flow Cytometric Screening Test for X-linked Lymphoproliferative Disease due to XIAP Deficiency

    PubMed Central

    Marsh, Rebecca A.; Villanueva, Joyce; Zhang, Kejian; Snow, Andrew L.; Su, Helen C.; Madden, Lisa; Mody, Rajen; Kitchen, Brenda; Marmer, Dan; Jordan, Michael B.; Risma, Kimberly; Filipovich, Alexandra; Bleesing, Jack J.

    2009-01-01

    Background Deficiency of X-linked Inhibitor of Apoptosis (XIAP), caused by BIRC4 gene mutations, is the second known cause of X-linked Lymphoproliferative Disease (XLP), a rare primary immunodeficiency that often presents with life-threatening hemophagocytic lymphohistiocytosis (HLH). Rapid diagnosis of the known genetic causes of HLH, including XIAP deficiency, facilitates the initiation of life-saving treatment and preparation for allogeneic hematopoietic cell transplantation (HCT). Until now, a rapid screening test for XIAP deficiency has not been available. Methods In order to develop a flow cytometric screening test for XIAP deficiency, we first used lymphoblastic cell lines generated from controls and patients with BIRC4 mutations to identify 2 commercially available antibodies specific for native intracellular XIAP. Next, we used these antibodies to study control whole blood leukocyte XIAP expression. We then studied XIAP expression in leukocytes from patients with XLP due to BIRC4 mutations, maternal carriers, and patients following HCT. Results XIAP was expressed by the majority of all whole blood nucleated cells in normal controls. In contrast, XIAP was absent or decreased in all lymphocyte subsets, monocytes and granulocytes from 4 unrelated patients with XLP due to BIRC4 mutations. Bimodal distribution of XIAP expression was evident in two maternal carriers, with significant skewing towards cells expressing normal XIAP. Bimodal distribution was also observed in a patient following HCT. Conclusions Flow cytometric analysis of intracellular XIAP provides a rapid screening test for XLP due to XIAP deficiency. It also allows carrier detection and can be used to monitor donor versus recipient reconstitution following HCT. PMID:19288545

  16. Accumulation of Self-Reactive Naďve and Memory B Cell Reveals Sequential Defects in B Cell Tolerance Checkpoints in Sjögren’s Syndrome

    PubMed Central

    Corsiero, Elisa; Sutcliffe, Nurhan; Pitzalis, Costantino; Bombardieri, Michele

    2014-01-01

    Sjögren’s syndrome (SS) is an autoimmune disease characterised by breach of self-tolerance towards nuclear antigens resulting in high affinity circulating autoantibodies. Although peripheral B cell disturbances have been described in SS, with predominance of naďve and reduction of memory B cells, the stage at which errors in B cell tolerance checkpoints accumulate in SS is unknown. Here we determined the frequency of self- and poly-reactive B cells in the circulating naďve and memory compartment of SS patients. Single CD27?IgD+ naďve, CD27+IgD+ memory unswitched and CD27+IgD? memory switched B cells were sorted by FACS from the peripheral blood of 7 SS patients. To detect the frequency of polyreactive and autoreactive clones, paired Ig VH and VL genes were amplified, cloned and expressed as recombinant monoclonal antibodies (rmAbs) displaying identical specificity of the original B cells. IgVH and VL gene usage and immunoreactivity of SS rmAbs were compared with those obtained from healthy donors (HD). From a total of 353 VH and 293 VL individual sequences, we obtained 114 rmAbs from circulating naďve (n?=?66) and memory (n?=?48) B cells of SS patients. Analysis of the Ig V gene repertoire did not show significant differences in SS vs. HD B cells. In SS patients, circulating naďve B cells (with germline VH and VL genes) displayed a significant accumulation of clones autoreactive against Hep-2 cells compared to HD (43.1% vs. 25%). Moreover, we demonstrated a progressive increase in the frequency of circulating anti-nuclear naďve (9.3%), memory unswitched (22.2%) and memory switched (27.3%) B cells in SS patients. Overall, these data provide novel evidence supporting the existence of both early and late defects in B cell tolerance checkpoints in patients with SS resulting in the accumulation of autoreactive naďve and memory B cells. PMID:25535746

  17. Human germinal center B cells differ from naive and memory B cells by their aggregated MHC class II-rich compartments lacking HLA-DO

    Microsoft Academic Search

    Cecile Chalouni; Jacques Banchereau; Anne B. Vogt; Virginia Pascual; Jean Davoust

    2003-01-01

    To generate memory B cells bearing high-affinity antibodies, naive B cells first encounter antigen in the T cell-rich areas of secondary lymphoid organs. There, they are activated by antigen-specific T cells and become germinal center (GC) founder B cells. GC founders enter the GC to become centroblasts that proliferate and mutate their BCR. Centroblasts differentiate into centrocytes that undergo selection,

  18. Cell extrinsic alterations in splenic B cell maturation in Flt3-ligand knockout mice.

    PubMed

    Dolence, Joseph J; Gwin, Kimberly A; Shapiro, Mariya B; Hsu, Fan-Chi; Shapiro, Virginia S; Medina, Kay L

    2015-06-01

    B lymphopoiesis in bone marrow (BM) is critical for maintaining a diverse peripheral B cell pool to fight infection and establish lifelong immunity. The generation of immature B cells is reduced in Flt3-ligand (FL-/-) mice leading to deficiencies in splenic B cells. Here, we sought to understand the cellular basis of the spleen B cell deficiency in FL-/- mice. Significant reductions in transitional (TS) and follicular (FO) B cells were found in FL-/- mice, and increased frequencies, but not absolute numbers, of marginal zone (MZ) B cells. BAFF-R expression on splenic B cells and serum levels of B cell activating factor (BAFF) was comparable to wildtype (WT) mice. Mixed BM chimeras revealed that the reductions in TS and FO B cells were cell extrinsic. FL administration into FL-/- mice restored the deficiency in TS B cells and normalized the MZ compartment. Ki67 analysis revealed a significant decrease in the proliferative capacity of TS B cells in FL-/- mice. A Bcl2 transgene did not rescue TS cells in FL-/- mice, uncoupling FL-deficiency to Bcl2-dependent survival pathways. Upregulation of CD1d expression and adoptive transfer experiments suggested MZ skewing in FL-/- mice. These findings support an integral role for Flt3 signaling in peripheral B cell maturation. PMID:26029370

  19. PI3 Kinase Signals BCR-Dependent Mature B Cell Survival

    E-print Network

    in the B cell habitat and is thus critically involved in controlling B cell numbers. In BAFF or BAFF. (2004) demonstrated that mature B cells undergo apoptosis upon in vivo BCR ablation or mutation of one of its signaling units, the Iga polypeptide chain, and disap- pear from the body with a half-life of 3

  20. Quorum Sensing Contributes to Activated IgM-Secreting B Cell Homeostasis

    PubMed Central

    Montaudouin, Caroline; Anson, Marie; Hao, Yi; Duncker, Susanne V.; Fernandez, Tahia; Gaudin, Emmanuelle; Ehrenstein, Michael; Kerr, William G.; Colle, Jean-Hervé; Bruhns, Pierre; Daëron, Marc; Freitas, António A.

    2013-01-01

    Maintenance of plasma IgM levels is critical for immune system function and homeostasis in humans and mice. However, the mechanisms that control homeostasis of the activated IgM-secreting B cells are unknown. After adoptive transfer into immune-deficient hosts, B lymphocytes expand poorly, but fully reconstitute the pool of natural IgM-secreting cells and circulating IgM levels. By using sequential cell transfers and B cell populations from several mutant mice, we were able to identify novel mechanisms regulating the size of the IgM-secreting B cell pool. Contrary to previous mechanisms described regulating homeostasis, which involve competition for the same niche by cells having overlapping survival requirements, homeostasis of the innate IgM-secreting B cell pool is also achieved when B cell populations are able to monitor the number of activated B cells by detecting their secreted products. Notably, B cell populations are able to assess the density of activated B cells by sensing their secreted IgG. This process involves the Fc?RIIB, a low-affinity IgG receptor that is expressed on B cells and acts as a negative regulator of B cell activation, and its intracellular effector the inositol phosphatase SHIP. As a result of the engagement of this inhibitory pathway, the number of activated IgM-secreting B cells is kept under control. We hypothesize that malfunction of this quorum-sensing mechanism may lead to uncontrolled B cell activation and autoimmunity. PMID:23209322

  1. Dysregulated TCL1 promotes multiple classes of mature B cell lymphoma

    Microsoft Academic Search

    Katrina K. Hoyer; Samuel W. French; Devin E. Turner; Mai T. N. Nguyen; Mathilde Renard; Cindy S. Malone; Sonja Knoetig; Chen-Feng Qi; Thomas T. Su; Hilde Cheroutre; Randolph Wall; David J. Rawlings; Herbert C. Morse III; Michael A. Teitell

    2002-01-01

    The TCL1 protooncogene is overexpressed in many mature B cell lymphomas, especially from AIDS patients. To determine whether aberrant expression promotes B cell transformation, we generated a murine model in which a TCL1 transgene was overexpressed at similar levels in both B and T cells. Strikingly, transgenic mice developed Burkitt-like lymphoma (BLL) and diffuse large B cell lymphoma (DLBCL) with

  2. Regulatory B cells preferentially accumulate in tumor-draining lymph nodes and promote tumor growth

    PubMed Central

    Ganti, Sheila N.; Albershardt, Tina C.; Iritani, Brian M.; Ruddell, Alanna

    2015-01-01

    Our previous studies found that B16-F10 melanoma growth in the rear footpad of immunocompetent mice induces marked B cell accumulation within tumor-draining popliteal lymph nodes (TDLN). This B cell accumulation drives TDLN remodeling that precedes and promotes metastasis, indicating a tumor-promoting role for TDLN B cells. Here we show that phenotypic characterization of lymphocytes in mice bearing B16-F10 melanomas identifies preferential accumulation of T2-MZP B cells in the TDLN. Comparison of non-draining LNs and spleens of tumor-bearing mice with LNs and spleens from naďve mice determined that this pattern of B cell accumulation was restricted to the TDLN. B cell-deficient and immunocompetent mice reconstituted with T2-MZP B cells but not with other B cell subsets displayed accelerated tumor growth, demonstrating that T2-MZP B cells possess regulatory activity in tumor-bearing mice. Unlike splenic regulatory B cells, however, these TDLN B cells did not exhibit increased IL-10 production, nor did they promote Treg generation in the TDLN. These findings demonstrate that tumors initially signal via the lymphatic drainage to stimulate the preferential accumulation of T2-MZP regulatory B cells. This local response may be an early and critical step in generating an immunosuppressive environment to permit tumor growth and metastasis. PMID:26193241

  3. Downregulation of FOXP1 is required during germinal center B-cell function

    PubMed Central

    Sagardoy, Ainara; Martinez-Ferrandis, Jose I.; Roa, Sergio; Bunting, Karen L.; Aznar, María Angela; Elemento, Olivier; Shaknovich, Rita; Fontán, Lorena; Fresquet, Vicente; Perez-Roger, Ignacio; Robles, Eloy F.; De Smedt, Linde; Sagaert, Xavier

    2013-01-01

    B-cell maturation and germinal center (GC) formation are dependent on the interplay between BCL6 and other transcriptional regulators. FOXP1 is a transcription factor that regulates early B-cell development, but whether it plays a role in mature B cells is unknown. Analysis of human tonsillar B-cell subpopulations revealed that FOXP1 shows the opposite expression pattern to BCL6, suggesting that FOXP1 regulates the transition from resting follicular B cell to activated GC B cell. Chromatin immunoprecipitation-on-chip and gene expression assays on B cells indicated that FOXP1 acts as a transcriptional activator and repressor of genes involved in the GC reaction, half of which are also BCL6 targets. To study FOXP1 function in vivo, we developed transgenic mice expressing human FOXP1 in lymphoid cells. These mice exhibited irregular formation of splenic GCs, showing a modest increase in naďve and marginal-zone B cells and a significant decrease in GC B cells. Furthermore, aberrant expression of FOXP1 impaired transcription of noncoding ?1 germline transcripts and inhibited efficient class switching to the immunoglobulin G1 isotype. These studies show that FOXP1 is physiologically downregulated in GC B cells and that aberrant expression of FOXP1 impairs mechanisms triggered by B-cell activation, potentially contributing to B-cell lymphomagenesis. PMID:23580662

  4. Cell extrinsic alterations in splenic B cell maturation in Flt3-ligand knockout mice

    PubMed Central

    Dolence, Joseph J; Gwin, Kimberly A; Shapiro, Mariya B; Hsu, Fan-Chi; Shapiro, Virginia S; Medina, Kay L

    2015-01-01

    B lymphopoiesis in bone marrow (BM) is critical for maintaining a diverse peripheral B cell pool to fight infection and establish lifelong immunity. The generation of immature B cells is reduced in Flt3-ligand (FL-/-) mice leading to deficiencies in splenic B cells. Here, we sought to understand the cellular basis of the spleen B cell deficiency in FL-/- mice. Significant reductions in transitional (TS) and follicular (FO) B cells were found in FL-/- mice, and increased frequencies, but not absolute numbers, of marginal zone (MZ) B cells. BAFF-R expression on splenic B cells and serum levels of B cell activating factor (BAFF) was comparable to wildtype (WT) mice. Mixed BM chimeras revealed that the reductions in TS and FO B cells were cell extrinsic. FL administration into FL-/- mice restored the deficiency in TS B cells and normalized the MZ compartment. Ki67 analysis revealed a significant decrease in the proliferative capacity of TS B cells in FL-/- mice. A Bcl2 transgene did not rescue TS cells in FL-/- mice, uncoupling FL-deficiency to Bcl2-dependent survival pathways. Upregulation of CD1d expression and adoptive transfer experiments suggested MZ skewing in FL-/- mice. These findings support an integral role for Flt3 signaling in peripheral B cell maturation. PMID:26029370

  5. Cerebrospinal fluid B cells from Multiple Sclerosis patients are subject to normal germinal center selection

    PubMed Central

    Harp, Christopher; Lee, Jane; Lambracht-Washington, Doris; Cameron, Elizabeth; Olsen, Gregory; Frohman, Elliot; Racke, Michael; Monson, Nancy

    2007-01-01

    Previous findings from our laboratory demonstrated that some clonally expanded cerebrospinal fluid (CSF) B cells from MS patients exhibit diminished mutation targeting patterns in comparison to typical B cells selected in the context of germinal centers (GCs). In order to determine whether the overall CSF B cell repertoires adhered to mutation patterns typical of GC-selected B cells, we analyzed the immunoglobulin repertoires from CSF B cells of 8 MS patients for mutation characteristics typical of GC-derived B cells. Mutation targeting was preserved. Thus, clonal expansion of some CSF B cells may occur independently of GC, but the CSF B cell pool is governed by typical GC selection. Interestingly, the heavy chain CDR3’s of CSF B cells from MS patients had a net acidic charge, similar to GC-derived B cells, but a tendency towards longer CDR3’s, consistent with autoreactive B cells. How these findings may support current hypotheses regarding the origin of CSF B cells is discussed. PMID:17169437

  6. Gene Expression Profiling of B Cell Chronic Lymphocytic Leukemia Reveals a Homogeneous Phenotype Related to Memory B Cells

    Microsoft Academic Search

    Ulf Klein; Yuhai Tu; Gustavo A. Stolovitzky; Michela Mattioli; Giorgio Cattoretti; Hervé Husson; Arnold Freedman; Giorgio Inghirami; Lilla Cro; Luca Baldini; Antonino Neri; Andrea Califano; Riccardo Dalla-Favera

    B cell-derived chronic lymphocytic leukemia (B-CLL) represents a common malignancy whose cell derivation and pathogenesis are unknown. Recent studies have shown that ? 50% of CLLs display hypermutated immunoglobulin variable region (IgV) sequences and a more fa- vorable prognosis, suggesting that they may represent a distinct subset of CLLs which have transited through germinal centers (GCs), the physiologic site of

  7. B cell stimulatory factor-1 enhances the IgE response of lipopolysaccharide-activated B cells.

    PubMed

    Coffman, R L; Ohara, J; Bond, M W; Carty, J; Zlotnik, A; Paul, W E

    1986-06-15

    Supernatants from some mouse helper T cell (TH) lines contain an activity that can enhance IgE production by lipopolysaccharide (LPS)-stimulated B cells by at least two orders of magnitude. During purification, this activity could not be resolved from B cell stimulatory factor-1 (BSF-1). Highly purified BSF-1 from a different source, the T lymphoma cell line EL-4, enhanced IgE production to the same extent as TH supernatants, which suggests that BSF-1 is responsible for this increase in IgE production. Monoclonal antibody to BSF-1 totally inhibits the IgE-enhancing activity of a TH supernatant, lending further support to this conclusion. The effects of BSF-1 on LPS-stimulated B cells are specific for IgE and, as previously reported, IgG1 and IgG3, because the levels of IgM, IgG2a, IgG2b, and IgA in the cultures change relatively little when BSF-1 is added. PMID:3486902

  8. Suppressed pro-inflammatory properties of circulating B cells in patients with multiple sclerosis treated with fingolimod, based on altered proportions of B-cell subpopulations.

    PubMed

    Miyazaki, Yusei; Niino, Masaaki; Fukazawa, Toshiyuki; Takahashi, Eri; Nonaka, Takayuki; Amino, Itaru; Tashiro, Jun; Minami, Naoya; Fujiki, Naoto; Doi, Shizuki; Kikuchi, Seiji

    2014-04-01

    The chief therapeutic mechanism of fingolimod in multiple sclerosis (MS) is considered to be sequestration of pathogenic lymphocytes into secondary lymphoid tissues. B cells have recently been recognized as important immune regulators in MS. In this study, the effects of fingolimod on B cells in MS patients were analyzed. MS patients treated with fingolimod (MS-F) had a significantly lower number of B cells in the circulation. The remaining B cells in the blood of MS-F had a reduced proportion of memory B cells and an increased proportion of naďve B cells, expressed lower levels of the costimulatory molecule CD80, and produced less tumor necrosis factor-? and more interleukin-10. These observations in MS-F were based on an increased proportion of the transitional B-cell subpopulation within the naďve B-cell compartment. The observed findings in B cells of MS-F might be related to the therapeutic effect of this drug in MS. PMID:24607506

  9. Increasing the efficacy of CD20 antibody therapy through the engineering of a new type II anti-CD20 antibody with enhanced direct and immune effector cell–mediated B-cell cytotoxicity

    PubMed Central

    Mössner, Ekkehard; Brünker, Peter; Moser, Samuel; Püntener, Ursula; Schmidt, Carla; Herter, Sylvia; Grau, Roger; Gerdes, Christian; Nopora, Adam; van Puijenbroek, Erwin; Ferrara, Claudia; Sondermann, Peter; Jäger, Christiane; Strein, Pamela; Fertig, Georg; Friess, Thomas; Schüll, Christine; Bauer, Sabine; Dal Porto, Joseph; Del Nagro, Christopher; Dabbagh, Karim; Dyer, Martin J. S.; Poppema, Sibrand; Klein, Christian

    2010-01-01

    CD20 is an important target for the treatment of B-cell malignancies, including non-Hodgkin lymphoma as well as autoimmune disorders. B-cell depletion therapy using monoclonal antibodies against CD20, such as rituximab, has revolutionized the treatment of these disorders, greatly improving overall survival in patients. Here, we report the development of GA101 as the first Fc-engineered, type II humanized IgG1 antibody against CD20. Relative to rituximab, GA101 has increased direct and immune effector cell-mediated cytotoxicity and exhibits superior activity in cellular assays and whole blood B-cell depletion assays. In human lymphoma xenograft models, GA101 exhibits superior antitumor activity, resulting in the induction of complete tumor remission and increased overall survival. In nonhuman primates, GA101 demonstrates superior B cell–depleting activity in lymphoid tissue, including in lymph nodes and spleen. Taken together, these results provide compelling evidence for the development of GA101 as a promising new therapy for the treatment of B-cell disorders. PMID:20194898

  10. Characterization of Regulatory B Cells in Graves’ Disease and Hashimoto’s Thyroiditis

    PubMed Central

    Kristensen, Birte; Hegedüs, Laszlo; Lundy, Steven K.; Brimnes, Marie K.; Smith, Terry J.; Nielsen, Claus H.

    2015-01-01

    A hallmark of regulatory B cells is IL-10 production, hence their designation as IL-10+ B cells. Little is known about the ability of self-antigens to induce IL-10+ B cells in Graves’ disease (GD), Hashimoto’s thyroiditis (HT), or other autoimmune disease. Here we pulsed purified B cells from 12 HT patients, 12 GD patients, and 12 healthy donors with the thyroid self-antigen, thyroglobulin (TG) and added the B cells back to the remaining peripheral blood mononuclear cells (PBMCs). This procedure induced IL-10+ B-cell differentiation in GD. A similar tendency was observed in healthy donors, but not in cells from patients with HT. In GD, B cells primed with TG induced IL-10-producing CD4+ T cells. To assess the maximal frequency of inducible IL-10+ B cells in the three donor groups PBMCs were stimulated with PMA/ionomycin. The resulting IL-10+ B-cell frequency was similar in the three groups and correlated with free T3 levels in GD patients. IL-10+ B cells from both patient groups displayed CD25 or TIM-1 more frequently than did those from healthy donors. B-cell expression of two surface marker combinations previously associated with regulatory B-cell functions, CD24hiCD38hi and CD27+CD43+, did not differ between patients and healthy donors. In conclusion, our findings indicate that autoimmune thyroiditis is not associated with reduced frequency of IL-10+ B cells. These results do not rule out regulatory B-cell dysfunction, however. The observed phenotypic differences between IL-10+ B cells from patients and healthy donors are discussed. PMID:26016954

  11. Activation-induced necroptosis contributes to B-cell lymphopenia in active systemic lupus erythematosus

    PubMed Central

    Fan, H; Liu, F; Dong, G; Ren, D; Xu, Y; Dou, J; Wang, T; Sun, L; Hou, Y

    2014-01-01

    B-cell abnormality including excessive activation and lymphopenia is a central feature of systemic lupus erythematosus (SLE). Although activation threshold, auto-reaction and death of B cells can be affected by intrinsical and/or external signaling, the underlying mechanisms are unclear. Herein, we demonstrate that co-activation of Toll-like receptor 7 (TLR7) and B-cell receptor (BCR) pathways is a core event for the survival/dead states of B cells in SLE. We found that the mortalities of CD19+CD27- and CD19+IgM+ B-cell subsets were increased in the peripheral blood mononuclear cells (PBMCs) of SLE patients. The gene microarray analysis of CD19+ B cells from active SLE patients showed that the differentially expressed genes were closely correlated to TLR7, BCR, apoptosis, necroptosis and immune pathways. We also found that co-activation of TLR7 and BCR could trigger normal B cells to take on SLE-like B-cell characters including the elevated viability, activation and proliferation in the first 3 days and necroptosis in the later days. Moreover, the necroptotic B cells exhibited mitochondrial dysfunction and hypoxia, along with the elevated expression of necroptosis-related genes, consistent with that in both SLE B-cell microarray and real-time PCR verification. Expectedly, pretreatment with the receptor-interacting protein kinase 1 (RIPK1) inhibitor Necrostatin-1, and not the apoptosis inhibitor zVAD, suppressed B-cell death. Importantly, B cells from additional SLE patients also significantly displayed high expression levels of necroptosis-related genes compared with those from healthy donors. These data indicate that co-activation of TLR7 and BCR pathways can promote B cells to hyperactivation and ultimately necroptosis. Our finding provides a new explanation on B-cell lymphopenia in active SLE patients. These data suggest that extrinsic factors may increase the intrinsical abnormality of B cells in SLE patients. PMID:25210799

  12. Characterization of tumor-associated B-cell subsets in patients with colorectal cancer

    PubMed Central

    Gryschok, Luise; Malcher, Joke; Wennhold, Kerstin; Garcia-Marquez, Maria; Herbold, Till; Neuhaus, Laura S.; Becker, Hans J.; Fiedler, Anne; Scherwitz, Pascal; Koslowsky, Thomas; Hake, Roland; Stippel, Dirk L.; Hölscher, Arnulf H.; Eidt, Sebastian; Hallek, Michael; Theurich, Sebastian; von Bergwelt-Baildon, Michael S.

    2014-01-01

    Purpose: A precise understanding of the mechanisms by which human immune cell subsets affect tumor biology will be critical for successful treatment of cancer using immunotherapeutic approaches. Recent evidence suggests that B cells can both promote and inhibit the development and progression of tumors. The aim of this study was to characterize the composition of the B-cell infiltrates in colorectal cancers (CRC) in order to gain further insight into the role of B cells in CRC. Experimental Design: In this study we characterized B-cell subsets in primary tumors (n=38), metastases (n=6) and blood (n=46) of 51 patients with a diagnosis of CRC and blood of 10 healthy controls. B-cell subsets were analyzed by flow cytometry or immunohistochemistry. Results: Peripheral blood of CRC patients contained a higher percentage of memory B cells than that of age-matched healthy controls. Furthermore, the percentage of B cells within tumors was higher than that in the peripheral blood of CRC patients while metastases were typically devoid of tumor-infiltrating B cells. Tumor-associated B cells were enriched for activated and terminally differentiated B cells. Relevant proportions of regulatory B cells could only be detected in advanced cancer and metastases. Conclusion: B cells constitute a significant proportion of the immune infiltrate in CRC. The B-cell infiltrate of primary CRC is characterized by an accumulation of terminally differentiated memory B cells or plasma cells suggestive of a specific immune response against the tumor. However advanced tumors and metastases are also infiltrated by a considerable number of regulatory B cells. PMID:25026291

  13. Characterization of Regulatory B Cells in Graves' Disease and Hashimoto's Thyroiditis.

    PubMed

    Kristensen, Birte; Hegedüs, Laszlo; Lundy, Steven K; Brimnes, Marie K; Smith, Terry J; Nielsen, Claus H

    2015-01-01

    A hallmark of regulatory B cells is IL-10 production, hence their designation as IL-10+ B cells. Little is known about the ability of self-antigens to induce IL-10+ B cells in Graves' disease (GD), Hashimoto's thyroiditis (HT), or other autoimmune disease. Here we pulsed purified B cells from 12 HT patients, 12 GD patients, and 12 healthy donors with the thyroid self-antigen, thyroglobulin (TG) and added the B cells back to the remaining peripheral blood mononuclear cells (PBMCs). This procedure induced IL-10+ B-cell differentiation in GD. A similar tendency was observed in healthy donors, but not in cells from patients with HT. In GD, B cells primed with TG induced IL-10-producing CD4+ T cells. To assess the maximal frequency of inducible IL-10+ B cells in the three donor groups PBMCs were stimulated with PMA/ionomycin. The resulting IL-10+ B-cell frequency was similar in the three groups and correlated with free T3 levels in GD patients. IL-10+ B cells from both patient groups displayed CD25 or TIM-1 more frequently than did those from healthy donors. B-cell expression of two surface marker combinations previously associated with regulatory B-cell functions, CD24hiCD38hi and CD27+CD43+, did not differ between patients and healthy donors. In conclusion, our findings indicate that autoimmune thyroiditis is not associated with reduced frequency of IL-10+ B cells. These results do not rule out regulatory B-cell dysfunction, however. The observed phenotypic differences between IL-10+ B cells from patients and healthy donors are discussed. PMID:26016954

  14. Epstein-Barr virus-associated persistent polyclonal B-cell lymphocytosis with a distinct 69-base pair deletion in the LMP1 oncogene

    Microsoft Academic Search

    C. Larcher; C. McQuain; C. Berger; M. Mitterer; P. J. Quesenberry; H. P. Huemer; H. Knecht

    1997-01-01

    Epstein-Barr virus (EBV) genomes have been detected in peripheral blood lymphocytes (PBL) of patients with persistent polyclonal\\u000a B-cell lymphocytosis (PPBL). This is consistent with the hypothesis that latent EBV infection is involved in the pathogenesis\\u000a of this disorder. Two EBV-encoded proteins expressed in viral latency are the latent membrane proteins 1 and 2A (LMP1 and\\u000a LMP2A). We have studied the

  15. CCL19 and CXCL13 synergistically regulate interaction between B cell acute lymphocytic leukemia CD23+CD5+ B Cells and CD8+ T cells.

    PubMed

    Wang, Xingbing; Yuling, He; Yanping, Jiang; Xinti, Tan; Yaofang, Yang; Feng, Yu; Ruijin, Xiao; Li, Wang; Lang, Chen; Jingyi, Liu; Zhiqing, Tang; Jingping, Ouyang; Bing, Xia; Li, Qiao; Chang, Alfred E; Sun, Zimin; Youxin, Jin; Jinquan, Tan

    2007-09-01

    Interacting with T cells, cytokine-producing B cells play a critical protective role in autoimmune diseases. However, the interaction between malignant B and T cells remains to be fully elucidated. In a previous study, we have reported that ligation of CCL19-CCR7 and CXCL13-CXCR5 activates paternally expressed gene 10 (PEG10), resulting in an enhancement of apoptotic resistance in B-cell acute lymphocytic leukemia (B-ALL) CD23+CD5+ B cells. Here, we report that B-ALL CD23+CD5+ B cells produce IL-10 at high level, which can be further elevated by costimulation with CCL19 and CXCL13. CCL19/CXCL13-activated B-ALL CD23+CD5+ B cells, in turn, increase IL-10 expression in syngeneic CD8+ T cells in a B cell-derived IL-10-dependent manner and requiring a cell-cell contact. IL-10 secreted from B-ALL CD23+CD5+ B cells in vitro impairs tumor-specific CTL responses of syngeneic CD8+ T cells. The impairment of cytotoxicity of syngeneic CD8+ T cells is escalated by means of CCL19/CXCL13-induced up-regulation of IL-10 from B-ALL CD23+CD5+ B cells. Moreover, using a short hairpin RNA to knockdown PEG10, we provide direct evidence that increased expression of PEG10 in B-ALL CD23+CD5+ B cells is involved in malignant B-T cell interaction, contributing to the up-regulation of IL-10 expression, as well as to the impairment of cytotoxicity of syngeneic CD8+ T cells. Thus, malignant B-ALL CD23+CD5+ B cells play an immunoregulatory role in controlling different inflammatory cytokine expressions. IL-10 may be one of the critical cellular factors conferring B-ALL CD23+CD5+ B cells to escape from host immune surveillance. PMID:17709502

  16. Mucosal immunoglobulins and B cells of Teleost fish

    PubMed Central

    Salinas, Irene; Zhang, Yong-An; Sunyer, J. Oriol

    2012-01-01

    As physical barriers that separate teleost fish from the external environment, mucosae are also active immunological sites that protect them against exposure to microbes and stressors. In mammals, the sites where antigens are sampled from mucosal surfaces and where stimulation of naive T and B lymphocytes occurs are known as inductive sites and are constituted by mucosa-associated lymphoid tissue (MALT). According to anatomical location, the MALT in teleost fish is subdivided into gut-associated lymphoid tissue (GALT), skin-associated lymphoid tissue (SALT), and gill-associated lymphoid tissue (GIALT). All MALT contain a variety of leukocytes, including, but not limited to, T cells, B cells, plasma cells, macrophages and granulocytes. Secretory immunoglobulins are produced mainly by plasmablasts and plasma cells, and play key roles in the maintenance of mucosal homeostasis. Until recently, teleost fish B cells were thought to express only two classes of immunoglobulins, IgM and IgD, in which IgM was thought to be the only one responding to pathogens both in systemic and mucosal compartments. However, a third teleost immunoglobulin class, IgT/IgZ, was discovered in 2005, and it has recently been shown to behave as the prevalent immunoglobulin in gut mucosal immune responses. The purpose of this review is to summarise the current knowledge of mucosal immunoglobulins and B cells of fish MALT. Moreover, we attempt to integrate the existing knowledge on both basic and applied research findings on fish mucosal immune responses, with the goal to provide new directions that may facilitate the development of novel vaccination strategies that stimulate not only systemic, but also mucosal immunity. PMID:22133710

  17. Expression of novel interleukin 2 binding molecules and their functional roles in human B cell differentiation.

    PubMed Central

    Tanaka, T; Saiki, O; Doi, S; Suemura, M; Negoro, S; Kishimoto, S

    1988-01-01

    Expressions and functional roles of novel IL-2 binding molecules (p70, 75) in the differentiation of B cells into Ig secreting cells were explored by using human several B cell lines and tonsillar B cells. Affinity-crosslinking studies revealed that five of nine B cell lines expressed p70 and p75 without detectable Tac antigen (p55) expression and the expression was associated with B cell maturation. In tonsillar B cells, small high-density B cells did not express p70 and p75, whereas large low-density B cells, which were thought to be activated in vivo, expressed them. Binding assays of radiolabeled IL-2 showed that the affinity of these molecules was intermediate (kD = 1-3 nM, 700-3,000 sites/cell). Furthermore, high concentrations of IL-2 (greater than 100 U/ml) induced Ig productions in large B cells and two of five cell lines. These results taken together suggest that B cells may express novel IL-2 binding molecules, associated with B cell differentiation and differentiate into Ig secreting cells by IL-2 through novel IL-2 binding molecules. Images PMID:2839549

  18. Altered B-cell homeostasis and excess BAFF in human chronic graft-versus-host disease

    PubMed Central

    Stevenson, Kristen E.; Kim, Haesook T.; Cutler, Corey S.; Bhuiya, Nazmim S.; Schowalter, Michael; Ho, Vincent T.; Alyea, Edwin P.; Koreth, John; Blazar, Bruce R.; Soiffer, Robert J.; Antin, Joseph H.; Ritz, Jerome

    2009-01-01

    Chronic graft-versus-host disease (cGVHD) causes significant morbidity and mortality in patients otherwise cured of malignancy after hematopoietic stem cell transplantation (HSCT). The presence of alloantibodies and high plasma B cell–activating factor (BAFF) levels in patients with cGVHD suggest that B cells play a role in disease pathogenesis. We performed detailed phenotypic and functional analyses of peripheral B cells in 82 patients after HSCT. Patients with cGVHD had significantly higher BAFF/B-cell ratios compared with patients without cGVHD or healthy donors. In cGVHD, increasing BAFF concentrations correlated with increased numbers of circulating pre–germinal center (GC) B cells and post-GC “plasmablast-like” cells, suggesting in vivo BAFF dependence of these 2 CD27+ B-cell subsets. Circulating CD27+ B cells in cGVHD comprised in vivo activated B cells capable of IgG production without requiring additional antigen stimulation. Serial studies revealed that patients who subsequently developed cGVHD had delayed reconstitution of naive B cells despite persistent BAFF elevation as well as proportional increase in CD27+ B cells in the first year after HSCT. These studies delineate specific abnormalities of B-cell homeostasis in patients with cGVHD and suggest that BAFF targeting agents may be useful in this disease. PMID:19168788

  19. Self-recognition and clonal selection: autoreactivity drives the generation of B cells.

    PubMed

    Herzog, Sebastian; Jumaa, Hassan

    2012-04-01

    The diversity of B cell receptor (BCR) specificities is generated by VDJ recombination of gene segments during early B cell development, a process which bears the risk of producing BCRs that recognize and lead to the destruction of self-structures. Traditional thoughts have mainly focused on how such putatively dangerous specificities are dealt with and in how they contribute to the development of autoimmune diseases. However, a positive or even necessary role of self-recognition during B cell development has rarely been taken into account. Now, considerable data reveal that the pre-B cell receptor (pre-BCR), which marks an important checkpoint during B cell development, acts as a surrogate autoreactive receptor. This review outlines how autoreactivity is necessary for efficient B cell development and how autoreactive receptors drive positive selection, leading to a diverse repertoire of receptor specificities in the mature B cell pool. PMID:22398125

  20. Tumor-infiltrating B cells come into vogue.

    PubMed

    Linnebacher, Michael

    2013-01-01

    Lymphocyte infiltration into solid tumors has been recognized as a main determinator of positive prognosis. For the most part this is attributed to cytotoxic T cells capable of directly destroying malignant cells. However, when considering the complex composition of the human immune system, recent findings of Nielsen et al on a potentially central role of tumor-infiltrating B cells is not really surprising. In this commentary article, I want to highlight the enormous potential impact of this observation for basic and translational research, prognostic procedures and ultimately for the development of future therapeutic concepts. PMID:23326156

  1. Primary B cell lymphoma of paranasal sinuses: a diagnostic surprise.

    PubMed

    Anand, T S; Saxena, Y K; Shashidhar, T B; Kumar, Soumitra

    2008-09-01

    Primary lymphomas of paranasal cavities are rather uncommon entities. They have a variable presentation from fulminant destructive manifestations to chronic indolent type of disease. Chronic indolent form may mimic invasive fungal sinusitis in its presentation. Unless high index of suspicion is held and appropriate histopathology sections are taken from specimen, its diagnosis can be deceitful. We here by report a case of primary lymphoma of the paranasal sinuses which was radiologically and clinically suspected to be a invasive fungal sinusitis and later was proven to be a B cell lymphoma. Clinical similarities between lymphoma and invasive fungal sinusitis along with management issues are discussed in this article. PMID:23120556

  2. A molecular mechanism for TNF-?-mediated down-regulation of B cell responses1

    PubMed Central

    Frasca, Daniela; Romero, Maria; Diaz, Alain; Alter-Wolf, Sarah; Ratliff, Michelle; Landin, Ana Marie; Riley, Richard L; Blomberg, Bonnie B.

    2011-01-01

    B cell function with age is decreased in class switch recombination (CSR), activation-induced cytidine deaminase (AID) and stability of E47 mRNA. The latter is regulated at least in part by tristetraprolin (TTP) which is increased in aged B cells and also negatively regulates TNF-?. Here, we investigate whether B cells produce TNF-?, whether this changes with age, and how this affects their function upon stimulation. Our hypothesis is that in aging there is a feedback mechanism of autocrine inflammatory cytokines (TNF-?) that lowers the expression of AID and CSR. Our results show that unstimulated B cells from old BALB/c mice make significantly more TNF-? mRNA and protein than B cells from young mice, but after stimulation the old make less than young, thus they are refractory to stimulation. The increase in TNF-? made by old B cells is primarily due to follicular, but not minor subsets of B cells. Pre-incubation of B cells with TNF-? before LPS stimulation decreases both young and old B cell responses. Importantly, B cell function was restored by adding anti-TNF-? antibody in cultured B cells. To address a molecular mechanism, we found that pre-incubation of B cells with TNF-?, before LPS stimulation, induces tristetraprolin, a physiological regulator of mRNA stability of the transcription factor E47, crucial for CSR. Finally, anti-TNF-? given in vivo was able to increase follicular B cell function in old but not in young follicular B cells. These results suggest new molecular mechanisms which contribute to reduced antibody responses in aging. PMID:22116831

  3. A Rare Case of Splenic Marginal Zone B-Cell Lymphoma Mimicking Relapsing Polychondritis of the Ear

    PubMed Central

    Huang, Gary J.; Mendes, Bryan; Sheykholeslami, Kianoush

    2014-01-01

    Relapsing polychondritis (RPC) is a poorly understood phenomenon associated with cartilaginous inflammation of the ear, nose, tracheobronchial tree, and peripheral joints. Many cases of RPC respond to anti-inflammatories and resolve with no further complications. However, RPC has also been linked to more insidious conditions such as malignancies, autoimmune disorders, vasculitis, or underlying infections. Given the spectrum of associated disorders, patients with RPC may need to be monitored for more insidious underlying conditions. In this case, we report a unique case of bilateral auricular inflammation and nasal inflammation mimicking RPC as the only presenting symptom of splenic marginal zone B-cell lymphoma and we survey related cases in the literature. PMID:25544924

  4. T cell-B cell thymic cross-talk: maintenance and function of thymic B cells requires cognate CD40-CD40 ligand interaction.

    PubMed

    Fujihara, Chiharu; Williams, Joy A; Watanabe, Masashi; Jeon, Hyein; Sharrow, Susan O; Hodes, Richard J

    2014-12-01

    Thymic development requires bidirectional interaction or cross-talk between developing T cells and thymic stromal cells, a relationship that has been best characterized for the interaction between thymocytes and thymic epithelial cells. We have characterized in this article the requirement for similar cross-talk in the maintenance and function of thymic B cells, another population that plays a role in selection of developing thymic T cells. We found that maintenance of thymic B cells is strongly dependent on the presence of mature single-positive thymocytes and on the interactions of these T cells with specific Ag ligand. Maintenance of thymic B cell number is strongly dependent on B cell-autonomous expression of CD40, but not MHC class II, indicating that direct engagement of CD40 on thymic B cells is necessary to support their maintenance and proliferation. Thymic B cells can mediate negative selection of superantigen-specific, self-reactive, single-positive thymocytes, and we show that CD40 expression on B cells is critical for this negative selection. Cross-talk with thymic T cells is thus required to support the thymic B cell population through a pathway that requires cell-autonomous expression of CD40, and that reciprocally functions in negative selection of autoreactive T cells. PMID:25344473

  5. Early B-cell-specific inactivation of ATM synergizes with ectopic CyclinD1 expression to promote pre-germinal center B-cell lymphomas in mice.

    PubMed

    Yamamoto, K; Lee, B J; Li, C; Dubois, R L; Hobeika, E; Bhagat, G; Zha, S

    2015-06-01

    Ataxia telangiectasia-mutated (ATM) kinase is a master regulator of the DNA damage response. ATM is frequently inactivated in human B-cell non-Hodgkin lymphomas, including ~50% of mantle cell lymphomas (MCLs) characterized by ectopic expression of CyclinD1. Here we report that early and robust deletion of ATM in precursor/progenitor B cells causes cell autonomous, clonal mature B-cell lymphomas of both pre- and post-germinal center (GC) origins. Unexpectedly, naive B-cell-specific deletion of ATM is not sufficient to induce lymphomas in mice, highlighting the important tumor suppressor function of ATM in immature B cells. Although E?CyclinD1 is not sufficient to induce lymphomas, E?CyclinD1 accelerates the kinetics and increases the incidence of clonal lymphomas in ATM-deficient B-cells and skews the lymphomas toward pre-GC-derived small lymphocytic neoplasms, sharing morphological features of human MCL. This is in part due to CyclinD1-driven expansion of ATM-deficient naive B cells with genomic instability, which promotes the deletions of additional tumor suppressor genes (i.e. Trp53, Mll2, Rb1 and Cdkn2a). Together these findings define a synergistic function of ATM and CyclinD1 in pre-GC B-cell proliferation and lymphomagenesis and provide a prototypic animal model to study the pathogenesis of human MCL. PMID:25676421

  6. Bruton's Tyrosine Kinase Cooperates with the B Cell Linker Protein SLP-65 as a Tumor Suppressor in Pre-B Cells

    PubMed Central

    Kersseboom, Rogier; Middendorp, Sabine; Dingjan, Gemma M.; Dahlenborg, Katarina; Reth, Michael; Jumaa, Hassan; Hendriks, Rudolf W.

    2003-01-01

    Expression of the pre-B cell receptor (pre-BCR) leads to activation of the adaptor molecule SLP-65 and the cytoplasmic kinase Btk. Mice deficient for one of these signaling proteins have an incomplete block in B cell development at the stage of large cycling pre-BCR+CD43+ pre-B cells. Our recent findings of defective SLP-65 expression in ?50% of childhood pre-B acute lymphoblastic leukemias and spontaneous pre-B cell lymphoma development in SLP-65?/? mice demonstrate that SLP-65 acts as a tumor suppressor. To investigate cooperation between Btk and SLP-65, we characterized the pre-B cell compartment in single and double mutant mice, and found that the two proteins have a synergistic role in the developmental progression of large cycling into small resting pre-B cells. We show that Btk/SLP-65 double mutant mice have a dramatically increased pre-B cell tumor incidence (?75% at 16 wk of age), as compared with SLP-65 single deficient mice (<10%). These findings demonstrate that Btk cooperates with SLP-65 as a tumor suppressor in pre-B cells. Furthermore, transgenic low-level expression of a constitutive active form of Btk, the E41K-Y223F mutant, prevented tumor formation in Btk/SLP-65 double mutant mice, indicating that constitutive active Btk can substitute for SLP-65 as a tumor suppressor. PMID:12835482

  7. Bruton's tyrosine kinase cooperates with the B cell linker protein SLP-65 as a tumor suppressor in Pre-B cells.

    PubMed

    Kersseboom, Rogier; Middendorp, Sabine; Dingjan, Gemma M; Dahlenborg, Katarina; Reth, Michael; Jumaa, Hassan; Hendriks, Rudolf W

    2003-07-01

    Expression of the pre-B cell receptor (pre-BCR) leads to activation of the adaptor molecule SLP-65 and the cytoplasmic kinase Btk. Mice deficient for one of these signaling proteins have an incomplete block in B cell development at the stage of large cycling pre-BCR+CD43+ pre-B cells. Our recent findings of defective SLP-65 expression in approximately 50% of childhood pre-B acute lymphoblastic leukemias and spontaneous pre-B cell lymphoma development in SLP-65-/- mice demonstrate that SLP-65 acts as a tumor suppressor. To investigate cooperation between Btk and SLP-65, we characterized the pre-B cell compartment in single and double mutant mice, and found that the two proteins have a synergistic role in the developmental progression of large cycling into small resting pre-B cells. We show that Btk/SLP-65 double mutant mice have a dramatically increased pre-B cell tumor incidence ( approximately 75% at 16 wk of age), as compared with SLP-65 single deficient mice (<10%). These findings demonstrate that Btk cooperates with SLP-65 as a tumor suppressor in pre-B cells. Furthermore, transgenic low-level expression of a constitutive active form of Btk, the E41K-Y223F mutant, prevented tumor formation in Btk/SLP-65 double mutant mice, indicating that constitutive active Btk can substitute for SLP-65 as a tumor suppressor. PMID:12835482

  8. Systematic comparison of gene expression between murine memory and naive B cells demonstrates that memory B cells have unique signaling capabilities.

    PubMed

    Tomayko, Mary M; Anderson, Shannon M; Brayton, Catherine E; Sadanand, Saheli; Steinel, Natalie C; Behrens, Timothy W; Shlomchik, Mark J

    2008-07-01

    Memory B cells play essential roles in the maintenance of long-term immunity and may be important in the pathogenesis of autoimmune disease, but how these cells are distinguished from their naive precursors is poorly understood. To address this, it would be important to understand how gene expression differs between memory and naive B cells to elucidate memory-specific functions. Using model systems that help overcome the lack of murine memory-specific markers and the low frequency of Ag-specific memory and naive cells, we undertook a global comparison of gene expression between memory B cells and their naive precursors. We identified genes with differential expression and confirmed the differential expression of many of these by quantitative RT-PCR and of some of these at the protein level. Our initial analysis revealed differential expression patterns of genes that regulate signaling. Memory B cells have increased expression of genes important in regulating adenosine signaling and in modulating cAMP responses. Furthermore, memory B cells up-regulate receptors that are essential for embryonic stem cell self-renewal. We further demonstrate that one of these, leukemia inhibitory factor receptor, can initiate functional signaling in memory B cells whereas it does not in naive B cells. Thus, memory and naive B cells are intrinsically wired to signal differently from one another and express a functional signaling pathway that is known to maintain stem cells in other lineages. PMID:18566367

  9. Mercury alters B-cell protein phosphorylation profiles.

    PubMed

    Caruthers, Nicholas J; Stemmer, Paul M; Shin, Namhee; Dombkowski, Alan; Caruso, Joseph A; Gill, Randal; Rosenspire, Allen

    2014-02-01

    Environmental exposure to mercury is suggested to contribute to human immune dysfunction. To shed light on the mechanism, we identified changes in the phosphoproteomic profile of the WEHI-231 B cell line after intoxication with Hg(2+). These changes were compared to changes in the phosphoproteome that were induced by pervanadate or okadaic acid exposure. Both 250 ?M HgCl2 and pervanadate, a known phosphotyrosine phosphatase inhibitor, caused an increase in the number of proteins identified after TiO2 affinity selection and LC-MS/MS analysis. Pervanadate treatment had a larger effect than Hg(2+) on the number of Scansite motifs that were tyrosine-phosphorylated, 17, and Ingenuity canonical signaling pathways activated, 4, with score >5.0. However, Hg(2+) had a more focused effect, primarily causing tyrosine-phosphorylation in src homology 2 domains in proteins that are in the B cell receptor signaling pathway. The finding that many of the changes induced by Hg(2+) overlap with those of pervanadate, indicates that at high concentrations Hg(2+) inhibits protein tyrosine phosphatases. PMID:24224561

  10. Mercury Alters B-Cell Protein Phosphorylation Profiles

    PubMed Central

    Carruthers, Nicholas J.; Stemmer, Paul M.; Shin, Namhee; Dombkowski, Alan; Caruso, Joseph A.; Gill, Randal; Rosenspire, Allen

    2014-01-01

    Environmental exposure to mercury is suggested to contribute to human immune dysfunction. To shed light on the mechanism we identified changes in the phosphoproteomic profile of the WEHI-231 B cell line after intoxication with Hg2+. These changes were compared to changes in the phosphoproteome that were induced by pervanadate or okadaic acid exposure. Both 250 ?M HgCl2 and pervanadate, a known phosphotyrosine phosphatase inhibitor, caused an increase in the number of proteins identified after TiO2 affinity selection and LC-MS/MS analysis. Pervanadate treatment had a larger effect than Hg2+ on the number of Scansite motifs which were tyrosine-phosphorylated, 17, and Ingenuity canonical signaling pathways activated, 4 with score > 5.0. However, Hg2+ had a more focused effect, primarily causing tyrosine-phosphorylation in SH2 domains in proteins that are in the B cell receptor signaling pathway. The finding that many of the changes induced by Hg2+ overlap with those of pervanadate, indicates that at high concentrations Hg2+ inhibits protein tyrosine phosphatases. PMID:24224561

  11. Towards the Generation of B-Cell Receptor Retrogenic Mice

    PubMed Central

    Freitag, Jenny; Heink, Sylvia; Roth, Edith; Wittmann, Jürgen; Jäck, Hans-Martin; Kamradt, Thomas

    2014-01-01

    Transgenic expression of B- and T-cell receptors (BCRs and TCRs, respectively) has been a standard tool to study lymphocyte development and function in vivo. The generation of transgenic mice is time-consuming and, therefore, a faster method to study the biology of defined lymphocyte receptors in vivo would be highly welcome. Using 2A peptide-linked multicistronic retroviral vectors to transduce stem cells, TCRs can be expressed rapidly in mice of any background. We aimed at adopting this retrogenic technology to the in vivo expression of BCRs. Using a well characterised BCR specific for hen egg lysozyme (HEL), we achieved surface expression of the retrogenically encoded BCR in a Rag-deficient pro B-cell line in vitro. In vivo, retrogenic BCRs were detectable only intracellularly but not on the surface of B cells from wild type or Rag2-deficient mice. This data, together with the fact that no BCR retrogenic mouse model has been published in the 7 years since the method was originally published for TCRs, strongly suggests that achieving BCR-expression in vivo with retrogenic technology is highly challenging if not impossible. PMID:25296340

  12. Gaucher disease and comorbidities: B-cell malignancy and parkinsonism.

    PubMed

    Cox, Timothy M; Rosenbloom, Barry E; Barker, Roger A

    2015-07-01

    Data emerging from the International Collaborative Gaucher Group (ICGG) Gaucher Registry together with other contemporary clinical surveys have revealed a close association between Gaucher disease and non-Hodgkin's B-cell lymphoma and myeloma and Gaucher disease and Parkinson's disease. Several possible explanations for increased B-cell proliferation and neoplasia in Gaucher disease have been proposed, including the possible influence of sphingosine (derived from the extra lysosomal metabolism of glucosylceramide), gene modifiers, splenectomy and immune system deregulation induced by cytokines, chemokines, and hydrolases released from Gaucher cells. Parkinson's disease is frequently seen in the otherwise-healthy relatives of Gaucher disease patients leading to the finding that GBA mutations represent a genetic risk factor for Parkinson's disease. The mechanism of the association between GBA mutations and Parkinson's disease has yet to be elucidated but the pathogenesis appears distinct from that of Gaucher disease. Several pathogenic pathways have been proposed including lysosomal and/or mitochondrial dysfunction. The effect of Gaucher disease specific therapies on the incidence of cancer or Parkinson's disease are not clear and will likely be evaluated in future ICGG Gaucher Registry studies. Am. J. Hematol. 90:S25-S28, 2015. © 2015 Wiley Periodicals, Inc. PMID:26096744

  13. A two-scale model for correlation between B cell VDJ usage in zebrafish

    NASA Astrophysics Data System (ADS)

    Pan, Keyao; Deem, Michael

    2011-03-01

    The zebrafish (Danio rerio) is one of the model animals for study of immunology. The dynamics of the adaptive immune system in zebrafish is similar to that in higher animals. In this work, we built a two-scale model to simulate the dynamics of B cells in primary and secondary immune reactions in zebrafish and to explain the reported correlation between VDJ usage of B cell repertoires in distinct zebrafish. The first scale of the model consists of a generalized NK model to simulate the B cell maturation process in the 10-day primary immune response. The second scale uses a delay ordinary differential equation system to model the immune responses in the 6-month lifespan of zebrafish. The generalized NK model shows that mature B cells specific to one antigen mostly possess a single VDJ recombination. The probability that mature B cells in two zebrafish have the same VDJ recombination increases with the B cell population size or the B cell selection intensity and decreases with the B cell hypermutation rate. The ODE model shows a distribution of correlation in the VDJ usage of the B cell repertoires in two six-month-old zebrafish that is highly similar to that from experiment. This work presents a simple theory to explain the experimentally observed correlation in VDJ usage of distinct zebrafish B cell repertoires after an immune response.

  14. B cell antigen presentation is sufficient to drive neuroinflammation in an animal model of multiple sclerosis.

    PubMed

    Parker Harp, Chelsea R; Archambault, Angela S; Sim, Julia; Ferris, Stephen T; Mikesell, Robert J; Koni, Pandelakis A; Shimoda, Michiko; Linington, Christopher; Russell, John H; Wu, Gregory F

    2015-06-01

    B cells are increasingly regarded as integral to the pathogenesis of multiple sclerosis, in part as a result of the success of B cell-depletion therapy. Multiple B cell-dependent mechanisms contributing to inflammatory demyelination of the CNS have been explored using experimental autoimmune encephalomyelitis (EAE), a CD4 T cell-dependent animal model for multiple sclerosis. Although B cell Ag presentation was suggested to regulate CNS inflammation during EAE, direct evidence that B cells can independently support Ag-specific autoimmune responses by CD4 T cells in EAE is lacking. Using a newly developed murine model of in vivo conditional expression of MHC class II, we reported previously that encephalitogenic CD4 T cells are incapable of inducing EAE when B cells are the sole APC. In this study, we find that B cells cooperate with dendritic cells to enhance EAE severity resulting from myelin oligodendrocyte glycoprotein (MOG) immunization. Further, increasing the precursor frequency of MOG-specific B cells, but not the addition of soluble MOG-specific Ab, is sufficient to drive EAE in mice expressing MHCII by B cells alone. These data support a model in which expansion of Ag-specific B cells during CNS autoimmunity amplifies cognate interactions between B and CD4 T cells and have the capacity to independently drive neuroinflammation at later stages of disease. PMID:25895531

  15. Differential Effects of Tacrolimus versus Sirolimus on the Proliferation, Activation and Differentiation of Human B Cells

    PubMed Central

    Xu, Luting; Mas, Valeria; Gallon, Lorenzo

    2015-01-01

    The direct effect of immunosuppressive drugs calcineurin inhibitor (Tacrolimus, TAC) and mTOR inhibitor (Sirolimus, SRL) on B cell activation, differentiation and proliferation is not well documented. Purified human B cells from healthy volunteers were stimulated through the B Cell Receptor with Anti-IgM + anti-CD40 + IL21 in the absence / presence of TAC or SRL. A variety of parameters of B cell activity including activation, differentiation, cytokine productions and proliferation were monitored by flow cytometry. SRL at clinically relevant concentrations (6 ng/ml) profoundly inhibited CD19+ B cell proliferation compared to controls whereas TAC at similar concentrations had a minimal effect. CD27+ memory B cells were affected more by SRL than naďve CD27- B cells. SRL effectively blocked B cell differentiation into plasma cells (CD19+CD138+ and Blimp1+/Pax5low cells) even at low dose (2 ng/ml), and totally eliminated them at 6 ng/ml. SRL decreased absolute B cell counts, but the residual responding cells acquired an activated phenotype (CD25+/CD69+) and increased the expression of HLA-DR. SRL-treated stimulated B cells on a per cell basis were able to enhance the proliferation of allogeneic CD4+CD25? T cells and induce a shift toward the Th1 phenotype. Thus, SRL and TAC have different effects on B lymphocytes. These data may provide insights into the clinical use of these two agents in recipients of solid organ transplants. PMID:26087255

  16. Immunoglobulin gamma 2b transgenes inhibit heavy chain gene rearrangement, but cannot promote B cell development

    PubMed Central

    1993-01-01

    Transgenic mice with a gamma 2b transgene were produced to investigate whether gamma 2b can replace mu in the development of B lymphocytes. Transgenic gamma 2b is present on the surface of B cells. Young transgenic mice have a dramatic decrease in B cell numbers, however, older mice have almost normal B cell numbers. Strikingly, all gamma 2b- expressing B cells in the spleen also express mu. The same is true for mice with a hybrid transgene in which the mu transmembrane and intracytoplasmic sequences replace those of gamma 2b (gamma 2b-mumem). The B cell defect is not due to toxicity of gamma 2b since crosses between gamma 2b transgenic and mu transgenic mice have normal numbers of B cells. Presence of the gamma 2b transgene strongly enhances the feedback inhibition of endogenous heavy chain gene rearrangement. Light chain genes are expressed normally, and the early expression of transgenic light chains does not improve B cell maturation. When the endogenous mu locus is inactivated, B cells do not develop at all in gamma 2b transgenic mice. The data suggest that gamma 2b cannot replace mu in promoting the developmental maturation of B cells, but that it can cause feedback inhibition of heavy chain gene rearrangement. Thus, the signals for heavy chain feedback and B cell maturation appear to be different. PMID:8245779

  17. B cells responses and cytokine production are regulated by their immune microenvironment.

    PubMed

    Vazquez, Monica I; Catalan-Dibene, Jovani; Zlotnik, Albert

    2015-08-01

    The adaptive immune system consists of two types of lymphocytes: T and B cells. These two lymphocytes originate from a common precursor, yet are fundamentally different with B cells mediating humoral immunity while T cells mediate cell mediated immunity. In cytokine production, naďve T cells produce multiple cytokines upon activation while naďve activated B cells do not. B cells are capable of producing cytokines, but their cytokine production depends on their differentiation state and activation conditions. Hence, unlike T cells that can produce a large amount of cytokines upon activation, B cells require specific differentiation and activation conditions to produce cytokines. Many cytokines act on B cells as well. Here, we discuss several cytokines and their effects on B cells including: Interleukins, IL-7, IL-4, IL-6, IL-10, and Interferons, IFN-?, IFN-?, IFN-?. These cytokines play important roles in the development, survival, differentiation and/or proliferation of B cells. Certain chemokines also play important roles in B cell function, namely antibody production. As an example, we discuss CCL28, a chemokine that directs the migration of plasma cells to mucosal sites. We conclude with a brief overview of B cells as cytokine producers and their likely functional consequences on the immune response. PMID:25742773

  18. B-cell development and functions and therapeutic options in adenosine deaminase–deficient patients

    PubMed Central

    Brigida, Immacolata; Sauer, Aisha V.; Ferrua, Francesca; Giannelli, Stefania; Scaramuzza, Samantha; Pistoia, Valentina; Castiello, Maria Carmina; Barendregt, Barbara H.; Cicalese, Maria Pia; Casiraghi, Miriam; Brombin, Chiara; Puck, Jennifer; Müller, Klaus; Notarangelo, Lucia Dora; Montin, Davide; van Montfrans, Joris M.; Roncarolo, Maria Grazia; Traggiai, Elisabetta; van Dongen, Jacques J. M.; van der Burg, Mirjam; Aiuti, Alessandro

    2015-01-01

    Background Adenosine deaminase (ADA) deficiency causes severe cellular and humoral immune defects and dysregulation because of metabolic toxicity. Alterations in B-cell development and function have been poorly studied. Enzyme replacement therapy (ERT) and hematopoietic stem cell (HSC) gene therapy (GT) are therapeutic options for patients lacking a suitable bone marrow (BM) transplant donor. Objective We sought to study alterations in B-cell development in ADA-deficient patients and investigate the ability of ERT and HSC-GT to restore normal B-cell differentiation and function. Methods Flow cytometry was used to characterize B-cell development in BM and the periphery. The percentage of gene-corrected B cells was measured by using quantitative PCR. B cells were assessed for their capacity to proliferate and release IgM after stimulation. Results Despite the severe peripheral B-cell lymphopenia, patients with ADA-deficient severe combined immunodeficiency showed a partial block in central BM development. Treatment with ERT or HSC-GT reverted most BM alterations, but ERT led to immature B-cell expansion. In the periphery transitional B cells accumulated under ERT, and the defect in maturation persisted long-term. HSC-GT led to a progressive improvement in B-cell numbers and development, along with increased levels of gene correction. The strongest selective advantage for ADA-transduced cells occurred at the transition from immature to naive cells. B-cell proliferative responses and differentiation to immunoglobulin secreting IgM after B-cell receptor and Toll-like receptor triggering were severely impaired after ERT and improved significantly after HSC-GT. Conclusions ADA-deficient patients show specific defects in B-cell development and functions that are differently corrected after ERT and HSC-GT. PMID:24506932

  19. Notch-regulated periphery B cell differentiation involves suppression of E protein function

    PubMed Central

    Zhang, Ping; Zhao, Ying; Sun, Xiao-Hong

    2013-01-01

    Notch signaling pathway plays important roles in promoting the generation of marginal zone (MZ) B cells at the expense of follicular (FO) B cells during periphery B cell maturation, but the underlying molecular mechanisms are not well understood. We hypothesize that Notch favors the generation of MZ B cells by down-regulating E protein activity. Here, we demonstrated that expression of Id2 and ankyrin-repeat SOCS box-containing protein 2 (Asb2) was elevated in MZ B cells and by Notch signaling. Id2 inhibits the DNA binding activity of E proteins whereas Asb2 facilitates E protein ubiquitination. Next, we examined the phenotypes of splenic B cells in mice expressing constitutively active Notch1 and/or two gain-of-function mutants of E proteins that counteract Id2-mediated inhibition or Notch-induced degradation. We found that up-regulation of E proteins promoted the formation of FO B cells while it suppressed the maturation of MZ B cells. In contrast, excessive amounts of Notch1 stimulated the differentiation of MZ B cells and inhibited the production of FO B cells. More interestingly, the effects of Notch1 were reversed by gain of E protein function. Furthermore, high levels of Bcl-6 expression in FO B cells was shown to be diminished by Notch signaling and restored by E proteins. In addition, E proteins facilitated and Notch hindered the differentiation of transitional B cells. Taken together, it appears that Notch regulates peripheral B cell differentiation, at least in part, through opposing E protein function. PMID:23752615

  20. Migration of immature and mature B cells in the aged microenvironment

    PubMed Central

    Minges Wols, Heather A; Johnson, Kara M; Ippolito, Jill A; Birjandi, Shirin Z; Su, Yan; Le, Phong T; Witte, Pamela L

    2010-01-01

    Studies in aged mice show that the architecture of B-cell areas appears disrupted and that newly made B cells fail to incorporate into the spleen. These observations may reflect altered migration of immature and mature B cells. Using adoptive transfer, we tested the effect of the aged microenvironment and the intrinsic ability of donor B cells from aged mice to migrate to spleens of intact hosts. Spleens of aged recipients were deficient in attracting young or old donor immature B cells. In contrast, immature and mature B cells maintained an intrinsic ability to migrate to young recipient spleens, except that as the aged immature B cells matured, fewer appeared to enter the recirculating pool. CXCL13 protein, which is necessary for the organization of B-cell compartments, was elevated with age and differences in CXCL13 distribution were apparent. In aged spleens, CXCL13 appeared less reticular, concentrated in patches throughout the follicles, and notably reduced in the MAdCAM-1+ marginal reticular cells located at the follicular edge. Despite these differences, the migration of young donor follicular B cells into the spleens of old mice was not impacted; whereas, migration of young donor marginal zone B cells was reduced in aged recipients. Finally, the aged bone marrow microenvironment attracted more donor mature B cells than did the young marrow. Message for CXCL13 was not elevated in the marrow of aged mice. These results suggest that the aged splenic microenvironment affects the migration of immature B cells more than mature follicular B cells. PMID:19845796

  1. STING Negatively Regulates Double-Stranded DNA-Activated JAK1-STAT1 Signaling via SHP-1/2 in B Cells

    PubMed Central

    Dong, Guanjun; You, Ming; Ding, Liang; Fan, Hongye; Liu, Fei; Ren, Deshan; Hou, Yayi

    2015-01-01

    Recognition of cytosolic DNA initiates a series of innate immune responses by inducing IFN-I production and subsequent triggering JAK1-STAT1 signaling which plays critical roles in the pathogenesis of infection, inflammation and autoimmune diseases through promoting B cell activation and antibody responses. The stimulator of interferon genes protein (STING) has been demonstrated to be a critical hub of type I IFN induction in cytosolic DNA-sensing pathways. However, it still remains unknown whether cytosolic DNA can directly activate the JAK1-STAT1 signaling or not. And the role of STING is also unclear in this response. In the present study, we found that dsDNA directly triggered the JAK1-STAT1 signaling by inducing phosphorylation of the Lyn kinase. Moreover, this response is not dependent on type I IFN receptors. Interestingly, STING could inhibit dsDNA-triggered activation of JAK1-STAT1 signaling by inducing SHP-1 and SHP-2 phosphorylation. In addition, compared with normal B cells, the expression of STING was significantly lower and the phosphorylation level of JAK1 was significantly higher in B cells from MRL/lpr lupus-prone mice, highlighting the close association between STING low-expression and JAK1-STAT1 signaling activation in B cells in autoimmune diseases. Our data provide a molecular insight into the novel role of STING in dsDNA-mediated inflammatory disorders. PMID:25947293

  2. Different sensitivity of germinal center B cell-like diffuse large B cell lymphoma cells towards ibrutinib treatment

    PubMed Central

    2014-01-01

    Background Although rituximab in the combination of CHOP chemotherapy has been widely used as the standard treatment for several kinds of B-cell non-Hodgkin lymphoma (B-NHL), a great number of B-NHL patients treated with this immunotherapy still develop primary and secondary resistance. Recently Bruton’s tyrosine kinase (Btk) inhibitor ibrutinib showed promising therapeutic effect in relapsed/refractory CLL and B-cell NHL, which provided essential alternatives for these patients. Methods The proliferation and apoptosis induction of tumor cells were measured by cell viability assay and Annexin-V staining. Western Blotting analysis and real-time PCR were used to detect the expression level of target proteins and chemokines production. Results We demonstrated that ibrutinib inhibited the proliferation and induced apoptosis of GCB-DLBCL cell lines through suppression of BCR signaling pathway and activation of caspase-3. Furthermore, the chemokines CCL3 and CCL4 production from tumor cells were also found to be attenuated by ibrutinib treatment. But different cell lines exhibited distinct sensitivity after ibrutinib treatment. Interestingly, the decreasing level of p-ERK after ibrutinib treatment, but not the basal expression level of Btk, correlated with different drug sensitivity. Conclusions Ibrutinib could be a potentially useful therapy for GCB-DLBCL and the decreasing level of p-ERK could become a useful biomarker to predict related therapeutic response. PMID:24693884

  3. In Vivo Ablation of Surface Immunoglobulin on Mature B Cells by Inducible Gene Targeting Results in Rapid Cell Death

    Microsoft Academic Search

    Kong-Peng Lam; Ralf Kühn; Klaus Rajewsky

    1997-01-01

    Gene targeting experiments have demonstrated that the expression of immunoglobulin heavy chain in the pre-B cell receptor (pBCR) and of heavy and light chains in the B cell antigen receptor (BCR) marks checkpoints in early B cell development that the cells have to pass to survive. To investigate whether the persistence of mature B cells in the peripheral immune system

  4. CD19 CAR-Targeted T Cells Induce Long-Term Remission and B Cell Aplasia in an Immunocompetent Mouse Model of B Cell Acute Lymphoblastic Leukemia

    PubMed Central

    Davila, Marco L.; Kloss, Christopher C.; Gunset, Gertrude; Sadelain, Michel

    2013-01-01

    Although many adults with B cell acute lymphoblastic leukemia (B-ALL) are induced into remission, most will relapse, underscoring the dire need for novel therapies for this disease. We developed murine CD19-specific chimeric antigen receptors (CARs) and an immunocompetent mouse model of B-ALL that recapitulates the disease at genetic, cellular, and pathologic levels. Mouse T cells transduced with an all-murine CD3?/CD28-based CAR that is equivalent to the one being used in our clinical trials, eradicate B-ALL in mice and mediate long-term B cell aplasias. In this model, we find that increasing conditioning chemotherapy increases tumor eradication, B cell aplasia, and CAR-modified T cell persistence. Quantification of recipient B lineage cells allowed us to estimate an in vivo effector to endogenous target ratio for B cell aplasia maintenance. In mice exhibiting a dramatic B cell reduction we identified a small population of progenitor B cells in the bone marrow that may serve as a reservoir for long-term CAR-modified T cell stimulation. Lastly, we determine that infusion of CD8+ CAR-modified T cells alone is sufficient to maintain long-term B cell eradication. The mouse model we report here should prove valuable for investigating CAR-based and other therapies for adult B-ALL. PMID:23585892

  5. Negative Selection of Self-Reactive Chicken B Cells Requires B Cell Receptor Signaling and Is Independent of the Bursal Microenvironment

    PubMed Central

    Davani, Dariush; Pancer, Zeev; Cheroutre, Hilde; Ratcliffe, Michael J. H.

    2014-01-01

    Although the negative selection of self-reactive B cells in the bone marrow of mammals has been clearly demonstrated, it remains unclear in models of gut-associated B cell lymphopoiesis, such as that of the chicken (Gallus gallus). We have generated chicken surface IgM–related receptors in which the diversity region of the lamprey variable lymphocyte receptor (VLR) has been fused to the C region of chicken surface IgM (T?). Expression of a VLR:T? receptor with specificity for PE supported normal development of B cells, whereas a VLR:T? receptor specific to hen egg lysozyme (a self-antigen with respect to chicken B cells) induced, in vivo, complete deletion of VLRHELT?-expressing B cells. In ovo i.v. injection of PE resulted in deletion of VLRPET?-expressing ? cells in the embryo spleen, demonstrating that negative selection was independent of the bursal microenvironment. Although chickens transduced with a murine CD8?:chicken Ig? fusion protein contained B cells expressing mCD8?:chIg?, cotransfection of the mCD8?:chIg? construct, together with thymus leukemia Ag (a natural ligand for mCD8?), resulted in reduced levels of mCD8?:chIg?-expressing B cells in inverse proportion to the levels of thymus leukemia Ag–expressing cells. Deletion of mCD8a: chIga-expressing cells was specific for B cells and required active signaling downstream of the mCD8?:chIg? receptor. Ag-mediated negative selection of developing chicken B cells can therefore occur independently of the bursal microenvironment and is dependent on signaling downstream of the BCR. PMID:24516196

  6. Rehabilitation or the death penalty: autoimmune B cells in the dock.

    PubMed

    Dahal, Lekh N; Cragg, Mark S

    2015-03-01

    CD20-based monoclonal antibodies have become established as treatments for lymphoma, rheumatoid arthritis, systemic lupus erythematosus, vasculitis and dermatomyositis, with the principle therapeutic mechanism relating to B-cell depletion through effector cell engagement. An article by Brühl et al. in this issue of the European Journal of Immunology [Eur. J. Immunol. 2015. 45: 705-715] reveals a fundamentally distinct mechanism of silencing autoimmune B-cell responses. Rather than B-cell depletion, the authors use anti-CD79b antibodies to induce B-cell tolerance and suppress humoral immune responses against collagen to prevent the development of arthritis in mice. Here we highlight the differences in the mechanisms used by anti-CD20 and anti-CD79b Ab therapy and discuss why depletion of B cells may not be required to treat autoimmune arthritis and other B-cell-associated pathologies. PMID:25639261

  7. CD4+ T cells and CD40 participate in selection and homeostasis of peripheral B cells.

    PubMed

    Schwartz, Marc A; Kolhatkar, Nikita S; Thouvenel, Chris; Khim, Socheath; Rawlings, David J

    2014-10-01

    Control of peripheral B cell development and homeostasis depends critically on coordinate signals received through the BAFFRs and BCRs. The extent to which other signals contribute to this process, however, remains undefined. We present data indicating that CD4(+) T cells directly influence naive B cell development via CD40 signaling. Loss of CD4(+) T cells or CD40-CD40L interaction leads to reduced B cell homeostatic proliferation and hindered B cell reconstitution posttransplantation. Furthermore, we demonstrate that in the absence of CD40 signals, these events are modulated by BCR self-reactivity. Strikingly, murine models lacking CD40 reveal a broadly altered BCR specificity and limited diversity by both single-cell cloning and high-throughput sequencing techniques. Collectively, our results imply that any setting of T cell lymphopenia or reduced CD40 function, including B cell recovery following transplantation, will impact the naive B cell repertoire. PMID:25172502

  8. The potential role of B cell-targeted therapies in multiple sclerosis.

    PubMed

    Boster, Aaron; Ankeny, Daniel P; Racke, Michael K

    2010-12-24

    Multiple sclerosis (MS) is an inflammatory demyelinating disease of the CNS. Until recently, most therapeutic interventions have targeted T cells in the treatment of MS. Recent data show that B cells also have a role in the pathogenesis of MS. The cerebrospinal fluid and CNS of MS patients contain B cells, plasma cells and immunoglobulins, and recent data indicate that B cells are involved in antigen presentation and T-cell activation, cytokine production, antibody secretion, demyelination and remyelination in MS. These advances in the understanding of B cells and their role in the pathophysiology of MS provide a strong rationale for B cell-targeted therapies. Recent clinical trials with rituximab highlight the possibility that B cells should be an important therapeutic target in patients with MS. PMID:21142258

  9. Primary B cell Lymphoma of the tongue: a case report

    PubMed Central

    Hmidi, Mounir; Touiheme, Nabil; Elboukhari, Ali; Kettani, Mounir; Elmejareb, Charafeddine; Messary, Abdelhamid

    2012-01-01

    Malignant lymphoma of the oral cavity is rare and of the tongue even rarer. Location of oral lymphomas is more frequent in masticatory mucosa than in movable mucosa; the lingual and buccal mucosa is rarely involved; whereas the gingival vestibule and Waldeyer's ring seem to be the most frequent site of occurrence. We describe a 78 year old male who presented with a mass lesion primarily involving the base of tongue and was diagnosed as diffuse large B cell lymphoma. The patient was treated with CHOP chemotherapy and radiotherapy. The lesion was completely disappeared). He has currently remained disease free for 16 months. Although oral lymphoma of tongue is very uncommon, it should always be considered in differential diagnosis of various benign and malignant lesions in this region. A proper clinical evaluation, histopathologic as well as immunohistochemical evaluation of biopsy specimen may aid in the diagnosis and thus, help in proper management. PMID:22826730

  10. Benchmarking B cell epitope prediction: underperformance of existing methods.

    PubMed

    Blythe, Martin J; Flower, Darren R

    2005-01-01

    Sequence profiling is used routinely to predict the location of B-cell epitopes. In the postgenomic era, the need for reliable epitope prediction is clear. We assessed 484 amino acid propensity scales in combination with ranges of plotting parameters to examine exhaustively the correlation of peaks and epitope location within 50 proteins mapped for polyclonal responses. After examining more than 10(6) combinations, we found that even the best set of scales and parameters performed only marginally better than random. Our results confirm the null hypothesis: Single-scale amino acid propensity profiles cannot be used to predict epitope location reliably. The implication for studies using such methods is obvious. PMID:15576553

  11. Changes in B Cell Populations and Merozoite Surface Protein-1-Specific Memory B Cell Responses after Prolonged Absence of Detectable P. falciparum Infection

    PubMed Central

    Ayieko, Cyrus; Maue, Alexander C.; Jura, Walter G. Z. O.; Noland, Gregory S.; Ayodo, George; Rochford, Rosemary; John, Chandy C.

    2013-01-01

    Clinical immunity to malaria declines in the absence of repeated parasite exposure. However, little is known about how B cell populations and antigen-specific memory B cells change in the absence of P. falciparum infection. A successful indoor residual insecticide spraying campaign in a highland area of western Kenya, led to an absence of blood-stage P. falciparum infection between March 2007 and April 2008. We assessed memory B cell responses in 45 adults at the beginning (April 2008) and end (April 2009) of a subsequent 12-month period during which none of the adults had evidence of asymptomatic parasitemia or clinical disease. Antibodies and memory B cells to the 42-kDa portion of the merozoite surface protein-1 (MSP-142) were measured using ELISA and ELISPOT assays, respectively. B cell populations were characterized by flow cytometry. From 2008 to 2009, the prevalence of MSP-142-specific memory B cells (45% vs. 55%, respectively, P?=?0.32) or antibodies (91% vs. 82%, respectively, P?=?0.32) did not differ significantly, although specific individuals did change from positive to negative and vice versa, particularly for memory B cells, suggesting possible low-level undetected parasitemia may have occurred in some individuals. The magnitude of MSP-142-specific memory B cells and levels of antibodies to MSP-142 also did not differ from 2008 to 2009 (P>0.10 for both). However, from 2008 to 2009 the proportions of both class-switched atypical (CD19+IgD-CD27-CD21-IgM-) and class-switched activated (CD19+IgD-CD27+CD21-IgM-) memory B cells decreased (both P<0.001). In contrast, class-switched resting classical memory B cells (CD19+IgD-CD27+CD21+IgM-) increased (P<0.001). In this area of seasonal malaria transmission, a one- year absence of detectable P. falciparum infection was not associated with changes in the prevalence or level of MSP-142 specific memory B cells, but was associated with major changes in overall memory B cell subsets. PMID:23826242

  12. Further evidence for a human B cell activating factor distinct from IL-4.

    PubMed

    Diu, A; Février, M; Mollier, P; Charron, D; Banchereau, J; Reinherz, E L; Thčze, J

    1990-01-01

    Supernatants from activated human T cell clones were previously shown to contain B cell-activating factor (BCAF), an activity which results in polyclonal resting B cell stimulation. In the present study, we investigate the relationship between this activity and human interleukin-4 which was also shown to act on resting B cells. The supernatant of the T cell clone TT9 contains IL-4 but anti-IL-4 antiserum does not affect the response of B cells as measured by thymidine uptake or cell volume increase. Furthermore, IL-4 induces Fc epsilon-receptor (CD23) expression on 30% of unstimulated human B cells, whereas BCAF-containing supernatants from clone P2, that do not contain detectable amounts of IL-4, promote B cell proliferation without inducing CD23 expression. Our results therefore establish that IL-4 and BCAF are distinct activities and suggest that they trigger different activation pathways in human B cells. In addition, culture of B cells with T cell supernatants for 72 hr induces a three- to fourfold increase in the expression of HLA-DR, -DP, and -DQ antigens in 50% of B cells. The addition of inhibiting concentrations of anti-IFN-gamma, LT, or IL-4 antisera to the cultures does not change these results. Finally, 30% of B cells cultured with T cell supernatants leave the G1 phase of the cell cycle and 20% reach mitosis. Taken together, our findings further support the existence of a B cell-activating factor responsible for the activation of resting human B cells. PMID:2136716

  13. A Conspicuous Role For B Cells In Sjögren’s Syndrome

    Microsoft Academic Search

    Pierre Youinou; Valérie Devauchelle; Pascal Hutin; Rozenn Le Berre; Alain Saraux; Jacques-Olivier Pers

    2007-01-01

    Although the relative contributions of T cells and B cells in Sjögren’s syndrome (SS) are far from being settled, recent studies\\u000a have suggested a crucial role for B cells in its pathophysiology. Early investigations have focused on the ability of B cells\\u000a to produce autoantibodies, and new studies have enlarged the range of their functions. For example, beyond the paradigm

  14. Identification of a Polyclonal B-Cell Activator in Plasmodium falciparum

    Microsoft Academic Search

    Daria Donati; Li Ping Zhang; Qijun Chen; Arnaud Chene; Kirsten Flick; Maja Nystrom; Mats Wahlgren; Maria Teresa Bejarano

    2004-01-01

    Polyclonal B-cell activation and hypergammaglobulinemia are prominent features of human malaria. We report here that Plasmodium falciparum-infected erythrocytes directly adhere to and activate peripheral blood B cells from nonimmune donors. The infected erythrocytes employ the cysteine-rich interdomain region 1 (CIDR1 )o fP. falciparum erythrocyte membrane protein 1 (PfEMP1) to interact with the B cells. Stimulation with recombinant CIDR1 induces proliferation,

  15. Tracking human antigen-specific memory B cells: a sensitive and generalized ELISPOT system

    Microsoft Academic Search

    Shane Crotty; Rachael D. Aubert; John Glidewell; Rafi Ahmed

    2004-01-01

    In the interest of better understanding the role of human memory B cells in protection against disease, we developed an assay to quantitate antigen-specific memory B cells in human blood. This assay utilizes a 6-day polyclonal stimulation of PBMC followed by an antigen-specific ELISPOT for the detection of memory B cells that have differentiated into antibody secreting cells (ASC) in

  16. B cell processing P-I-G Dec 2013 1 | P a g e

    E-print Network

    Maizels, Rick

    B cell processing P-I-G Dec 2013 1 | P a g e Protocol for purification of B-cells from frozen PBMC. Resuspend up to 108 cells in 500 L of buffer (Scale up if more cells used) #12;B cell processing P-I-G Dec to resuspend cell pellet then resuspend 10 mL thawing medium. Repeat step 6. 8. Flick the tube gently

  17. Evidence for functional trace amine associated receptor-1 in normal and malignant B cells

    Microsoft Academic Search

    Agata M. Wasik; Mark J. Millan; Thomas Scanlan; Nicholas M. Barnes; John Gordon

    Following the observation that dopaminergic components are present in normal and malignant B cells, we now provide evidence that they additionally express the functionally related trace amine-associated receptor-1 (TAAR1). Immunodetectable TAAR1 was found in lines derived from a broad range of B-cell malignancy; and in tonsillar B cells, particularly when activated. L3055 Burkitt's lymphoma cells were shown to respond to

  18. Function and regulation of self-reactive marginal zone B cells in autoimmune arthritis.

    PubMed

    Palm, Anna-Karin E; Friedrich, Heike C; Mezger, Anja; Salomonsson, Maya; Myers, Linda K; Kleinau, Sandra

    2015-07-01

    Polyreactive innate-type B cells account for many B cells expressing self-reactivity in the periphery. Improper regulation of these B cells may be an important factor that underlies autoimmune disease. Here we have explored the influence of self-reactive innate B cells in the development of collagen-induced arthritis (CIA), a mouse model of rheumatoid arthritis. We show that splenic marginal zone (MZ), but not B-1 B cells exhibit spontaneous IgM reactivity to autologous collagen II in na?¨ve mice. Upon immunization with heterologous collagen II in complete Freund's adjuvant the collagen-reactive MZ B cells expanded rapidly, while the B-1 B cells showed a modest anti-collagen response. The MZ B cells were easily activated by toll-like receptor (TLR) 4 and 9-ligands in vitro, inducing proliferation and cytokine secretion, implying that dual engagement of the B-cell receptor and TLRs may promote the immune response to self-antigen. Furthermore, collagen-primed MZ B cells showed significant antigen-presenting capacity as reflected by cognate T-cell proliferation in vitro and induction of IgG anti-collagen antibodies in vivo. MZ B cells that were deficient in complement receptors 1 and 2 demonstrated increased proliferation and cytokine production, while Fc? receptor IIb deficiency of the cells lead to increased cytokine production and antigen presentation. In conclusion, our data highlight self-reactive MZ B cells as initiators of the autoimmune response in CIA, where complement and Fc receptors are relevant in controlling the self-reactivity in the cells.Cellular & Molecular Immunology advance online publication, 11 May 2015; doi:10.1038/cmi.2015.37. PMID:25958842

  19. T-Cell\\/Histiocyte-Rich B-Cell Lymphoma: Biology, Diagnosis, and Management

    Microsoft Academic Search

    Jeremy S. Abramson

    T-cell\\/histiocyte-rich B-cell lymphoma (T\\/HRBCL) is an uncommon morphologic variant of diffuse large B-cell lymphoma (DLBCL). Pathologically, it is dis- tinguished by <10% malignant B cells amid a majority population of reactive T lymphocytes and histiocytes. Diagnosis of this entity is occasionally difficult, as it may appear similar to other lymphoid diseases, such as nodular lymphocyte-predominant Hodgkin's lym- phoma and classic

  20. CmC(A\\/T)GG DNA methylation in mature B cell lymphoma gene silencing

    Microsoft Academic Search

    Cindy Sue Malone; Maurine D. Miner; Jeanette R. Doerr; James P. Jackson; Steven E. Jacobsen; Randolph Wall; Michael Teitell

    2001-01-01

    DNA methylation has been linked to gene silencing in cancer. Primary effusion lymphoma (PEL) and myeloma are lymphoid malignancies that arise from terminally differentiated B cells. Interestingly, PEL do not express immunoglobulins or most B lineage-specific genes. The B cell-specific B29 (IgbyCD79b) gene is silenced in PEL and some myelomas but is expressed in other normal and malignant B cells.

  1. Impact of myelin-specific antigen presenting B cells on T cell activation in multiple sclerosis

    Microsoft Academic Search

    Christopher T. Harp; Amy E. Lovett-Racke; Michael K. Racke; Elliot M. Frohman; Nancy L. Monson

    2008-01-01

    The role of B cells in the pathogenesis of Multiple Sclerosis (MS) is incompletely understood. Here we define a possible role for B cells as myelin-specific antigen presenting cells (B-APCs) in MS. Peripheral blood B cells (PBBC) isolated from both MS patients and healthy controls (HC) were activated in vitro with either CD40L\\/IL-4 or a Class B CpG oligodeoxynucleotide (CpG

  2. Metabolic activity is necessary for activation of T suppressor cells by B cells

    Microsoft Academic Search

    K. L. Elkins; P. W. Stashak; P. J. Baker

    1990-01-01

    Ag-primed B cells must express cell-surface IgM, but not IgD or Ia Ag, and must remain metabolically active, in order to activate suppressor T cells (Ts) specific for type III pneumococcal polysaccharide. Ag-primed B cells that were gamma-irradiated with 1000r, or less, retained the ability to activate Ts; however, Ag-primed B cells exposed to UV light were not able to

  3. Splenectomy Associated Changes in IgM Memory B Cells in an Adult Spleen Registry Cohort

    Microsoft Academic Search

    Paul U. Cameron; Penelope Jones; Malgorzata Gorniak; Kate Dunster; Eldho Paul; Sharon Lewin; Ian Woolley; Denis Spelman

    2011-01-01

    Asplenic patients have a lifelong risk of overwhelming post-splenectomy infection and have been reported to have low numbers of peripheral blood IgM memory B cells. The clinical value of quantitation of memory B cells as an indicator of splenic abnormality or risk of infection has been unclear. To assess changes in B cell sub-populations after splenectomy we studied patients recruited

  4. Uptake and Presentation of Myelin Basic Protein by Normal Human B Cells

    PubMed Central

    Brimnes, Marie Klinge; Hansen, Bjarke Endel; Nielsen, Leif Kofoed; Dziegiel, Morten Hanefeld; Nielsen, Claus Henrik

    2014-01-01

    B cells may play both pathogenic and protective roles in T-cell mediated autoimmune diseases such as multiple sclerosis (MS). These functions relate to the ability of B cells to bind and present antigens. Under serum-free conditions we observed that 3–4% of circulating B cells from healthy donors were capable of binding the MS-associated self-antigen myelin basic protein (MBP) and of presenting the immunodominant peptide MBP85-99, as determined by staining with the mAb MK16 recognising the peptide presented by HLA-DR15-positive cells. In the presence of serum, however, the majority of B cells bound MBP in a complement-dependent manner, and almost half of the B cells became engaged in presentation of MBP85-99. Even though complement receptor 1 (CR1, CD35) and CR2 (CD21) both contributed to binding of MBP to B cells, only CR2 was important for the subsequent presentation of MBP85-99. A high proportion of MBP85-99 presenting B cells expressed CD27, and showed increased expression of CD86 compared to non-presenting B cells. MBP-pulsed B cells induced a low frequency of IL-10-producing CD4+ T cells in 3 out of 6 donors, indicating an immunoregulatory role of B cells presenting MBP-derived peptides. The mechanisms described here refute the general assumption that B-cell presentation of self-antigens requires uptake via specific B-cell receptors, and may be important for maintenance of tolerance as well as for driving T-cell responses in autoimmune diseases. PMID:25401487

  5. FcE RECEPTOR, A SPECIFIC DIFFERENTIATION MARKER TRANSIENTLY EXPRESSED ON MATURE B CELLS BEFORE ISOTYPE SWITCHING

    Microsoft Academic Search

    HITOSHI KIKUTANI; MASAKI SUEMURA; HAJIME OWAKI; HIROSHIGE NAKAMURA; RYOICHI SATO; KATSUHIKO YAMASAKI; EDWARD L. BARSUMIAN; RICHARD R. HARDY; TADAMITSU KISHIMOTO

    B lymphocytes originate from pluripotent hematopoietic stem cells and differ- entiate into antibody-secreting cells through multistep differentiation stages, such as pre-B cells, immature B cells with surface IgM, and mature B cells with surface IgM and IgD . A number of human B cell antigens have been defined by in Abs (I-10) . However, most B cell-specific mAbs, except for

  6. Nek2 is a novel regulator of B cell development and immunological response.

    PubMed

    Gu, Zhimin; Zhou, Wen; Huang, Junwei; Yang, Ye; Wendlandt, Erik; Xu, Hongwei; He, Xiao; Tricot, Guido; Zhan, Fenghuang

    2014-01-01

    The serine/threonine kinase Nek2 is commonly found upregulated in a wide variety of neoplasms including diffuse large B cell lymphoma and multiple myeloma. High expression of Nek2 is implicated in the induction of chromosomal instability, promotion of cell proliferation, and drug resistance in tumor cells as well as a marker for poor clinical outcomes. Despite its well recorded involvement in chromosomal instability and neoplastic growth, little is known about the involvement of Nek2 in B cell development. Here we report the development of a transgenic mouse line with conditional expression of Nek2 in the B cell lineage and the effects it has on the development of B cells. Interestingly, we found that the overexpression of Nek2 does not induce spontaneous tumor formation within the transgenic mice up to 24 months after induction. Instead, overexpression of Nek2 in the B cell lineage affects the development of B cells by increasing the proportion of immature B cells in the bone marrow and decreasing B-1 B cells in peritoneal cavity. Furthermore, Nek2 transgenic mice develop spontaneous germinal centers and exhibit an enhanced T cell dependent immune response. Altogether, our data demonstrates a novel role for Nek2 in regulating B cell development and the immune response. PMID:25485281

  7. Carabin deficiency in B cells increases BCR-TLR9 costimulation-induced autoimmunity

    PubMed Central

    Schickel, Jean-Nicolas; Pasquali, Jean-Louis; Soley, Anne; Knapp, Anne-Marie; Decossas, Marion; Kern, Aurélie; Fauny, Jean-Daniel; Marcellin, Luc; Korganow, Anne-Sophie; Martin, Thierry; Soulas-Sprauel, Pauline

    2012-01-01

    The mechanisms behind flares of human autoimmune diseases in general, and of systemic lupus in particular, are poorly understood. The present scenario proposes that predisposing gene defects favour clinical flares under the influence of external stimuli. Here, we show that Carabin is low in B cells of (NZB × NZW) F1 mice (murine SLE model) long before the disease onset, and is low in B cells of lupus patients during the inactive phases of the disease. Using knock-out and B-cell-conditional knock-out murine models, we identify Carabin as a new negative regulator of B-cell function, whose deficiency in B cells speeds up early B-cell responses and makes the mice more susceptible to anti-dsDNA production and renal lupus flare after stimulation with a Toll-like Receptor 9 agonist, CpG-DNA. Finally, in vitro analysis of NF?B activation and Erk phosphorylation in TLR9- and B-cell receptor (BCR)-stimulated Carabin-deficient B cells strongly suggests how the internal defect synergizes with the external stimulus and proposes Carabin as a natural inhibitor of the potentially dangerous crosstalk between BCR and TLR9 pathways in self-reactive B cells. PMID:23109291

  8. Pathogenic functions of B cells in autoimmune diseases: IFN-? production joins the criminal gang.

    PubMed

    Fillatreau, Simon

    2015-04-01

    B-cell depletion therapy has emerged as a powerful strategy to intercept the progression of T-cell-mediated autoimmune diseases such as rheumatoid arthritis, type 1 diabetes, or relapsing remitting multiple sclerosis. However, its mode of action remains incompletely defined, reflecting our incomplete understanding of the pathogenic functions of B cells in such pathologies. B cells can contribute to immune responses through the production of antibodies, presentation of antigen to T cells, and production of cytokines. In this issue of the European Journal of Immunology [Eur. J. Immunol. 2015. 45: 988-998], Olalekan et al. demonstrate that IFN-? production by B cells is essential for the development of arthritis in mice. Lack of IFN-? expression in B cells results in reduced autoimmune T-cell responses and autoantibody levels, impacting the arthritogenic reaction akin to that in B-cell depletion therapy. Together with other reports, the article by Olalekan et al. emphasizes the importance of cytokine-producing B cells in the pathogenesis of autoimmune diseases. In this commentary, I discuss how these findings shed new light on the roles of B cells as drivers of autoimmune pathogenesis, and how they more generally contribute to our understanding of the role of B cells in immunity. PMID:25727209

  9. The TNF-family cytokine TL1A inhibits proliferation of human activated B cells.

    PubMed

    Cavallini, Chiara; Lovato, Ornella; Bertolaso, Anna; Pacelli, Luciano; Zoratti, Elisa; Zanolin, Elisabetta; Krampera, Mauro; Zamň, Alberto; Tecchio, Cristina; Cassatella, Marco A; Pizzolo, Giovanni; Scupoli, Maria T

    2013-01-01

    Death receptor (DR3) 3 is a member of the TNFR superfamily. Its ligand is TNF-like ligand 1A (TL1A), a member of the TNF superfamily. TL1A/DR3 interactions have been reported to modulate the functions of T cells, NK, and NKT cells and play a crucial role in driving inflammatory processes in several T-cell-dependent autoimmune diseases. However, TL1A expression and effects on B cells remain largely unknown. In this study, we described for the first time that B cells from human blood express significant amounts of DR3 in response to B cell receptor polyclonal stimulation. The relevance of these results has been confirmed by immunofluorescence analysis in tonsil and spleen tissue specimens, which showed the in situ expression of DR3 in antigen-stimulated B cells in vivo. Remarkably, we demonstrated that TL1A reduces B-cell proliferation induced by anti-IgM-antibodies and IL-2 but did not affect B-cell survival, suggesting that TL1A inhibits the signal(s) important for B-cell proliferation. These results revealed a novel function of TL1A in modulating B-cell proliferation in vitro and suggest that TL1A may contribute to homeostasis of effector B-cell functions in immune response and host defense, thus supporting the role of the TL1A/DR3 functional axis in modulating the adaptive immune response. PMID:23565196

  10. The TNF-Family Cytokine TL1A Inhibits Proliferation of Human Activated B Cells

    PubMed Central

    Cavallini, Chiara; Lovato, Ornella; Bertolaso, Anna; Pacelli, Luciano; Zoratti, Elisa; Zanolin, Elisabetta; Krampera, Mauro; Zamň, Alberto; Tecchio, Cristina; Cassatella, Marco A.; Pizzolo, Giovanni; Scupoli, Maria T.

    2013-01-01

    Death receptor (DR3) 3 is a member of the TNFR superfamily. Its ligand is TNF-like ligand 1A (TL1A), a member of the TNF superfamily. TL1A/DR3 interactions have been reported to modulate the functions of T cells, NK, and NKT cells and play a crucial role in driving inflammatory processes in several T-cell-dependent autoimmune diseases. However, TL1A expression and effects on B cells remain largely unknown. In this study, we described for the first time that B cells from human blood express significant amounts of DR3 in response to B cell receptor polyclonal stimulation. The relevance of these results has been confirmed by immunofluorescence analysis in tonsil and spleen tissue specimens, which showed the in situ expression of DR3 in antigen-stimulated B cells in vivo. Remarkably, we demonstrated that TL1A reduces B-cell proliferation induced by anti-IgM-antibodies and IL-2 but did not affect B-cell survival, suggesting that TL1A inhibits the signal(s) important for B-cell proliferation. These results revealed a novel function of TL1A in modulating B-cell proliferation in vitro and suggest that TL1A may contribute to homeostasis of effector B-cell functions in immune response and host defense, thus supporting the role of the TL1A/DR3 functional axis in modulating the adaptive immune response. PMID:23565196

  11. Nek2 Is a Novel Regulator of B Cell Development and Immunological Response

    PubMed Central

    Zhou, Wen; Huang, Junwei; Yang, Ye; Wendlandt, Erik; Xu, Hongwei; Zhan, Fenghuang

    2014-01-01

    The serine/threonine kinase Nek2 is commonly found upregulated in a wide variety of neoplasms including diffuse large B cell lymphoma and multiple myeloma. High expression of Nek2 is implicated in the induction of chromosomal instability, promotion of cell proliferation, and drug resistance in tumor cells as well as a marker for poor clinical outcomes. Despite its well recorded involvement in chromosomal instability and neoplastic growth, little is known about the involvement of Nek2 in B cell development. Here we report the development of a transgenic mouse line with conditional expression of Nek2 in the B cell lineage and the effects it has on the development of B cells. Interestingly, we found that the overexpression of Nek2 does not induce spontaneous tumor formation within the transgenic mice up to 24 months after induction. Instead, overexpression of Nek2 in the B cell lineage affects the development of B cells by increasing the proportion of immature B cells in the bone marrow and decreasing B-1 B cells in peritoneal cavity. Furthermore, Nek2 transgenic mice develop spontaneous germinal centers and exhibit an enhanced T cell dependent immune response. Altogether, our data demonstrates a novel role for Nek2 in regulating B cell development and the immune response. PMID:25485281

  12. Neutrophil activation and B-cell stimulation in the pathogenesis of Felty's syndrome.

    PubMed

    Dwivedi, Nishant; Radic, Marko

    2012-01-01

    Felty's syndrome (FS) is a severe arthritic disorder that features chronic neutrophil activation and progresses to neutropenia and susceptibility to unabated infections. The life?threatening manifestations of FS have focused the attention of clinical experimenters who have made persistent efforts to find new and effective therapies. This review highlights important milestones in the research on FS and draws attention to recent studies on the antigen specificity of antibodies present in patients' sera. Recent data have indicated that immunoglobulins G (IgGs) in patients with FS bind selectively and specifically to deiminated histones and neutrophil extracellular chromatin traps (NETs). Deimination is the conversion of certain arginine residues in proteins to citrullines by the enzyme peptidylarginine deiminase 4. Earlier observations had indicated that IgGs in FS patients avidly bind to citrullinated peptides. These observations suggest that NETosis, the type of cell death that is defined by the release of NETs, provides autoantigens that stimulate B cell responses in this patient group. This insight parallels recent observations in other autoimmune conditions and lends support to the paradigm that NETosis plays a leading role in the pathogenesis of antiself immune responses.  PMID:22814518

  13. CD317 is over-expressed in B-cell chronic lymphocytic leukemia, but not B-cell acute lymphoblastic leukemia

    PubMed Central

    Gong, Shunyou; Osei, Ebenezer S; Kaplan, David; Chen, Youhai H; Meyerson, Howard

    2015-01-01

    CD317 was first identified as a multiple myeloma-associated antigen. Here we report the expression of CD317 in normal B cells and B-cell malignancies. In normal bone marrow, CD317 demonstrates a biphasic expression pattern, with higher expression on stage 1 and stage 3 hematogones, but not on stage 2 hematogones. CD317 is over-expressed in B-cell chronic lymphocytic leukemia, and appears associated with negative CD38 expression. Moreover, CD317 is barely detectable in B-cell acute lymphoblastic leukemia. Our results suggest that CD317 expression might be of prognostic significance for B-CLL, and CD317 could be used as a new marker for minimal residual disease detection in B-ALL. PMID:25973046

  14. T-cell-rich B-cell lymphoma: a clinicopathologic study of 21 cases and comparison with 43 cases of diffuse large B-cell lymphoma

    Microsoft Academic Search

    Hilal Aki; Nukhet Tuzuner; Seniz Ongoren; Zafer Baslar; Teoman Soysal; Burhan Ferhanoglu; Ismet Sahinler; Y?ld?z Ayd?n; Birsen Ulku; Gulten Aktuglu

    2004-01-01

    Clinicopathologic features of 21 patients with T-cell-rich B-cell lymphoma (TCRBCL) were reviewed and compared to 43 patients with diffuse large B-cell lymphoma (DLBCL) to determine if there were distinguishing clinical characteristics and differences in response or survival to CHOP therapy. For the diagnosis of TCRBCL, the current WHO criteria was used. In all of our cases, the majority of cells

  15. The Bruton tyrosine kinase inhibitor PCI-32765 blocks B-cell activation and is efficacious in models of autoimmune disease and B-cell malignancy

    PubMed Central

    Honigberg, Lee A.; Smith, Ashley M.; Sirisawad, Mint; Verner, Erik; Loury, David; Chang, Betty; Li, Shyr; Pan, Zhengying; Thamm, Douglas H.; Miller, Richard A.; Buggy, Joseph J.

    2010-01-01

    Activation of the B-cell antigen receptor (BCR) signaling pathway contributes to the initiation and maintenance of B-cell malignancies and autoimmune diseases. The Bruton tyrosine kinase (Btk) is specifically required for BCR signaling as demonstrated by human and mouse mutations that disrupt Btk function and prevent B-cell maturation at steps that require a functional BCR pathway. Herein we describe a selective and irreversible Btk inhibitor, PCI-32765, that is currently under clinical development in patients with B-cell non-Hodgkin lymphoma. We have used this inhibitor to investigate the biologic effects of Btk inhibition on mature B-cell function and the progression of B cell-associated diseases in vivo. PCI-32765 blocked BCR signaling in human peripheral B cells at concentrations that did not affect T cell receptor signaling. In mice with collagen-induced arthritis, orally administered PCI-32765 reduced the level of circulating autoantibodies and completely suppressed disease. PCI-32765 also inhibited autoantibody production and the development of kidney disease in the MRL-Fas(lpr) lupus model. Occupancy of the Btk active site by PCI-32765 was monitored in vitro and in vivo using a fluorescent affinity probe for Btk. Active site occupancy of Btk was tightly correlated with the blockade of BCR signaling and in vivo efficacy. Finally, PCI-32765 induced objective clinical responses in dogs with spontaneous B-cell non-Hodgkin lymphoma. These findings support Btk inhibition as a therapeutic approach for the treatment of human diseases associated with activation of the BCR pathway. PMID:20615965

  16. B-cell receptor signaling as a driver of lymphoma development and evolution

    PubMed Central

    Niemann, Carsten U.; Wiestner, Adrian

    2014-01-01

    The B-cell receptor (BCR) is essential for normal B-cell development and maturation. In an increasing number of B-cell malignancies, BCR signaling is implicated as a pivotal pathway in tumorigenesis. Mechanisms of BCR activation are quite diverse and range from chronic antigenic drive by microbial or viral antigens to autostimulation of B-cells by self-antigens to activating mutations in intracellular components of the BCR pathway. Hepatitis C virus infection can lead to the development of splenic marginal zone lymphoma, while Helicobacter pylori infection is associated with the development of mucosa-associated lymphoid tissue lymphomas. In some of these cases, successful treatment of the infection removes the inciting antigen and results in resolution of the lymphoma. Chronic lymphocytic leukemia has been recognized for decades as a malignancy of auto-reactive B-cells and its clinical course is in part determined by the differential response of the malignant cells to BCR activation. In a number of B-cell malignancies, activating mutations in signal transduction components of the BCR pathway have been identified; prominent examples are activated B-cell-like (ABC) diffuse large B-cell lymphomas (DLBCL) that carry mutations in CD79B and CARD11 and displays chronic active BCR signaling resulting in constitutive activation of the NF-?B pathway. Despite considerable heterogeneity in biology and clinical course, many mature B-cell malignancies are highly sensitive to kinase inhibitors that disrupt BCR signaling. Thus, targeted therapy through inhibition of BCR signaling is emerging as a new treatment paradigm for many B-cell malignancies. Here, we review the role of the BCR in the pathogenesis of B-cell malignancies and summarize clinical results of the emerging class of kinase inhibitors that target this pathway. PMID:24060900

  17. Interleukin 21 Signaling in B Cells Is Required for Efficient Establishment of Murine Gammaherpesvirus Latency

    PubMed Central

    Collins, Christopher M.; Speck, Samuel H.

    2015-01-01

    The human gammaherpesviruses take advantage of normal B cell differentiation pathways to establish life-long infection in memory B cells. Murine gammaherpesvirus 68 (MHV68) infection of laboratory strains of mice also leads to life-long infection in memory B cells. To gain access to the memory B cell population, MHV68 infected B cells pass through the germinal center reaction during the onset of latency and require signals from T follicular helper (TFH) cells for proliferation. Interleukin 21 (IL-21), one of the secreted factors produced by TFH cells, plays an important role in both the maintenance of the germinal center response as well as in the generation of long-lived plasma cells. Using IL-21R deficient mice, we show that IL-21 signaling is required for efficient establishment of MHV68 infection. In the absence of IL-21 signaling, fewer infected splenocytes are able to gain access to either the germinal center B cell population or the plasma cell population – the latter being a major site of MHV68 reactivation. Furthermore, the germinal center B cell population in IL-21R-/- mice is skewed towards the non-proliferating centrocyte phenotype, resulting in reduced expansion of infected B cells. Additionally, the reduced frequency of infected plasma cells results in a significant reduction in the frequency of splenocytes capable of reactivating virus. This defect in establishment of MHV68 infection is intrinsic to B cells, as MHV68 preferentially establishes infection in IL-21R sufficient B cells in mixed bone marrow chimeric mice. Taken together, these data indicate that IL-21 signaling plays multiple roles during establishment of MHV68 infection, and identify IL-21 as a critical TFH cell-derived factor for efficient establishment of gammaherpesvirus B cell latency. PMID:25875847

  18. CD11c-Expressing B Cells Are Located at the T Cell/B Cell Border in Spleen and Are Potent APCs.

    PubMed

    Rubtsov, Anatoly V; Rubtsova, Kira; Kappler, John W; Jacobelli, Jordan; Friedman, Rachel S; Marrack, Philippa

    2015-07-01

    In addition to the secretion of Ag-specific Abs, B cells may play an important role in the generation of immune responses by efficiently presenting Ag to T cells. We and other investigators recently described a subpopulation of CD11c(+) B cells (Age/autoimmune-associated B cells [ABCs]) that appear with age, during virus infections, and at the onset of some autoimmune diseases and participate in autoimmune responses by secreting autoantibodies. In this study, we assessed the ability of these cells to present Ag and activate Ag-specific T cells. We demonstrated that ABCs present Ag to T cells, in vitro and in vivo, better than do follicular B cells (FO cells). Our data indicate that ABCs express higher levels of the chemokine receptor CCR7, have higher responsiveness to CCL21 and CCL19 than do FO cells, and are localized at the T/B cell border in spleen. Using multiphoton microscopy, we show that, in vivo, CD11c(+) B cells form significantly more stable interactions with T cells than do FO cells. Together, these data identify a previously undescribed role for ABCs as potent APCs and suggest another potential mechanism by which these cells can influence immune responses and/or the development of autoimmunity. PMID:26034175

  19. In aged mice, low surrogate light chain promotes pro-B-cell apoptotic resistance, compromises the PreBCR checkpoint, and favors generation of autoreactive, phosphorylcholine-specific B cells

    PubMed Central

    Ratliff, Michelle; Alter, Sarah; McAvoy, Kelly; Frasca, Daniela; Wright, Jacqueline A; Zinkel, Sandra S; Khan, Wasif N; Blomberg, Bonnie B; Riley, Richard L

    2015-01-01

    In aged mice, new B-cell development is diminished and the antibody repertoire becomes more autoreactive. Our studies suggest that (i) apoptosis contributes to reduced B lymphopoiesis in old age and preferentially eliminates those B-cell precursors with higher levels of the surrogate light chain (SLC) proteins (?5/VpreB) and (ii) ?5low B-cell precursors generate new B cells which show increased reactivity to the self-antigen/bacterial antigen phosphorylcholine (PC). Pro-B cells in old bone marrow as well as pro-B cells from young adult ?5-deficient mice are resistant to cytokine-induced apoptosis (TNF?; TGF?), indicating that low ?5 expression in pro-B cells is sufficient to cause increased survival. Transfer of TNF?-producing ‘age-associated B cells’ (ABC; CD21/35? CD23?) or follicular (FO) B cells from aged mice into RAG-2 KO recipients led to preferential loss of ?5high pro-B cells, but retention of ?5low, apoptosis-resistant pro-B cells. In old mice, there is increased reactivity to PC in both immature bone marrow B cells and mature splenic FO B cells. In young mice, absence of ?5 expression led to a similar increase in PC reactivity among bone marrow and splenic B cells. We propose that in old age, increased apoptosis, mediated in part by TNF?-producing B cells, results in preferential loss of SLChigh pro-B cells within the bone marrow. Further B-cell development then occurs via an ‘SLClow’ pathway that not only impairs B-cell generation, but promotes autoreactivity within the naďve antibody repertoires in the bone marrow and periphery. PMID:25727904

  20. CVID-associated TACI mutations affect autoreactive B cell selection and activation

    PubMed Central

    Romberg, Neil; Chamberlain, Nicolas; Saadoun, David; Gentile, Maurizio; Kinnunen, Tuure; Ng, Yen Shing; Virdee, Manmeet; Menard, Laurence; Cantaert, Tineke; Morbach, Henner; Rachid, Rima; Martinez-Pomar, Natalia; Matamoros, Nuria; Geha, Raif; Grimbacher, Bodo; Cerutti, Andrea; Cunningham-Rundles, Charlotte; Meffre, Eric

    2013-01-01

    Common variable immune deficiency (CVID) is an assorted group of primary diseases that clinically manifest with antibody deficiency, infection susceptibility, and autoimmunity. Heterozygous mutations in the gene encoding the tumor necrosis factor receptor superfamily member TACI are associated with CVID and autoimmune manifestations, whereas two mutated alleles prevent autoimmunity. To assess how the number of TACI mutations affects B cell activation and tolerance checkpoints, we analyzed healthy individuals and CVID patients carrying one or two TACI mutations. We found that TACI interacts with the cleaved, mature forms of TLR7 and TLR9 and plays an important role during B cell activation and the central removal of autoreactive B cells in healthy donors and CVID patients. However, only subjects with a single TACI mutation displayed a breached immune tolerance and secreted antinuclear antibodies (ANAs). These antibodies were associated with the presence of circulating B cell lymphoma 6–expressing T follicular helper (Tfh) cells, likely stimulating autoreactive B cells. Thus, TACI mutations may favor CVID by altering B cell activation with coincident impairment of central B cell tolerance, whereas residual B cell responsiveness in patients with one, but not two, TACI mutations enables autoimmune complications. PMID:24051380

  1. Anti B cell therapy (rituximab) in the treatment of autoimmune diseases

    Microsoft Academic Search

    Hanadi Kazkaz; David Isenberg

    2004-01-01

    B cells play an important role in the pathogenesis of many autoimmune diseases. Selective targeting of these cells has been recently achieved using a chimeric monoclonal antibody against the pan B cell surface marker CD20 (rituximab). This antibody was originally developed for the treatment of non-Hodgkin’s lymphoma. It was found to be effective, well tolerated and had a very good

  2. Innate Response Activator (IRA) B Cells Reside in Human Tonsils and Internalize Bacteria In Vitro

    PubMed Central

    Pancotto, Laura; Ruggiero, Paolo; Rosa, Domenico; Manetti, Andrea; Romano, Antonio; Montagnani, Francesca; Bertholet, Sylvie; Castellino, Flora; Del Giudice, Giuseppe

    2015-01-01

    Innate response activator (IRA) B cells have been described in mice as a subset of B-1a B cells that produce granulocyte/macrophage colony-stimulating factor (GM-CSF) and have been found in the spleen upon activation. In humans, identification, tissue localization and functionality of these lymphocytes are poorly understood. We hypothesized that IRA B cells could reside in human palatine tonsils, which are a first line of defense from infection of the upper respiratory tract. In the present work, we used flow cytometry and confocal microscopy to identify and characterize human IRA (hIRA) B cells in tonsils. We show that CD19+CD20+GM-CSF+ B cells are present in the tonsils of all the subjects studied at a frequency ranging between ~0.2% and ~0.4% of the conventional CD19+CD20+GM-CSF- B cells. These cells reside within the B cell follicles, are mostly IgM+IgD+, express CD5 and show phagocytic activity. Our results support a role for hIRA B cells in the effector immune response to infections in tonsils. PMID:26066485

  3. A multi-scale model for correlation in B cell VDJ usage of zebrafish

    NASA Astrophysics Data System (ADS)

    Pan, Keyao; Deem, Michael W.

    2011-10-01

    The zebrafish (Danio rerio) is one of the model animals used for the study of immunology because the dynamics in the adaptive immune system of zebrafish are similar to that in higher animals. In this work, we built a multi-scale model to simulate the dynamics of B cells in the primary and secondary immune responses of zebrafish. We use this model to explain the reported correlation between VDJ usage of B cell repertoires in individual zebrafish. We use a delay ordinary differential equation (ODE) system to model the immune responses in the 6-month lifespan of a zebrafish. This mean field theory gives the number of high-affinity B cells as a function of time during an infection. The sequences of those B cells are then taken from a distribution calculated by a 'microscopic' random energy model. This generalized NK model shows that mature B cells specific to one antigen largely possess a single VDJ recombination. The model allows first-principle calculation of the probability, p, that two zebrafish responding to the same antigen will select the same VDJ recombination. This probability p increases with the B cell population size and the B cell selection intensity. The probability p decreases with the B cell hypermutation rate. The multi-scale model predicts correlations in the immune system of the zebrafish that are highly similar to that from experiment.

  4. B Cells use Conserved Polarity Cues to Regulate Their Antigen Processing and Presentation Functions.

    PubMed

    Yuseff, Maria-Isabel; Lennon-Duménil, Ana Maria

    2015-01-01

    The ability of B cells to produce high-affinity antibodies and to establish immunological memory in response to a wide range of pathogenic antigens is an essential part of the adaptive immune response. The initial step that triggers a humoral immune response involves the acquisition of antigens by B cells via their surface immunoglobulin, the B cell receptor (BCR). BCR-engaged antigens are transported into specialized lysosomal compartments where proteolysis and production of MHC class II-peptide complexes occur, a process referred to as antigen processing. Expression of MHC class II complexes at the B cell surface allows them to interact with T cells and to receive their help to become fully activated. In this review, we describe how B cells rely on conserved cell polarity mechanisms to coordinate local proteolytic secretion and mechanical forces at the B cell synapse enabling them to efficiently acquire and present extracellular antigens. We foresee that the mechanisms that dictate B cell activation can be used to tune B cell responses in the context of autoimmune diseases and cancer. PMID:26074919

  5. Whole-genome fingerprint of the DNA methylome during human B cell differentiation.

    PubMed

    Kulis, Marta; Merkel, Angelika; Heath, Simon; Queirós, Ana C; Schuyler, Ronald P; Castellano, Giancarlo; Beekman, Renée; Raineri, Emanuele; Esteve, Anna; Clot, Guillem; Verdaguer-Dot, Néria; Duran-Ferrer, Martí; Russińol, Nuria; Vilarrasa-Blasi, Roser; Ecker, Simone; Pancaldi, Vera; Rico, Daniel; Agueda, Lidia; Blanc, Julie; Richardson, David; Clarke, Laura; Datta, Avik; Pascual, Marien; Agirre, Xabier; Prosper, Felipe; Alignani, Diego; Paiva, Bruno; Caron, Gersende; Fest, Thierry; Muench, Marcus O; Fomin, Marina E; Lee, Seung-Tae; Wiemels, Joseph L; Valencia, Alfonso; Gut, Marta; Flicek, Paul; Stunnenberg, Hendrik G; Siebert, Reiner; Küppers, Ralf; Gut, Ivo G; Campo, Elías; Martín-Subero, José I

    2015-07-01

    We analyzed the DNA methylome of ten subpopulations spanning the entire B cell differentiation program by whole-genome bisulfite sequencing and high-density microarrays. We observed that non-CpG methylation disappeared upon B cell commitment, whereas CpG methylation changed extensively during B cell maturation, showing an accumulative pattern and affecting around 30% of all measured CpG sites. Early differentiation stages mainly displayed enhancer demethylation, which was associated with upregulation of key B cell transcription factors and affected multiple genes involved in B cell biology. Late differentiation stages, in contrast, showed extensive demethylation of heterochromatin and methylation gain at Polycomb-repressed areas, and genes with apparent functional impact in B cells were not affected. This signature, which has previously been linked to aging and cancer, was particularly widespread in mature cells with an extended lifespan. Comparing B cell neoplasms with their normal counterparts, we determined that they frequently acquire methylation changes in regions already undergoing dynamic methylation during normal B cell differentiation. PMID:26053498

  6. Excessive amounts of mu heavy chain block B-cell development

    PubMed Central

    Zhu, Lingqiao; Chang, Cheong-Hee

    2011-01-01

    Antigen-independent B-cell development occurs in several stages that depend on the expression of Ig heavy and light chain. We identified a line of mice that lacked mature B cells in the spleen. This mouse line carried approximately 11 copies of a transgene of the murine heavy chain constant region locus, and B-lineage cells expressed excessive amounts of the intracellular ? heavy chain. B-cell development failed in the bone marrow at the pro/pre B-cell transition, and examination of other lines with various copy numbers of the same transgene suggested that deficiencies in B-cell development increased with increased transgene copy number. Expression of a transgenic (Tg) light chain along with the Tg ? heavy chain led to minimal rescue of B-cell development in the bone marrow and B cells in the spleen. There are several potential mechanisms for the death of pro/pre B cells as a consequence of excess heavy chain expression. PMID:21727177

  7. Evaluating the B-cell density with various activation functions using White Noise Path Integral Approach

    NASA Astrophysics Data System (ADS)

    Aban, C. J. G.; Bacolod, R. O.; Confesor, M. N. P.

    2015-06-01

    A The White Noise Path Integral Approach is used in evaluating the B-cell density or the number of B-cell per unit volume for a basic type of immune system response based on the modeling done by Perelson and Wiegel. From the scaling principles of Perelson [1], the B- cell density is obtained where antigens and antibodies mutates and activation function f(|S-SA|) is defined describing the interaction between a specific antigen and a B-cell. If the activation function f(|S-SA|) is held constant, the major form of the B-cell density evaluated using white noise analysis is similar to the form of the B-cell density obtained by Perelson and Wiegel using a differential approach.A piecewise linear functionis also used to describe the activation f(|S-SA|). If f(|S-SA|) is zero, the density decreases exponentially. If f(|S-SA|) = S-SA-SB, the B- cell density increases exponentially until it reaches a certain maximum value. For f(|S-SA|) = 2SA-SB-S, the behavior of B-cell density is oscillating and remains to be in small values.

  8. DNase I hypersensitive sites flank the mouse class II major histocompatibility complex during B cell development.

    PubMed

    Carson, S

    1991-09-25

    The mouse class II major histocompatibility complex (MHC) encodes a polymorphic, multigene family important in the immune response, and is expressed mainly on mature B cells, on certain types of dendritic cells and is also inducible by gamma-interferon on antigen presenting cells. To study the regulatory elements which control this expression pattern, we have examined the chromatin structure flanking the class II MHC region, in particular during B cell differentiation. Using a panel of well-characterised mouse cell lines specific for different stages of B cell development (pre-B, B, plasma cell) as well as non-B cell lines, we have mapped the DNase I hypersensitive (DHS) sites adjacent to the mouse MHC class II region. The results presented show, for the first time that there are specific hypersensitive sites flanking the class II MHC locus during pre B cell, B cell and plasma cell stages of B cell differentiation, irrespective of the status of class II MHC expression. These hypersensitive sites are not found in T cell, fibroblast or uninduced myelomonocytic cell lines. This suggests that these DHS sites define a developmentally stable, chromatin structure, which can be used as a marker of B cell lineage commitment and may indicate that a combination of these hypersensitive sites reflect regulatory proteins involved in the immediate expression of a particular class II MHC gene or possibly control of the entire locus. PMID:1923768

  9. Eicosapentaenoic and docosahexaenoic acid ethyl esters differentially enhance B-cell activity in murine obesity.

    PubMed

    Teague, Heather; Harris, Mitchel; Fenton, Jenifer; Lallemand, Perrine; Shewchuk, Brian M; Shaikh, Saame Raza

    2014-05-17

    EPA and DHA are not biologically equivalent; however, their individual activity on B cells is unknown. We previously reported fish oil enhanced murine B-cell activity in obesity. To distinguish between the effects of EPA and DHA, we studied the ethyl esters of EPA and DHA on murine B-cell function as a function of time. We first demonstrate that EPA and DHA maintained the obese phenotype, with no improvements in fat mass, adipose inflammatory cytokines, fasting insulin, or glucose clearance. We then tested the hypothesis that EPA and DHA would increase the frequency of splenic B cells. EPA and DHA differentially enhanced the frequency and/or percentage of select B-cell subsets, correlating with increased natural serum IgM and cecal IgA. We next determined the activities of EPA and DHA on ex vivo production of cytokines upon lipopolysaccharide stimulation of B cells. EPA and DHA, in a time-dependent manner, enhanced B-cell cytokines with DHA notably increasing IL-10. At the molecular level, EPA and DHA differentially enhanced the formation of ordered microdomains but had no effect on Toll-like receptor 4 mobility. Overall, the results establish differential effects of EPA and DHA in a time-dependent manner on B-cell activity in obesity, which has implications for future clinical studies. PMID:24837990

  10. Blood B Cell and Regulatory Subset Content in Multiple Sclerosis Patients

    PubMed Central

    Habib, Jakob; Deng, Jiusheng; Lava, Neil; Tyor, William; Galipeau, Jacques

    2015-01-01

    Objective B cell targeted therapies have been effective in slowing multiple sclerosis (MS) disease progression suggesting a direct causal link for this lymphoid subset. A small subset of B cells with regulative properties (Bregs) exists in peripheral blood, and induction of Bregs ameliorates experimental autoimmune encephalomyelitis (EAE), the murine model for MS. Therefore the frequency of B cell subsets and regulatory B cells in particular in peripheral blood of MS patients is of interest. Methods The phenotype and frequency of B cell subsets in peripheral blood from 32 MS patients and 34 healthy controls (HC) were examined using flow cytometry. Results We found that there is an increase in CD19+ cell number in MS 1347 ± 159 cells/?L, (average ± SEM) compared to HC, 935 ± 129 cells/?L and no apparent deficiency in B-cells with a regulatory phenotype. In addition, we observed a loss of correlation between CD19+ B cells and total lymphocyte count in MS. Conclusion These findings suggest altered blood B-cell homeostasis in MS patients.

  11. Ikaros is absolutely required for pre-B cell differentiation by attenuating IL-7 signals

    PubMed Central

    Heizmann, Beate

    2013-01-01

    Pre-B cell receptor (pre-BCR) signaling and migration from IL-7–rich environments cooperate to drive pre-B cell differentiation via transcriptional programs that remain unclear. We show that the Ikaros transcription factor is required for the differentiation of large pre-B to small pre-B cells. Mice deleted for Ikaros in pro/pre-B cells show a complete block of differentiation at the fraction C? stage, and Ikaros-null pre-B cells cannot differentiate upon withdrawal of IL-7 in vitro. Restoration of Ikaros function rescues pre-B cell differentiation in vitro and in vivo and depends on DNA binding. Ikaros is required for the down-regulation of the pre-BCR, Ig? germline transcription, and Ig L chain recombination. Furthermore, Ikaros antagonizes the IL-7–dependent regulation of >3,000 genes, many of which are up- or down-regulated between fractions C? and D. Affected genes include those important for survival, metabolism, B cell signaling, and function, as well as transcriptional regulators like Ebf1, Pax5, and the Foxo1 family. Our data thus identify Ikaros as a central regulator of IL-7 signaling and pre-B cell development. PMID:24297995

  12. b-cell ABCA1 influences insulin secretion, glucose homeostasis and response to thiazolidinedione treatment

    E-print Network

    Cai, Long

    b-cell ABCA1 influences insulin secretion, glucose homeostasis and response to thiazolidinedione cholesterol transporter, in cholesterol homeostasis and insulin secretion in b-cells. Mice with specific but normal insulin sensitivity. Islets isolated from these mice showed altered cholesterol homeostasis

  13. Predicting Protective Linear B-cell Epitopes using Evolutionary Information Yasser EL-Manzalawy1

    E-print Network

    Honavar, Vasant

    Predicting Protective Linear B-cell Epitopes using Evolutionary Information Yasser EL-Manzalawy1-cell epitopes plays an important role in vac- cine design, immunodiagnostic tests, and antibody produc- tion, there is an urgent need for computational methods for reliable identification of putative B-cell epitopes from

  14. PREDICTING FLEXIBLE LENGTH LINEAR B-CELL EPITOPES Yasser EL-Manzalawy1,2,5

    E-print Network

    Honavar, Vasant

    121 PREDICTING FLEXIBLE LENGTH LINEAR B-CELL EPITOPES Yasser EL-Manzalawy1,2,5 , Drena Dobbs3,ddobbs, honavar}@iastate.edu Identifying B-cell epitopes play an important role in vaccine design-cell epitopes are highly desirable. We explore two machine learning approaches for predicting flexible length

  15. B-CELL EPITOPE PREDICTION Julia V. Ponomarenko and Marc H.V. van Regenmortel

    E-print Network

    Bourne, Philip E.

    35 B-CELL EPITOPE PREDICTION Julia V. Ponomarenko and Marc H.V. van Regenmortel INTRODUCTION When of an antigen is called a B-cell epitope or an antigenic determinant. If an antigen is a protein, an epitope may-dimensional space. Since other types of epitopes, such as T-cell epitopes, are not discussed in this chapter, B

  16. Rituximab induces sustained reduction of pathogenic B cells in patients with peripheral nervous system autoimmunity

    PubMed Central

    Maurer, Michael A.; Rakocevic, Goran; Leung, Carol S.; Quast, Isaak; Luka?išin, Martin; Goebels, Norbert; Münz, Christian; Wardemann, Hedda; Dalakas, Marinos; Lünemann, Jan D.

    2012-01-01

    The B cell–depleting IgG1 monoclonal antibody rituximab can persistently suppress disease progression in some patients with autoimmune diseases. However, the mechanism underlying these long-term beneficial effects has remained unclear. Here, we evaluated Ig gene usage in patients with anti–myelin-associated glycoprotein (anti-MAG) neuropathy, an autoimmune disease of the peripheral nervous system that is mediated by IgM autoantibodies binding to MAG antigen. Patients with anti-MAG neuropathy showed substantial clonal expansions of blood IgM memory B cells that recognized MAG antigen. The group of patients showing no clinical improvement after rituximab therapy were distinguished from clinical responders by a higher load of clonal IgM memory B cell expansions before and after therapy, by persistence of clonal expansions despite efficient peripheral B cell depletion, and by a lack of substantial changes in somatic hypermutation frequencies of IgM memory B cells. We infer from these data that the effectiveness of rituximab therapy depends on efficient depletion of noncirculating B cells and is associated with qualitative immunological changes that indicate reconfiguration of B cell memory through sustained reduction of autoreactive clonal expansions. These findings support the continued development of B cell–depleting therapies for autoimmune diseases. PMID:22426210

  17. A Transcriptional Regulatory Switch Underlying B-Cell Terminal Differentiation and Its Disruption by Dioxin (S)

    EPA Science Inventory

    The terminal differentiation of B cells in lymphoid organs into antibody-secreting plasma cells upon antigen stimulation is a crucial step in the humoral immune response. The architecture of the B-cell transcriptional regulatory network consists of coupled mutually-repressive fee...

  18. Villous B cells of the small intestine are specialized for invariant NK T cell dependence.

    PubMed

    Velázquez, Peter; Wei, Bo; McPherson, Michael; Mendoza, Lesley Marie A; Nguyen, Sandra L; Turovskaya, Olga; Kronenberg, Mitchell; Huang, Tiffany T; Schrage, Matthew; Lobato, Lynn N; Fujiwara, Daisuke; Brewer, Sarah; Arditi, Moshe; Cheng, Genhong; Sartor, R Balfour; Newberry, Rodney D; Braun, Jonathan

    2008-04-01

    B cells are important in mucosal microbial homeostasis through their well-known role in secretory IgA production and their emerging role in mucosal immunoregulation. Several specialized intraintestinal B cell compartments have been characterized, but the nature of conventional B cells in the lamina propria is poorly understood. In this study, we identify a B cell population predominantly composed of surface IgM(+) IgD(+) cells residing in villi of the small intestine and superficial lamina propria of the large intestine, but distinct from the intraepithelial compartment or organized intestinal lymphoid structures. Small intestinal (villous) B cells are diminished in genotypes that alter the strength of BCR signaling (Bruton tyrosine kinase(xid), Galphai2(-/-)), and in mice lacking cognate BCR specificity. They are not dependent on enteric microbial sensing, because they are abundant in mice that are germfree or genetically deficient in TLR signaling. However, villous B cells are reduced in the absence of invariant NK T cells (Jalpha18(-/-) or CD1d(-/-) mice). These findings define a distinct population of conventional B cells in small intestinal villi, and suggest an immunologic link between CD1-restricted invariant NK T cells and this B cell population. PMID:18354186

  19. Adaptive immunity depends on the presence of B cells and T cells. Or does

    E-print Network

    Cai, Long

    Adaptive immunity depends on the presence of B cells and T cells. Or does it? Now von Andrian and colleagues show that in the classic example of adaptive immunity, the hapten- induced contact-lived adaptive recall responses independently of B cells and T cells. A widely used model of CHS involves

  20. PI3K? inhibition hits a sensitive spot in B cell malignancies.

    PubMed

    Vanhaesebroeck, Bart; Khwaja, Asim

    2014-03-17

    A PI3K?-selective inhibitor shows impressive clinical activity in chronic lymphocytic leukemia and indolent B cell non-Hodgkin's lymphomas. In these malignancies, the PI3K pathway is not mutationally activated as in many other cancers, but it is important for mediating supportive cues from the cancer microenvironment and the B cell antigen receptor. PMID:24651009

  1. Microfluidic squeezing for intracellular antigen loading in polyclonal B-cells as cellular vaccines

    E-print Network

    Lee Szeto, Gregory

    B-cells are promising candidate autologous antigen-presenting cells (APCs) to prime antigen-specific T-cells both in vitro and in vivo. However to date, a significant barrier to utilizing B-cells as APCs is their low ...

  2. Suppression of B cell lymphomagenesis by the BH3-only proteins Bmf and Bad

    PubMed Central

    Frenzel, Anna; Labi, Verena; Chmelewskij, Waldemar; Ploner, Christian; Geley, Stephan; Fiegl, Heidelinde; Tzankov, Alexandar; Villunger, Andreas

    2012-01-01

    Oncogenic c-Myc is known to balance excessive proliferation by apoptosis that can be triggered by p53-dependent and p53-independent signaling networks. Here, we provide evidence that the “BH3-only” pro-apoptotic Bcl-2 family members Bmf and Bad are potent antagonists of c-Myc-driven B cell lymphomagenesis. Tumor formation was preceded by accumulation of preneoplastic pre-B and immature IgM+ B cells in hematopoietic organs of E?-myc/bmf?/? mice, whereas E?-myc/bad?/? mice showed an increase of pre-B cells limited to the spleen. While loss of Bad had no impact on the tumor immunophenotype, Bmf-deficiency favored the development of IgM+ B cell over pre-B cell tumors. This phenomenon was due to a strong protection of immature IgM+ B cells from oncogene-driven apoptosis caused by loss of bmf and c-Myc-induced repression of Bmf expression in premalignant pre-B cells. Steady-state levels of B cell apoptosis were also reduced in the absence of Bad, in support of its role as a sentinel for trophic factor-deprivation. Loss of Bmf reduced the pressure to inactivate p53, whereas Bad-deficiency did not, identifying Bmf as a novel component of the p53-independent tumor suppressor pathway triggered by c-Myc. PMID:19965635

  3. G-Rich Proto-Oncogenes Are Targeted for Genomic Instability in B-Cell Lymphomas

    E-print Network

    Maizels, Nancy

    G-Rich Proto-Oncogenes Are Targeted for Genomic Instability in B-Cell Lymphomas Michelle L. Genomic instability of a subset of proto- oncogenes, including c-MYC, BCL6, RhoH, PIM1, and PAX5, can growth. Lymphomas in which these proto-oncogenes are unstable derive from germinal center B cells

  4. Study of BKM120 & Rituximab in Patients With Relapsed or Refractory Indolent B-Cell Lymphoma

    ClinicalTrials.gov

    2015-04-09

    Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Nodal Marginal Zone B-cell Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Splenic Marginal Zone Lymphoma; Waldenström Macroglobulinemia

  5. B Cells use Conserved Polarity Cues to Regulate Their Antigen Processing and Presentation Functions

    PubMed Central

    Yuseff, Maria-Isabel; Lennon-Duménil, Ana Maria

    2015-01-01

    The ability of B cells to produce high-affinity antibodies and to establish immunological memory in response to a wide range of pathogenic antigens is an essential part of the adaptive immune response. The initial step that triggers a humoral immune response involves the acquisition of antigens by B cells via their surface immunoglobulin, the B cell receptor (BCR). BCR-engaged antigens are transported into specialized lysosomal compartments where proteolysis and production of MHC class II-peptide complexes occur, a process referred to as antigen processing. Expression of MHC class II complexes at the B cell surface allows them to interact with T cells and to receive their help to become fully activated. In this review, we describe how B cells rely on conserved cell polarity mechanisms to coordinate local proteolytic secretion and mechanical forces at the B cell synapse enabling them to efficiently acquire and present extracellular antigens. We foresee that the mechanisms that dictate B cell activation can be used to tune B cell responses in the context of autoimmune diseases and cancer.

  6. Primary Bone Marrow B-Cell Lymphoma: Report of Four Cases

    Microsoft Academic Search

    JAMES A. STRAUCHEN

    Bone marrow involvement is infrequent at presentation in cases of diffuse large B-cell lymphoma. We report four adult patients with diffuse large B-cell lymphoma in whom bone marrow involvement with hematologic manifestations was the predominant clinical feature at presentation. Three patients pre- sented with a leukoerythroblastic blood picture and one with pancytopenia. In each case, the unusual hematologic manifestations, with

  7. Novel Suppressive Function of Transitional 2 B Cells in Experimental Arthritis1

    Microsoft Academic Search

    Jamie G. Evans; Karina A. Chavez-Rueda; Ayad Eddaoudi; Almut Meyer-Bahlburg; David J. Rawlings; Michael R. Ehrenstein; Claudia Mauri

    The immune system contains natural regulatory cells important in the maintenance of tolerance. Although this suppressive function is usually attributed to CD4 regulatory T cells, recent reports have revealed an immunoregulatory role for IL-10- producing B cells in the context of several autoimmune diseases including collagen-induced arthritis. In the present study, we attribute this suppressive function to a B cell

  8. Identification of a negative regulatory role for spi-C in the murine B cell lineage.

    PubMed

    Li, Stephen K H; Solomon, Lauren A; Fulkerson, Patricia C; DeKoter, Rodney P

    2015-04-15

    Spi-C is an E26 transformation-specific family transcription factor that is highly related to PU.1 and Spi-B. Spi-C is expressed in developing B cells, but its function in B cell development and function is not well characterized. To determine whether Spi-C functions as a negative regulator of Spi-B (encoded by Spib), mice were generated that were germline knockout for Spib and heterozygous for Spic (Spib(-/-)Spic(+/-)). Interestingly, loss of one Spic allele substantially rescued B cell frequencies and absolute numbers in Spib(-/-) mouse spleens. Spib(-/-)Spic(+/-) B cells had restored proliferation compared with Spib(-/-) B cells in response to anti-IgM or LPS stimulation. Investigation of a potential mechanism for the Spib(-/-)Spic(+/-) phenotype revealed that steady-state levels of Nfkb1, encoding p50, were elevated in Spib(-/-)Spic(+/-) B cells compared with Spib(-/-) B cells. Spi-B was shown to directly activate the Nfkb1 gene, whereas Spi-C was shown to repress this gene. These results indicate a novel role for Spi-C as a negative regulator of B cell development and function. PMID:25769919

  9. Blood . Author manuscript An in vitro model of differentiation of memory B cells into plasmablasts

    E-print Network

    Paris-Sud XI, Université de

    Blood . Author manuscript Page /1 14 An in vitro model of differentiation of memory B cells secreting PCs starting from memory B cells+ (MBCs) in a 3-step- and 10-day (D) culture, including a 6-fold after immunization of healthy donors. This model will facilitate further studies in PCin vitro biology

  10. Analysis and classification of B-cell infiltrates in lupus and ANCA-associated nephritis

    Microsoft Academic Search

    Oliver M Steinmetz; Joachim Velden; Ursula Kneissler; Marlies Marx; Antje Klein; Udo Helmchen; Rolf A K Stahl; Ulf Panzer

    2008-01-01

    Intrarenal B cell infiltrates resembling secondary lymphoid tissue have been found in several forms of inflammatory kidney disease. Their role in renal inflammation is not well defined, perhaps because B cell clusters have been regarded as a single entity while being quite heterogeneous. Therefore we characterized intrarenal lymphoid clusters of 32 patients diagnosed with lupus nephritis and 16 with ANCA

  11. Karyotype stability of the DT40 chicken B cell line: Macrochromosome variation and cytogenetic mosaicism

    E-print Network

    Delany, Mary E.

    Karyotype stability of the DT40 chicken B cell line: Macrochromosome variation and cytogenetic for publication by Herbert Macgregor 23 January 2004 Key words: aneuploidy, chicken, chromosomes, cytogenetics, DT40, karyotype, mosaicism Abstract The DT40 transformed chicken B-cell line is an important and widely

  12. A multi-scale model for correlation in B cell VDJ usage of zebrafish

    PubMed Central

    Pan, Keyao; Deem, Michael W

    2015-01-01

    The zebrafish (Danio rerio) is one of the model animals for study of immunology because the dynamics in the adaptive immune system of zebrafish are similar to that in higher animals. In this work, we built a multi-scale model to simulate the dynamics of B cells in the primary and secondary immune responses of zebrafish. We use this model to explain the reported correlation between VDJ usage of B cell repertoires in individual zebrafish. We use a delay ordinary differential equation (ODE) system to model the immune responses in the 6-month lifespan of a zebrafish. This mean field theory gives the number of high affinity B cells as a function of time during an infection. The sequences of those B cells are then taken from a distribution calculated by a “microscopic” random energy model. This generalized NK model shows that mature B cells specific to one antigen largely possess a single VDJ recombination. The model allows first-principles calculation of the probability, p, that two zebrafish responding to the same antigen will select the same VDJ recombination. This probability p increases with the B cell population size and the B cell selection intensity. The probability p decreases with the B cell hypermutation rate. The multi-scale model predicts correlations in the immune system of the zebrafish that are highly similar to that from experiment. PMID:21832808

  13. Microfluidic squeezing for intracellular antigen loading in polyclonal B-cells as cellular vaccines.

    PubMed

    Lee Szeto, Gregory; Van Egeren, Debra; Worku, Hermoon; Sharei, Armon; Alejandro, Brian; Park, Clara; Frew, Kirubel; Brefo, Mavis; Mao, Shirley; Heimann, Megan; Langer, Robert; Jensen, Klavs; Irvine, Darrell J

    2015-01-01

    B-cells are promising candidate autologous antigen-presenting cells (APCs) to prime antigen-specific T-cells both in vitro and in vivo. However to date, a significant barrier to utilizing B-cells as APCs is their low capacity for non-specific antigen uptake compared to "professional" APCs such as dendritic cells. Here we utilize a microfluidic device that employs many parallel channels to pass single cells through narrow constrictions in high throughput. This microscale "cell squeezing" process creates transient pores in the plasma membrane, enabling intracellular delivery of whole proteins from the surrounding medium into B-cells via mechano-poration. We demonstrate that both resting and activated B-cells process and present antigens delivered via mechano-poration exclusively to antigen-specific CD8(+)T-cells, and not CD4(+)T-cells. Squeezed B-cells primed and expanded large numbers of effector CD8(+)T-cells in vitro that produced effector cytokines critical to cytolytic function, including granzyme B and interferon-?. Finally, antigen-loaded B-cells were also able to prime antigen-specific CD8(+)T-cells in vivo when adoptively transferred into mice. Altogether, these data demonstrate crucial proof-of-concept for mechano-poration as an enabling technology for B-cell antigen loading, priming of antigen-specific CD8(+)T-cells, and decoupling of antigen uptake from B-cell activation. PMID:25999171

  14. Hapten-specific naďve B cells are biomarkers of vaccine efficacy against drugs of abuse.

    PubMed

    Taylor, J J; Laudenbach, M; Tucker, A M; Jenkins, M K; Pravetoni, M

    2014-03-01

    Vaccination against drugs of abuse shows efficacy in animal models, yet few subjects achieve effective serum antibody titers in clinical studies. A barrier to translation is the lack of pre-vaccination screening assays that predict the most effective conjugate vaccines or subjects amenable to vaccination. To address this obstacle, we developed a fluorescent antigen-based enrichment method paired with flow cytometry to characterize hapten-specific B cells. Using this approach, we studied naďve and activated B cells specific for structurally-related model haptens based on derivatization of the morphinan structure at the C6 position on oxycodone or at the C8 position on hydrocodone, and showing different pre-clinical efficacy against the prescription opioid oxycodone. Prior to vaccination, naďve B cells exhibited relatively higher affinity for the more effective C6-derivatized oxycodone-based hapten (6OXY) and the 6OXY-specific naďve B cell population contained a higher number of B cells with greater affinity for free oxycodone. Higher affinity of naďve B cells for hapten or oxycodone reflected greater efficacy of vaccination in blocking oxycodone distribution to brain in mice. Shortly after immunization, activated hapten-specific B cells were detected prior to oxycodone-specific serum antibodies and provided earlier evidence of vaccine failure or success. Analysis of hapten-specific naďve and activated B cells may aid rational vaccine design and provide screening tools to predict vaccine clinical efficacy against drugs of abuse or other small molecules. PMID:24462800

  15. Monitoring of immune cell response to B cell depletion therapy and nerve root injury using SPIO enhanced MRI

    NASA Astrophysics Data System (ADS)

    Thorek, Daniel L.

    2009-12-01

    Magnetic resonance (MR) is a robust platform for non-invasive, high-resolution anatomical imaging. However, MR imaging lacks the requisite sensitivity and contrast for imaging at the cellular level. This represents a clinical impediment to greater diagnostic accuracy. Recent advances have allowed for the in vivo visualization of populations and even of individual cells using superparamagnetic iron oxide (SPIO) MR contrast agents. These nanoparticles, commonly manifested as a core of a single iron oxide crystal or cluster of crystals coated in a biocompatible shell, function to shorten proton relaxation times. In MR imaging these constructs locally dephase protons, resulting in a decrease in signal (hypointensity) localized to the region of accumulation of SPIO. In the context of immune cell imaging, SPIO can provide insight into the cellular migration patterns, trafficking, temporal dynamics and progression of diseases and their related pathological states. Furthermore, by visualizing the presence and activity of immune cells, SPIO-enabled cellular imaging can help evaluate the efficacy of therapy in immune disorders. This thesis examines the production, modification and application of SPIO in a range of in vitro and in vivo immune-response-relevant cellular systems. The role of different nanoparticle characteristics including diameter, surface charge and concentration are investigated in the labeling of T cells in culture. Following optimization of SPIO loading conditions for lymphocytes, the effect these particles have on the activation of primary B cells are elucidated. B cells are tracked using a variety of modalities, with and without the application of B cell depleting therapy. This is to evaluate the efficacy of SPIO as in vivo marker for B cell distribution. Unmodified SPIO were applied to monitor macrophage infiltration in a transient nerve root compression model, with implications for neck pain diagnosis and treatment. Nanoparticle accumulation and MR hypointensity was correlated to the presence of activated macrophage at the site of injury. Taken together, the application of SPIO to study nanoparticle uptake in vitro and visualization of immune cells in vivo provide a basis for advanced study and diagnosis of diverse pathologies.

  16. Hormonal milieu at time of B cell activation controls duration of autoantibody response

    PubMed Central

    Jeganathan, Venkatesh; Peeva, Elena; Diamond, Betty

    2015-01-01

    A strong gender bias is seen in many autoimmune diseases including systemic lupus erythematosus (SLE). To investigate the basis for the female preponderance in SLE, we have been studying BALB/c mice in which B cells express the R4A heavy chain of an anti-DNA antibody in association with an endogenous light chain repertoire (R4Atg mice). In unmanipulated mice, approximately 5% of B cells express the R4A transgene. R4Atg mice do not spontaneously develop elevated serum titers of anti-DNA antibodies. Administration of either estradiol (E2) or prolactin (Pr) results in escape from tolerance of autoreactive B cells, expressed as an increase in transgene-expressing B cells and elevated serum titers of anti-DNA antibodies. We previously demonstrated that autoreactive B cells maturing in an estrogenic milieu develop as marginal zone (MZ) B cells; when these same B cells mature in the presence of increased prolactin, they develop as follicular (Fo) B cells. To determine the long term consequence of this differential maturation of DNA-reactive B cells, we treated R4Atg BALB/c mice with E2 or Pr for 6 weeks until serum titers of anti-DNA antibody were high, at which time hormonal exposure was discontinued. In E2-treated mice, the anti-DNA titers remained high even 3 months after discontinuation of hormone exposure. Nascent B cells underwent normal tolerance induction, but existing autoreactive MZ B cells persisted and continued to secrete autoantibody. In contrast, Pr caused only a short-term increase in anti-DNA antibody titers. By 3 months after cessation of hormone treatment, serum anti-DNA antibody titers and B cell subsets were indistinguishable from those in placebo (P) treated mice. These findings suggest that autoantibody responses are sustained for variable lengths of time depending on the B cell subset producing the autoantibodies. This observation may be relevant to understanding the heterogeneous presentation of patients with SLE and to the design of therapies targeting speci?c B-cell populations in autoimmune disease. PMID:24685232

  17. Directed Ig class switch recombination in activated murine B cells.

    PubMed Central

    Winter, E; Krawinkel, U; Radbruch, A

    1987-01-01

    Immunoglobulin class switch recombination occurs at frequencies of up to 10%/cell/generation in activated murine B-lymphocytes. We analysed cH gene rearrangements and switch recombinations from active and inactive IgH loci of B-cells activated in various ways and immortalized by cell fusion. Although about half of the IgM+ cells show rearrangement of c mu genes, the deletion of c mu is a rare event. Half of the IgG3+ and IgG1+ cells show rearrangement of c mu genes on the inactive IgH locus and the other half of the IgG+ cells have deleted c mu from both IgH loci by switch recombination. This recombination is directed to the same switch regions on both IgH loci in 60-80% of all cases. Interleukin 4 may play a critical role in programming murine B-lymphocytes for specific switch recombination. Images Fig. 1. Fig. 2. Fig. 6. PMID:3038529

  18. Stereotyped B-cell receptors in chronic lymphocytic leukemia.

    PubMed

    Agathangelidis, Andreas; Vardi, Anna; Baliakas, Panagiotis; Stamatopoulos, Kostas

    2014-10-01

    Over the last decade, immunogenetic analysis of B-cell receptor immunoglobulins (BcR IGs) has proved to be a particularly fruitful field in chronic lymphocytic leukemia (CLL), not only for understanding disease pathogenesis but also for discriminating clinical subgroups with markedly distinct course and outcome. Of utmost importance was the identification of quasi-identical BcR IGs among unrelated patients with CLL, fittingly coined as "stereotypy," that set the wheels in motion for unraveling the role of antigen(s) in the selection and expansion of the leukemic clones. The categorization of CLL clones into "subsets" according to shared BcR IG structural characteristics provided a compartmentalized view of this otherwise heterogeneous disease, which eventually led to defining strikingly homogeneous groups of patients in terms of: (i) functional properties of the clonal BcR IGs, e.g. BcR reactivity and signaling; (ii) clonal genetic landscape, e.g. genomic aberrations, gene expression/methylation profiles, microRNA signatures; and (iii) clinical course and outcome. The remarkable restriction of the CLL IG gene repertoire, resulting to a great degree from the high impact of BcR IG stereotypy, may also prompt speculations regarding CLL ontogenesis. Overall, the BcR IG molecule justifiably lies at the heart of CLL clinical research, holding the promise of subset-tailored therapies. PMID:24397617

  19. Antibody and B cell responses to Plasmodium sporozoites

    PubMed Central

    Dups, Johanna N.; Pepper, Marion; Cockburn, Ian A.

    2014-01-01

    Antibodies are capable of blocking infection of the liver by Plasmodium sporozoites. Accordingly the induction of anti-sporozoite antibodies is a major aim of various vaccine approaches to malaria. In recent years our knowledge of the specificity and quantities of antibodies required for protection has been greatly expanded by clinical trials of various whole sporozoite and subunit vaccines. Moreover, the development of humanized mouse models and transgenic parasites have also aided our ability to assess the specificity of antibodies and their ability to block infection. Nonetheless, considerable gaps remain in our knowledge – in particular in understanding what antigens are recognized by infection blocking antibodies and in knowing how we can induce robust, long-lived antibody responses. Maintaining high levels of circulating antibodies is likely to be of primary importance, as antibodies must block infection in the short time it takes for sporozoites to reach the liver from the skin. It is clear that a better understanding of the development of protective B cell-mediated immunity will aid the development and refinement of malaria vaccines. PMID:25477870

  20. Persistent antigen and germinal center B cells sustain T follicular helper cell responses and phenotype.

    PubMed

    Baumjohann, Dirk; Preite, Silvia; Reboldi, Andrea; Ronchi, Francesca; Ansel, K Mark; Lanzavecchia, Antonio; Sallusto, Federica

    2013-03-21

    T follicular helper (Tfh) cells provide help to B cells and are crucial for establishment of germinal center (GC) reactions, including production of high-affinity antibodies and generation of memory B cells and long-lived plasma cells. Here we report that the magnitude of the Tfh cell response was dictated by the amount of antigen and directly correlated with the magnitude of the GC B cell response. In addition, maintenance of the Tfh cell phenotype required sustained antigenic stimulation by GC B cells. In lymphopenic conditions, a strong and prolonged Tfh cell response led to bystander B cell activation, hypergammaglobulinemia, and production of poly- and self-reactive antibodies. These data demonstrate that antigen dose determines the size and duration of the Tfh cell response and GC reaction, highlight the transient nature of the Tfh cell phenotype, and suggest a link between overstimulation of Tfh cells and the development of dysregulated humoral immune responses. PMID:23499493

  1. B cells Regulate Macrophage Phenotype and Response to Chemotherapy in Squamous Carcinomas

    PubMed Central

    Medler, Terry R.; Gunderson, Andrew J.; Johansson, Magnus; Bornstein, Sophia; Bergsland, Emily; Steinhoff, Martin; Li, Yijin; Gong, Qian; Ma, Yan; Wiesen, Jane F.; Wong, Melissa H.; Kulesz-Martin, Molly; Irving, Bryan; Coussens, Lisa M.

    2014-01-01

    SUMMARY B cells foster squamous cell carcinogenesis (SCC) through deposition of immunoglobulin-containing immune complexes in premalignant tissue and Fc?receptor-dependent activation of myeloid cells. Since human SCCs of the vulva and head and neck exhibited hallmarks of B cell infiltration, we examined B cell-deficient mice and found reduced ability to support SCC growth. Although ineffective as a single agent, treatment of mice bearing pre-existing SCCs with B cell-depleting ?CD20 monoclonal antibodies improved response to platinum- and taxol-based chemotherapy. Improved chemo-responsiveness was dependent on altered chemokine expression by macrophages that fostered tumor infiltration of activated CD8+ T cells via CCR5-dependent mechanisms. These data reveal that B cells, and the downstream myeloid-based pathways they regulate, represent tractable targets for anti-cancer therapy in select tumors. PMID:24909985

  2. B cells in spontaneous autoimmune diseases of the central nervous system.

    PubMed

    Berer, Kerstin; Wekerle, Hartmut; Krishnamoorthy, Gurumoorthy

    2011-06-01

    B cells and their secreted products participate in the intricate network of pathogenic and regulatory immune responses. In human autoimmune diseases like rheumatoid arthritis, systemic lupus erythematosus and type 1 diabetes, a role for B cells and antibodies is well established. However, in multiple sclerosis (MS), despite the presence of autoantibodies, B cells were less considered as a major participant of autoimmune processes, until recently. Several lines of evidence now indicate a more active role for B cells in disease pathogenesis. In this review, we discuss the diverse roles of B cells in autoimmune diseases with particular focus on multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE) as well as the recently generated spontaneous EAE mouse models. PMID:21146219

  3. The tipping points in the initiation of B cell signalling: how small changes make big differences

    PubMed Central

    Pierce, Susan K.; Liu, Wanli

    2012-01-01

    B cells are selected by the binding of antigen to clonally distributed B cell receptors (BCRs), triggering signalling cascades that result in B cell activation. With the recent application of high-resolution live-cell imaging, we are gaining an understanding of the events that initiate BCR signalling within seconds of its engagement with antigen. These observations are providing a molecular explanation for fundamental aspects of B cell responses, including antigen affinity discrimination and the value of class switching, as well as insights into the underlying causes of B cell tumorigenesis. Advances in our understanding of the earliest molecular events that follow antigen binding to the BCR may provide a general framework for the initiation of signalling in the adaptive immune system. PMID:20935671

  4. Regulation of type 2 immunity to H. polygyrus by effector B cells

    PubMed Central

    Wojciechowski, Wojciech; Harris, David P.; Sprague, Frank; Mousseau, Betty; Makris, Melissa; Kusser, Kim; Honjo, Tasuko; Mohrs, Katja; Mohrs, Markus; Randall, Troy; Lund, Frances E.

    2009-01-01

    Summary Immunity to the intestinal parasite, Heligomosomoides polygyrus, is dependent on the successful generation of Th2 memory cells. We show that B cells contribute to immunity against H. polygyrus by producing antibody and by promoting expansion and differentiation of primary and memory Th2 cells. We also demonstrate that cytokine-producing “effector” B cells are essential for effective immunity to H. polygyrus. TNF? production by B cells is necessary for sustained Ab production, while IL-2 production by B cells is necessary for Th2 expansion and differentiation. These results show that B cells mediate protection to pathogens not only by presenting antigen and secreting antibody but also by producing cytokines that regulate the quality and magnitude of humoral and cellular immune responses. PMID:19249230

  5. Cytomegalovirus (CMV) seropositivity decreases B cell responses to the influenza vaccine.

    PubMed

    Frasca, Daniela; Diaz, Alain; Romero, Maria; Landin, Ana Marie; Blomberg, Bonnie B

    2015-03-17

    Cytomegalovirus (CMV)-seropositivity has been shown to have a negative effect on influenza vaccine-specific antibody responses. In this paper, we confirm and extend these results showing for the first time, a negative association between CMV-seropositivity and B cell predictive biomarkers of optimal vaccine responses. These biomarkers are switched memory B cells and AID in CpG-stimulated B cell cultures measured before vaccination which positively correlate with the serum response to the influenza vaccine. We also found that CMV-seropositivity is associated with increased levels of B cell-intrinsic inflammation and these both correlate with lower B cell function. Finally, CMV-seropositivity is associated with decreased percentages of individuals responding to the vaccine in both young and elderly individuals. PMID:25659271

  6. How B cells capture, process and present antigens: a crucial role for cell polarity.

    PubMed

    Yuseff, Maria-Isabel; Pierobon, Paolo; Reversat, Anne; Lennon-Duménil, Ana-Maria

    2013-07-01

    B cells are key components of the adaptive immune response. Their differentiation into either specific memory B cells or antibody-secreting plasma cells is a consequence of activation steps that involve the processing and presentation of antigens. The engagement of B cell receptors by surface-tethered antigens leads to the formation of an immunological synapse that coordinates cell signalling events and that promotes antigen uptake for presentation on MHC class II molecules. In this Review, we discuss membrane trafficking and the associated molecular mechanisms that are involved in antigen extraction and processing at the B cell synapse, and we highlight how B cells use cell polarity to coordinate the complex events that ultimately lead to efficient humoral responses. PMID:23797063

  7. Marine fish oils are not equivalent with respect to B-cell membrane organization and activation.

    PubMed

    Gurzell, Eric A; Teague, Heather; Duriancik, David; Clinthorne, Jonathan; Harris, Mitchel; Shaikh, Saame Raza; Fenton, Jenifer I

    2015-04-01

    We previously reported that docosahexaenoic-acid (DHA)-enriched fish oil (DFO) feeding altered B-cell membrane organization and enhanced B-cell function. The purpose of this study was to evaluate whether menhaden oil (MO) and eicosapentaenoic-acid (EPA)-enriched fish oil (EFO) alters B-cell function/phenotype similarly. Mice were fed control (CON), MO, EFO or DFO diets for 5weeks. We evaluated the fatty acid composition of B-cell phospholipids, membrane microdomain organization, ex vivo B-cell functionality and in vivo B-cell subsets. Red blood cells and B cells were found to be strongly (r>0.85) and significantly (P<.001) correlated for major n-3 and n-6 long-chain polyunsaturated fatty acids (LCPUFAs). Compared to CON, MO and DFO resulted in decreased clustering of membrane microdomains, whereas EFO increased clustering. All fish oil treatments had 1.12-1.60 times higher CD40 expression following stimulation; however, we observed 0.86 times lower major histocompatibility complex class II expression and 0.7 times lower interleukin (IL)-6 production from EFO, but 3.25 times higher interferon-? from MO and 1.5 times higher IL-6 from DFO. By 90min of incubation, MO had 1.11 times higher antigen uptake compared to CON, whereas EFO was 0.86 times lower. All fish oil treatments resulted in decreasingly mature splenic and bone marrow B-cell subsets. We conclude that diets high in n-3 LCPUFAs may elicit similar B-cell phenotypes but different organizational and functional outcomes. More specifically, these data suggest that the EPA and DHA content of a diet influences immunological outcomes, highlighting the importance of understanding how specific n-3 LCPUFAs modulate B-cell development and function. PMID:25616447

  8. Murine complement receptor 1 is required for germinal center B cell maintenance but not initiation

    PubMed Central

    Donius, Luke R.; Weis, Janis J.; Weis, John H.

    2014-01-01

    Germinal centers are the anatomic sites for the generation of high affinity immunoglobulin expressing plasma cells and memory B cells. The germinal center B cells that are precursors of these cells circulate between the light zone B cell population that interact with antigen laden follicular dendritic cells (FDC) and the proliferative dark zone B cell population. Antigen retention by follicular dendritic cells is dependent on Fc receptors and complement receptors, and complement receptor 1 (Cr1) is the predominant complement receptor expressed by FDC. The newly created Cr1KO mouse was used to test the effect of Cr1-deficiency on the kinetics of the germinal center reaction and the generation of IgM and switched memory B cell formation. Immunization of Cr1KO mice with a T cell-dependent antigen resulted in the normal initial expansion of B cells with a germinal center phenotype however these cells were preferentially lost in the Cr1KO animal over time (days). Bone marrow chimera animals documented the surprising finding that the loss of germinal center B cell maintenance was linked to the expression of Cr1 on B cells, not the FDC. Cr1-deficiency further resulted in antigen-specific IgM titer and IgM memory B cell reductions, but not antigen-specific IgG after 35-37 days. Investigations of nitrophenyl (NP)-specific IgG demonstrated that Cr1 is not necessary for affinity maturation during the response to particulate antigen. These data, along with those generated in our initial description of the Cr1KO animal describe unique functions of Cr1 on the surface of both B cells and FDC. PMID:24636730

  9. Wiskott-Aldrich Syndrome protein deficiency perturbs the homeostasis of B-cell compartment in humans.

    PubMed

    Castiello, Maria Carmina; Bosticardo, Marita; Pala, Francesca; Catucci, Marco; Chamberlain, Nicolas; van Zelm, Menno C; Driessen, Gertjan J; Pac, Malgorzata; Bernatowska, Ewa; Scaramuzza, Samantha; Aiuti, Alessandro; Sauer, Aisha V; Traggiai, Elisabetta; Meffre, Eric; Villa, Anna; van der Burg, Mirjam

    2014-05-01

    Wiskott-Aldrich Syndrome protein (WASp) regulates the cytoskeleton in hematopoietic cells and mutations in its gene cause the Wiskott-Aldrich Syndrome (WAS), a primary immunodeficiency with microthrombocytopenia, eczema and a higher susceptibility to develop tumors. Autoimmune manifestations, frequently observed in WAS patients, are associated with an increased risk of mortality and still represent an unsolved aspect of the disease. B cells play a crucial role both in immune competence and self-tolerance and defects in their development and function result in immunodeficiency and/or autoimmunity. We performed a phenotypical and molecular analysis of central and peripheral B-cell compartments in WAS pediatric patients. We found a decreased proportion of immature B cells in the bone marrow correlating with an increased presence of transitional B cells in the periphery. These results could be explained by the defective migratory response of WAS B cells to SDF-1?, essential for the retention of immature B cells in the BM. In the periphery, we observed an unusual expansion of CD21(low) B-cell population and increased plasma BAFF levels that may contribute to the high susceptibility to develop autoimmune manifestations in WAS patients. WAS memory B cells were characterized by a reduced in vivo proliferation, decreased somatic hypermutation and preferential usage of IGHV4-34, an immunoglobulin gene commonly found in autoreactive B cells. In conclusion, our findings demonstrate that WASp-deficiency perturbs B-cell homeostasis thus adding a new layer of immune dysregulation concurring to the increased susceptibility to develop autoimmunity in WAS patients. PMID:24369837

  10. Tumor necrosis factor alpha is an autocrine growth factor for normal human B cells.

    PubMed Central

    Boussiotis, V A; Nadler, L M; Strominger, J L; Goldfeld, A E

    1994-01-01

    Transcription of the human tumor necrosis factor alpha (TNF-alpha) gene is one of the earliest events that occurs after stimulation of B or T cells via their antigen receptors. Antibody directed at surface immunoglobulin (anti-Ig) on B cells has previously been shown to induce a rapid burst of TNF-alpha gene transcription, which can be blocked by the immunosuppressants cyclosporin A (CsA) and FK506. Here, TNF-alpha gene transcription is shown also to be highly and rapidly induced in human B cells after stimulation via the CD40 and interleukin 4 pathways, which similarly is inhibited by CsA and a panel of CsA or FK506 analogues that block calcineurin phosphatase activity. Endogenous TNF-alpha produced after stimulation was involved in B-cell proliferation since anti-TNF-alpha monoclonal antibody inhibited both anti-Ig- and anti-CD40-induced B-cell proliferative responses. Moreover, addition of TNF-alpha during stimulation resulted in augmentation of B-cell proliferation, which was also inhibited by anti-TNF-alpha monoclonal antibody. Although lymphotoxin alpha (LT-alpha) mRNA is induced by both pathways, it is not blocked by CsA, whereas LT-beta mRNA is constitutively expressed in B cells. Thus, TNF-alpha is a necessary autocrine growth factor for human B cells stimulated via two independent CsA-sensitive pathways and plays a role similar to that of interleukin 2 in T-cell proliferation. The autocrine nature of TNF-alpha in activated B cells implies a potential role for this cytokine in infection-related polyclonal B-cell expansion and in B-cell malignancies. Images PMID:7518925

  11. Regulation of the development of the hepatic B cell compartment during Schistosoma mansoni infection.

    PubMed

    Fairfax, Keke C; Everts, Bart; Smith, Amber M; Pearce, Edward J

    2013-10-15

    During infection with the helminth parasite Schistosoma mansoni, Ab regulates hepatic inflammation, and local production of Ig in the liver appears to play a role in this process. Exploring the development of the B cell response during infection, we found that parasite-specific IgG1-secreting plasma cells appeared first in the hepatic and mesenteric lymph nodes (LNs) and then at later times in the spleen, liver, and bone marrow. The LN B cell population peaked between weeks 10 and 12 of infection, and then contracted at a time that coincided with the expansion of the hepatic IgG1(+) B cell compartment, suggesting that B cells migrate from LNs to liver. CXCL9 and -16 expression in the liver increased during the time frame of B cell recruitment. Expression of the CXCL16 receptor CXCR6 was increased on B cells within the hepatic LNs, but not the mesenteric LNs. CXCR3, the receptor for CXCL9, was broadly expressed on IgG1(+) B cells in LNs and liver during infection. Increased hepatic expression of CXCL9 and -16 failed to occur if the IL-10R was blocked in vivo, an intervention associated with decreased liver B cell infiltration and the development of severe disease. Hepatic LN IgG1(+) cells migrated toward CXCL9 and -16 in vitro and to the liver in a pertussis toxin-sensitive fashion. Our data suggest that the coordinated expression of CXCL9 and -16 in the liver and of CXCR6 and CXCR3 on responding B cells within the hepatic LNs underpins establishment of the hepatic B cell infiltrate during chronic schistosomiasis. PMID:24038090

  12. IL-35-producing B cells are critical regulators of immunity during autoimmune and infectious diseases.

    PubMed

    Shen, Ping; Roch, Toralf; Lampropoulou, Vicky; O'Connor, Richard A; Stervbo, Ulrik; Hilgenberg, Ellen; Ries, Stefanie; Dang, Van Duc; Jaimes, Yarúa; Daridon, Capucine; Li, Rui; Jouneau, Luc; Boudinot, Pierre; Wilantri, Siska; Sakwa, Imme; Miyazaki, Yusei; Leech, Melanie D; McPherson, Rhoanne C; Wirtz, Stefan; Neurath, Markus; Hoehlig, Kai; Meinl, Edgar; Grützkau, Andreas; Grün, Joachim R; Horn, Katharina; Kühl, Anja A; Dörner, Thomas; Bar-Or, Amit; Kaufmann, Stefan H E; Anderton, Stephen M; Fillatreau, Simon

    2014-03-20

    B lymphocytes have critical roles as positive and negative regulators of immunity. Their inhibitory function has been associated primarily with interleukin 10 (IL-10) because B-cell-derived IL-10 can protect against autoimmune disease and increase susceptibility to pathogens. Here we identify IL-35-producing B cells as key players in the negative regulation of immunity. Mice in which only B cells did not express IL-35 lost their ability to recover from the T-cell-mediated demyelinating autoimmune disease experimental autoimmune encephalomyelitis (EAE). In contrast, these mice displayed a markedly improved resistance to infection with the intracellular bacterial pathogen Salmonella enterica serovar Typhimurium as shown by their superior containment of the bacterial growth and their prolonged survival after primary infection, and upon secondary challenge, compared to control mice. The increased immunity found in mice lacking IL-35 production by B cells was associated with a higher activation of macrophages and inflammatory T cells, as well as an increased function of B cells as antigen-presenting cells (APCs). During Salmonella infection, IL-35- and IL-10-producing B cells corresponded to two largely distinct sets of surface-IgM(+)CD138(hi)TACI(+)CXCR4(+)CD1d(int)Tim1(int) plasma cells expressing the transcription factor Blimp1 (also known as Prdm1). During EAE, CD138(+) plasma cells were also the main source of B-cell-derived IL-35 and IL-10. Collectively, our data show the importance of IL-35-producing B cells in regulation of immunity and highlight IL-35 production by B cells as a potential therapeutic target for autoimmune and infectious diseases. This study reveals the central role of activated B cells, particularly plasma cells, and their production of cytokines in the regulation of immune responses in health and disease. PMID:24572363

  13. Identification of protective linear B-cell epitopes on the subolesin/akirin orthologues of Ornithodoros spp. soft ticks.

    PubMed

    Manzano-Román, Raúl; Díaz-Martín, Verónica; Oleaga, Ana; Pérez-Sánchez, Ricardo

    2015-02-18

    Subolesin/akirin is a protective antigen that is highly conserved across hematophagous vector species and is therefore potentially useful for the development of a universal vaccine for vector control, including soft ticks. Recent results have shown that in Ornithodoros erraticus and O. moubata soft ticks, RNAi-mediated subolesin gene knockdown inhibits tick oviposition and fertility by more than 90%; however, vaccination with recombinant subolesins resulted in remarkably low protective efficacies (5-24.5% reduction in oviposition). Here we report that vaccination with subolesin recombinants induces non-protective antibodies mainly directed against immunodominant linear B-cell epitopes located on highly structured regions of the subolesin protein, probably unrelated to its biological activity, while leaving the unstructured/disordered regions unrecognized. Accordingly, for a new vaccine trial we designed four synthetic peptides (OE1, OE2, OM1 and OM2) from the unrecognized/disordered regions of the Ornithodoros subolesin sequences and coupled them to keyhole limpet haemocyanin (KLH). These KLH-peptide conjugates induced the synthesis of antibodies that recognized linear B-cell epitopes located on the unstructured loops of the subolesin protein and provided up to 70.1% and 83.1% vaccine efficacies in O. erraticus and O. moubata, respectively. These results show that the protective effect of subolesin-based vaccines is highly dependent on the particular epitope recognized by antibodies on the subolesin sequence and strongly suggest that the biological activity of subolesin is exerted through its unstructured regions. The results reported here contribute to our understanding of the mechanism of protection of subolesin-based vaccines and reveal novel protective peptides that could be included among the array of candidate antigens useful for developing anti-vector vaccines based on subolesin/akirin. PMID:25597941

  14. Multiple genetic alterations in primary cutaneous large B-cell lymphoma, leg type support a common lymphomagenesis with activated B-cell-like diffuse large B-cell lymphoma.

    PubMed

    Pham-Ledard, Anne; Prochazkova-Carlotti, Martina; Andrique, Laetitia; Cappellen, David; Vergier, Béatrice; Martinez, Fabian; Grange, Florent; Petrella, Tony; Beylot-Barry, Marie; Merlio, Jean-Philippe

    2014-03-01

    Primary cutaneous large B-cell lymphoma, leg type has been individualized from nodal diffuse large B-cell lymphoma. The objective of this study was to screen primary cutaneous large B-cell lymphoma, leg type for genetic alterations recently described in nodal diffuse large B-cell lymphoma. Skin biopsies from 23 patients were analyzed for IRF4, BCL2, BCL6, and MYC expression. FISH testing was performed for BCL2, BCL6, MYC with separation probes and for CDKN2A and PRDM1/BLIMP1 deletion. Multiple sequential FISH analyses with up to six probes were performed to define samples with multiple cytogenetic alterations. MYD88 mutations were studied by Sanger sequencing. All cases but one displayed at least one genetic alteration (96%). Nine patients exhibited a single genetic mutation and 12 combined several alterations (52%). We observed a split for BCL2, BCL6, or MYC in 1/23, 6/23, and 3/23 of cases, respectively. No double-hit lymphoma was observed. CDKN2A deletion was detected by FISH in only 5/23 cases. BLIMP1 and/or 6q deletion was observed at a higher rate in 10/20 of cases. No correlation between rearrangement and immunohistochemical expression was found for BCL2 or MYC. FISH tracking of sequential hybridizations showed that several alterations were carried by the same nuclei. The p.L265P MYD88 mutation was found in 11/18 (61%) of cases. Contrary to most cutaneous lymphomas that rarely harbor primary genetic alteration of their nodal histological equivalent, primary cutaneous large B-cell lymphoma, leg type seems to be a 'cutaneous counterpart' of activated B-cell-like diffuse large B-cell lymphoma with a similar cytogenetic profile and a high rate of MYD88 oncogenic L265P mutation. This also suggests a common lymphomagenesis with NF-?B activation, strong IRF4 expression and terminal B-cell differentiation blockage. Our data support the use of therapies targeting NF-?B, as most patients displayed disease progression and resistance to conventional therapies. PMID:24030746

  15. The Epstein-Barr Virus BamHI C Promoter Is Not Essential for B Cell Immortalization In Vitro, but It Greatly Enhances B Cell Growth Transformation

    PubMed Central

    Nagra, Jasdeep; Rowe, Martin; Bell, Andrew I.; Rickinson, Alan B.

    2014-01-01

    ABSTRACT Epstein-Barr virus (EBV) infection of B cells leads to the sequential activation of two viral promoters, Wp and Cp, resulting in the expression of six EBV nuclear antigens (EBNAs) and the viral Bcl2 homologue BHRF1. The viral transactivator EBNA2 is required for this switch from Wp to Cp usage during the initial stages of infection. EBNA2-dependent Cp transcription is mediated by the EBNA2 response element (E2RE), a region that contains at least two binding sites for cellular factors; one of these sites, CBF1, interacts with RBP-JK, which then recruits EBNA2 to the transcription initiation complex. Here we demonstrate that the B cell-specific transcription factor BSAP/Pax5 binds to a second site, CBF2, in the E2RE. Deletion of the E2RE in the context of a recombinant virus greatly diminished levels of Cp-initiated transcripts during the initial stages of infection but did not affect the levels of Wp-initiated transcripts or EBNA mRNAs. Consistent with this finding, viruses deleted for the E2RE were not markedly impaired in their ability to induce B cell transformation in vitro. In contrast, a larger deletion of the entire Cp region did reduce EBNA mRNA levels early after infection and subsequently almost completely ablated lymphoblastoid cell line (LCL) outgrowth. Notably, however, rare LCLs could be established following infection with Cp-deleted viruses, and these were indistinguishable from wild-type-derived LCLs in terms of steady-state EBV gene transcription. These data indicate that, unlike Wp, Cp is dispensable for the virus' growth-transforming activity. IMPORTANCE Epstein-Barr virus (EBV), a B lymphotropic herpesvirus etiologically linked to several B cell malignancies, efficiently induces B cell proliferation leading to the outgrowth of lymphoblastoid cell lines (LCLs). The initial stages of this growth-transforming infection are characterized by the sequential activation of two viral promoters, Wp and Cp, both of which appear to be preferentially active in target B cells. In this work, we have investigated the importance of Cp activity in initiating B cell proliferation and maintaining LCL growth. Using recombinant viruses, we demonstrate that while Cp is not essential for LCL outgrowth in vitro, it enhances transformation efficiency by >100-fold. We also show that Cp, like Wp, interacts with the B cell-specific activator protein BSAP/Pax5. We suggest that EBV has evolved this two-promoter system to ensure efficient colonization of the host B cell system in vivo. PMID:25540367

  16. Antigen-specific lymphoproliferative responses to tetanus toxoid: a means for the evaluation of Marek's disease virus-induced immunosuppression in chickens

    Microsoft Academic Search

    S. K. Reddy; M. Suresh; K. Karaca; J. M. Sharma; J. McMillen; R. D. Schwartz

    1996-01-01

    Antigen-specific lymphoproliferative responses were examined in chickens following immunization with tetanus toxoid (Ttx). The immune competence of chickens was assessed by mitogen assay utilizing phytohemagglutinin (PHA)-stimulation and Ttx-specific antigen proliferation assay (Ttx-APA). Immune spleen cells but not peripheral blood leucocytes demonstrated specific proliferation following stimulation in vitro in a Ttx-APA. In this study, we examined firstly the effects of Marek's

  17. Missense mutations in SH2D1A identified in patients with X-linked lymphoproliferative disease differentially affect the expression and function of SAP

    Microsoft Academic Search

    Nathan J. Hare; Cindy S. Ma; Frank Alvaro; Kim E. Nichols; Stuart G. Tangye

    2006-01-01

    X-linked lymphoproliferative disease (XLP) is an immunodeficiency resulting from mutations in SH2D1A, which encodes signalling lymphocytic activation molecule (SLAM)-associated protein (SAP). In addition to SLAM, SAP associates with several other cell-surface receptors including 2B4 (CD244), Ly9 (CD229), CD84 and NTB-A. SAP contains a single src-homology-2 domain and acts as an intracellular adaptor protein by recruiting the protein tyrosine kinase FynT

  18. Single-dose pegfilgrastim is comparable to daily filgrastim in mobilizing peripheral blood stem cells: a case-matched study in patients with lymphoproliferative malignancies

    Microsoft Academic Search

    Mervi Putkonen; Auvo Rauhala; Tarja-Terttu Pelliniemi; Kari Remes

    2009-01-01

    Pegfilgrastim (PEGFIL) has been found to be comparable to daily filgrastim (FIL) in managing chemotherapy-induced neutropenia.\\u000a In the present study, we evaluated the ability of PEGFIL to mobilize stem cells in 38 consecutive patients with lymphoproliferative\\u000a diseases (multiple myeloma, n?=?18; lymphomas, n?=?15; chronic lymphocytic leukemia, n?=?5). Patients were mobilized using PEGFIL (6–18 mg as a single dose) during 2005–2006; 32 then

  19. Comparative Analysis of Human Cytomegalovirus-Specific CD4+ T-Cell Frequency and Lymphoproliferative Response in Human Immunodeficiency Virus-Positive Patients

    Microsoft Academic Search

    GIAMPIERO PICCININI; GIUDITTA COMOLLI; EMILIA GENINI; DANIELE LILLERI; ROBERTO GULMINETTI; RITA MACCARIO; MARIA GRAZIA REVELLO; GIUSEPPE GERNA

    2001-01-01

    Evaluation of human cytomegalovirus (HCMV)-specific T-helper immunity could contribute in optimizing anti-HCMV therapy in human immunodeficiency virus (HIV)-infected patients. Testin the lymphoproliferative response (LPR) is the standard technique used to evaluate T-helper response, but its use in the routine diagnostic laboratory setting can be problematic. The most promising new alternative technique is the determination of HCMV-specific CD4 T-cell frequency by

  20. Activation and Adoptive Transfer of Epstein-Barr Virus-Specific Cytotoxic T Cells in Solid Organ Transplant Patients with Posttransplant Lymphoproliferative Disease

    Microsoft Academic Search

    Rajiv Khanna; Scott Bell; Martina Sherriti; Andrew Galbraith; Scott R. Burrows; Lee Rafter; Belinda Clarke; Richard Slaughter; Michael C. Falk; Jo Douglass; Trevor Williams; Suzanne L. Ellioti; Denis J. Moss

    1999-01-01

    The treatment of Epstein-Barr virus (EBV)-associated lymphoproliferative disease (PTLD) in EBV seronegative solid organ transplant recipients who acquire their EBV infection after engraftment poses a considerable challenge because of underlying immunosuppression that inhibits the virus-specific cytotoxic T cell (CTL) response in vivo. We have developed a protocol for activating autologous EBV-specific CTL lines from these patients and show their potential

  1. Fine mapping of canine parvovirus B cell epitopes.

    PubMed

    López de Turiso, J A; Cortés, E; Ranz, A; García, J; Sanz, A; Vela, C; Casal, J I

    1991-10-01

    In this report we describe the topological mapping of neutralizing domains of canine parvovirus (CPV). We obtained 11 CPV-specific monoclonal antibodies (MAbs), six of which are neutralizing. The reactivities were as determined by ELISA and Western blot (immunoblot) analysis. VP2, the most abundant protein of the CPV capsid, seemed to contain all the neutralization sites. Also, an almost full-length genomic clone of CPV was constructed in the bacterial plasmid pUC18 to enable expression of CPV proteins. All the neutralizing MAbs recognized recombinant VP2 when it was expressed as a free protein in Escherichia coli but not when expressed as a fusion protein with glutathione-S-transferase. When two large fragments containing about 85% and 67% of the C terminus of VP2 were expressed, no neutralization sites were detected. When fusion proteins containing the N terminus were expressed, two linear determinants were mapped, one between residues 1 to 10 of VP2, and the other between amino acids 11 and 23. The peptide 11 GQPAVRNERATGS 23, recognized by MAb 3C9, was synthesized chemically and checked for immunogenicity, not being able to induce neutralizing activity. Although the antibody response in rabbits to all the fusion proteins was uniformly high, the anti-CPV response was very variable. Protein from pCPVEx11, which contains a T cell epitope (peptide PKIFINLAKKKKAG) present in the VP1-specific region as well as the B cell epitopes, seemed to be the most effective in inducing virus neutralization. PMID:1919526

  2. Targeting malignant B cells with an immunotoxin against ROR1.

    PubMed

    Baskar, Sivasubramanian; Wiestner, Adrian; Wilson, Wyndham H; Pastan, Ira; Rader, Christoph

    2012-01-01

    The selective cell surface expression of receptor tyrosine kinase-like orphan receptor 1 (ROR1) in chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL) has made ROR1 a novel and promising target for therapeutic monoclonal antibodies (mAbs). Four mouse mAbs generated by hybridoma technology exhibited specific binding to human ROR1. Epitope mapping studies showed that two mAbs (2A2 and 2D11) recognized N-terminal epitopes in the extracellular region of ROR1 and the other two (1A1 and 1A7) recognized C-terminal epitopes. A ROR1- immunotoxin (BT-1) consisting of truncated Pseudomonas exotoxin A (PE38) and the VH and VL fragments of 2A2-IgG was made recombinantly. Both 2A2-IgG and BT-1 showed dose-dependent and selective binding to primary CLL and MCL cells and MCL cell lines. Kinetic analyses revealed 0.12-nM (2A2-IgG) to 65-nM (BT-1) avidity/affinity to hROR1, depicting bivalent and monovalent interactions, respectively. After binding to cell surface ROR1, 2A2-IgG and BT-1 were partially internalized by primary CLL cells and MCL cell lines, and BT-1 induced profound apoptosis of ROR1-expressing MCL cell lines in vitro (EC 50 = 16 pM-16 nM), but did not affect ROR1-negative cell lines. Our data suggest that ROR1-immunotoxins such as BT-1 could serve as targeted therapeutic agents for ROR1-expressing B cell malignancies and other cancers. PMID:22531447

  3. Targeting malignant B cells with an immunotoxin against ROR1

    PubMed Central

    Baskar, Sivasubramanian; Wiestner, Adrian; Wilson, Wyndham H.; Pastan, Ira; Rader, Christoph

    2012-01-01

    The selective cell surface expression of receptor tyrosine kinase-like orphan receptor 1 (ROR1) in chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL) has made ROR1 a novel and promising target for therapeutic monoclonal antibodies (mAbs). Four mouse mAbs generated by hybridoma technology exhibited specific binding to human ROR1. Epitope mapping studies showed that two mAbs (2A2 and 2D11) recognized N-terminal epitopes in the extracellular region of ROR1 and the other two (1A1 and 1A7) recognized C-terminal epitopes. A ROR1- immunotoxin (BT-1) consisting of truncated Pseudomonas exotoxin A (PE38) and the VH and VL fragments of 2A2-IgG was made recombinantly. Both 2A2-IgG and BT-1 showed dose-dependent and selective binding to primary CLL and MCL cells and MCL cell lines. Kinetic analyses revealed 0.12-nM (2A2-IgG) to 65-nM (BT-1) avidity/affinity to hROR1, depicting bivalent and monovalent interactions, respectively. After binding to cell surface ROR1, 2A2-IgG and BT-1 were partially internalized by primary CLL cells and MCL cell lines, and BT-1 induced profound apoptosis of ROR1-expressing MCL cell lines in vitro (EC50 = 16 pM–16 nM), but did not affect ROR1-negative cell lines. Our data suggest that ROR1-immunotoxins such as BT-1 could serve as targeted therapeutic agents for ROR1-expressing B cell malignancies and other cancers. PMID:22531447

  4. Dynamics of macrophage trogocytosis of rituximab-coated B cells.

    PubMed

    Pham, Theodore; Mero, Patricia; Booth, James W

    2011-01-01

    Macrophages can remove antigen from the surface of antibody-coated cells by a process termed trogocytosis. Using live cell microscopy and flow cytometry, we investigated the dynamics of trogocytosis by RAW264.7 macrophages of Ramos B cells opsonized with the anti-CD20 monoclonal antibody rituximab. Spontaneous and reversible formation of uropods was observed on Ramos cells, and these showed a strong enrichment in rituximab binding. RAW-Ramos conjugate interfaces were highly enriched in rituximab, and transfer of rituximab to the RAW cells in submicron-sized puncta occurred shortly after cell contact. Membrane from the target cells was concomitantly transferred along with rituximab to a variable extent. We established a flow cytometry-based approach to follow the kinetics of transfer and internalization of rituximab. Disruption of actin polymerization nearly eliminated transfer, while blocking phosphatidylinositol 3-kinase activity only resulted in a delay in its acquisition. Inhibition of Src family kinase activity both slowed acquisition and reduced the extent of trogocytosis. The effects of inhibiting these kinases are likely due to their role in efficient formation of cell-cell conjugates. Selective pre-treatment of Ramos cells with phenylarsine oxide blocked uropod formation, reduced enrichment of rituximab at cell-cell interfaces, and reduced the efficiency of trogocytic transfer of rituximab. Our findings highlight that dynamic changes in target cell shape and surface distribution of antigen may significantly influence the progression and extent of trogocytosis. Understanding the mechanistic determinants of macrophage trogocytosis will be important for optimal design of antibody therapies. PMID:21264210

  5. Characterization of the human B cell stimulatory factor 1 receptor

    PubMed Central

    1987-01-01

    125I-labeled recombinant human B cell stimulatory factor 1 (BSF-1) was used to characterize receptors specific for this lymphokine on in vitro cell lines representing human B, T, and hematopoietic lineages, as well as on adherent cell lines of epithelial and endothelial origin, and on primary human gingival fibroblasts. BSF-1 binding was extremely rapid and saturable at both 4 and 37 degrees C, with a slow dissociation rate. On all human cell types examined, BSF-1 bound to a single class of high-affinity receptor (less than 3,000 receptors per cell) with a Ka of 0.5-1.0 X 10(10)/M. Human BSF-1 also bound to cell lines of simian but not murine origin. Comparison of kinetic characteristics obtained with a yeast-derived hyperglycosylated form of BSF-1 (Mr 60,000) and N-glycanase-treated, sugar-free BSF-1 (Mr 15,000) showed no significant differences. Among a panel of lymphokines and growth hormones, only unlabeled human BSF-1 was able to compete for the binding of 125I-labeled human BSF-1. Affinity crosslinking experiments resulted in the identification on both Raji cells and on primary human gingival fibroblasts of a receptor subunit with an average Mr of 139,000. These studies show that the BSF-1 receptor on human cells has an extremely broad cellular distribution, while further supporting the notion that the ability of BSF-1 to mediate a spectrum of biological activities cannot be accounted for by overt differences in the receptor for this lymphokine on different cell lineages. PMID:3496417

  6. MYC alterations in diffuse large B-cell lymphomas.

    PubMed

    Karube, Kennosuke; Campo, Elias

    2015-04-01

    MYC is a transcription factor associated with numerous physiological functions, including apoptosis, and strong oncogenic potential. MYC expression is tightly regulated in normal lymphoid cells with high levels in the initial steps of the secondary lymphoid follicle formation and in a subset of centrocytes of the germinal center light zone. BCL6 and BLIMP1 repress MYC expression in normal germinal center B and plasma cells, respectively. Paradoxically, most lymphomas with MYC genetic alterations originate from cells that usually do not express MYC, suggesting that these tumors need to develop additional oncogenic events to overcome the MYC regulatory mechanisms and also its proapoptotic function. MYC rearrangements, and to a lesser extent gene amplifications, have been detected in approximately 5% to 14% of diffuse large B-cell lymphoma (DLBCL) and these alterations are frequently associated with BCL2 or BCL6 rearrangements. The concurrent presence of these alterations confers a more aggressive behavior to the tumors with poor outcome of the patients. BCL2 and MYC protein may also be coexpressed in DLBCL independently of gene alterations and this double expression also confers poor prognosis, although not as dismal as that of double genetic hits. Additional factors may modulate the biological effect of the double hit lesions because tumors in which MYC is translocated to non-IGH partner or MYC and BCL2 protein that are expressed at lower levels may have a less aggressive behavior. Further studies are needed to define the clinical implications of MYC aberrations in DLBCL and determine the most appropriate diagnostic strategy to identify these tumors. PMID:25805589

  7. Cbl-b Negatively Regulates B Cell Antigen Receptor Signaling in Mature B Cells through Ubiquitination of the Tyrosine Kinase Syk

    PubMed Central

    Sohn, Hae Won; Gu, Hua; Pierce, Susan K.

    2003-01-01

    Members of the Cbl family of molecular adaptors play key roles in regulating tyrosine kinase-dependent signaling in a variety of cellular systems. Here we provide evidence that in B cells Cbl-b functions as a negative regulator of B cell antigen receptor (BCR) signaling during the normal course of a response. In B cells from Cbl-b–deficient mice cross-linking the BCRs resulted in sustained phosphorylation of Ig?, Syk, and phospholipase C (PLC)-?2, leading to prolonged Ca2+ mobilization, and increases in extracellular signal–regulated kinase (ERK) and c-Jun NH2-terminal protein kinase (JNK) phosphorylation and surface expression of the activation marker, CD69. Image analysis following BCR cross-linking showed sustained polarization of the BCRs into large signaling-active caps associated with phosphorylated Syk in Cbl-b–deficient B cells in contrast to the BCRs in Cbl-b–expressing B cells that rapidly proceeded to form small, condensed, signaling inactive caps. Significantly, prolonged phosphorylation of Syk correlated with reduced ubiquitination of Syk indicating that Cbl-b negatively regulates BCR signaling by targeting Syk for ubiquitination. PMID:12771181

  8. Transient B-Cell Depletion Combined With Apoptotic Donor Splenocytes Induces Xeno-Specific T- and B-Cell Tolerance to Islet Xenografts

    PubMed Central

    Wang, Shusen; Tasch, James; Kheradmand, Taba; Ulaszek, Jodie; Ely, Sora; Zhang, Xiaomin; Hering, Bernhard J.; Miller, Stephen D.; Luo, Xunrong

    2013-01-01

    Peritransplant infusion of apoptotic donor splenocytes cross-linked with ethylene carbodiimide (ECDI-SPs) has been demonstrated to effectively induce allogeneic donor-specific tolerance. The objective of the current study is to determine the effectiveness and additional requirements for tolerance induction for xenogeneic islet transplantation using donor ECDI-SPs. In a rat-to-mouse xenogeneic islet transplant model, we show that rat ECDI-SPs alone significantly prolonged islet xenograft survival but failed to induce tolerance. In contrast to allogeneic donor ECDI-SPs, xenogeneic donor ECDI-SPs induced production of xenodonor-specific antibodies partially responsible for the eventual islet xenograft rejection. Consequently, depletion of B cells prior to infusions of rat ECDI-SPs effectively prevented such antibody production and led to the indefinite survival of rat islet xenografts. In addition to controlling antibody responses, transient B-cell depletion combined with ECDI-SPs synergistically suppressed xenodonor-specific T-cell priming as well as memory T-cell generation. Reciprocally, after initial depletion, the recovered B cells in long-term tolerized mice exhibited xenodonor-specific hyporesponsiveness. We conclude that transient B-cell depletion combined with donor ECDI-SPs is a robust strategy for induction of xenodonor-specific T- and B-cell tolerance. This combinatorial therapy may be a promising strategy for tolerance induction for clinical xenogeneic islet transplantation. PMID:23852699

  9. Expression of ? and K Genes Can Occur in all B Cells and is Initiated Around the Same Pre-B-Cell Developmental Stage

    PubMed Central

    Doglio, Lynn; Kim, Joo Yeun; Bozek, Grazyna

    1994-01-01

    Transgenic mice that carry a ?2 transgene under the control of the V?2 promoter and the E?2-4 enhancer (?2E? mice) are described. A high proportion of B cells in the spleen and the bone marrow express the ? transgene on the cell membrane. ?2 protein is synthesized by all ?2E?-derived spleen B-cell hybridomas that have retained the transgene, suggesting that all B cells have the ability to express ? genes. Feedback inhibition of endogenous K-gene rearrangement is significant, but not complete. The results are similar to those with transgenic mice expressing the same ?2 transgene under the control of the heavy-chain enhancer (?2EH mice). Although the ?2EH transgene is expressed before the ?2E? transgene, feedback inhibition seems to occur at about the same stage of B-cell development, regardless of the timing of expression of the ? transgenes. Apparently, feedback is not necessarily coincident with the assembly of a heavy-chain/light-chain complex in pre-B cells. Expression of ? in the normal fetal liver coincides with the expression of K; thus, it appears that ?-gene transcription is not delayed. The differential rearrangement of K and ? genes is discussed in the light of these findings. PMID:7620323

  10. Germinal center B cells govern their own fate via antibody feedback

    PubMed Central

    Zhang, Yang; Meyer-Hermann, Michael; George, Laura A.; Figge, Marc Thilo; Khan, Mahmood; Goodall, Margaret; Young, Stephen P.; Reynolds, Adam; Falciani, Francesco; Waisman, Ari; Notley, Clare A.; Ehrenstein, Michael R.; Kosco-Vilbois, Marie

    2013-01-01

    Affinity maturation of B cells in germinal centers (GCs) is a process of evolution, involving random mutation of immunoglobulin genes followed by natural selection by T cells. Only B cells that have acquired antigen are able to interact with T cells. Antigen acquisition is dependent on the interaction of B cells with immune complexes inside GCs. It is not clear how efficient selection of B cells is maintained while their affinity matures. Here we show that the B cells’ own secreted products, antibodies, regulate GC selection by limiting antigen access. By manipulating the GC response with monoclonal antibodies of defined affinities, we show that antibodies in GCs are in affinity-dependent equilibrium with antibodies produced outside and that restriction of antigen access influences B cell selection, seen as variations in apoptosis, plasma cell output, T cell interaction, and antibody affinity. Feedback through antibodies produced by GC-derived plasma cells can explain how GCs maintain an adequate directional selection pressure over a large range of affinities throughout the course of an immune response, accelerating the emergence of B cells of highest affinities. Furthermore, this mechanism may explain how spatially separated GCs communicate and how the GC reaction terminates. PMID:23420879

  11. Pro-B cells sense productive immunoglobulin heavy chain rearrangement irrespective of polypeptide production

    PubMed Central

    Lutz, Johannes; Heideman, Marinus R.; Roth, Edith; van den Berk, Paul; Müller, Werner; Raman, Chander; Wabl, Matthias; Jacobs, Heinz; Jäck, Hans-Martin

    2011-01-01

    B-lymphocyte development is dictated by the protein products of functionally rearranged Ig heavy (H) and light (L) chain genes. Ig rearrangement begins in pro-B cells at the IgH locus. If pro-B cells generate a productive allele, they assemble a pre-B cell receptor complex, which signals their differentiation into pre-B cells and their clonal expansion. Pre-B cell receptor signals are also thought to contribute to allelic exclusion by preventing further IgH rearrangements. Here we show in two independent mouse models that the accumulation of a stabilized ?H mRNA that does not encode ?H chain protein specifically impairs pro-B cell differentiation and reduces the frequency of rearranged IgH genes in a dose-dependent manner. Because noncoding IgH mRNA is usually rapidly degraded by the nonsense-mediated mRNA decay machinery, we propose that the difference in mRNA stability allows pro-B cells to distinguish between productive and nonproductive Ig gene rearrangements and that ?H mRNA may thus contribute to efficient H chain allelic exclusion. PMID:21670279

  12. B Cells in Rheumatoid Arthritis: From Pathogenic Players to Disease Biomarkers

    PubMed Central

    Bugatti, Serena; Vitolo, Barbara; Caporali, Roberto; Montecucco, Carlomaurizio; Manzo, Antonio

    2014-01-01

    The therapeutic benefit of depleting B cells in rheumatoid arthritis (RA) has refocused attention on B cells with increasing awareness on their role in autoimmunity and their function beyond autoantibody production. The rapid increase in our comprehension of B-cell pathobiology is progressively opening novel perspectives in the area of B cell-targeted therapies with the expectation to define more specific approaches able to preserve the homeostasis of the humoral response while disrupting the pathogenic components. In parallel, B-cell activity in RA is starting to be explored in its clinical value, in search of novel biomarkers embedded in the pathogenic process that could help classifying the disease and predicting its heterogeneous outcome beyond inflammation dynamics. In this review, we summarize current knowledge on the multiple roles that B cells play in several aspects of RA. We also analyze their distribution and potential function in different anatomic compartments with specific reference to the main sites in which the disease may be sustained and exert its detrimental effects: the systemic circulation, synovium, bone marrow, and draining lymph nodes. We also highlight novel data encouraging further research in the field of biomarkers related to B cells and their regulatory factors. PMID:24877127

  13. Apoptotic marginal zone deletion of anti-Sm/ribonucleoprotein B cells.

    PubMed

    Kishi, Yusuke; Higuchi, Tetsuya; Phoon, Shirly; Sakamaki, Yasuo; Kamiya, Koki; Riemekasten, Gabriela; Akiyoshi, Kazunari; Weigert, Martin G; Tsubata, Takeshi

    2012-05-15

    CD40L is excessively produced in both human and murine lupus and plays a role in lupus pathogenesis. To address how excess CD40L induces autoantibody production, we crossed CD40L-transgenic mice with the anti-DNA H-chain transgenic mouse lines 3H9 and 56R, well-characterized models for studying B-cell tolerance to nuclear antigens. Excess CD40L did not induce autoantibody production in 3H9 mice in which anergy maintains self-tolerance, nor did it perturb central tolerance, including deletion and receptor editing, of anti-DNA B cells in 56R mice. In contrast, CD40L/56R mice restored a large number of marginal zone (MZ) B cells reactive to Sm/ribonucleoprotein (RNP) and produced autoantibody, whereas these B cells were deleted by apoptosis in MZ of 56R mice. Thus, excess CD40L efficiently blocked tolerance of Sm/RNP-reactive MZ B cells, leading to production of anti-Sm/RNP antibody implicated in the pathogenesis of lupus. These results suggest that self-reactive B cells such as anti-Sm/RNP B cells, which somehow escape tolerance in the bone marrow and migrate to MZ, are tolerized by apoptotic deletion in MZ and that a break in this tolerance may play a role in the pathogenesis of lupus. PMID:22547827

  14. Rac-mediated Stimulation of Phospholipase C?2 Amplifies B Cell Receptor-induced Calcium Signaling.

    PubMed

    Walliser, Claudia; Tron, Kyrylo; Clauss, Karen; Gutman, Orit; Kobitski, Andrei Yu; Retlich, Michael; Schade, Anja; Röcker, Carlheinz; Henis, Yoav I; Nienhaus, G Ulrich; Gierschik, Peter

    2015-07-10

    The Rho GTPase Rac is crucially involved in controlling multiple B cell functions, including those regulated by the B cell receptor (BCR) through increased cytosolic Ca(2+). The underlying molecular mechanisms and their relevance to the functions of intact B cells have thus far remained unknown. We have previously shown that the activity of phospholipase C?2 (PLC?2), a key constituent of the BCR signalosome, is stimulated by activated Rac through direct protein-protein interaction. Here, we use a Rac-resistant mutant of PLC?2 to functionally reconstitute cultured PLC?2-deficient DT40 B cells and to examine the effects of the Rac-PLC?2 interaction on BCR-mediated changes of intracellular Ca(2+) and regulation of Ca(2+)-regulated and nuclear-factor-of-activated-T-cell-regulated gene transcription at the level of single, intact B cells. The results show that the functional Rac-PLC?2 interaction causes marked increases in the following: (i) sensitivity of B cells to BCR ligation; (ii) BCR-mediated Ca(2+) release from intracellular stores; (iii) Ca(2+) entry from the extracellular compartment; and (iv) nuclear translocation of the Ca(2+)-regulated nuclear factor of activated T cells. Hence, Rac-mediated stimulation of PLC?2 activity serves to amplify B cell receptor-induced Ca(2+) signaling. PMID:25903139

  15. Targeting Bruton's tyrosine kinase with ibrutinib in B-cell malignancies.

    PubMed

    Wang, Y; Zhang, L L; Champlin, R E; Wang, M L

    2015-05-01

    The B-cell receptor signaling pathway, which is critical to the development and maturation of normal B-cells, is emerging as an attractive therapeutic target in B-cell malignancies. Ibrutinib is a potent irreversible inhibitor of Bruton's tyrosine kinase (Btk), a key kinase important for signal transduction in the B-cell receptor (BCR) pathway. In preclinical studies, ibrutinib potently bound to Btk, inhibited BCR signaling, and decreased tumor cell proliferation and survival in many B-cell malignancy models. Excellent safety and efficacy data in clinical trials have led to US Food and Drug Administration (FDA) approval of ibrutinib for previously treated mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL), as well as CLL with 17p deletion. Ongoing clinical studies have also demonstrated great potency of ibrutinib in treating other types of non-Hodgkin's lymphoma (NHL), including diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), and Waldenström's macroglobulinemia (WM). Combination of ibrutinib with chemoimmunotherapy and other promising novel agents in B-cell malignancy therapy has also been under clinical investigation. PMID:25669675

  16. CD5+ B cells from individuals with systemic lupus erythematosus express granzyme B.

    PubMed

    Hagn, Magdalena; Ebel, Verena; Sontheimer, Kai; Schwesinger, Elisabeth; Lunov, Oleg; Beyer, Thamara; Fabricius, Dorit; Barth, Thomas F E; Viardot, Andreas; Stilgenbauer, Stephan; Hepp, Julia; Scharffetter-Kochanek, Karin; Simmet, Thomas; Jahrsdörfer, Bernd

    2010-07-01

    Recently, we reported that IL-21 induces granzyme B (GzmB) and GzmB-dependent apoptosis in malignant CD5(+) B cells from patients with chronic lymphocytic leukemia. Several autoimmune diseases (AD) are associated with enhanced frequencies of CD5(+) B cells. Since AD are also associated with elevated IL-21 and GzmB levels, we postulated a link between CD5(+) B cells, IL-21 and GzmB. Here, we demonstrate that IL-21 and GzmB serum levels are highly correlated in subjects with systemic lupus erythematosus (SLE) and that freshly isolated CD5(+) SLE B cells constitutively express GzmB. IL-21 directly induced GzmB expression and secretion by CD5(+) B cells from several AD and from cord blood in vitro, and the simultaneous presence of BCR stimulation strongly enhanced this process. Furthermore, IL-21 suppressed both viability and expansion of CD5(+) B cells from SLE individuals. In summary, our study may explain the elevated levels of IL-21 and GzmB in SLE and other AD. Moreover, our data suggest that IL-21 may have disease-modifying characteristics by inducing GzmB in CD5(+) B cells and by suppressing their expansion. Our results provide the rationale for further evaluation of the therapeutic potential of IL-21 in certain AD such as SLE. PMID:20394077

  17. Transduction of CpG DNA-stimulated primary human B cells with bicistronic lentivectors.

    PubMed

    Kvell, Krisztian; Nguyen, Tuan H; Salmon, Patrick; Glauser, Frédéric; Werner-Favre, Christiane; Barnet, Marc; Schneider, Pascal; Trono, Didier; Zubler, Rudolf H

    2005-11-01

    Recently, using HIV-1-derived lentivectors, we obtained efficient transduction of primary human B lymphocytes cocultured with murine EL-4 B5 thymoma cells, but not of isolated B cells activated by CD40 ligation. Coculture with a cell line is problematic for gene therapy applications or study of gene functions. We have now found that transduction of B cells in a system using CpG DNA was comparable to that in the EL-4 B5 system. A monocistronic vector with a CMV promoter gave 32 +/- 4.7% green fluorescent protein (GFP)+ cells. A bicistronic vector, encoding IL-4 and GFP in the first and second cistrons, respectively, gave 14.2 +/- 2.1% GFP+ cells and IL-4 secretion of 1.3 +/- 0.2 ng/10(5) B cells/24 h. This was similar to results obtained in CD34+ cells using the elongation factor-1alpha promoter. Activated memory and naive B cells were transducible. After transduction with a bicistronic vector encoding a viral FLIP molecule, vFLIP was detectable by FACS or Western blot in GFP+, but not in GFP-, B cells, and 57% of sorted GFP+ B cells were protected against Fas ligand-induced cell death. This system should be useful for gene function research in primary B cells and development of gene therapies. PMID:16005685

  18. CD22 ligand-binding and signaling domains reciprocally regulate B-cell Ca2+ signaling

    PubMed Central

    Müller, Jennifer; Obermeier, Ingrid; Wöhner, Miriam; Brandl, Carolin; Mrotzek, Sarah; Angermüller, Sieglinde; Maity, Palash C.; Reth, Michael; Nitschke, Lars

    2013-01-01

    A high proportion of human B cells carry B-cell receptors (BCRs) that are autoreactive. Inhibitory receptors such as CD22 can downmodulate autoreactive BCR responses. With its extracellular domain, CD22 binds to sialic acids in ?2,6 linkages in cis, on the surface of the same B cell or in trans, on other cells. Sialic acids are self ligands, as they are abundant in vertebrates, but are usually not expressed by pathogens. We show that cis-ligand binding of CD22 is crucial for the regulation of B-cell Ca2+ signaling by controlling the CD22 association to the BCR. Mice with a mutated CD22 ligand-binding domain of CD22 showed strongly reduced Ca2+ signaling. In contrast, mice with mutated CD22 immunoreceptor tyrosine-based inhibition motifs have increased B-cell Ca2+ responses, increased B-cell turnover, and impaired survival of the B cells. Thus, the CD22 ligand-binding domain has a crucial function in regulating BCR signaling, which is relevant for controlling autoimmunity. PMID:23836650

  19. Thymic B Cells Are Licensed to Present Self Antigens for Central T Cell Tolerance Induction.

    PubMed

    Yamano, Tomoyoshi; Nedjic, Jelena; Hinterberger, Maria; Steinert, Madlen; Koser, Sandra; Pinto, Sheena; Gerdes, Norbert; Lutgens, Esther; Ishimaru, Naozumi; Busslinger, Meinrad; Brors, Benedikt; Kyewski, Bruno; Klein, Ludger

    2015-06-16

    Thymic antigen-presenting cells (APCs) such as dendritic cells and medullary thymic epithelial cells (mTECs) use distinct strategies of self-antigen expression and presentation to mediate central tolerance. The thymus also harbors B cells; whether they also display unique tolerogenic features and how they genealogically relate to peripheral B cells is unclear. Here, we found that Aire is expressed in thymic but not peripheral B cells. Aire expression in thymic B cells coincided with major histocompatibility class II (MHCII) and CD80 upregulation and immunoglobulin class-switching. These features were recapitulated upon immigration of naive peripheral B cells into the thymus, whereby this intrathymic licensing required CD40 signaling in the context of cognate interactions with autoreactive CD4(+) thymocytes. Moreover, a licensing-dependent neo-antigen selectively upregulated in immigrating B cells mediated negative selection through direct presentation. Thus, autoreactivity within the nascent T cell repertoire fuels a feed forward loop that endows thymic B cells with tolerogenic features. PMID:26070482

  20. Identification of phenotypic markers of B cells from patients with Chagas disease.

    PubMed

    Fares, R C G; Correa-Oliveira, R; de Araújo, F F; Keesen, T S L; Chaves, A T; Fiuza, J A; Ferreira, K S; Rocha, M O C; Gomes, J A S

    2013-07-01

    Chagas disease was discovered more than a hundred years ago, but its pathogenesis is still not completely understood. Autoimmunity is one of the mechanisms shown to contribute to its pathogenesis, which may indicate an important participation of B lymphocytes. Patients with Chagas disease have shown increased percentage of B cells producing IL-10. However, there are no reports of the phenotypic markers of B cells producing IL-10 in patients with Chagas disease. For the first time in the literature, we evaluated the phenotypic profile of distinct markers of B cells from peripheral blood of noninfected individuals and patients with Chagas disease. Our results showed that patients with Chagas disease had a higher expression of CD21 and CD24 on the surface of CD19+ B cells, while CD43 and CD23 were expressed equally in all groups. Moreover, the expression of MHC-II (HLA-DR), CD80, CD86, caspase-3, granzyme B and intracellular IL-10 and TGF-? by CD19+ B cells was higher in patients with Chagas disease. The results of IL-10 production within CD19+ CD5+ CD1d+ B cells showed a higher percentage of this cytokine in patients with Chagas disease. Thus, our data bring a new knowledge about distinct markers of B cells in immune responses of Chagas disease. PMID:23607422

  1. Monte Carlo Study of Single Molecule Diffusion Can Elucidate the Mechanism of B Cell Synapse Formation

    PubMed Central

    Tsourkas, Philippos K.; Longo, Marjorie L.; Raychaudhuri, Subhadip

    2008-01-01

    B cell receptors have been shown to cluster at the intercellular junction between a B cell and an antigen-presenting cell in the form of a segregated pattern of B cell receptor/antigen complexes known as an immunological synapse. We use random walk-based theoretical arguments and Monte Carlo simulations to study the effect of diffusion of surface-bound molecules on B cell synapse formation. Our results show that B cell synapse formation is optimal for a limited range of receptor-ligand complex diffusion coefficient values, typically one-to-two orders of magnitude lower than the diffusion coefficient of free receptors. Such lower mobility of receptor-ligand complexes can significantly affect the diffusion of a tagged receptor or ligand in an affinity dependent manner, as the binding/unbinding of such receptor or ligand molecules crucially depends on affinity. Our work shows how single molecule tracking experiments can be used to estimate the order of magnitude of the diffusion coefficient of receptor-ligand complexes, which is difficult to measure directly in experiments due to the finite lifetime of receptor-ligand bonds. We also show how such antigen movement data at the single molecule level can provide insight into the B cell synapse formation mechanism. Thus, our results can guide further single molecule tracking experiments to elucidate the synapse formation mechanism in B cells, and potentially in other immune cells. PMID:18456833

  2. Eosinophilic Disorders

    MedlinePLUS

    ... Google+ LinkedIn Merck Manuals Consumer Version Blood Disorders White Blood Cell Disorders Eosinophilic Disorders Idiopathic hypereosinophilic syndrome Resources In This Article Drugs Mentioned In This ...

  3. Rictor Is Required for Early B Cell Development in Bone Marrow

    PubMed Central

    Gu, Jie; Zhang, Liyan; Hao, Sha; Liang, Haoyue; Wang, Xiaomin; Wang, Weili; Xu, Jing; Liu, Hanzhi; Liu, Bin; Cheng, Tao; Yuan, Weiping

    2014-01-01

    The development of early B cells, which are generated from hematopoietic stem cells (HSCs) in a series of well-characterized stages in bone marrow (BM), represents a paradigm for terminal differentiation processes. Akt is primarily regulated by phosphorylation at Thr308 by PDK1 and at Ser473 by mTORC2, and Akt signaling plays a key role in hematopoiesis. However, the role of mTORC2 in the development of early B cells remains poorly understood. In this study, we investigated the functional role of mTORC2 by specifically deleting an integral component, Rictor, in a hematopoietic system. We demonstrated that the deletion of Rictor induced an aberrant increase in the FoxO1 and Rag-1 proteins in BM B cells and that this increase was accompanied by a significant decrease in the abundance of B cells in the peripheral blood (PB) and the spleen, suggesting impaired development of early B cells in adult mouse BM. A BM transplantation assay revealed that the B cell differentiation defect induced by Rictor deletion was not affected by the BM microenvironment, thus indicating a cell-intrinsic mechanism. Furthermore, the knockdown of FoxO1 in Rictor-deleted HSCs and hematopoietic progenitor cells (HPCs) promoted the maturation of B cells in the BM of recipient mice. In addition, we revealed that treatment with rapamycin (an mTORC1 inhibitor) aggravated the deficiency in B cell development in the PB and BM. Taken together, our results provide further evidence that Rictor regulates the development of early B cells in a cell-intrinsic manner by modifying the expression of FoxO1 and Rag-1. PMID:25084011

  4. To B or not to B cells-mediate a healthy start to life.

    PubMed

    Nguyen, T G; Ward, C M; Morris, J M

    2013-02-01

    Maternal immune responses during pregnancy are critical in programming the future health of a newborn. The maternal immune system is required to accommodate fetal immune tolerance as well as to provide a protective defence against infections for the immunocompromised mother and her baby during gestation and lactation. Natural immunity and antibody production by maternal B cells play a significant role in providing such immunoprotection. However, aberrations in the B cell compartment as a consequence of maternal autoimmunity can pose serious risks to both the mother and her baby. Despite their potential implication in shaping pregnancy outcomes, the role of B cells in human pregnancy has been poorly studied. This review focuses on the role of B cells and the implications of B cell depletion therapy in pregnancy. It highlights the evidence of an association between aberrant B cell compartment and obstetric conditions. It also alludes to the potential mechanisms that amplify these B cell aberrances and thereby contribute to exacerbation of some maternal autoimmune conditions and poor neonatal outcomes. Clinical and experimental evidence suggests strongly that maternal autoantibodies contribute directly to the pathologies of obstetric and neonatal conditions that have significant implications for the lifelong health of a newborn. The evidence for clinical benefit and safety of B cell depletion therapies in pregnancy is reviewed, and an argument is mounted for further clinical evaluation of B cell-targeted therapies in high-risk pregnancy, with an emphasis on improving neonatal outcomes and prevention of neonatal conditions such as congenital heart block and fetal/neonatal alloimmune thrombocytopenia. PMID:23286939

  5. Genetic immunization converts the trypanosoma cruzi B-Cell mitogen proline racemase to an effective immunogen.

    PubMed

    Bryan, Marianne A; Norris, Karen A

    2010-02-01

    Trypanosoma cruzi is the etiologic agent of Chagas' disease. Acute T. cruzi infection results in polyclonal B-cell activation and delayed specific humoral immunity. T. cruzi proline racemase (TcPRAC), a T. cruzi B-cell mitogen, may contribute to this dysfunctional humoral response. Stimulation of murine splenocytes with recombinant protein (rTcPRAC) induced B-cell proliferation, antibody secretion, interleukin-10 (IL-10) production, and upregulation of CD69 and CD86 on B cells. Marginal zone (MZ) B cells are more responsive to T-cell-independent (TI) rTcPRAC stimulation than are follicular mature (FM) B cells in terms of proliferation, antibody secretion, and IL-10 production. During experimental T. cruzi infection, TcPRAC-specific IgG remained undetectable when responses to other T. cruzi antigens developed. Conversely, intradermal genetic immunization via gene gun (GG) delivered TcPRAC as an immunogen, generating high-titer TcPRAC-specific IgG without B-cell dysfunction. TcPRAC GG immunization led to antigen-specific splenic memory B-cell and bone marrow plasma cell formation. TcPRAC-specific IgG bound mitogenic rTcPRAC, decreasing subsequent B-cell activation. GG immunization with rTcPRAC DNA was nonmitogenic and did not affect the generation of specific IgG to another T. cruzi antigen, complement regulatory protein (CRP). These data demonstrate the utility of genetic immunization for the conversion of a protein mitogen to an effective antigen. Furthermore, coimmunization of TcPRAC with another T. cruzi antigen indicates the usefulness of this approach for multivalent vaccine development. PMID:19917711

  6. Interleukin 21-induced granzyme B-expressing B cells infiltrate tumors and regulate T cells.

    PubMed

    Lindner, Stefanie; Dahlke, Karen; Sontheimer, Kai; Hagn, Magdalena; Kaltenmeier, Christof; Barth, Thomas F E; Beyer, Thamara; Reister, Frank; Fabricius, Dorit; Lotfi, Ramin; Lunov, Oleg; Nienhaus, G Ulrich; Simmet, Thomas; Kreienberg, Rolf; Möller, Peter; Schrezenmeier, Hubert; Jahrsdörfer, Bernd

    2013-04-15

    The pathogenic impact of tumor-infiltrating B cells is unresolved at present, however, some studies suggest that they may have immune regulatory potential. Here, we report that the microenvironment of various solid tumors includes B cells that express granzyme B (GrB, GZMB), where these B cells can be found adjacent to interleukin (IL)-21-secreting regulatory T cells (Treg) that contribute to immune tolerance of tumor antigens. Because Tregs and plasmacytoid dendritic cells are known to modulate T-effector cells by a GrB-dependent mechanism, we hypothesized that a similar process may operate to modulate regulatory B cells (Breg). IL-21 induced outgrowth of B cells expressing high levels of GrB, which thereby limited T-cell proliferation by a GrB-dependent degradation of the T-cell receptor ?-chain. Mechanistic investigations into how IL-21 induced GrB expression in B cells to confer Breg function revealed a CD19(+)CD38(+)CD1d(+)IgM(+)CD147(+) expression signature, along with expression of additional key regulatory molecules including IL-10, CD25, and indoleamine-2,3-dioxygenase. Notably, induction of GrB by IL-21 integrated signals mediated by surface immunoglobulin M (B-cell receptor) and Toll-like receptors, each of which were enhanced with expression of the B-cell marker CD5. Our findings show for the first time that IL-21 induces GrB(+) human Bregs. They also establish the existence of human B cells with a regulatory phenotype in solid tumor infiltrates, where they may contribute to the suppression of antitumor immune responses. Together, these findings may stimulate novel diagnostic and cell therapeutic approaches to better manage human cancer as well as autoimmune and graft-versus-host pathologies. PMID:23384943

  7. Characterization of B cells in muscle-specific kinase antibody myasthenia gravis

    PubMed Central

    Yi, John S.; Sanders, Donald B.; Guidon, Amanda C.; Juel, Vern C.; Massey, Janice M.; Howard, James F.; Scuderi, Flavia; Bartoccioni, Emanuela; Evoli, Amelia; Weinhold, Kent J.

    2015-01-01

    Objective: To characterize B-cell subsets in patients with muscle-specific tyrosine kinase (MuSK) myasthenia gravis (MG). Methods: In accordance with Human Immunology Project Consortium guidelines, we performed polychromatic flow cytometry and ELISA assays in peripheral blood samples from 18 patients with MuSK MG and 9 healthy controls. To complement a B-cell phenotype assay that evaluated maturational subsets, we measured B10 cell percentages, plasma B cell–activating factor (BAFF) levels, and MuSK antibody titers. Immunologic variables were compared with healthy controls and clinical outcome measures. Results: As expected, patients treated with rituximab had high percentages of transitional B cells and plasmablasts and thus were excluded from subsequent analysis. The remaining patients with MuSK MG and controls had similar percentages of total B cells and naďve, memory, isotype-switched, plasmablast, and transitional B-cell subsets. However, patients with MuSK MG had higher BAFF levels and lower percentages of B10 cells. In addition, we observed an increase in MuSK antibody levels with more severe disease. Conclusions: We found prominent B-cell pathology in the distinct form of MG with MuSK autoantibodies. Increased BAFF levels have been described in other autoimmune diseases, including acetylcholine receptor antibody–positive MG. This finding suggests a role for BAFF in the survival of B cells in MuSK MG, which has important therapeutic implications. B10 cells, a recently described rare regulatory B-cell subset that potently blocks Th1 and Th17 responses, were reduced, which suggests a potential mechanism for the breakdown in immune tolerance in patients with MuSK MG. PMID:25745635

  8. High frequency of MYD88 mutations in vitreoretinal B-cell lymphoma: a valuable tool to improve diagnostic yield of vitreous aspirates.

    PubMed

    Bonzheim, Irina; Giese, Sabrina; Deuter, Christoph; Süsskind, Daniela; Zierhut, Manfred; Waizel, Maria; Szurman, Peter; Federmann, Birgit; Schmidt, Janine; Quintanilla-Martinez, Leticia; Coupland, Sarah E; Bartz-Schmidt, Karl Ulrich; Fend, Falko

    2015-07-01

    Vitreoretinal diffuse large B-cell lymphoma is a rare disorder, occurring as primary ocular disease or as secondary involvement by primary central nervous system lymphoma. It is usually diagnosed by cytologic, immunocytochemical, and molecular examination of vitreous aspirates. However, distinguishing vitreoretinal diffuse large B-cell lymphoma from uveitis remains difficult, and clonality analysis may be either unsuccessful or misleading. Diffuse large B-cell lymphoma arising in immune-privileged sites (eg, the central nervous system) shows a high frequency of MYD88 mutations. Therefore, we retrospectively assessed the frequency of MYD88 mutations in vitreoretinal lymphoma (VRL) and their diagnostic potential in 75 vitrectomy samples of 69 patients, and validated our results in a separate cohort (n = 21). MYD88 mutations were identified in 20 of 29 (69%) clinically, histologically, and molecularly confirmed VRL, including 6 cases of the test cohort initially diagnosed as reactive (3/6) or suspicious (3/6) for lymphoma. MYD88 mutations, especially L265P, are very frequent in VRL and their detection significantly improves the diagnostic yield of vitrectomy specimens. PMID:25900979

  9. Fas Receptor Expression in Germinal-Center B Cells Is Essential for T and B Lymphocyte Homeostasis

    Microsoft Academic Search

    Zhenyue Hao; Gordon S. Duncan; Jane Seagal; Yu-Wen Su; Claire Hong; Jillian Haight; Nien-Jung Chen; Andrew Elia; Andrew Wakeham; Wanda Y. Li; Jennifer Liepa; Geoffrey A. Wood; Stefano Casola; Klaus Rajewsky; Tak W. Mak

    2008-01-01

    SUMMARY Fas is highly expressed in activated and germinal center (GC) B cells but can potentially be inactivated by misguided somatic hypermutation. We employed conditional Fas-deficient mice to investigate the physiological functions of Fas in various B cell sub- sets. B cell-specific Fas-deficient mice developed fatal lymphoproliferation due to activation of B cells and T cells. Ablation of Fas specifically

  10. Blimp1 Is Required for the Formation of Immunoglobulin Secreting Plasma Cells and Pre-Plasma Memory B Cells

    Microsoft Academic Search

    Miriam Shapiro-Shelef; Kuo-I Lin; Louise J McHeyzer-Williams; Jerry Liao; Michael G McHeyzer-Williams; Kathryn Calame

    2003-01-01

    Blimp-1 is a transcriptional repressor able to drive the terminal differentiation of B cells into Ig-secreting plasma cells. We have created mice with a B cell-specific deletion of prdm1, the gene encoding Blimp-1. B cell development and the number of B cells responding to antigen appear to be normal in these mice. However, in response to either TD or TI

  11. Oblimersen Sodium and Rituximab in Treating Patients With Recurrent B-cell Non-Hodgkin Lymphoma

    ClinicalTrials.gov

    2014-05-13

    Cutaneous B-cell Non-Hodgkin Lymphoma; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Intraocular Lymphoma; Nodal Marginal Zone B-cell Lymphoma; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Grade III Lymphomatoid Granulomatosis; Recurrent Adult Immunoblastic Large Cell Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Small Lymphocytic Lymphoma; Small Intestine Lymphoma; Splenic Marginal Zone Lymphoma; Testicular Lymphoma; Waldenström Macroglobulinemia

  12. Induction of the c-myc protooncogene after antigen binding to hapten- specific B cells

    PubMed Central

    1986-01-01

    The stimulation of hapten-specific B cell populations with the thymus- dependent antigen, TNP-KLH, was found to induce elevated levels of c- myc mRNA by 2 h. A similar treatment with carrier protein alone did not elevate c-myc mRNA above the level seen in the nonstimulated, resting B cells. These results indicate that antigen binding to the sIg receptor, in the absence of Th cell involvement, directly signals the antigen- binding cell and implicates the active participation of sIg during the process of antigen-mediated B cell activation. PMID:3489063

  13. Intravascular large B-cell lymphoma: remission after rituximab-cyclophosphamide, doxorubicin, vincristine, and prednisolone chemotherapy.

    PubMed

    Horváth, Barbara; Demeter, Judit; Eros, Nóra; Hársing, Judit; Csomor, Judit; Matolcsy, András; Bottlik, Gyula; Gyori, Gabriella; Marschalkó, Márta; Kárpáti, Sarolta

    2009-11-01

    Intravascular lymphoma is an uncommon, very aggressive extranodal non-Hodgkin lymphoma that most frequently involves the skin and central nervous system. Most cases are of B-cell origin; T-cell phenotype is extremely rare. Malignant cells proliferate within the lumens of capillaries, arterioles, venules, and small arteries; vascular occlusion is responsible for the clinical signs and symptoms. The prognosis of this high-grade B-cell lymphoma has improved since the introduction of the anti-CD20 monoclonal antibody, rituximab. We describe a case of B-cell intravascular lymphoma successfully treated with rituximab and cyclophosphamide, doxorubicin, vincristine, and prednisolone. PMID:19632742

  14. Loss of signalling via G?13 in germinal centre B-cell-derived lymphoma.

    PubMed

    Muppidi, Jagan R; Schmitz, Roland; Green, Jesse A; Xiao, Wenming; Larsen, Adrien B; Braun, Sterling E; An, Jinping; Xu, Ying; Rosenwald, Andreas; Ott, German; Gascoyne, Randy D; Rimsza, Lisa M; Campo, Elias; Jaffe, Elaine S; Delabie, Jan; Smeland, Erlend B; Braziel, Rita M; Tubbs, Raymond R; Cook, J R; Weisenburger, Dennis D; Chan, Wing C; Vaidehi, Nagarajan; Staudt, Louis M; Cyster, Jason G

    2014-12-11

    Germinal centre B-cell-like diffuse large B-cell lymphoma (GCB-DLBCL) is a common malignancy, yet the signalling pathways that are deregulated and the factors leading to its systemic dissemination are poorly defined. Work in mice showed that sphingosine-1-phosphate receptor-2 (S1PR2), a G?12 and G?13 coupled receptor, promotes growth regulation and local confinement of germinal centre B cells. Recent deep sequencing studies of GCB-DLBCL have revealed mutations in many genes in this cancer, including in GNA13 (encoding G?13) and S1PR2 (refs 5,6, 7). Here we show, using in vitro and in vivo assays, that GCB-DLBCL-associated mutations occurring in S1PR2 frequently disrupt the receptor's Akt and migration inhibitory functions. G?13-deficient mouse germinal centre B cells and human GCB-DLBCL cells were unable to suppress pAkt and migration in response to S1P, and G?13-deficient mice developed germinal centre B-cell-derived lymphoma. Germinal centre B cells, unlike most lymphocytes, are tightly confined in lymphoid organs and do not recirculate. Remarkably, deficiency in G?13, but not S1PR2, led to germinal centre B-cell dissemination into lymph and blood. GCB-DLBCL cell lines frequently carried mutations in the G?13 effector ARHGEF1, and Arhgef1 deficiency also led to germinal centre B-cell dissemination. The incomplete phenocopy of G?13- and S1PR2 deficiency led us to discover that P2RY8, an orphan receptor that is mutated in GCB-DLBCL and another germinal centre B-cell-derived malignancy, Burkitt's lymphoma, also represses germinal centre B-cell growth and promotes confinement via G?13. These findings identify a G?13-dependent pathway that exerts dual actions in suppressing growth and blocking dissemination of germinal centre B cells that is frequently disrupted in germinal centre B-cell-derived lymphoma. PMID:25274307

  15. Primary precursor B cell lymphoblastic lymphoma of uterine corpus: case report and review of the literature

    Microsoft Academic Search

    Shi-sheng TanXing-chen; Xing-chen Peng; Ying Cao

    Introduction  Primary lymphomas of the female genital tract are rare. Most involve the cervix rather than the uterine corpus. Many cases\\u000a of primary endometrial lymphoma are diagnosed as diffuse large B cell type, whereas the precursor B cell lymphoblastic type\\u000a is extremely rare.\\u000a \\u000a \\u000a \\u000a \\u000a Materials and methods  We report a case of precursor B cell lymphoblastic lymphoma of uterine corpus which was successfully

  16. T-BAM/CD40-L on helper T lymphocytes augments lymphokine-induced B cell Ig isotype switch recombination and rescues B cells from programmed cell death.

    PubMed

    Lederman, S; Yellin, M J; Cleary, A M; Pernis, A; Inghirami, G; Cohn, L E; Covey, L R; Lee, J J; Rothman, P; Chess, L

    1994-03-01

    An important component of T cell help for B lymphocyte differentiation is the contact-dependent signaling mediated by the T cell-B cell activating molecule (T-BAM/CD40-L), an activation-induced surface membrane protein on CD4+ T helper cells in lymphoid follicles that interacts with the B cell surface molecule, CD40. The present study dissects the roles of T-BAM/CD40-L in helper function by means of a neutralizing anti-T-BAM/CD40-L mAb (5c8), a T-BAM/CD40-L-expressing T cell tumor subclone (Jurkat D1.1), and a T-BAM/CD40-L-responsive IgM+ B cell tumor of germinal center origin (RAMOS 266). Like activated T cells, D1.1 cells induce B cells to synthesize IgG, IgA, and IgE in a process that is specifically inhibited by the mAb 5c8. Although rIL-4 alone, but not Jurkat D1.1, induces IgH C gamma mRNA transcripts in RAMOS 266, the T-BAM/CD40-L molecule on D1.1 acts on rIL-4-primed RAMOS B cells to augment expression of C gamma transcripts. In addition, IgG+ RAMOS 266 clones were expanded from D1.1- and rIL-4-stimulated cultures that had undergone deletional IgH isotype switch recombination events. Furthermore, T-BAM/CD40-L signals delivered by the D1.1 clone dramatically rescue RAMOS 266 from mAb anti-IgM-induced apoptosis. Taken together, these data support the idea that T-BAM/CD40-L plays important roles in inducing Ig isotype switch recombination and the clonal selection of isotype-switched B cells. PMID:7907632

  17. Can cutaneous low-grade B-cell lymphoma transform into primary cutaneous diffuse large B-cell lymphoma? An immunohistochemical study of 82 cases.

    PubMed

    Plaza, Jose A; Kacerovska, Denisa; Sangueza, Martin; Schieke, Stefan; Buonaccorsi, Noelle; Suster, Saul; Kazakov, Dmitry V

    2014-06-01

    Low-grade B-cell lymphomas of the skin, especially, primary cutaneous follicle center cell lymphoma has several distinctive features when compared with nodal/systemic follicular lymphomas, as they are frequently negative for bcl-2 and CD10, and only fewer than 25% of the cases show a bcl-2 rearrangement. The risk of transformation of a cutaneous low-grade B-cell lymphoma, such as primary cutaneous follicle center cell lymphoma, to primary cutaneous diffuse large B-cell lymphomas (PCDLBCL) has not been clearly delineated in the literature. Transformation of systemic/nodal follicular lymphoma into aggressive DLBCL is associated with rapid disease progression, refractoriness to treatment, and poor prognosis. The authors studied 82 cases of primary cutaneous DLBCL using antibodies for follicular dendritic cells (FDCs), CD21, and CD35 to detect networks of FDCs that could possibly indicate transformation of preexisting low-grade B-cell lymphoma to PCDLBCL. All cases were classified as PCDLBCL using strict histologic and immunophenotypic criteria. Fifty-three cases were classified as primary cutaneous DLBCL of "leg type," and 29 cases were classified as primary cutaneous DLBCL, "NOS" category. Immunohistochemical studies were performed in all 82 cases; in 15 cases, a CD21/CD35+ network of FDCs was noted within the tumor, indicating the presence of remnants of residual germinal centers, suggesting the possibility of a transformed low-grade B-cell lymphoma. In summary, the authors' findings seem to indicate that some cases of primary cutaneous DLBCL may result from transformation of a low-grade B-cell lymphoma. Further studies are necessary to evaluate the significance of their findings by using ancillary techniques including genetic analysis. PMID:24698933

  18. Expansion of IgG+ B-Cells during Mitogen Stimulation for Memory B-Cell ELISpot Analysis Is Influenced by Size and Composition of the B-Cell Pool

    PubMed Central

    Langhorne, Jean; Sauerwein, Robert W.

    2014-01-01

    The memory B-cell (MBC) ELISpot assay is the main technique used to measure antigen-specific MBCs as a readout of humoral immune memory. This assay relies on the ability of MBCs to differentiate into antibody-secreting cells (ASC) upon polyclonal stimulation. The total number of IgG+ ASCs generated by mitogen-stimulation is often used as a reference point; alternatively antigen-specific MBCs are expressed as a frequency of post-culture peripheral blood mononuclear cells (PBMC) as a surrogate for absolute frequencies. Therefore, it is important to know whether IgG+ B-cells are uniformly expanded during the preceding mitogen-culture as a true reflection of MBC frequencies ex vivo. We systematically compared B-cell phenotype and proportions before and after mitogen stimulation in cultures of 269 peripheral blood mononuclear cell samples from 62 volunteers by flow cytometry and analyzed the number of resulting ASCs. Our data show that the number of total IgG+ ASCs detected by ELISpot after mitogen stimulation correlates with the proportion of IgG+ MBCs ex vivo, highlighting its general robustness for comparisons of study cohorts at group level. The expansion of total and IgG+ B-cells during mitogen-stimulation, however, was not identical in all cultures, but influenced by size and composition of the ex vivo B-cell compartment. The uncorrected readout of antigen-specific MBCs per million post-culture PBMCs therefore only preserves the quality, but not the magnitude of differences in the ex vivo MBC response between groups or time points, particularly when comparing samples where the B-cell compartment substantially differs between cohorts or over time. Therefore, expressing antigen-specific cells per total IgG+ ASCs is currently the best measure to correct for mitogen-culture effects. Additionally, baseline information on the size and composition of the ex vivo