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Sample records for b-cell lymphoproliferative disorders

  1. Molecular and cytogenetic characterization of expanded B-cell clones from multiclonal versus monoclonal B-cell chronic lymphoproliferative disorders

    PubMed Central

    Henriques, Ana; Rodrguez-Caballero, Arancha; Criado, Ignacio; Langerak, Anton W.; Nieto, Wendy G.; Lcrevisse, Quentin; Gonzlez, Marcos; Corteso, Emlia; Paiva, Artur; Almeida, Julia; Orfao, Alberto

    2014-01-01

    Chronic antigen-stimulation has been recurrently involved in the earlier stages of monoclonal B-cell lymphocytosis, chronic lymphocytic leukemia and other B-cell chronic lymphoproliferative disorders. The expansion of two or more B-cell clones has frequently been reported in individuals with these conditions; potentially, such coexisting clones have a greater probability of interaction with common immunological determinants. Here, we analyzed the B-cell receptor repertoire and molecular profile, as well as the phenotypic, cytogenetic and hematologic features, of 228 chronic lymphocytic leukemia-like and non-chronic lymphocytic leukemia-like clones comparing multiclonal (n=85 clones from 41 cases) versus monoclonal (n=143 clones) monoclonal B-cell lymphocytosis, chronic lymphocytic leukemia and other B-cell chronic lymphoproliferative disorders. The B-cell receptor of B-cell clones from multiclonal cases showed a slightly higher degree of HCDR3 homology than B-cell clones from mono clonal cases, in association with unique hematologic (e.g. lower B-lymphocyte counts) and cytogenetic (e.g. lower frequency of cytogenetically altered clones) features usually related to earlier stages of the disease. Moreover, a subgroup of coexisting B-cell clones from individual multiclonal cases which were found to be phylogenetically related showed unique molecular and cytogenetic features: they more frequently shared IGHV3 gene usage, shorter HCDR3 sequences with a greater proportion of IGHV mutations and del(13q14.3), than other unrelated B-cell clones. These results would support the antigen-driven nature of such multiclonal B-cell expansions, with potential involvement of multiple antigens/epitopes. PMID:24488564

  2. SIGLEC-G deficiency increases susceptibility to develop B-cell lymphoproliferative disorders

    PubMed Central

    Simonetti, Giorgia; Bertilaccio, Maria Teresa Sabrina; Rodriguez, Tania Veliz; Apollonio, Benedetta; Dagklis, Antonis; Rocchi, Martina; Innocenzi, Anna; Casola, Stefano; Winkler, Thomas H.; Nitschke, Lars; Ponzoni, Maurilio; Caligaris-Cappio, Federico; Ghia, Paolo

    2014-01-01

    The sialic-acid-binding immunoglobulin-like lectin SIGLEC-G is a negative regulator of B-cell receptor-mediated calcium signaling. Its deficiency leads to reduced turnover and increased proliferation and survival of murine B-1a cells. Siglecg?/? mice show a premature expansion of polyclonal CD5+ B cells in the spleen and the peritoneal cavity. Here we studied the fate of B lymphocytes in Siglecg?/? mice over time. We demonstrate that in aging animals SIGLEC-G deficiency promotes progressive accumulation of monoclonal B lymphocytes and increases the susceptibility to develop B-cell lymphoproliferative disorders. Lymphoid tumors arising in aged Siglecg?/? mice are monoclonal and histologically heterogeneous as they include diffuse large B-cell lymphoma, follicular lymphoma, and medium-to-large B-cell monomorphic lymphoma but surprisingly not chronic lymphocytic leukemia. The tumors express high levels of BCL-2 and are transplantable. In keeping with these findings we have also observed a remarkable down-regulation of the human ortholog SIGLEC10 in human B-cell lymphoma and leukemia cell lines. Taken together, these observations indicate that the down-regulation of negative B-cell receptor regulators such as SIGLEC-G/SIGLEC10 may represent another mechanism relevant to the pathogenesis of B-cell lymphomas. PMID:24859880

  3. Aggressive EBV-associated lymphoproliferative disorder: a prodrome to diffuse large B-cell lymphoma?

    PubMed

    Batra, Rashmi; Medeiros, Bruno C; Zehnder, James L; Warnke, Roger A; Natkunam, Yasodha

    2012-05-01

    A 19-year-old male patient presented with intermittent high fever and left cervical lymphadenopathy. The lymph node biopsy findings were interpreted as "Epstein-Barr virus (EBV)-associated lymphoproliferative disorder consistent with infectious mononucleosis." No molecular studies were performed at that time. The patient was followed without treatment. Five months later, the patient again presented with fever, lymphadenopathy, and splenomegaly. The lymph node biopsy showed features of a diffuse large B-cell lymphoma. Molecular studies on this lymph node biopsy showed a clonal EBV population, although polymerase chain reaction studies failed to reveal a clonal B-cell or T-cell population. A concurrent bone marrow biopsy showed features consistent with hemophagocytic syndrome. He had elevated ferritin, soluble interleukin-2 receptors and persistent EBV viremia. The patient responded to Rituxan for a short period with undetectable EBV levels. Subsequent right cervical lymph node, liver, and jejunal biopsies showed involvement by diffuse large B-cell lymphoma and the patient expired soon thereafter. PMID:22505014

  4. Crystal-storing histiocytosis involving the kidney in a low-grade B-cell lymphoproliferative disorder.

    PubMed

    Sethi, Sanjeev; Cuiffo, Barry P; Pinkus, Geraldine S; Rennke, Helmut G

    2002-01-01

    Intracellular crystal formation in histiocytes in multiple myeloma and other lymphoproliferative disorders is an uncommon presentation. In all cases, crystal formation is associated with accumulation of histiocytes containing light chain or immunoglobulin inclusions, and the disorder has been termed crystal-storing histiocytosis. We report a case of crystal-storing histiocytosis affecting the kidney with prominent infiltration of the mesangium by large mononuclear and multinuclear cells that contained eosinophilic crystalline material in the setting of a low-grade B-cell lymphoproliferative disorder. The interstitium did not contain similar crystal-containing histiocytes. On electron microscopy, the mononuclear and multinuclear cells in the mesangium were filled with rhomboid and needle-shaped crystals. Immunofluorescence studies showed the material to be positive for lambda light chains but negative for kappa light chains. To our knowledge, this is the first report of crystal-storing histiocytosis involving the kidney in a low-grade B-cell lymphoproliferative disorder with an immunophenotype of a marginal zone lymphoma and of exclusive expansion of the mesangium by infiltrating histiocytes containing needle-shaped and rhomboid crystals that were positive for lambda light chains. We report this case to illustrate an unusual finding of mesangial infiltration by crystal-storing histiocytes, and we review the literature of renal involvement by crystal-storing histiocytosis and crystal deposition in lymphoproliferative disorders. PMID:11774118

  5. Composite Epstein-Barr Virus-Associated B-Cell Lymphoproliferative Disorder and Tubular Adenoma in a Rectal Polyp.

    PubMed

    Lo, Amy A; Gao, Juehua; Rao, M Sambasivia; Yang, Guang-Yu

    2016-02-01

    Composite tumors are formed when there is intermingling between two components of separate tumors seen histologically. Cases demonstrating composite tubular adenoma with other types of tumors in the colon are rare. Composite tubular adenomas with nonlymphoid tumors including carcinoids, microcarcinoids, and small cell undifferentiated carcinoma have been reported in the literature. The occurrence of composite lymphoma and tubular adenoma within the colorectal tract is extremely rare. Only three cases have been reported and include one case of mantle cell lymphoma and two cases of diffuse large B-cell lymphoma arising in composite tubular adenomas. We present the first case of composite Epstein-Barr virus-associated B-cell lymphoproliferative disorder and tubular adenoma in a rectal polyp with a benign endoscopic appearance. PMID:26353852

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

    PubMed Central

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

    2015-01-01

    EpsteinBarr 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

  7. [EBV-associated B-cell lymphoproliferative disorder of the elderly successfully treated with autologous peripheral blood stem cell transplantation and locoregional radiotherapy].

    PubMed

    Sugino, Noriko; Nakamura, Chishiho; Fujii, Sumie; Matsui, Yusuke; Kaneko, Hitomi; Watanabe, Mitsumasa; Miura, Yasuo; Wakasa, Tomoko; Tsudo, Mitsuru

    2011-03-01

    Age-related EBV-associated B-cell lymphoproliferative disorder is a highly aggressive lymphoma, and a standard therapy for this disease has not yet been established. A 58-year-old male was admitted to our hospital because of fever and lymphadenopathy across the whole body. Neck lymph node biopsy showed hemorrhagic and geographic necrosis with Hodgkin-like large cells against a background of small lymphocytes. The large cells were positive for CD30 and EBER. The patient was diagnosed as having age-related EBV-associated B-cell lymphoproliferative disorder. Although there was no response to CHOP therapy, he obtained partial response after 3 courses of DeVIC therapy. Because his lymphoma was highly aggressive and chemotherapy-resistant, he underwent autologous stem cell transplantation with a conditioning regimen including ranimustine, etoposide, cytarabine, and melphalan. After stem cell transplantation and subsequent radiotherapy to the residual lesion, the patient achieved complete remission. This is the first report of successful autologous stem cell transplantation for a patient with age-related EBV-associated B-cell lymphoproliferative disorder. PMID:21471700

  8. Posttransplant Lymphoproliferative Disorders

    PubMed Central

    Ibrahim, Hazem A. H.; Naresh, Kikkeri N.

    2012-01-01

    Posttransplant lymphoproliferative disorders (PTLDs) are a group of diseases that range from benign polyclonal to malignant monoclonal lymphoid proliferations. They arise secondary to treatment with immunosuppressive drugs given to prevent transplant rejection. Three main pathologic subsets/stages of evolution are recognised: early, polymorphic, and monomorphic lesions. The pathogenesis of PTLDs seems to be multifactorial. Among possible infective aetiologies, the role of EBV has been studied in depth, and the virus is thought to play a central role in driving the proliferation of EBV-infected B cells that leads to subsequent development of the lymphoproliferative disorder. It is apparent, however, that EBV is not solely responsible for the neoplastic state. Accumulated genetic alterations of oncogenes and tumour suppressor genes (deletions, mutations, rearrangements, and amplifications) and epigenetic changes (aberrant hypermethylation) that involve tumour suppressor genes are integral to the pathogenesis. Antigenic stimulation also plays an evident role in the pathogenesis of PTLDs. Plasmacytoid dendritic cells (PDCs) that are critical to fight viral infections have been thought to play a pathogenetically relevant role in PTLDs. Furthermore, regulatory T cells (Treg cells), which are modulators of immune reactions once incited, seem to have an important role in PTLDs where antigenic stimulation is key for the pathogenesis. PMID:22570658

  9. CD8-positive T-cell lymphoproliferative disorder associated with Epstein-Barr virus-infected B-cells in a rheumatoid arthritis patient under methotrexate treatment.

    PubMed

    Koji, Hitoshi; Yazawa, Takuya; Nakabayashi, Kimimasa; Fujioka, Yasunori; Kamma, Hiroshi; Yamada, Akira

    2016-03-01

    We report a 48-year-old female who developed lymphoproliferative disorder (LPD) during treatment of rheumatoid arthritis (RA) with methotrexate (MTX). She presented with multiple tumors in the cervical lymph nodes (LNs), multiple lung shadows and round shadows in both kidneys with pancytopenia and a high CRP level. The LN showed CD8-positive T-cell LPD associated with Epstein-Barr (EB) virus-infected B-cells. Clonality assays for immunoglobulin (Ig) heavy chain and T-cell receptor gamma (TCRγ) were negative. The cessation of MTX without chemotherapy resulted in the complete disappearance of the tumors and abnormal clinical features. We compared this case with previously published ones and discuss the pathological findings, presuming that the proliferation of CD8 T-cells was a reactive manifestation to reactivated EB virus-infected B-cells. PMID:24386983

  10. Chronic Lymphocytic Leukemia and Other Lymphoproliferative Disorders.

    PubMed

    Wall, Sarah; Woyach, Jennifer A

    2016-02-01

    Chronic lymphocytic leukemia affects less than 1% of US adults but is the most common leukemia and primarily affects older patients. Non-Hodgkin lymphomas are the seventh most common cancers in the United States and also primarily affect older patients. In general, older patients should be treated differently than their younger, fitter counterparts. Fitness level and comorbidities should be taken into account when planning treatment. First-line treatment of most of these B-cell lymphoproliferative disorders consists of chemoimmunotherapy. In relapsed and refractory disease, there is a growing role for therapies targeting the B-cell receptor signaling pathway. PMID:26614867

  11. 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

  12. Hepatitis C virus-related lymphoproliferative disorders: An overview

    PubMed Central

    Zignego, Anna Linda; Giannini, Carlo; Ferri, Clodoveo

    2007-01-01

    Hepatitis C virus (HCV) is a global health problem affecting 3% of the world's population (about 180 million) and a cause of both hepatic and extrahepatic diseases. B-cell lymphoproliferative disorders, whose prototype is mixed cryoglobulinemia, represent the most closely related as well as the most investigated HCV-related extrahepatic disorder. The association between extrahepatic (lymphoma) as well as hepatic malignancies (hepatocellular carcinoma) has justified the inclusion of HCV among human cancer viruses. HCV-associated manifestations also include porphyria cutanea tarda, lichen planus, nephropathies, thyreopathies, sicca syndrome, idiopathic pulmonary fibrosis, diabetes, chronic polyarthritis, sexual dysfunctions, cardiopathy/atherosclerosis, and psychopathological disorders. A pathogenetic link between HCV virus and some lymphoproliferative disorders was confirmed by their responsiveness to antiviral therapy, which is now considered the first choice treatment. The aim of the present paper is to provide an overview of extrahepatic manifestations of HCV infection with particular attention to B-cell lymphoproliferative disorders. Available pathogenetic hypotheses and suggestions about the most appropriate, currently available, therapeutic approaches will also be discussed. PMID:17552031

  13. ?-HHVs and HHV-8 in Lymphoproliferative Disorders

    PubMed Central

    Quadrelli, C.; Barozzi, P.; Riva, G.; Vallerini, D.; Zanetti, E.; Potenza, L.; Forghieri, F.; Luppi, M.

    2011-01-01

    Similarly to Epstein-Barr virus (EBV), the human herpesvirus-8 (HHV-8) is a ?-herpesvirus, recently recognized to be associated with the occurrence of rare B cell lymphomas and atypical lymphoproliferations, especially in the human immunodeficiency virus (HIV) infected subjects. Moreover, the human herpesvirus-6 (HHV-6), a ?-herpesvirus, has been shown to be implicated in some non-malignant lymph node proliferations, such as the Rosai Dorfman disease, and in a proportion of Hodgkins lymphoma cases. HHV-6 has a wide cellular tropism and it might play a role in the pathogenesis of a wide variety of human diseases, but given its ubiquity, disease associations are difficult to prove and its role in hematological malignancies is still controversial. The involvement of another ?-herpesvirus, the human cytomegalovirus (HCMV), has not yet been proven in human cancer, even though recent findings have suggested its potential role in the development of CD4+ large granular lymphocyte (LGL) lymphocytosis. Here, we review the current knowledge on the pathogenetic role of HHV-8 and human ?-herpesviruses in human lymphoproliferative disorders. PMID:22110893

  14. Posttransplant lymphoproliferative disorders in transplant recipients.

    PubMed

    Timurağaoğlu, A; Uğur-Bilgin, A; Colak, D; Tuncer, M; Gölbaşi, I; Hazar, V; Kiliçarsłan, B; Undar, L; Demirbaş, A

    2006-03-01

    Posttransplant lymphoproliferative disorder (PTLD) is a serious complication of organ transplantation, with a reported incidence between 0.8% and 32%. The incidence of PTLD mainly depends on the transplanted organ, the immunosuppressive drugs, the viral serology, and the age of the recipient. The aim of our study was to analyze our patients diagnosed with PTLD. Among 1040 transplantations, including 931 renal, 14 heart, 55 liver and 40 allogeneic peripheral blood stem cell (PBSC), 8 patients (7 male, 1 female) were diagnosed with PTLD. Five patients had undergone renal, one cardiac, one liver, and one PBSC transplantations. Four patients were diagnosed within the first year of transplantation. Six patients presented with abdominal disease, one with convulsions, and one with peripheral lymph node involvement. According to the World Health Organization classification system, six patients were diagnosed as diffuse large B-cell lymphoma, one patient Burkitt's lymphoma, and one polymorphic PTLD. At the time of diagnosis, 7 patients showed positive Epstein-Barr virus (EBV) and cytomegalovirus (CMV) Ig G and negative Ig M; one patient, positive EBV Ig M and negative CMV Ig G and M. EBV viral load was extremely high in the plasma of two patients by polymerase chain reaction. One of these patient's pathologic tissue revealed positive EBV DNA, which was not detected in six of the other eight patients. This patient was an 8-year-old boy diagnosed with Burkitt's lymphoma at 31 months after liver transplantation. Seven patients died of disease or complications of chemotherapy. Only one patient survived after the diagnosis of PTLD. In conclusion, even with treatment the mortality rate was high among our patients with PTLD. To decrease the incidence of PTLD and related mortality, risk factors must be evaluated in multicenter studies. PMID:16549195

  15. Mutlifocal osseous posttransplantation lymphoproliferative disorder: case report.

    PubMed

    Lo, Ryan; Michalicek, Zachary; Lazarus, Martin

    2015-07-01

    Posttransplant lymphoproliferative disorder (PTLD) is a known complication of organ transplantation, but musculoskeletal involvement of PTLD remains very rare. We present a case of recurrent PTLD of the bone in a heart transplant patient that was misdiagnosed as gout for several years. There are only a few cases of osseous PTLD in the literature, and we hope to better characterize its imaging findings on multiple imaging modalities. PMID:25680332

  16. Vaccine strategies to treat lymphoproliferative disorders.

    PubMed

    Radford, Kristen J; Vari, Frank; Hart, Derek N J

    2005-12-01

    Lymphoproliferative disorders, including follicular lymphoma (FL), multiple myeloma (MM) and chronic lymphatic leukaemia (CLL), are slowly progressive malignancies which remain incurable despite advances in therapy. Harnessing the immune system to recognise and destroy tumours is a promising new approach to treating these diseases. Dendritic cells (DC) are unique antigen-presenting cells that play a central role in the initiation and direction of immune responses. DC loaded ex vivo with tumour-associated antigens and administered as a vaccine have already shown promise in early clinical trials for a number of lymphoproliferative disorders, but the need for improvement is widely agreed. Recent advances in the understanding of basic DC biology and lessons from early clinical trials have provided exciting new insights into the generation of anti-tumour immune responses and the design of vaccine strategies. In this review we provide an overview of our current understanding of DC biology and their function in patients with lymphoproliferative disorders. We discuss the current status of clinical trials and new approaches to exploit the antigen presenting capacity of DC to design vaccines of the future. PMID:16373232

  17. Loss-of-function of the protein kinase C δ (PKCδ) causes a B-cell lymphoproliferative syndrome in humans

    PubMed Central

    Kuehn, Hye Sun; Niemela, Julie E.; Rangel-Santos, Andreia; Zhang, Mingchang; Pittaluga, Stefania; Stoddard, Jennifer L.; Hussey, Ashleigh A.; Evbuomwan, Moses O.; Priel, Debra A. Long; Kuhns, Douglas B.; Park, C. Lucy; Fleisher, Thomas A.; Uzel, Gulbu

    2013-01-01

    Defective lymphocyte apoptosis results in chronic lymphadenopathy and/or splenomegaly associated with autoimmune phenomena. The prototype for human apoptosis disorders is the autoimmune lymphoproliferative syndrome (ALPS), which is caused by mutations in the FAS apoptotic pathway. Recently, patients with an ALPS-like disease called RAS-associated autoimmune leukoproliferative disorder, in which somatic mutations in NRAS or KRAS are found, also were described. Despite this progress, many patients with ALPS-like disease remain undefined genetically. We identified a homozygous, loss-of-function mutation in PRKCD (PKCδ) in a patient who presented with chronic lymphadenopathy, splenomegaly, autoantibodies, elevated immunoglobulins and natural killer dysfunction associated with chronic, low-grade Epstein-Barr virus infection. This mutation markedly decreased protein expression and resulted in ex vivo B-cell hyperproliferation, a phenotype similar to that of the PKCδ knockout mouse. Lymph nodes showed intense follicular hyperplasia, also mirroring the mouse model. Immunophenotyping of circulating lymphocytes demonstrated expansion of CD5+CD20+ B cells. Knockdown of PKCδ in normal mononuclear cells recapitulated the B-cell hyperproliferative phenotype in vitro. Reconstitution of PKCδ in patient-derived EBV-transformed B-cell lines partially restored phorbol-12-myristate-13-acetate–induced cell death. In summary, homozygous PRKCD mutation results in B-cell hyperproliferation and defective apoptosis with consequent lymphocyte accumulation and autoantibody production in humans, and disrupts natural killer cell function. PMID:23430113

  18. Practical Management of CD30? Lymphoproliferative Disorders.

    PubMed

    Hughey, Lauren C

    2015-10-01

    Primary cutaneous CD30? lymphoproliferative disorders (LPDs) account for approximately 25% of cutaneous lymphomas. Although these LPDs are clinically heterogeneous, they can be indistinguishable histologically. Lymphomatoid papulosis rarely requires systemic treatment; however, multifocal primary cutaneous anaplastic large cell cutaneous lymphoma and large cell transformation of mycosis fungoides are typically treated systemically. As CD30? LPDs are rare, there is little published evidence to support a specific treatment algorithm. Most studies are case reports, small case series, or retrospective reviews. This article discusses various treatment choices for each of the CD30? disorders and offers practical pearls to aid in choosing an appropriate regimen. PMID:26433852

  19. Folliculotropic Mycosis Fungoides as a Posttransplant Lymphoproliferative Disorder.

    PubMed

    Spence-Shishido, Allyson; Streicher, Jenna L; George, Roshan P; Parker, Sareeta R; Lawley, Leslie P

    2015-09-01

    Posttransplant lymphoproliferative disorder (PTLD) is a known complication of solid organ transplantation. The majority are B cell in origin and related to Epstein-Barr virus infection. T-cell PTLD is much less common; most are Epstein-Barr virus negative and have a worse prognosis. Primary cutaneous T-cell lymphoma (CTCL) as a presentation of PTLD is rare. CTCL has a less favorable prognosis in transplant patients compared with that in immune-competent patients. Herein, we report a case of a 13-year-old boy who developed folliculotropic mycosis fungoides, a rare subtype of CTCL, subsequent to renal transplantation. To our knowledge, this is the first report of this type of PTLD in a pediatric patient. PMID:26283779

  20. Primary central nervous system posttransplant lymphoproliferative disorders.

    PubMed

    Castellano-Sanchez, Amilcar A; Li, Shiyong; Qian, Jiang; Lagoo, Anand; Weir, Edward; Brat, Daniel J

    2004-02-01

    Posttransplant lymphoproliferative disorders (PTLDs) represent a spectrum ranging from Epstein-Barr virus (EBV)-driven polyclonal lymphoid proliferations to EBV+ or EBV- malignant lymphomas. Central nervous system (CNS) PTLDs have not been characterized fully. We reviewed the clinical, radiologic, and pathologic features of 12 primary CNS PTLDs to define them more precisely. Patients included 10 males and 2 females (median age, 43.4 years) who were recipients of kidney (n = 5), liver (n = 2), heart (n = 2), peripheral blood stem cells (n = 2), or bone marrow (n = 1). All received immunosuppressive therapy. CNS symptoms developed 3 to 131 months (mean, 31 months) after transplantation. By neuroimaging, most showed multiple (3 to 9) intra-axial, contrast-enhancing lesions. Histologic sections showed marked expansion of perivascular spaces by large, cytologically malignant lymphoid cells that were CD45+, CD20+, EBV+ and showed light chain restriction or immunoglobulin gene rearrangement. In distinction to PTLDs in other organ systems, CNS PTLDs were uniformly high-grade lymphomas that fulfilled the World Health Organization criteria for monomorphic PTLDs. Extremely short survival periods were noted for each CNS PTLD that followed peripheral blood stem cell transplantation. Survival of others with CNS PTLD varied; some lived more than 2 years. PMID:14983939

  1. Posttransplant lymphoproliferative disorders following liver transplantation: Where are we now?

    PubMed Central

    Dierickx, Daan; Cardinaels, Nina

    2015-01-01

    Liver transplantation has emerged as a life-saving treatment for several patients with acute liver failure, end stage liver disease and primary hepatic malignancies. However, long term immunosuppressive therapy aiming to reduce the risk of transplant rejection increases the incidence of several complications including malignancies. This is illustrated by the observation of a high ratio between observed and expected cases of lymphoproliferative disorders following liver transplantation. Despite a huge heterogeneity in morphological appearance of these disorders ranging from reactive-like lesions to real lymphomas, they are collectively termed posttransplant lymphoproliferative disorders. In this review we will provide an overview of this rare but challenging disorder as a complication of liver transplantation. PMID:26494960

  2. Risk factors for lymphoproliferative disorders after allogeneic hematopoietic cell transplantation

    PubMed Central

    Gilbert, Ethel S.; Rizzo, J. Douglas; Soci, Grard; Banks, Peter M.; Sobocinski, Kathleen A.; Horowitz, Mary M.; Jaffe, Elaine S.; Kingma, Douglas W.; Travis, Lois B.; Flowers, Mary E.; Martin, Paul J.; Deeg, H. Joachim; Curtis, Rochelle E.

    2009-01-01

    We evaluated 26?901 patients who underwent allogeneic hematopoietic cell transplantation (HCT) at 271 centers worldwide to define patterns of posttransplantation lymphoproliferative disorders (PTLDs). PTLDs developed in 127 recipients, with 105 (83%) cases occurring within 1 year after transplantation. In multivariate analyses, we confirmed that PTLD risks were strongly associated (P < .001) with T-cell depletion of the donor marrow, antithymocyte globulin (ATG) use, and unrelated or HLA-mismatched grafts (URD/HLA mismatch). Significant associations were also confirmed for acute and chronic graft-versus-host disease. The increased risk associated with URD/HLA-mismatched donors (RR = 3.8) was limited to patients with T-cell depletion or ATG use (P = .004). New findings were elevated risks for age 50 years or older at transplantation (RR = 5.1; P < .001) and second transplantation (RR = 3.5; P < .001). Lower risks were found for T-cell depletion methods that remove both T and B cells (alemtuzumab and elutriation, RR = 3.1; P = .025) compared with other methods (RR = 9.4; P = .005 for difference). The cumulative incidence of PTLDs was low (0.2%) among 21?686 patients with no major risk factors, but increased to 1.1%, 3.6%, and 8.1% with 1, 2, and more than 3 major risk factors, respectively. Our findings identify subgroups of patients who underwent allogeneic HCT at elevated risk of PTLDs for whom prospective monitoring of Epstein-Barr virus activation and early treatment intervention may be particularly beneficial. PMID:19264919

  3. HTLV Tax gene expression in patients with lymphoproliferative disorders.

    PubMed Central

    Cardoso, E A; Miranda, N; Gameiro, P; Frade, M J; Figueiredo, M; Parreira, A

    1996-01-01

    AIMS: To study the expression of the human T lymphotropic virus (HTLV) Tax gene in peripheral blood mononuclear cells. METHODS: Blood was collected from 72 patients with lymphoproliferative disorders. Serum from all patients was assayed for antibodies directed against HTLV-I structural proteins by ELISA and western blotting. RNA was purified from fresh blood cells and amplified by reverse transcription polymerase chain reaction (RT-PCR). After Southern blotting, the PCR products were hybridised with a 32P end-labelled probe specific for the Tax gene. RESULTS: All samples were seronegative. A specific band for the Tax gene was found in five samples. Each of the patients positive for Tax gene expression had a different type of lymphoproliferative disorder. CONCLUSIONS: Infection by HTLV-I cannot be assessed solely by immunological assays, particularly when only disrupted virions are used. Sensitive molecular biology assays are essential for detecting viral gene expression in fresh blood cells. Images PMID:8944616

  4. Single-Fraction Radiotherapy for CD30+ Lymphoproliferative Disorders

    PubMed Central

    Gentile, Michelle S.; Martinez-Escala, Maria Estela; Thomas, Tarita O.; Guitart, Joan; Rosen, Steven; Kuzel, Timothy; Mittal, Bharat B.

    2015-01-01

    Objectives. CD30+ lymphoproliferative disorder is a rare variant of cutaneous T-cell lymphoma. Sustained complete response following first-line treatments is rare. This retrospective review evaluates the response of refractory or recurrent lesions to palliative radiation therapy. Methods. The records of 6 patients with 12 lesions, treated with radiation therapy, were reviewed. All patients received previous first-line treatments. Patients with clinical and pathological evidence of symptomatic CD30+ lymphoproliferative disorder, with no history of other cutaneous T-cell lymphoma variants, and with no prior radiation therapy to the index site were included. Results. The median age of patients was 50.5 years (range, 1583 years). Median size of the treated lesions was 2.5?cm (range, 27?cm). Four sites were treated with a single fraction of 750800?cGy (n = 3) and 8 sites were treated with 40004500?cGy in 200250?cGy fractions (n = 3). Radiation therapy was administered with electrons and bolus. Median follow-up was 113 months (range, 16147 months). For all sites, there was 100% complete response with acute grade 1-2 dermatitis. Conclusions. For recurrent and symptomatic radiation-nave CD30+ lymphoproliferative disorder lesions, palliative radiation therapy shows excellent response. A single fraction of 750800?cGy is as effective as a multifractionated course and more convenient. PMID:26504818

  5. PTEN and PI-3 kinase inhibitors control LPS signaling and the lymphoproliferative response in the CD19+ B cell compartment

    SciTech Connect

    Singh, Alok R.; Peirce, Susan K.; Joshi, Shweta; Durden, Donald L.

    2014-09-10

    Pattern recognition receptors (PRRs), e.g. toll receptors (TLRs) that bind ligands within the microbiome have been implicated in the pathogenesis of cancer. LPS is a ligand for two TLR family members, TLR4 and RP105 which mediate LPS signaling in B cell proliferation and migration. Although LPS/TLR/RP105 signaling is well-studied; our understanding of the underlying molecular mechanisms controlling these PRR signaling pathways remains incomplete. Previous studies have demonstrated a role for PTEN/PI-3K signaling in B cell selection and survival, however a role for PTEN/PI-3K in TLR4/RP105/LPS signaling in the B cell compartment has not been reported. Herein, we crossed a CD19cre and PTEN{sup fl/fl} mouse to generate a conditional PTEN knockout mouse in the CD19+ B cell compartment. These mice were further crossed with an IL-14α transgenic mouse to study the combined effect of PTEN deletion, PI-3K inhibition and expression of IL-14α (a cytokine originally identified as a B cell growth factor) in CD19+ B cell lymphoproliferation and response to LPS stimulation. Targeted deletion of PTEN and directed expression of IL-14α in the CD19+ B cell compartment (IL-14+PTEN-/-) lead to marked splenomegaly and altered spleen morphology at baseline due to expansion of marginal zone B cells, a phenotype that was exaggerated by treatment with the B cell mitogen and TLR4/RP105 ligand, LPS. Moreover, LPS stimulation of CD19+ cells isolated from these mice display increased proliferation, augmented AKT and NFκB activation as well as increased expression of c-myc and cyclinD1. Interestingly, treatment of LPS treated IL-14+PTEN-/- mice with a pan PI-3K inhibitor, SF1126, reduced splenomegaly, cell proliferation, c-myc and cyclin D1 expression in the CD19+ B cell compartment and normalized the splenic histopathologic architecture. These findings provide the direct evidence that PTEN and PI-3K inhibitors control TLR4/RP105/LPS signaling in the CD19+ B cell compartment and that pan PI-3 kinase inhibitors reverse the lymphoproliferative phenotype in vivo. - Highlights: • First genetic evidence that PTEN controls LPS/TLR4 signaling in B lymphocytes. • Evidence that PTEN regulates LPS induced lymphoproliferation in vivo. • PI-3 kinase inhibitors block LPS induced lymphoproliferation in vivo.

  6. Syk-induced phosphatidylinositol-3-kinase activation in Epstein-Barr virus posttransplant lymphoproliferative disorder.

    PubMed

    Hatton, O; Lambert, S L; Phillips, L K; Vaysberg, M; Natkunam, Y; Esquivel, C O; Krams, S M; Martinez, O M

    2013-04-01

    Posttransplant lymphoproliferative disorder (PTLD)-associated Epstein-Barr virus (EBV)+ B cell lymphomas are serious complications of solid organ and bone marrow transplantation. The EBV protein LMP2a, a B cell receptor (BCR) mimic, provides survival signals to virally infected cells through Syk tyrosine kinase. Therefore, we explored whether Syk inhibition is a viable therapeutic strategy for EBV-associated PTLD. We have shown that R406, the active metabolite of the Syk inhibitor fostamatinib, induces apoptosis and cell cycle arrest while decreasing downstream phosphatidylinositol-3'-kinase (PI3K)/Akt signaling in EBV+ B cell lymphoma PTLD lines in vitro. However, Syk inhibition did not inhibit or delay the in vivo growth of solid tumors established from EBV-infected B cell lines. Instead, we observed tumor growth in adjacent inguinal lymph nodes exclusively in fostamatinib-treated animals. In contrast, direct inhibition of PI3K/Akt significantly reduced tumor burden in a xenogeneic mouse model of PTLD without evidence of tumor growth in adjacent inguinal lymph nodes. Taken together, our data indicate that Syk activates PI3K/Akt signaling which is required for survival of EBV+ B cell lymphomas. PI3K/Akt signaling may be a promising therapeutic target for PTLD, and other EBV-associated malignancies. PMID:23398911

  7. Post-kidney transplant large bowel lymphoproliferative disorder.

    PubMed

    Singh, Neeraj; Samavedi, Singh; Rajab, Amer

    2014-05-01

    Epstein-Barr virus (EBV)-associated post-transplant lymphoproliferative disorder (PTLD) is a serious complication of organ transplantation. The gastrointestinal (GI) tract is a common site involved, but non-specific signs and symptoms often delay the diagnosis. We report a case of EBV-associated GI-PTLD in a 68-year-old kidney transplant patient who received the kidney ten months earlier. He presented with chronic diarrhea and developed massive pneumo-peritoneum secondary to multiple colonic perforations. PMID:24821162

  8. 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

  9. Hematopoietic Neoplasias in Horses: Myeloproliferative and Lymphoproliferative Disorders

    PubMed Central

    MUOZ, Ana; RIBER, Cristina; TRIGO, Pablo; CASTEJN, 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

  10. Multispectral Imaging Approach to the Diagnosis of a CD20+ Cutaneous T-cell Lymphoproliferative Disorder: A Case Report.

    PubMed

    Salva, Katrin A; Bennett, Daniel; Longley, Jack; Guitart, Joan; Wood, Gary S

    2015-10-01

    Expression of the pan B-cell marker CD20 by T-cell lymphoproliferative disorders is exceedingly rare. We present a 52-year-old man with a unilesional cutaneous CD20 T-cell lymphoproliferative disorder. Multispectral imaging analysis of CD3-CD20 double-stained lesional tissue sections allowed (1) the visualization of double-positive T lymphocytes in situ with sensitivity superior to that of conventional immunohistochemistry and (2) the quantitative assessment of marker coexpression. Here, 23% of CD3 signals in the patient's lesion were also CD20, whereas 38% of CD20 signals were also CD3. In contrast, both parameters were below 1% in the tonsil control. Overall, the percentage of double-positive cells in lesional skin was 35%, although only 0.4% of such cells were detected in the tonsil. This is the first demonstration of aberrant CD20 expression by skin-infiltrating T cells using multispectral imaging. PMID:26381030

  11. Role of IgG4 serology in identifying common orbital lymphoproliferative disorders

    PubMed Central

    Li, Jing; Ma, Jian-Min; Ge, Xin

    2016-01-01

    AIM To explore the role of IgG4 serology in identifying common orbital lymphoproliferative disorders. METHODS Eighty-one patients with orbital lymphoproliferative diseases were treated in the Department of Ocular Oncology, Beijing Tongren Hospital, Capital Medical University between September 2010 and December 2012. Serum IgG4 levels were measured in 46 cases of idiopathic orbital inflammatory pseudotumor (IOIP), 17 benign lymphoepithelial lesion (BLEL), 12 cases of orbital mucosa-associated lymphoid tissue (MALT), and 6 cases of diffuse large B-cell lymphoma (DLBL) using immuno-scatter turbidmetry (ISTM). RESULTS The frequency of elevated IgG4 levels in patients with IOIP, BLEL, MALT, and DLBL was 30.43% (14/46), 76.47% (13/17), 8.33% (1/12), and 0.00 (0/6), respectively. Among the patients with elevated serum IgG4 levels, all IgG-IOIP patients were male, and 92.31% of the IgG4-BLEL patients were female (12/13). The mean serum IgG4 level of IgG4-IOIP patients was lower than that of individuals with IgG4-BLEL, but the variation in serum IgG4 levels was larger in IgG4-IOIP than IgG4-BLEL patients. Only one case of IgG4-MALT with elevated serum IgG4 levels had a medical history >10y, which was significantly longer than the MALT patients with normal serum IgG4 levels. There was no significant elevation of serum IgG4 levels in patients with DLBL. CONCLUSION Detecting serum IgG4 levels plays an important role in the differential diagnosis of orbital lymphoproliferative diseases. PMID:26949650

  12. Monoclonal B-cell lymphocytosis in individuals from sporadic (non-familial) chronic lymphocytic leukemia families persists over time, but does not progress to chronic B-cell lymphoproliferative diseases

    PubMed Central

    Matos, Daniel Mazza; Furtado, Felipe Magalhes; Falco, Roberto Passetto

    2015-01-01

    Background Monoclonal B-cell lymphocytosis is classified as high-count or clinical monoclonal B-cell lymphocytosis and low-count or population monoclonal B-cell lymphocytosis. Previously, 167 first-degree relatives pertaining to sporadic (non-familial) chronic lymphocytic leukemia families were studied and the presence of seven monoclonal B-cell lymphocytosis individuals was reported. Objective The aim of this report is to describe the outcomes of five of the original monoclonal B-cell lymphocytosis individuals. Methods Flow cytometry analysis was performed on mononuclear cells previously isolated from peripheral blood samples. A strategy of sequential gating designed to identify the population of CD19+/CD5+ B-lymphocytes was used and, subsequently, the monoclonal B-cell lymphocytosis cells were characterized by the CD20weak/CD79bweak/negative phenotype. Results The monoclonal B-cell lymphocytosis clone showed consistent stability over time with little variations in size. After a median follow-up of 7.6 years, none of the five monoclonal B-cell lymphocytosis individuals progressed to chronic lymphocytic leukemia or other B-cell lymphoproliferative disease. Conclusions The data of this study suggest that chronic lymphocytic leukemia-like monoclonal B-cell lymphocytosis detected in the context of sporadic chronic lymphocytic leukemia families is not prone to clinical evolution and could be just a sign of immune senescence. PMID:26408361

  13. Treatment of Recurrent Posttransplant Lymphoproliferative Disorder with Autologous Blood Stem Cell Transplant

    PubMed Central

    Malhotra, Bharat; Rahal, Ahmad K.; Farhoud, Hussam; Moore, Dennis F.; Kallail, K. James

    2015-01-01

    Background. Posttransplant lymphoproliferative disorders (PTLDs) occur after solid organ transplantation. Treatment guidelines include reduction in immunosuppression (RIS), radiation, rituximab, chemotherapy, and immunological agents. We present a rare case of recurrent diffuse large B-cell lymphoma presenting as a PTLD in a heart transplant patient treated with autologous blood stem cell transplant (ASCT) after failure of conventional therapy. Case Presentation. A 66-year-old male presented with a neck mass. He has a history of Hodgkin's disease status after staging laparotomy with splenectomy and heart transplantation due to dilated nonischemic cardiomyopathy 8 years prior to the development of PTLD. His examination was remarkable for right submandibular swelling. An excisional biopsy confirmed the diagnosis of diffuse large B-cell NHL. Patient received RIS, rituximab, chemotherapy, and radiation therapy with a complete remission. His lymphoma relapsed and he subsequently was treated with RICE salvage chemotherapy and consolidative high-dose chemotherapy with BEAC regimen followed by ASCT resulting in a complete remission. Conclusion. Patients with PTLD present a difficult therapeutic challenge. In this case, the patient's prior history of Hodgkin's disease, splenectomy, and a heart transplant appear to be unique features, the significance of which is unclear. ASCT might be a promising therapy for patients with relapsed or refractory PTLD. PMID:26688773

  14. Cell sizing in chronic lymphoproliferative disorders: an aid to differential diagnosis.

    PubMed Central

    Alexander, H D; Markey, G M; Nolan, R L; Morris, T C

    1992-01-01

    AIMS: To determine if leucocyte volume distribution analysis (LVDA), obtained using a Coulter Counter Model S Plus IV, can be used to aid differentiation of chronic lymphoproliferative disorder (CLPD) subtypes. METHODS: Mean lymphocyte volume and lymphocyte distribution width were measured on each patient (n = 90) using a hard copy of an amplified LVDA histogram. The mean lymphocyte volume was taken as the mean of the values on either side of the peak at half maximum height. The lymphocyte distribution width was taken as the range of cell values between the two values used to calibrate the mean lymphocyte volume. A template showing typical histograms from commonly occurring CLPD was also produced on an acetate sheet. This was used to examine the histogram from each new patient to evaluate its usefulness as an alternative to the calculation of mean lymphocyte volume and lymphocyte distribution width. RESULTS: Mean lymphocyte volume and lymphocyte distribution width were significantly higher in B cell lymphocytic leukaemia of mixed cell type (B CLL/PL), B cell non-Hodgkin's lymphoma with peripheral blood spill, hairy cell leukaemia and T cell prolymphocytic leukaemia than in B cell chronic lymphocytic leukaemia (B CLL). The mean lymphocyte volume, but not the lymphocyte distribution width, was also significantly higher in T cell chronic lymphocytic leukaemia than in B CLL. The template gave an immediate preliminary indication of possible subtype(s) of disorder and could be used as an alternative to measurement of mean lymphocyte volume and lymphocyte distribution width. CONCLUSIONS: Electronic haematology analysers producing an LVDA provide a useful, cost effective cell sizing analysis which can aid the differentiation of subtypes of CLPD. Images PMID:1430257

  15. Post-transplant lymphoproliferative disorders with naso- and oropharyngeal manifestation.

    PubMed

    Akbas, Ayla; Tiede, Christina; Lemound, Juliana; Maecker-Kolhoff, Britta; Kreipe, Hans; Hussein, Kais

    2015-11-01

    The nasopharyngeal/oropharyngeal lymphatic tissues represent the anatomical site of Epstein-Barr virus (EBV) entry. Post-transplant lymphoproliferative disorders (PTLD) are often associated with EBV, but little is known about the characteristics of nasopharyngeal/oropharyngeal mass-forming PTLD. Retrospective evaluation of our own PTLD database (n=79) and the PubMed() database (n=61) has been performed. Sinonasal/oro-/nasopharyngeal lymphatic masses were early lesions (n=54/140, 38.5%), polymorphic PTLD (n=32/140, 23%), monomorphic B-PTLD (n=47/140, 33.5%) and T-PTLD (n=7/140, 5%). One-fourth of lesions manifested as masses in the Waldeyer's ring, and in two-thirds of cases, swelling of tonsils was related to manifestation of benign early lesions. Tonsil infiltration by polymorphic PTLD and monomorphic PTLD was present in one-third of cases. Extratonsillar masses were mainly monomorphic PTLD. Meta-analysis of our data in combination with previously published data revealed that lung transplantation and young patients are at a higher risk for earlier manifestation of monomorphic PTLD. Therapy is similar to PTLD therapy strategies, in general reduced immunosuppression and chemotherapy for polymorphic and monomorphic PTLD, and diagnostic and therapeutic surgical gross tumour resection of tonsillar/adenoid lesions. In summary, it is relevant for the clinical differential diagnosis that oro-/nasopharyngeal aggressive PTLD manifested in ~30% as tonsillar masses and >90% at extratonsillar sites. PMID:26147593

  16. Viruses, Immunity and Unusual Lymphoproliferative Disorders of the Chest: Integrating Imaging With Pathogenesis and Clinical Presentations.

    PubMed

    Law, Amy; Shmukler, Anna; Burns, Judah; Haramati, Linda Broyde

    2016-01-01

    Unusual lymphoproliferative diseases result from the stimulation of intrathoracic lymphoid tissue by viruses and immune dysfunction, ranging from benign hyperplasia to malignant transformation. We review the clinical, radiological, and histopathological findings of unusual lymphoproliferative disorders, which have been linked to viruses or immune dysfunction, focusing on thoracic manifestations. Understanding these advances in science enhances the radiologist's skills in integrating the imaging findings to the clinical scenario to suggest the correct diagnosis. PMID:26484956

  17. Syk-Induced Phosphatidylinositol-3-Kinase Activation in Epstein-Barr Virus Post-Transplant Lymphoproliferative Disorder

    PubMed Central

    Hatton, O.; Lambert, S. L.; Phillips, L. K.; Vaysberg, M.; Natkunam, Y.; Esquivel, C. O.; Krams, S. M.; Martinez, O. M.

    2012-01-01

    Post-transplant lymphoproliferative disorder (PTLD)-associated Epstein Barr virus (EBV)+ B-cell lymphomas are serious complications of solid organ and bone marrow transplantation. The EBV protein LMP2a, a B-cell receptor (BCR) mimic, provides survival signals to virally-infected cells through Syk tyrosine kinase. Therefore, we explored whether Syk inhibition is a viable therapeutic strategy for EBV-associated PTLD. We have shown that R406, the active metabolite of the Syk inhibitor fostamatinib, induces apoptosis and cell cycle arrest while decreasing downstream phosphatidylinositol-3′-kinase (PI3K)/Akt signaling in EBV+ B-cell lymphoma PTLD lines in vitro. However, Syk inhibition did not inhibit or delay the in vivo growth of solid tumors established from EBV-infected B-cell lines. Instead, we observed tumor growth in adjacent inguinal lymph nodes exclusively in fostamatinib-treated animals. In contrast, direct inhibition of PI3K/Akt significantly reduced tumor burden in a xenogeneic mouse model of PTLD without evidence of tumor growth in adjacent inguinal lymph nodes. Taken together, our data indicate that Syk activates PI3K/Akt signaling which is required for survival of EBV+ B-cell lymphomas. PI3K/Akt signaling may be a promising therapeutic target for PTLD, and other EBV-associated malignancies. PMID:23398911

  18. Post-Transplant Lymphoproliferative Disorders: Role of Viral Infection, Genetic Lesions and Antigen Stimulation in the Pathogenesis of the Disease

    PubMed Central

    Capello, Daniela; Gaidano, Gianluca

    2009-01-01

    Post-transplant lymphoproliferative disorders (PTLD) are a life-threatening complication of solid organ transplantation or, more rarely, hematopoietic stem cell transplantation. The majority of PTLD is of B-cell origin and associated with EpsteinBarr virus (EBV) infection. PTLD generally display involvement of extranodal sites, aggressive histology and aggressive clinical behavior. The molecular pathogenesis of PTLD involves infection by oncogenic viruses, namely EBV, as well as genetic or epigenetic alterations of several cellular genes. At variance with lymphoma arising in immunocompetent hosts, whose genome is relatively stable, a fraction of PTLD are characterized by microsatellite instability as a consequence of defects in the DNA mismatch repair mechanism. Apart from microsatellite instability, molecular alterations of cellular genes recognized in PTLD include alterations of cMYC, BCL6, TP53, DNA hypermethylation, and aberrant somatic hypermutation of protooncogenes. The occurrence of IGV mutations in the overwhelming majority of PTLD documents that malignant transformation targets germinal centre (GC) B-cells and their descendants both in EBVpositive and EBVnegative cases. Analysis of phenotypic markers of B-cell histogenesis, namely BCL6, MUM1 and CD138, allows further distinction of PTLD histogenetic categories. PTLD expressing the BCL6+/MUM1+/-/CD138? profile reflect B-cells actively experiencing the GC reaction, and comprise diffuse large B-cell lymphoma (DLBCL) centroblastic and Burkitt lymphoma. PTLD expressing the BCL6?/MUM1+/CD138? phenotype putatively derive from B-cells that have concluded the GC reaction, and comprise the majority of polymorphic PTLD and a fraction of DLBCL immunoblastic. A third group of PTLD is reminiscent of post-GC and preterminally differentiated B-cells that show the BCL6?/MUM1+/CD138+ phenotype, and are morphologically represented by either polymorphic PTLD or DLBCL immunoblastic. PMID:21416004

  19. 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

  20. Post-transplant lymphoproliferative disorders: from epidemiology to pathogenesis-driven treatment.

    PubMed

    Petrara, Maria Raffaella; Giunco, Silvia; Serraino, Diego; Dolcetti, Riccardo; De Rossi, Anita

    2015-12-01

    Post-transplant lymphoproliferative disorders (PTLDs) represent the most severe complication of both solid organ and hematopoietic stem cell transplantation. The Epstein-Barr Virus (EBV) is the main driver of PTLD, particularly those occurring early after transplantation. EBV-driven malignancies are associated with selective expression of latent viral proteins, but uncontrolled lytic replication may favor early phases of cell transformation. Besides immunodepression, persistent immune activation and chronic inflammation play an important role in both virus reactivation and expansion of EBV-infected B cells. EBV-induced immortalization requires the expression of telomerase. TERT, the rate-limiting component of the telomerase complex, is central in the switch from the lytic to the latent viral program, and TERT inhibition induces the EBV lytic cycle and cell death. Immunotherapy and combination of EBV lytic cycle inducers with antiviral drugs are promising strategies to improve the treatment of PTLD patients. This review is aimed at providing an update on the intriguing association between EBV and PTLD, mainly focusing on cases arising after kidney and liver transplantation, which account for the vast majority of transplants. PMID:26279520

  1. EpsteinBarr virus-positive T/NK-cell lymphoproliferative disorders

    PubMed Central

    Cai, Qingqing; Chen, Kailin; Young, Ken H

    2015-01-01

    EpsteinBarr virus, a ubiquitous human herpesvirus, can induce both lytic and latent infections that result in a variety of human diseases, including lymphoproliferative disorders. The oncogenic potential of EpsteinBarr virus is related to its ability to infect and transform B lymphocytes into continuously proliferating lymphoblastoid cells. However, EpsteinBarr virus has also been implicated in the development of T/natural killer cell lymphoproliferative diseases. EpsteinBarr virus encodes a series of products that mimic several growth, transcription and anti-apoptotic factors, thus usurping control of pathways that regulate diverse homeostatic cellular functions and the microenvironment. However, the exact mechanism by which EpsteinBarr virus promotes oncogenesis and inflammatory lesion development remains unclear. EpsteinBarr virus-associated T/natural killer cell lymphoproliferative diseases often have overlapping clinical symptoms as well as histologic and immunophenotypic features because both lymphoid cell types derive from a common precursor. Accurate classification of EpsteinBarr virus-associated T/natural killer cell lymphoproliferative diseases is a prerequisite for appropriate clinical management. Currently, the treatment of most T/natural killer cell lymphoproliferative diseases is less than satisfactory. Novel and targeted therapies are strongly required to satisfy clinical demands. This review describes our current knowledge of the genetics, oncogenesis, biology, diagnosis and treatment of EpsteinBarr virus-associated T/natural killer cell lymphoproliferative diseases. PMID:25613730

  2. B-cell survival factors in autoimmune rheumatic disorders

    PubMed Central

    Morais, Sandra A.; Vilas-Boas, Andreia

    2015-01-01

    Autoimmune rheumatic disorders have complex etiopathogenetic mechanisms in which B cells play a central role. The importance of factors stimulating B cells, notably the B-cell activating factor (BAFF) and A proliferation inducing ligand (APRIL) axis is now recognized. BAFF and APRIL are cytokines essential for B-cell proliferation and survival from the immature stages to the development of plasma cells. Their levels are increased in some subsets of patients with autoimmune disorders. Several recent biologic drugs have been developed to block this axis, namely belimumab [already licensed for systemic lupus erythematosus (SLE) treatment], tabalumab, atacicept and blisibimod. Many clinical trials to evaluate the safety and efficacy of these drugs in several autoimmune disorders are ongoing, or have been completed recently. This review updates the information on the use of biologic agents blocking BAFF/APRIL for patients with SLE, rheumatoid arthritis, Sjögren’s syndrome and myositis. PMID:26288664

  3. Ibrutinib: another weapon in our arsenal against lympho-proliferative disorders.

    PubMed

    Cabras, Maria Giuseppina; Angelucci, Emanuele

    2015-12-01

    In Volume 16, issue 12 of Expert Opinion on Pharmacotherapy, an important article on the new drug ibrutinib was published. This new drug promises to further improve outcome in the treatment of several lympho-proliferative disorders. In this editorial, the most important findings of the article looking particularly to the integration of ibrutinib in current clinical practice will be summarized. Finally this editorial will focus on the next challenges for scientists and physicians in the treatment of lympho-proliferative disorders. PMID:26549294

  4. The MYC/miR-17-92 axis in lymphoproliferative disorders: A common pathway with therapeutic potential

    PubMed Central

    Hernndez, Luis; Gattei, Valter

    2015-01-01

    MicroRNAs (miRNAs) represent a class of small non-coding single-stranded RNA molecules acting as master regulators of gene expression post transcriptionally by inhibiting the translation or inducing the degradation of target messenger RNAs (mRNAs). In particular, the miR-17-92 cluster is widely expressed in many different cell types and is essential for many developmental and pathogenic processes. As a strong oncogene, miR-17-92 can regulate multiple cellular processes that favor malignant transformation, promoting cell survival, rapid cell proliferation, and increased angiogenesis. The miR-17-92 cluster has been reported to be involved in hematopoietic malignancies including diffuse large B-cell lymphoma, mantle cell lymphoma, Burkitt's lymphoma, and chronic lymphocytic leukemia. Given the multiple and potent effects on cellular proliferation and apoptosis exerted by the miR-17-92 cluster, miRNAs belonging to the cluster surely represent attractive targets for cancer therapy also in the context of lymphoproliferative disorders. In the present review, we focus on the role of the miR-17-92 cluster in lymphoproliferative disorders, including diagnostic/prognostic implications, and on the potential applications of anti-miRNAs based therapies targeting miRNAs belonging to the cluster. PMID:26305986

  5. Yttrium Y 90 Ibritumomab Tiuxetan and Rituximab in Treating Patients With Post-Transplant Lymphoproliferative Disorder

    ClinicalTrials.gov

    2013-01-24

    Post-transplant Lymphoproliferative Disorder; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Stage III Adult Burkitt Lymphoma; Stage III Adult Diffuse Large Cell Lymphoma; Stage IV Adult Burkitt Lymphoma; Stage IV Adult Diffuse Large Cell Lymphoma; Waldenström Macroglobulinemia

  6. Lymphoproliferative disorders in inflammatory bowel disease patients on immunosuppression: Lessons from other inflammatory disorders

    PubMed Central

    Lam, Grace Y; Halloran, Brendan P; Peters, Anthea C; Fedorak, Richard N

    2015-01-01

    Immunosuppressive agents, such as thiopurines, methotrexate, and biologics, have revolutionized the treatment of inflammatory bowel disease (IBD). However, a number of case reports, case control studies and retrospective studies over the last decade have identified a concerning link between immunosuppression and lymphoproliferative disorders (LPDs), the oncological phenomenon whereby lymphocytes divide uncontrollably. These LPDs have been associated with Epstein-Barr virus (EBV) infection in which the virus provides the impetus for malignant transformation while immunosuppression hampers the immune systems ability to detect and clear these malignant cells. As such, the use of immunosuppressive agents may come at the cost of increased risk of developing LPD. While little is known about the LPD risk in IBD, more is known about immunosuppression in the post-transplantation setting and the development of EBV associated post-transplantation lymphoproliferative disorders (PTLD). In review of the PTLD literature, evidence is available to demonstrate that certain immune suppressants such as cyclosporine and T-lymphocyte modulators in particular are associated with an increased risk of PTLD development. As well, high doses of immunosuppressive agents and multiple immunosuppressive agent use are also linked to increased PTLD development. Here, we discuss these findings in context of IBD and what future studies can be taken to understand and reduce the risk of EBV-associated LPD development from immunosuppression use in IBD. PMID:26600976

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

    PubMed

    Ribera, Jordi; Zamora, Lurdes; Junc, Jordi; Rodrguez, Ins; Marc, Silvia; Cabezn, Marta; Mill, 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

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

    PubMed

    Ribera, Jordi; Zamora, Lurdes; Junc, Jordi; Rodrguez, Ins; Marc, Silvia; Cabezn, Marta; Mill, 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. Epstein-Barr virus latent membrane protein-1 oncogene deletion in post-transplantation lymphoproliferative disorders.

    PubMed Central

    Scheinfeld, A. G.; Nador, R. G.; Cesarman, E.; Chadburn, A.; Knowles, D. M.

    1997-01-01

    Epstein-Barr virus (EBV) latent membrane protein 1 (LMP1) is a multifunctional oncoprotein. A 30-bp deletion of the 3' end of the LMP1 gene (del-LMP1) has been identified in some EBV isolates. This deleted LMP1 gene encodes a protein, altered on the carboxy terminus, which is thought to have greater oncogenic potential than the wild type. Recently, it was suggested that del-LMP1 plays a role in the development of malignant lymphomas occurring in immunocompromised patients. To further elucidate the role of del-LMP1 in post-transplantation lymphoproliferative disorders (PT-LPDs) we analyzed 58 PT-LPD lesions from 36 heart and kidney organ transplant recipients. Overall, del-LMP1 was detected in 44% of the cases. Four plasmacytic hyperplasias (36%), eight polymorphic B-cell hyperplasias/polymorphic B-cell lymphomas (38%), and five malignant lymphomas/multiple myelomas (71%) exhibited del-LMP1. Two of the three patients displaying disease progression showed wild-type LMP1 gene (w-LMP1) and one showed del-LMP1. LMP1 status remained the same in all three patients during disease progression. In patients undergoing biopsy of multiple separate PT-LPD lesions representing different clonal lymphoid proliferations, LMP1 status was the same in all of the lesions in each patient. Furthermore, although the polyclonal lesions harbor multiple EBV infectious events, they either showed w- or del-LMP1 but not both. Analysis of the tissues without an apparent PT-LPD (peripheral blood, bone marrow, or colon) revealed EBV and LMP1 type identical to that found in the lesions. In conclusion, the presence or absence of del-LMP1 in PT-LPDs does not correlate with the histopathological category or the malignant nature of the lymphoid proliferation. LMP1 status does not change during disease progression and is the same within multiple lesions occurring in the same patient regardless of their clonal relationship. These findings suggest that 1) EBV infection in patients with PT-LPDs occurs with a w- or del-LMP1-type EBV isolate and does not change once a patient acquires the virus and 2) the infection is an early event in the development of PT-LPDs and transformation is induced regardless of the type of LMP1. Images Figure 1 Figure 2 Figure 3 PMID:9284829

  10. Comparison of non-myeloablative conditioning regimens for lymphoproliferative disorders.

    PubMed

    Hong, S; Le-Rademacher, J; Artz, A; McCarthy, P L; Logan, B R; Pasquini, M C

    2015-03-01

    Hematopoietic cell transplantation (HCT) with non-myeloablative (NMA) conditioning for lymphoproliferative diseases (LD) includes fludarabine with and without low-dose TBI. Transplant outcomes were compared among patients aged ?40 years with LD who received a HCT with TBI (N=382) or no-TBI (N=515) NMA from 2001 to 2011. The groups were comparable except for donor, graft, prophylaxis for GVHD, disease status and year of HCT. Cumulative incidences of grades II-IV GVHD at 100 days were 29% and 20% (P=0.001) and of chronic GVHD at 1 year were 54% and 44% (P=0.004) for TBI and no-TBI, respectively. Multivariate analysis of progression/relapse, treatment failure and mortality showed no outcome differences by conditioning. Full donor chimerism at day 100 was observed in 82% vs 64% in the TBI and no-TBI groups, respectively (P=0.006). Subsets of the four most common conditioning/GVHD prophylaxis combinations demonstrated higher rates of grades II-IV acute (P<0.001) and chronic GVHD (P<0.001) among recipients of TBI-mycophenolate mofetil (MMF) compared with other combinations. TBI-based NMA conditioning induces faster full donor chimerism, but overall survival outcomes are comparable to no-TBI regimens. Combinations of TBI and MMF are associated with higher rates of GVHD without impact on survival outcomes in patients with LD. PMID:25437248

  11. Comparison of Non-myeloablative Conditioning Regimens for Lymphoproliferative Disorders

    PubMed Central

    Hong, Sanghee; Le-Rademacher, Jennifer; Artz, Andrew; McCarthy, Philip L.; Logan, Brent R.; Pasquini, Marcelo C.

    2014-01-01

    Hematopoietic cell transplantation (HCT) with non-myeloablative conditioning (NMA) for lymphoproliferative diseases (LD) includes fludarabine with and without low-dose total body irradiation (TBI). Transplant outcomes were compared among patients ?40 years with LD who received a HCT with TBI (N=382) and no-TBI (N=515) NMA from 2001 to 2011. The groups were comparable except for donor, graft, prophylaxis for graft-versus-host disease (GVHD), disease status and year of HCT. Cumulative incidences of grades IIIV GVHD at 100 days, were 29% and 20% (p=0.001), and chronic GVHD at 1 year were 54% and 44% (p=0.004) for TBI and no-TBI, respectively. Multivariate analysis of progression/relapse, treatment failure and mortality showed no outcome differences by conditioning. Full donor chimerism at day 100 was observed in 82% vs. 64% in the TBI and no-TBI groups, respectively (p=0.006). Subset of four most common conditioning/ GVHD prophylaxis combinations demonstrated higher rates of grades IIIV acute (p<0.001) and chronic GVHD (p<0.001) among recipients of TBI-mycophenolate mofetil (MMF) compared to other combinations. TBI-based NMA conditioning induces faster full donor chimerism but overall survival outcomes are comparable to no-TBI regimens. Combination of TBI and MMF are associated with higher rates of GVHD without impact on survival outcomes in patients with LD. PMID:25437248

  12. Deficiency of Rap1-binding protein RAPL causes lymphoproliferative disorders through mislocalization of p27kip1.

    PubMed

    Katagiri, Koko; Ueda, Yoshihiro; Tomiyama, Takashi; Yasuda, Kaneki; Toda, Yoshinobu; Ikehara, Susumu; Nakayama, Keiichi I; Kinashi, Tatsuo

    2011-01-28

    RAPL (an alternative spliced form of Rassf5) is a critical Ras-related protein1 (Rap1) effector that regulates lymphocyte adhesion. Here, we have shown that in addition to this previously described function, RAPL also negatively controls lymphocyte proliferation and prevents autoimmunity and lymphoma. RAPL-deficient mice experienced age-related lupus-like glomerulonephritis and developed B cell lymphomas. RAPL-deficient lymphocytes showed hyperproliferation by enhanced S phase entry after antigen receptor ligation. Compared to wild-type cells, RAPL-deficient naive lymphocytes had a 2- to 3-fold increase in Cdk2 kinase activity with a cytoplasmic mislocalization of the cyclin-dependent kinase inhibitor p27(kip1). RAPL was found to suppress the phosphorylation of p27(kip1) on serine 10 (S10) and promoted p27(kip1) nuclear translocation. An S10A mutation in p27(kip1) corrected its cytoplasmic accumulation, reduced hyperproliferation in RAPL-deficient lymphocytes, and suppressed glomerulonephritis and development of B cell lymphoma. Thus, RAPL serves as a checkpoint for S phase entry to prevent lymphoproliferative disorders through the spatial regulation of p27(kip1). PMID:21194982

  13. Late Onset Epstein Barr Virus Seropositive Posttransplant Lymphoproliferative Disorder in Two Renal Transplant Receivers

    PubMed Central

    Payda?, Saime; Payda?, Semra; Balal, Mustafa; A?kal?n, Arbil; Ergin, Melek; Grkan, Emel; Ba?lam??l?, Fikri

    2013-01-01

    Posttransplant malignancy is one of the most important complications of organ transplantation. Immunosuppressive drugs, viral infections such as human herpes virus 8 or Epstein-Barr virus, exposure to carcinogenic factors such as sun, and host factors can be etiologic factors in the development of malignant disease. In this paper we report 2 cases of late posttransplant lymphoproliferative disorder with malign behavior. Conflict of interest:None declared. PMID:24385813

  14. Post-transplant lymphoproliferative disorder following cytomegalovirus reactivation in a lung recipient.

    PubMed

    Aoyama, Akihiro; Omasa, Mitsugu; Kondo, Nobuyuki; Chen, Fengshi; Date, Hiroshi; Bando, Toru

    2010-05-01

    Post-transplant lymphoproliferative disorder (PTLD) is a life-threatening complication after lung transplantation, for which several risk factors including pretransplant seronegativity for Epstein-Barr virus are known. However, the impact of cytomegalovirus on PTLD remains to be determined. Here, we describe a case of Epstein-Barr virus-associated polymorphic PTLD that developed shortly after treatment for cytomegalovirus reactivation in a lung transplant recipient who was preoperatively seropositive for both cytomegalovirus and Epstein-Barr virus. PMID:20449718

  15. Posttransplant lymphoproliferative disorder presenting as a small bowel obstruction in a patient with pancreas transplantation alone

    PubMed Central

    Kruel, Cleber R.; Shiller, S. Michelle; Anthony, Tiffany L.; Goldstein, Robert M.; Kim, Peter T. W.; Levy, Marlon F.; McKenna, Gregory J.; Onaca, Nicholas; Testa, Giuliano; Klintmalm, Goran B.

    2014-01-01

    Posttransplant lymphoproliferative disorder (PTLD) is a well-known complication associated with the transplant recipient. We chronicle a case of PTLD in a failed graft presenting as a small bowel obstruction in a pancreas-only transplant patient. While typical symptoms may be elusive in the complex immunosuppressed patient, graft pain along with persistent graft pancreatitis and a positive Epstein-Barr viremia should raise suspicion for an underlying PTLD. PMID:25484508

  16. Croup as Unusual Presentation of Post-transplantation Lymphoproliferative Disorder after Liver Transplantation in an 18-month-old Child

    PubMed Central

    Keshtkari, A.; Dehghani, S. M.; Haghighat, M.; Imanieh, M. H.; Nasimfard, A.; Yousefi, G.; Javaherizadeh, H.

    2016-01-01

    Post-transplantation lymphoproliferative disorder (PTLD) is a serious complication of solid organ transplantation that occurs due to immunosuppression and other risk factors. PTLD may present with involvement of other organs and with unusual presentation. The presentation is often extranodal (e.g., in the gastrointestinal tract, lung, or the central nervous system). Herein, we report on a 1.5-year-old girl who underwent liver transplantation almost 5 months prior to admission. She was on medications such as tacrolimus and prednisolone. Her presentation was started with symptoms of the upper respiratory infection followed by croupy cough and respiratory distress with no response to usual treatments. She had respiratory arrest during broncoscopy. Therefore, emergency tracheostomy was done. Biopsy from the paratracheal mass revealed large B cell non-Hodgkin lymphoma (PTLD, monomorphic and high grade). This case presentation shows that persistent upper airway symptoms, particularly stridor and croupy cough, in children who underwent liver transplant should be further evaluated; the physician needs to have a high degree of clinical suspicion for the diagnosis of PTLD in this situation. PMID:26889375

  17. Croup as Unusual Presentation of Post-transplantation Lymphoproliferative Disorder after Liver Transplantation in an 18-month-old Child.

    PubMed

    Keshtkari, A; Dehghani, S M; Haghighat, M; Imanieh, M H; Nasimfard, A; Yousefi, G; Javaherizadeh, H

    2016-01-01

    Post-transplantation lymphoproliferative disorder (PTLD) is a serious complication of solid organ transplantation that occurs due to immunosuppression and other risk factors. PTLD may present with involvement of other organs and with unusual presentation. The presentation is often extranodal (e.g., in the gastrointestinal tract, lung, or the central nervous system). Herein, we report on a 1.5-year-old girl who underwent liver transplantation almost 5 months prior to admission. She was on medications such as tacrolimus and prednisolone. Her presentation was started with symptoms of the upper respiratory infection followed by croupy cough and respiratory distress with no response to usual treatments. She had respiratory arrest during broncoscopy. Therefore, emergency tracheostomy was done. Biopsy from the paratracheal mass revealed large B cell non-Hodgkin lymphoma (PTLD, monomorphic and high grade). This case presentation shows that persistent upper airway symptoms, particularly stridor and croupy cough, in children who underwent liver transplant should be further evaluated; the physician needs to have a high degree of clinical suspicion for the diagnosis of PTLD in this situation. PMID:26889375

  18. 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

  19. Methotrexate-associated lymphoproliferative disorders of the tongue developing in patients with rheumatoid arthritis: a report of 2 cases and a review.

    PubMed

    Hashimoto, Kengo; Nagao, Toru; Saito, Terumi; Kinoshita, Hiroyuki

    2015-01-01

    Incidences of lymphoproliferative disorders (LPDs) in patients with compromised immune systems associated with immunosuppressants such as methotrexate (MTX) administered for the treatment of rheumatoid arthritis (RA) are reportedly increasing. Although extranodal lesions develop in half of the patients with MTX-associated LPDs, only a few studies have reported on intraoral lesions. We evaluated 2 elderly women with MTX-associated LPDs who had received MTX for the treatment of RA and presented with atypical ulceration of the tongue. Biopsy specimens demonstrated polymorphous B-cell LPD, probably associated with MTX. Epstein-Barr virus (EBV) was identified by immunohistochemistry for latent membrane protein 1 and by EBV-encoded RNA in situ hybridization. After MTX withdrawal, in both cases, ulcers showed complete regression at 8 weeks, and no subsequent treatment was required. Close monitoring of LPDs is mandatory, because recurrence within 10 months has been reported in half of the patients in whom LPDs had initially regressed. PMID:24927637

  20. Combined immunodeficiency with life-threatening EBV-associated lymphoproliferative disorder in patients lacking functional CD27.

    PubMed

    Salzer, Elisabeth; Daschkey, Svenja; Choo, Sharon; Gombert, Michael; Santos-Valente, Elisangela; Ginzel, Sebastian; Schwendinger, Martina; Haas, Oskar A; Fritsch, Gerhard; Pickl, Winfried F; Frster-Waldl, Elisabeth; Borkhardt, Arndt; Boztug, Kaan; Bienemann, Kirsten; Seidel, Markus G

    2013-03-01

    CD27, a tumor necrosis factor receptor family member, interacts with CD70 and influences T-, B- and NK-cell functions. Disturbance of this axis impairs immunity and memory generation against viruses including Epstein Barr virus (EBV), influenza, and others. CD27 is commonly used as marker of memory B cells for the classification of B-cell deficiencies including common variable immune deficiency. Flow cytometric immunophenotyping including expression analysis of CD27 on lymphoid cells was followed by capillary sequencing of CD27 in index patients, their parents, and non-affected siblings. More comprehensive genetic analysis employed single nucleotide polymorphism-based homozygosity mapping and whole exome sequencing. Analysis of exome sequencing data was performed at two centers using slightly different data analysis pipelines, each based on the Genome Analysis ToolKit Best Practice version 3 recommendations. A comprehensive clinical characterization was correlated to genotype. We report the simultaneous confirmation of human CD27 deficiency in 3 independent families (8 patients) due to a homozygous mutation (p. Cys53Tyr) revealed by whole exome sequencing, leading to disruption of an evolutionarily conserved cystein knot motif of the transmembrane receptor. Phenotypes varied from asymptomatic memory B-cell deficiency (n=3) to EBV-associated hemophagocytosis and lymphoproliferative disorder (LPD; n=3) and malignant lymphoma (n=2; +1 after LPD). Following EBV infection, hypogammaglobulinemia developed in at least 3 of the affected individuals, while specific anti-viral and anti-polysaccharide antibodies and EBV-specific T-cell responses were detectable. In severely affected patients, numbers of iNKT cells and NK-cell function were reduced. Two of 8 patients died, 2 others underwent allogeneic hematopoietic stem cell transplantation successfully, and one received anti-CD20 (rituximab) therapy repeatedly. Since homozygosity mapping and exome sequencing did not reveal additional modifying factors, our findings suggest that lack of functional CD27 predisposes towards a combined immunodeficiency associated with potentially fatal EBV-driven hemo-phagocytosis, lymphoproliferation, and lymphoma development. PMID:22801960

  1. Combined immunodeficiency with life-threatening EBV-associated lymphoproliferative disorder in patients lacking functional CD27

    PubMed Central

    Salzer, Elisabeth; Daschkey, Svenja; Choo, Sharon; Gombert, Michael; Santos-Valente, Elisangela; Ginzel, Sebastian; Schwendinger, Martina; Haas, Oskar A.; Fritsch, Gerhard; Pickl, Winfried F.; Frster-Waldl, Elisabeth; Borkhardt, Arndt; Boztug, Kaan; Bienemann, Kirsten; Seidel, Markus G.

    2013-01-01

    CD27, a tumor necrosis factor receptor family member, interacts with CD70 and influences T-, B- and NK-cell functions. Disturbance of this axis impairs immunity and memory generation against viruses including Epstein Barr virus (EBV), influenza, and others. CD27 is commonly used as marker of memory B cells for the classification of B-cell deficiencies including common variable immune deficiency. Flow cytometric immunophenotyping including expression analysis of CD27 on lymphoid cells was followed by capillary sequencing of CD27 in index patients, their parents, and non-affected siblings. More comprehensive genetic analysis employed single nucleotide polymorphism-based homozygosity mapping and whole exome sequencing. Analysis of exome sequencing data was performed at two centers using slightly different data analysis pipelines, each based on the Genome Analysis ToolKit Best Practice version 3 recommendations. A comprehensive clinical characterization was correlated to genotype. We report the simultaneous confirmation of human CD27 deficiency in 3 independent families (8 patients) due to a homozygous mutation (p. Cys53Tyr) revealed by whole exome sequencing, leading to disruption of an evolutionarily conserved cystein knot motif of the transmembrane receptor. Phenotypes varied from asymptomatic memory B-cell deficiency (n=3) to EBV-associated hemophagocytosis and lymphoproliferative disorder (LPD; n=3) and malignant lymphoma (n=2; +1 after LPD). Following EBV infection, hypogammaglobulinemia developed in at least 3 of the affected individuals, while specific anti-viral and anti-polysaccharide antibodies and EBV-specific T-cell responses were detectable. In severely affected patients, numbers of iNKT cells and NK-cell function were reduced. Two of 8 patients died, 2 others underwent allogeneic hematopoietic stem cell transplantation successfully, and one received anti-CD20 (rituximab) therapy repeatedly. Since homozygosity mapping and exome sequencing did not reveal additional modifying factors, our findings suggest that lack of functional CD27 predisposes towards a combined immunodeficiency associated with potentially fatal EBV-driven hemo-phagocytosis, lymphoproliferation, and lymphoma development. PMID:22801960

  2. Monomorphic post-transplant T-lymphoproliferative disorder after autologous stem cell transplantation for multiple myeloma.

    PubMed

    Ishikawa, Tetsuya; Shimizu, Hiroaki; Takei, Toshifumi; Koya, Hiroko; Iriuchishima, Hirono; Hosiho, Takumi; Hirato, Junko; Kojima, Masaru; Handa, Hiroshi; Nojima, Yoshihisa; Murakami, Hirokazu

    2016-01-01

    We report a rare case of T cell type monomorphic post-transplant lymphoproliferative disorders (PTLD) after autologous stem cell transplantation. A 53-year-old man with multiple myeloma received autologous stem cell transplantation and achieved a very good partial response. Nine months later, he developed a high fever and consciousness disturbance, and had multiple swollen lymph nodes and a high titer of Epstein-Barr (EB) virus DNA in his peripheral blood. Neither CT nor MRI of the brain revealed any abnormalities. Cerebrospinal fluid contained no malignant cells, but the EB virus DNA titer was high. Lymph node biopsy revealed T cell type monomorphic PTLD. Soon after high-dose treatment with methotrexate and cytosine arabinoside, the high fever and consciousness disturbance subsided, and the lymph node swelling and EB virus DNA disappeared. Given the efficacy of chemotherapy in this case, we concluded that the consciousness disturbance had been induced by central nervous system involvement of monomorphic PTLD. PMID:26861102

  3. Post-transplant lymphoproliferative disorders and Epstein-Barr virus DNAemia in a cohort of lung transplant recipients

    PubMed Central

    2011-01-01

    Background Post-transplant lymphoproliferative disorders (PTLD) are serious complications in lung transplant recipients. No consensus on EBV DNAemia levels predictive of PTLD has been reached. In addition, in many instances EBV DNAemia is determined in patients with suggestive symptoms only. Methods The characteristics of five patients with PTLD as well as the prevalence of EBV DNAmia in a cohort of 137 consecutive patients receiving lung transplantation are described. Results Twenty-six out of 137 patients (18.9%) were excluded from the analysis because lost at follow-up or dead from PTLD-independent reasons within three months of transplantation. EBV DNA in peripheral blood mononuclear cells (PBMC) was determined in 83/111 patients (74.8%) because of potential PTLD-related symptoms, while 28 patients (25.2%) showed no symptoms and were not examined. EBV DNAemia was positive in 53/83 patients (63.8%), and negative in 30/83 patients (36.2%). PTLD was diagnosed in five (4.5%) patients at a median time of 270 (range 120-870) days following transplantation. All five PTLD (three large B-cell lymphomas, one Hodgkin lymphoma and one possible pre-neoplastic lesion) were potentially associated with EBV infection. However, only 3/5 patients with PTLD had detectable EBV DNAemia: < 1,000 copies EBV DNA/1 × 105 PBMC in one patient and > 1,000 copies EBV DNA/1 × 105 PBMC in two patients. Conclusion A systematic multidisciplinary (clinical, radiologic, virologic and histologic) approach is mandatory for the diagnosis and management of PTLD in lung transplant recipients, while monitoring of symptomatic patients only may provide an incomplete or late picture of the clinical problem. In addition, staining for EBV antigens and quantification of EBV DNA in biopsy specimens should always be performed to understand the role of EBV infection in the pathogenesis of PTLD. PMID:21892950

  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

    2015-11-12

    Post-Transplant Lymphoproliferative Disorder; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent B-Cell Non-Hodgkin Lymphoma; Refractory B-Cell Non-Hodgkin Lymphoma; Refractory Burkitt Lymphoma; Refractory Diffuse Large B-Cell Lymphoma

  5. Posttransplant lymphoproliferative disorder presenting as multiple cystic lesions in a renal transplant recipient.

    PubMed

    Moir, J A G; Simms, R J; Wood, K M; Talbot, D; Kanagasundaram, N S

    2012-01-01

    We report a case of a 67-year-old man who experienced allograft dysfunction following a renal transplantation from a donation after cardiac death. The postoperative course was initially complicated by episodes of E. coli urinary sepsis causing pyrexia and a raised creatinine level. Ultrasound scanning 5 weeks posttransplant revealed mild hydronephrosis with several parenchymal cystic areas measuring up to 2 cm with appearances suggestive of fungal balls. Aspirated fluid again grew Escherichia coli, and this was treated with the appropriate antimicrobial therapy. The patient continued to have episodes of culture-negative sepsis; therefore, a computed tomography scan was performed 6 months posttransplant, which revealed multiple lesions in the renal cortex as well as liver and spleen. Subsequent biopsy revealed an Epstein-Barr virus-driven lymphoproliferation consistent with a polymorphic posttransplantation lymphoproliferative disorder (PTLD). This rare case of PTLD presenting as multiple renal, hepatic and splenic lesions emphasizes the need for a high index of clinical suspicion for this condition. Abnormal para-renal allograft masses should be biopsied to allow swift and effective management of a disease that can disseminate and become significantly more challenging to manage. PMID:22244123

  6. Posttransplant lymphoproliferative disorder in adult liver transplant recipients: a report of seventeen cases.

    PubMed

    Patel, Himisha; Vogl, Dan T; Aqui, Nicole; Shaked, Abraham; Olthoff, Kim; Markmann, James; Reddy, Rajender; Stadtmauer, Edward A; Schuster, Stephen; Tsai, Donald E

    2007-05-01

    Posttransplant lymphoproliferative disorder (PTLD) is a major complication of liver transplantation, but previous descriptions have been limited to case reports and small case series. We report a retrospective analysis of 17 consecutive cases of PTLD associated with liver transplantation. The median age at PTLD diagnosis was 47 years (range 19 - 63) with a median time of 25 months from liver transplantation to PTLD diagnosis (range 3 - 75). PTLD location was frequently extranodal (71%) and involved the transplanted liver (41%). PTLD histology consisted of nine (53%) monomorphic and eight (47%) polymorphic disease. EBV was present by in situ hybridization in 11 (79%) of 14 cases evaluated. Initial therapy included reduction in immunosuppression (RI) alone in 13 (76%) of 17 patients, resulting in 6 (46%) complete responses (CR) and 7 (54%) progressive disease (PD). Monoclonal CD20 antibody (rituximab) and CHOP chemotherapy were used as initial therapy or as second line after RI failure. Currently, five patients (29%) are alive in CR. Although detection and treatment of PTLD in liver transplant recipients remains problematic and upfront mortality is still high, long-term survival is possible. Further studies are necessary to better define treatment strategies. PMID:17487731

  7. Approaches to Managing Autoimmune Cytopenias in Novel Immunological Disorders with Genetic Underpinnings Like Autoimmune Lymphoproliferative Syndrome

    PubMed Central

    Rao, V. Koneti

    2015-01-01

    Autoimmune lymphoproliferative syndrome (ALPS) is a rare disorder of apoptosis. It is frequently caused by mutations in FAS (TNFRSF6) gene. Unlike most of the self-limiting autoimmune cytopenias sporadically seen in childhood, multi lineage cytopenias due to ALPS are often refractory, as their inherited genetic defect is not going to go away. Historically, more ALPS patients have died due to overwhelming sepsis following splenectomy to manage their chronic cytopenias than due to any other cause, including malignancies. Hence, current recommendations underscore the importance of avoiding splenectomy in ALPS, by long-term use of corticosteroid-sparing immunosuppressive agents like mycophenolate mofetil and sirolimus. Paradigms learnt from managing ALPS patients in recent years is highlighted here and can be extrapolated to manage refractory cytopenias in patients with as yet undetermined genetic bases for their ailments. It is also desirable to develop international registries for children with rare and complex immune problems associated with chronic multilineage cytopenias in order to elucidate their natural history and long-term comorbidities due to the disease and its treatments. PMID:26258116

  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. Epstein-Barr Virus-associated lymphoproliferative disorders: experimental and clinical developments

    PubMed Central

    Geng, Lingyun; Wang, Xin

    2015-01-01

    Epstein-Barr Virus (EBV), the first human virus related to oncogenesis, was initially identified in a Burkitt lymphoma cell line in 1964. EBV infects over 90% of the world’s population. Most infected people maintain an asymptomatic but persistent EBV infection lifelong. However, in some individuals, EBV infection has been involved in the development of cancer and autoimmune disease. Nowadays, oncogenic potential of EBV has been intensively studied in a wide range of human neoplasms, including Hodgkin’s lymphoma (HL), non-Hodgkin’s lymphoma (NHL), nasopharyngeal carcinoma (NPC), gastric carcinoma (GC), etc. EBV encodes a series of viral protein and miRNAs, promoting its persistent infection and the transformation of EBV-infected cells. Although the exact role of EBV in the oncogenesis remains to be clarified, novel diagnostic and targeted therapeutic approaches are encouraging for the management of EBV-related malignancies. This review mainly focuses on the experimental and clinical advances of EBV-associated lymphoproliferative disorders. PMID:26628948

  10. Epstein-Barr virus (EBV)-associated posttransplant lymphoproliferative disorder appearing as mandibular gingival ulcers.

    PubMed

    Amorim Pellicioli, Ana Carolina; Luciano, Aline Alves; Rangel, Ana Lúcia Carrinho Ayroza; de Oliveira, Greison Rabelo; Santos Silva, Alan Roger; de Almeida, Oslei Paes; Vargas, Pablo Agustin

    2016-04-01

    Posttransplant lymphoproliferative disorders (PTLDs) comprise a spectrum of complications that affect immunocompromised patients following hematopoietic stem cell transplantation or solid organ transplantation. Its incidence varies depending on the transplanted organ, occurring in approximately 2.3% of kidney transplantations. A 31-year-old woman was referred to the Dental Clinic of the State University of Western Paraná for evaluation of an oral lesion. Her medical history revealed a previous diagnosis of hypertension, Epstein-Barr virus (EBV) seropositivity, and kidney transplantation 12 years prior. She was under standard immunosuppressive therapy. Intraoral examination identified a gingival necrotic lesion with extension to the posterior right lower alveolar bone. An incisional biopsy was performed. Histologic examination showed lymphocytic proliferation of cells with small and hyperchromatic nuclei, atypical mitosis, and cells with large and pale nuclei showing prominent nucleoli permeating connective tissue, muscle fibers, and adipocytes. Correlation of clinical, histologic, and immunohistochemical findings led to a diagnosis of polymorphic EBV-associated PTLD rich in B and T cells. PMID:26321430

  11. Detection of monoclonal T populations in patients with KIR-restricted chronic lymphoproliferative disorder of NK cells

    PubMed Central

    Gattazzo, Cristina; Teramo, Antonella; Passeri, Francesca; De March, Elena; Carraro, Samuela; Trimarco, Valentina; Frezzato, Federica; Berno, Tamara; Baril, Gregorio; Martini, Veronica; Piazza, Francesco; Trentin, Livio; Facco, Monica; Semenzato, Gianpietro; Zambello, Renato

    2014-01-01

    The etiology of chronic large granular lymphocyte proliferations is largely unknown. Although these disorders are characterized by the expansion of different cell types (T and natural killer) with specific genetic features and abnormalities, several lines of evidence suggest a common pathogenetic mechanism. According to this interpretation, we speculated that in patients with natural killer-type chronic lymphoproliferative disorder, together with natural killer cells, also T lymphocytes undergo a persistent antigenic pressure, possibly resulting in an ultimate clonal T-cell selection. To strengthen this hypothesis, we evaluated whether clonal T-cell populations were detectable in 48 patients with killer immunoglobulin-like receptor-restricted natural killer-type chronic lymphoproliferative disorder. At diagnosis, in half of the patients studied, we found a clearly defined clonal T-cell population, despite the fact that all cases presented with a well-characterized natural killer disorder. Follow-up analysis confirmed that the TCR gamma rearrangements were stable over the time period evaluated; furthermore, in 7 patients we demonstrated the appearance of a clonal T subset that progressively matures, leading to a switch between killer immunoglobulin-like receptor-restricted natural killer-type disorder to a monoclonal T-cell large granular lymphocytic leukemia. Our results support the hypothesis that a common mechanism is involved in the pathogenesis of these disorders. PMID:25193965

  12. Effect of Irradiation on Incidence of Post-Transplant Lymphoproliferative Disorder after Hematopoietic Cell Transplantation in Miniature Swine.

    PubMed

    Matar, Abraham J; Patil, Aarti R; Al-Musa, Ahmad; Hanekamp, Isabel; Sachs, David H; Huang, Christene A; Duran-Struuck, Raimon

    2015-10-01

    Post-transplant lymphoproliferative disease (PTLD) is a major complication of clinical organ and cell transplantation. Conditioning and immunosuppressive regimens that significantly impair T cell immunity, including depleting antibodies and calcineurin inhibitors, increase the risk of PTLD after transplantation. Swine PTLD has been shown to closely resemble human PTLD in morphology, histology, and viral-driven reactivation of B cells. Previously, we reported high incidences of PTLD after hematopoietic cell transplantation (HCT) in miniature swine recipients conditioned with thymic irradiation (TI) in addition to T cell depletion and cyclosporine A monotherapy after transplantation. Replacement of TI with 100 cGy of total body irradiation resulted in similar numbers of B cells early post-transplantation, greater numbers of T cells at day 0, and markedly decreased incidence of PTLD, suggesting that a threshold number of T cells may be necessary to prevent subsequent B cell proliferation and development of overt PTLD. Results from this large cohort of animals provide insight into the important effect of irradiation and T cell immunity on the incidence of PTLD after HCT and reinforce the pig model as a valuable tool for the study of PTLD and HCT. PMID:26210443

  13. Reactivation of Epstein-Barr virus in B cells of patients with chronic hepatitis C.

    PubMed

    Shimozuma, Yuu; Ito, Takayoshi; Inokuchi, Momoko; Uchikoshi, Manabu; Miyashita, Miyuki; Nozawa, Hisako; Shimazaki, Tomoe; Hiroishi, Kazumasa; Imawari, Michio

    2010-12-01

    Hepatitis C virus (HCV) infection is associated with lymphoproliferative disorders. HCV infection of B cells is a predictive factor for lymphoproliferative disorders in patients with chronic hepatitis C, although its molecular mechanisms remain unknown. Epstein-Barr virus (EBV) is a B cell-tropic virus with the potential to cause lymphoproliferative disorders, and its reactivation is induced by several viruses and cytokines. The possibility that HCV infection triggers reactivation of EBV and induces lymphoproliferative disorders were investigated. Expression of EBV mRNAs was analyzed by RT-PCR in patients infected with HCV and control subjects, and correlations between reactivation of EBV and markers for lymphoproliferative disorders were investigated. BZLF1 mRNA, a starter molecule of reactivation, was detected in peripheral blood mononuclear cells from 12 of 52 (23%), patients infected with HCV and the frequency was higher than in healthy subjects [3 of 43 (9%), P = 0.032]. But the presence of the BZLF1 mRNA was not associated with an abnormality of markers for lymphoproliferative disorders. This study on BZLF1 mRNA expression among lymphoid cell subsets showed that reactivation of EBV was observed specifically in B cells. The BZLF1 mRNA disappeared following anti-viral therapy and remained negative after eradication of HCV in patients with a sustained viral response, while the EBER1 RNA, a marker for persistence of EBV, was detected throughout the therapy. Infection with HCV induces reactivation of EBV in B cells, but this reactivation was not associated directly with lymphoproliferative disorders triggered by HCV. PMID:20981794

  14. PCR Analysis of IgH and TCR-? Gene Rearrangements as a Confirmatory Diagnostic Tool for Lymphoproliferative Disorders.

    PubMed

    Poopak, Behzad; Valeshabad, Ali Kord; Elahi, Fazel; Rezvani, Hamid; Khosravipour, Gelareh; Jahangirpour, Mohammad Ali; Bolouri, Shirin; Golkar, Tolou; Salari, Fatemeh; Shahjahani, Mohammad; Saki, Najmaldin

    2015-03-01

    This study investigates PCR analysis of immunoglobulin heavy chain (IgH) and T cell receptor (TCR) gene rearrangements on paraffin-embedded tissue sections and bone marrow aspirates of patients suspected to have lymphoproliferative disorders but with inconclusive diagnosis in histopathological examination. 130 samples of patients with inconclusive immunohistochemistry results were evaluated for clonal rearrangement of IgH and TCR genes. Based on histopathology examination, the patients were divided into three groups: the first group without any definite diagnosis of lymphoproliferative disorders (60 cases, 46.2%), the second group suspected to have a lymphoproliferative disorder but in favor of benign disorders (19 cases, 14.6%) and the third group suspect to lymphoproliferative disorders but relatively in favor of malignant disorders (51 cases, 39.2%). After DNA extraction and quality control, semi-nested PCR was performed using consensus primers for amplification of TCR-? and CDR-3 regions of IgH genes. PCR products were analyzed after heteroduplex analysis using polyacrylamide gel electrophoresis, and were subject to silver staining. Totally, in over half of the cases (55.4%), a monoclonal pattern was found in IgH or TCR-? genes rearrangements. Monoclonal IgH gene rearrangement was detected in 48.1% of patients, whereas monoclonal TCR-? gene rearrangement was found in 33.6% of them, which was not statistically significant (P=0.008). Only in 32 patients (24.6%) were the results of TCR-? and IgH gene rearrangements consistent with respect to the presence (2.3%) or absence (22.3%) of monoclonality. Finally, PCR analysis of TCR-? and IgH gene rearrangements led to definite diagnosis in 105 patients (80.8%), and only 25 cases (19.2%) remained inconclusive. Our results emphasize the usefulness of gene rearrangement study in cases without a definite diagnosis in immunohistochemistry studies. Multiple PCR analysis results when combined with patient's clinical course and immunohistochemistry can lead to early diagnosis and subsequent therapy. PMID:25548443

  15. Posttransplant lymphoproliferative disorder presenting as a nonhealing extraction socket: a case report and review of the literature.

    PubMed

    Cole-Hawkins, Holly; Fyfe, Eithne; Price, Chris; Pring, Miranda

    2012-05-01

    Posttransplant lymphoproliferative disorder (PTLD) is a well-recognized complication of long-term immunosuppression following hematopoietic or solid organ transplantation and is associated with significant morbidity and mortality. We present a unique case of PTLD that manifested with a nonhealing dental extraction socket 17 years after renal transplantation. We summarize the existing literature and present a review of an additional 25 cases. These highlight the variable clinical presentations of PTLD within the oral cavity and clear potential for delayed presentation at this anatomical subsite. PMID:22668635

  16. A case of Epstein-Barr virus associated post-transplant lymphoproliferative disorder with CNS involvement: pathological findings at both biopsy and autopsy.

    PubMed

    Suzuki, Makiko; Kosugi, Isao; Terada, Tatsuhiro; Shirakawa, Kentarou; Suzuki, Hitoshi; Kono, Satoshi; Miyajima, Hiroaki

    2011-08-01

    Post-transplant lymphoproliferative disorder (PTLD) with CNS involvement is an uncommon and fatal side effect of immunosuppressants. A 55-year-old man presented with non-fluent aphasia, fever, neck stiffness and disturbance of consciousness. Twenty-one years previously, the patient had undergone kidney transplantation for chronic renal failure. Brain MRI revealed multiple lesions in the bilateral cerebrum, right cerebellum and medulla oblongata. The brain biopsy showed EBV-positive lymphocytes infiltrating into the subarachnoid and Virchow-Robins space. The diagnosis of PTLD was made and the patient received a reduction in immunosuppressants. However, the patient died of massive bleeding from a rectal ulcer 3 months after the onset. An autopsy conducted 1 month after the biopsy revealed a diffuse large B-cell lymphoma at the biopsy site and extracranial PTLD lesions. Moreover, a human cytomegalovirus infection involving the rectum, pancreas, trachea and bladder was confirmed. Comparisons with past cases clarified the characteristics of this case, in particular, the clinicopathological involvement of leptomeninges. In addition, there have so far been only a limited number of such reports demonstrating detailed pathological findings, including both biopsy and autopsy findings. We herein describe the relationship between clinical and pathological findings and demonstrate the way CNS PTLD lesion progresses. PMID:21134001

  17. Post-Transplant Lymphoproliferative Disorder (PTLD) Manifesting in the Oral Cavity of a 13-Year-Old Liver Transplant Recipient (LTx).

    PubMed

    Krasuska-S?awi?ska, Ewa; Minko-Chojnowska, Izabela; Paw?owska, Joanna; Dembowska-Bagi?ska, Bo?enna; Pronicki, Maciej; Olczak-Kowalczyk, Dorota

    2015-01-01

    BACKGROUND Post-transplant lymphoproliferative disorder (PTLD) is a potential complication of solid organ or bone marrow transplants. The main PTLD risk factors are: the Epstein-Barr virus (EBV), transplant type, and use of immunosuppressants. It mainly consists of an uncontrolled growth of lymphocytes in transplant recipients under chronic immunosuppressive therapy. About 85% of PTLDs are EBV-containing B-cell proliferations; 14% are T-cell proliferations, of which only 40% contain EBV; and the remaining 1% is NK-cell or plasmocyte proliferations. PTLD may present various clinical manifestations, from non-specific mononucleosis-like syndrome to graft or other organ damage resulting from pathologic lymphocyte infiltration. PTLD may manifest in the oral cavity. CASE REPORT The objective of this study was to present the case of a 13-year-old female living-donor liver transplant recipient, resulting from biliary cirrhosis caused by congenital biliary atresia, with exophytic fibrous lesions on buccal mucosa and tongue. Exophytic and hyperplastic lesion of oral mucosa were removed and histopathological examination revealed polymorphic PTLD. The patient underwent 6 cycles of CHOP chemotherapy and all the oral lesions regressed completely. CONCLUSIONS All oral pathological lesions in organ transplant recipients need to be surgically removed and histopathologically examined because they present an increased risk of neoplastic transformations such as PTLD. PMID:26285106

  18. Contrast-enhanced ultrasound findings of post-transplant lymphoproliferative disorder in a transplanted kidney: A case report and literature review

    PubMed Central

    Lampe, Alyssa; Duddalwar, Vinay A; Djaladat, Hooman; Aron, Manju; Gulati, Mittul

    2015-01-01

    Post-transplant lymphoproliferative disorder occurs in approximately one percent of kidney transplant recipients. We evaluated a seventy-seven year-old man with a solid mass in his transplant kidney. On contrast enhanced ultrasound, the mass enhanced but remained persistently hypovascular throughout exam. The enhancement pattern of the mass differed from that typical of clear cell renal cell carcinoma, the main differential diagnosis. Final pathology after partial nephrectomy confirmed post-transplant lymphoproliferative disorder. This is the first report of contrast enhanced ultrasound findings in a renal mass diagnosed as post-transplant lymphoproliferative disorder. Contrast enhanced ultrasound has a promising role in imaging of renal masses, particularly relevant in transplant patients due to the lack of nephrotoxicity. PMID:26629291

  19. The emergence of CD20-/CD19- tumor cells after rituximab therapy for Epstein-Barr virus-associated post-transplant lymphoproliferative disorder complicated with hemophagocytic lymphohistiocytosis.

    PubMed

    Yamamoto, Nobuyuki; Nishimura, Noriyuki; Takeuchi, Mai; Ito, Tomoo; Yokozaki, Hiroshi; Hirase, Satoshi; Kubokawa, Ikuko; Mori, Takeshi; Yanai, Tomoko; Hayakawa, Akira; Takeshima, Yasuhiro; Nishio, Hisahide; Matsuo, Masafumi; Imadome, Ken-Ichi; Iijima, Kazumoto

    2014-12-01

    Post-transplant lymphoproliferative disorder (PTLD) is a well-recognized aggressive disease commonly associated with Epstein-Barr virus (EBV) infection after hematopoietic stem cell transplantation (HSCT). Although rituximab (RTX) is incorporated into the first-line therapy for EBV-PTLD patients, the outcome of the clinically overt disease is still not optimal mainly due to the regrowth of tumor cells. The proliferation of CD20-/CD19+ tumor cells is increasingly reported in RTX-treated EBV-PTLD patients, whereas the emergence of CD20-/CD19- tumor cells is barely recognized. Here, we report a fatal case of an 18-year-old patient who developed EBV-PTLD after allogeneic HSCT for anaplastic large-cell lymphoma. On day 60 after HSCT, the patient developed abdominal pain, watery diarrhea, and low-grade fever. Colon biopsy revealed the proliferation of CD20+/CD19+/EBV-encoded RNA (EBER)+ tumor cells, and an increase of EBV DNA was detected in peripheral blood (PB). He was treated with RTX for EBV-PTLD and was cleared of EBV DNA in PB. However, he manifested high-grade fever, pancytopenia, and elevated soluble interleukin-2 receptor with a prominent hemophagocytosis in bone marrow aspirates and was treated with etoposide for hemophagocytic lymphohistiocytosis (HLH) complication. He then developed EBV DNA positivity in PB and finally died of Bacteroides fragilis sepsis subsequent to bloody stool and ileus on day 163. Autopsy revealed erosion and bleeding in the whole colon with the proliferation of CD20-/CD19-/EBER+ tumor cells. Immunohistochemical analysis uncovered the CD3-/CD56-/CD79a+/CD79b+ B-cell origin of tumor cells. This case clinically demonstrates the removal of both CD20 and CD19 antigens from EBER+ B cells in an RTX-treated EBV-PTLD patient with HLH complication. PMID:24169729

  20. X-Linked Lymphoproliferative Disease (XLP)

    MedlinePLUS

    ... Read more information on enabling JavaScript. Skip Content Marketing Share this: Main Content Area X-Linked Lymphoproliferative Disease (XLP) Epstein-Barr virus (green dots) is shown inside B cells (blue circles) ...

  1. Hepatitis C infection and lymphoproliferative disease: accidental comorbidities?

    PubMed

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

    2014-11-21

    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

  2. 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

  3. Recursive partitioning analysis of prognostic factors in post-transplant lymphoproliferative disorders (PTLD): a 120 case single institution series.

    PubMed

    Montanari, Francesca; Radeski, Dejan; Seshan, Venkatraman; Alobeid, Bachir; Bhagat, Govind; O'Connor, Owen A

    2015-11-01

    The post-transplant lymphoproliferative disorders (PTLD) comprise a heterogeneous group of lymphocytic and plasma cell proliferations occurring in recipients of tissue allografts in the setting of immunosuppression. We describe our experience of 120 patients with PTLD seen between 1990 and 2009, one of the largest series reported by a single institution. Post-transplant lymphoproliferative disorders characteristics were analysed with regard to paediatric and adult patients, and with regard to the decade of diagnosis, 1990-1999 (pre-rituximab era) versus 2000-2009 (the rituximab era). We present a new prognostic score using the recursive partitioning model, consisting of the Eastern Cooperative Oncology Group (ECOG) score (0-1 vs. 2-4), age [paediatrics (<16years old), adults (16-60years old) and elderly (>60years old)] and CD20 status (positive vs negative); separating patients into 4 risk categories based on overall survival. Low-risk included paediatric patients with ECOG score of 0-1; intermediate-low-risk included adults aged 16-60years with an ECOG score of 0-1; intermediate-high-risk included elderly patients with an ECOG score 0-1 or paediatric patients and adults aged 16-60years with an ECOG score of 2-4 and CD20 positive; high-risk group included patients of any age with an ECOG score of 2-4 and CD20 negative, and elderly patients with an ECOG score of 2-4 with CD20-positive PTLD. PMID:26250758

  4. Methotrexate-related lymphoproliferative disorder of the stomach in a patient with rheumatoid arthritis: a case of disease regression after methotrexate cessation.

    PubMed

    Ikeda, Kazuki; Nakamura, Takefumi; Kinoshita, Takahiro; Fujiwara, Mikio; Uose, Suguru; Someda, Hitoshi; Miyoshi, Takashi; Io, Katsuhiro; Nagai, Ken-Ichi

    2016-02-01

    We report the case of a 78-year-old woman with methotrexate-related gastric lymphoproliferative disorder (LPD). The patient had a history of rheumatoid arthritis (RA) and had been treated with methotrexate (MTX). Endoscopic examination revealed round elevated lesions in the stomach, and a biopsy specimen showed atypical lymphoid cell proliferation. Immunohistological study found these atypical cells to be positive for L-26 but not for CD3 or EBER. Therefore, we made a diagnosis of MTX-related LPD showing features of diffuse large B-cell lymphoma. Combined positron emission tomography-computed tomography (PET-CT) using 18F-fluorodeoxyglucose (FDG) showed increased avidity in the stomach in addition to slightly increased FDG-avidity in the mediastinum and left chest wall. We decided not to start chemotherapy but to discontinue administration of MTX, with follow-up using endoscopy and PET-CT. The endoscopic examinations after cessation of MTX demonstrated gradual regression of the elevated lesions. PET-CT 6months after cessation showed no increased FDG avidity in the stomach. While disease regression was observed in the stomach, the other FDG-avid spots remained unchanged on PET-CT. Therefore, we performed chemotherapy as additional therapy. On PET-CT after chemotherapy, the FDG-avid spots remained unchanged for more than 1year, and we eventually concluded that they were RA-related inflammatory lesions. In patients with MTX-related LPD, cessation of MTX may be a therapeutic option, but careful follow-up and chemotherapy in accordance with the clinical course are essential. PMID:26733461

  5. The ambiguous boundary between EBV-related hemophagocytic lymphohistiocytosis and systemic EBV-driven T cell lymphoproliferative disorder

    PubMed Central

    Smith, Megan C; Cohen, Daniel N; Greig, Bruce; Yenamandra, Ashwini; Vnencak-Jones, Cindy; Thompson, Mary Ann; Kim, Annette S

    2014-01-01

    Epstein Barr virus (EBV)-related hemophagocytic lymphohistiocytosis (EBV-HLH) is a form of acquired, infection-related HLH which typically represents a fulminant presentation of an acute EBV infection of CD8+ T cells with 30-50% mortality rate. Systemic EBV-positive lymphoproliferative disease of childhood (SE-LPD) is a rare T cell lymphoproliferative disorder predominantly arising in the setting of acute EBV infection, often presenting with HLH. Since both entities have been associated with clonal T cell populations, the discrimination between these diseases is often ambiguous. We report a unique case of a 21 years old female who presented with clinical and laboratory findings of florid HLH in the setting of markedly elevated EBV titers (>1 million) and an aberrant T cell population shown to be clonal by flow cytometry, karyotype, and molecular studies. This case raises the differential of EBV-HLH versus SE-LPD. Review of the literature identified 74 cases of reported EBV-HLH and 21 cases of SE-LPD with associated HLH in 25 studies. Of those cases with available outcome data, 62 of 92 cases (67%) were fatal. Of 60 cases in which molecular clonality was demonstrated, 37 (62%) were fatal, while all 14 cases (100%) demonstrating karyotypic abnormalities were fatal. Given the karyotypic findings in this sentinel case, a diagnosis of SE-LPD was rendered. The overlapping clinical and pathologic findings suggest that EBV-HLH and SE-LPD are a biologic continuum, rather than discrete entities. The most clinically useful marker of mortality was an abnormal karyotype rather than other standards of clonality assessment. PMID:25337215

  6. CD30-Positive T-Cell Lymphoproliferative Disease of the Oral Mucosa in Children: A Manifestation of Epstein-Barr Virus-Associated T-Lymphoproliferative Disorder

    PubMed Central

    Hong, Mineui; Ko, Young Hyeh

    2015-01-01

    Eosinophilic ulcer of the oral mucosa (EUOM) is a very rare, benign, self-limiting ulcerative lesion of the oral cavity of unknown pathogenesis, and belongs to the same spectrum of CD30+ T-cell lymphoproliferative disease (LPD) of the oral mucosa. The etiology and pathogenesis of the disease are unknown. We report two cases in children who were initially diagnosed with EUOM and CD30+ T-cell LPD, respectively. However, retrospective analysis revealed that a majority of infiltrated atypical T cells were positive for Epstein-Barr virus (EBV). The present cases suggest that the pathogenesis and etiology of EUOM or CD30+ T-cell LPD occurring in children are different from those in adults. EUOM or CD30+ T-cell LPD in children is a manifestation of EBV-positive T-cell LPD, and should therefore be distinguished from the disease in adults. PMID:26420252

  7. Outcomes of kidney retransplantation in recipients with prior post-transplant lymphoproliferative disorder.

    PubMed

    Rouphael, Bassem; Lankireddy, Srilakshmi; Lazaryan, Aleksandr; Kukla, Aleksandra; Ibrahim, Hassan N; Matas, Arthur J; Issa, Naim

    2016-01-01

    Post-transplant lymphoproliferative disease (PTLD) is an uncommon but serious complication of solid organ transplantation. Reduction in immunosuppression is the mainstay of PTLD treatment, but it may precipitate graft loss. Retransplantation remains controversial, as immunosuppression resumption may trigger PTLD relapse. Herein, we describe the experience of eight patients who underwent kidney retransplantation after successful PTLD treatment. Epstein-Barr virus (EBV) serology was not known before the first transplantation. PTLD was diagnosed 62.5months (range 5-323months) after transplantation and was confined to the renal allograft (n=1), lymph nodes (n=2), gastrointestinal tract (n=4), or central nervous system (n=1). Immunosuppression tapering (8/8), chemotherapy (6/8), oral cavity lymphoma excision (1/8), and allograft nephrectomy (1/8) led to hematological remission in all patients. Retransplantation was performed at a median of 55.5months (range 29-95months) after PTLD diagnosis. After a median follow-up of 62.5months (range 2-125months) allograft survival was 87.5% (seven functioning grafts, one failed graft from chronic rejection), with no recurrence of PTLD. In all, five patients remain alive; the other three died from causes other than PTLD. In conclusion, kidney retransplantation appears to be safe in patients with prior PTLD and without major risk of hematological recurrence provided that PTLD has remitted. PMID:26497471

  8. Alvocidib, Fludarabine Phosphate, and Rituximab in Treating Patients With Lymphoproliferative Disorders or Mantle Cell Lymphoma

    ClinicalTrials.gov

    2013-06-03

    B-cell Chronic Lymphocytic Leukemia; Contiguous Stage II Grade 1 Follicular Lymphoma; Contiguous Stage II Grade 2 Follicular Lymphoma; Contiguous Stage II Mantle Cell Lymphoma; Contiguous Stage II Marginal Zone Lymphoma; Contiguous Stage II Small Lymphocytic Lymphoma; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Nodal Marginal Zone B-cell Lymphoma; Noncontiguous Stage II Grade 1 Follicular Lymphoma; Noncontiguous Stage II Grade 2 Follicular Lymphoma; Noncontiguous Stage II Mantle Cell Lymphoma; Noncontiguous Stage II Marginal Zone Lymphoma; Noncontiguous Stage II Small Lymphocytic Lymphoma; Progressive Hairy Cell Leukemia, Initial Treatment; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Small Lymphocytic Lymphoma; Refractory Chronic Lymphocytic Leukemia; Refractory Hairy Cell Leukemia; Splenic Marginal Zone Lymphoma; Stage I Chronic Lymphocytic Leukemia; Stage I Grade 1 Follicular Lymphoma; Stage I Grade 2 Follicular Lymphoma; Stage I Mantle Cell Lymphoma; Stage I Marginal Zone Lymphoma; Stage I Small Lymphocytic Lymphoma; Stage II Chronic Lymphocytic Leukemia; Stage III Chronic Lymphocytic Leukemia; Stage III Grade 1 Follicular Lymphoma; Stage III Grade 2 Follicular Lymphoma; Stage III Mantle Cell Lymphoma; Stage III Marginal Zone Lymphoma; Stage III Small Lymphocytic Lymphoma; Stage IV Chronic Lymphocytic Leukemia; Stage IV Grade 1 Follicular Lymphoma; Stage IV Grade 2 Follicular Lymphoma; Stage IV Mantle Cell Lymphoma; Stage IV Marginal Zone Lymphoma; Stage IV Small Lymphocytic Lymphoma; Untreated Hairy Cell Leukemia; Waldenström Macroglobulinemia

  9. The weight of interleukin-6 in B cell-related autoimmune disorders.

    PubMed

    Youinou, Pierre; Jamin, Christophe

    2009-01-01

    Interleukin (IL)-6 is a prevailing factor of polyclonal B-cell activation of B cells, and thereby of their tolerance breach. Its receptor (R) complex consists of a transducing unit, and a membrane-bound or soluble protein. Many activities ascribed to this cytokine are generated by the soluble IL-6R. Evidence has however been gleaned in autoimmune diseases that the system is instrumental in rheumatoid arthritis (RA), Sjgren's syndrome and systemic lupus erythematosus (SLE). To gain insight into the understanding of the mechanisms behind these observations, a prime example is the recombination-activating gene (Rag) machinery in B lymphocytes. It is interesting that the expression of Rags is favored by IL-6, and repressed by anti-IL-6R antibody (Ab) in RA and SLE. Not surprisingly, clinical benefits are reported in the treatment of autoimmune disorders with anti-IL-6R Ab, and other perspectives about to be open in biotherapy. PMID:19307104

  10. Primary mucosal CD30-positive T-cell lymphoproliferative disorders of the head and neck rarely involving epiglottis: clinicopathological, immunohistomchemical and genetic features of a case

    PubMed Central

    Zhou, Jun; Wang, Guannan; Zhang, Dandan; Yin, Yuhui; Pang, Xia; Zhang, Jing; Zhang, Yanpin; Li, Wencai

    2015-01-01

    A case of primary mucosal CD30-positive T-cell lymphoproliferative disorder of the head and neck rarely involving epiglottis in a 59-year-old male was reported. Histologically, the ulcerative mucosa was affected by sheets of mixed inflammatory infiltration, with scattered large atypical lymphoid cells arranging in an individual or small clusters with focal epidermotropism. Immunohistochemically, tumor cells were uniformly immunoreactive to antibodies against CD2, CD3, CD7, CD43, CD4, TIA-1, with a heterogeneous expression of CD30, but negative for CD20, CD79a, CD21, CD8, CD56, ALK, EMA, granzyme B. Epstein-Barr virus encoded RNA (EBER) were detected. Genetically, T-cell receptor (TCR) ? gene showed an oligoclonal rearrangement. This first case developing in epiglottis demonstrates mucosal CD30-positive T-cell lymphoproliferative disorders are characteristic of a broad clinicopathologic spectrum similar to the counterpart in the skin with a favorable prognosis. PMID:26617911

  11. Comparison of two real-time quantitative polymerase chain reaction strategies for minimal residual disease evaluation in lymphoproliferative disorders: correlation between immunoglobulin gene mutation load and real-time quantitative polymerase chain reaction performance.

    PubMed

    Della Starza, Irene; Cavalli, Marzia; Del Giudice, Ilaria; Barbero, Daniela; Mantoan, Barbara; Genuardi, Elisa; Urbano, Marina; Mannu, Claudia; Gazzola, Anna; Ciabatti, Elena; Guarini, Anna; Foà, Robin; Galimberti, Sara; Piccaluga, Pierpaolo; Gaidano, Gianluca; Ladetto, Marco; Monitillo, Luigia

    2014-09-01

    We compared two strategies for minimal residual disease evaluation of B-cell lymphoproliferative disorders characterized by a variable immunoglobulin heavy chain (IGH) genes mutation load. Twenty-five samples from chronic lymphocytic leukaemia (n = 18) or mantle cell lymphoma (n = 7) patients were analyzed. Based on IGH variable region genes, 22/25 samples carried > 2% mutations, 20/25 > 5%. In the IGH joining region genes, 23/25 samples carried > 2% mutations, 18/25 > 5%. Real-time quantitative polymerase chain reaction was performed on IGH genes using two strategies: method A utilizes two patient-specific primers, whereas method B employs one patient-specific and one germline primer, with different positions on the variable, diversity and joining regions. Twenty-three samples (92%) resulted evaluable using method A, only six (24%) by method B. Method B poor performance was specifically evident among mutated IGH variable/joining region cases, although no specific mutation load above, which the real-time quantitative polymerase chain reaction failed was found. The molecular strategies for minimal residual disease evaluation should be adapted to the B-cell receptor features of the disease investigated. PMID:24254547

  12. Ocrelizumab, a humanized monoclonal antibody against CD20 for inflammatory disorders and B-cell malignancies.

    PubMed

    Hutas, Gabor

    2008-11-01

    Biogen Idec Inc, Genentech Inc, Roche Holding AG and Chugai Pharmaceutical Co Ltd are developing ocrelizumab, a humanized mAb against CD20, for the potential treatment of inflammatory disorders and B-cell malignancies. Ocrelizumab is undergoing phase III clinical trials for rheumatoid arthritis and lupus nephritis, and phase II trials for multiple sclerosis and hematological cancer. Previously, ocrelizumab was also being developed for the treatment of systemic lupus erythematosus (SLE) and neuromyelitis optica; however, development for SLE has been discontinued. No development has been reported for neuromyelitis optica and as of January 2007, this indication had been removed from the company pipeline. PMID:18951300

  13. Methotrexate-associated lymphoproliferative disorders: management by watchful waiting and observation of early lymphocyte recovery after methotrexate withdrawal.

    PubMed

    Inui, Yumiko; Matsuoka, Hiroshi; Yakushijin, Kimikazu; Okamura, Atsuo; Shimada, Takaki; Yano, Shingo; Takeuchi, Mai; Ito, Mitsuhiro; Murayama, Tohru; Yamamoto, Katsuya; Itoh, Tomoo; Aiba, Keisuke; Minami, Hironobu

    2015-11-01

    No optimum treatment of iatrogenic immunodeficiency-associated lymphoproliferative disorders due to methotrexate in patients with rheumatoid arthritis (MTX-LPD) has yet been established, although MTX withdrawal is known to have a substantial effect on tumor regression. Here, we retrospectively analyzed 20 cases of MTX-LPD. Tumor shrinkage occurred in 18 of 20 cases, but only following MTX withdrawal. This tumor regression ratio was considerably better than in previous reports, and appeared due to longer "watchful waiting." Lymphocyte recovery at 2 weeks after MTX withdrawal was significantly higher in cases with tumor regression in 1 month than in those without tumor regression (p = 0.001). Median time to maximal efficacy after MTX cessation in cases without chemotherapy was 12 weeks (range 2-76). In conclusion, watchful waiting for a longer period after MTX cessation with observation of early lymphocyte recovery and uninterrupted continuation of other anti-rheumatoid drugs may be an acceptable management plan for MTX-LPD. PMID:25721751

  14. Phenotypic profile of expanded NK cells in chronic lymphoproliferative disorders: a surrogate marker for NK-cell clonality

    PubMed Central

    Bárcena, Paloma; Jara-Acevedo, María; Tabernero, María Dolores; López, Antonio; Sánchez, María Luz; García-Montero, Andrés C.; Muñoz-García, Noemí; Vidriales, María Belén; Paiva, Artur; Lecrevisse, Quentin; Lima, Margarida; Langerak, Anton W.; Böttcher, Sebastian; van Dongen, Jacques J.M.

    2015-01-01

    Currently, the lack of a universal and specific marker of clonality hampers the diagnosis and classification of chronic expansions of natural killer (NK) cells. Here we investigated the utility of flow cytometric detection of aberrant/altered NK-cell phenotypes as a surrogate marker for clonality, in the diagnostic work-up of chronic lymphoproliferative disorders of NK cells (CLPD-NK). For this purpose, a large panel of markers was evaluated by multiparametric flow cytometry on peripheral blood (PB) CD56low NK cells from 60 patients, including 23 subjects with predefined clonal (n = 9) and polyclonal (n = 14) CD56low NK-cell expansions, and 37 with CLPD-NK of undetermined clonality; also, PB samples from 10 healthy adults were included. Clonality was established using the human androgen receptor (HUMARA) assay. Clonal NK cells were found to show decreased expression of CD7, CD11b and CD38, and higher CD2, CD94 and HLADR levels vs. normal NK cells, together with a restricted repertoire of expression of the CD158a, CD158b and CD161 killer-associated receptors. In turn, NK cells from both clonal and polyclonal CLPD-NK showed similar/overlapping phenotypic profiles, except for high and more homogeneous expression of CD94 and HLADR, which was restricted to clonal CLPD-NK. We conclude that the CD94hi/HLADR+ phenotypic profile proved to be a useful surrogate marker for NK-cell clonality. PMID:26556869

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

    ClinicalTrials.gov

    2016-01-28

    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; 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

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

    PubMed

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

    2015-03-27

    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

  17. 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

  18. Spectrum of Epstein-Barr virus-associated T-cell lymphoproliferative disorder in adolescents and young adults in Taiwan.

    PubMed

    Wang, Ren-Ching; Chang, Sheng-Tsung; Hsieh, Yen-Chuan; Huang, Wan-Ting; Hsu, Jeng-Dong; Tseng, Chih-En; Wang, Ming-Chung; Hwang, Wei-Shou; Wang, John; Chuang, Shih-Sung

    2014-01-01

    Epstein-Barr Virus (EBV) is a herpesvirus usually infecting B-cells but may occasionally infect T- or natural killer (NK)-cells. EBV-associated T- or NK-cell lymphoproliferations represent a continuous spectrum of diseases ranging from asymptomatic infection, infectious mononucleosis (IM), to clonal and malignant lymphoproliferations including systemic EBV-positive T/NK-cell lymphoproliferative disease (EBV-T/NK-LPD) of childhood and hydroa-vacciniforme-like lymphoma of the skin. The clonal diseases are more prevalent in East Asia and exhibit overlapping clinical and pathological features with chronic active EBV infection. Here we report our experience on 10 cases of EBV-associated T-cell lymphoproliferation from Taiwan including five males and five females with a median age of 18 years old (range, 15-28). The most common clinical symptoms were fever, neck mass and hepatosplenomegaly. Eight of these patients showed elevated lactate dehydrogenase level and half of the patients had cytopenia. All patients had either elevated EBV antibody titers or increased serum EBV DNA levels. Five cases were clinically IM-like with polyclonal (3 cases) or clonal (2 cases) T-cell lymphoproliferation. Two patients each had chronic active EBV infection (CAEBV) and hemophagocytic lymphohistiocytosis (HLH). One patient had both CAEBV and HLH. One of the HLH patients with marrow infiltration by intra-sinusoidal large atypical lymphocytes experienced a fulminant course. In a median follow-up time of 21.5 months, seven patients were free of disease, one was alive with disease, and two died of disease in 31 and 3 months, respectively, despite chemotherapy. We confirmed a wide clinicopathological range of EVB-associated T-cell lymphoproliferation in Taiwan. Furthermore, monomorphic LPD and the single case with fulminant course as defined by Ohshima et al (Pathol Int 2018) as categories A3 and B, respectively, died of disease despite chemotherapy. Our report, the largest series in the recent decade from Taiwan, adds to the understanding of these rare diseases with variable clinical and histopathological presentations. PMID:24966953

  19. Posttransplant Lymphoproliferative Disorder of the Thorax: CT and FDG-PET Features in a Single Tertiary Referral Center

    PubMed Central

    Yoon, Ga Young; Kim, Mi Young; Huh, Joo Rryung; Jo, Kyung-Wook; Shim, Tae Sun

    2015-01-01

    Abstract To investigate the chest computed tomography (CT) and F-18 fluoro-2-deoxy-d-glucose positron emission tomographic (FDG-PET) findings of posttransplant lymphoproliferative disorder (PTLD) in the thorax. From November 2004 to February 2013, the cases of 12 adult patients (3 female and 9 male, age range 3468, and median age 46 years) with proven PTLD were retrospectively reviewed. The transplanted organs included the kidney (5/12), liver (4/12), heart (1/12), combined kidney and pancreas (1/12), and hematopoietic stem cell (1/12). We investigated the relationship of the EpsteinBarr virus (EBV) to the patients long-term follow-up, and evaluated the characteristics of the lesions on the chest CT and FDG-PET. The lesions were classified into 2 patterns: that of lymph node and lung involvement. The interval between the transplantation and the onset of PTLD was 2 to 128 months (median, 49). Positive EBV-encoded RNA in the pathologic specimens was found in 10 patients (83.3%). Eight patients were positive for EBV PCR in their blood, and 3 patients showed seroconversion without antiviral therapy. The responses to treatment were complete in 7 cases (58.3%), partial remission in 4 cases (33.3%), and undetermined in 1 case (8.3%). The more common chest CT patterns showed lymph node involvement (10/12) rather than lung involvement (3/12). The median maximum-standardized uptake value on the FDG-PET scans was 7.7 (range, 2.725.5). In patients with PTLD involving the thorax, lymphadenopathy was the more common manifestation on the chest CT rather than lung involvement. The lesions showed hypermetabolism on FDG-PET. PMID:26252295

  20. A Case Series of Primary Central Nervous System Post-Transplant Lymphoproliferative Disorder: Imaging and Clinical Characteristics

    PubMed Central

    Lake, Wendell; Chang, Julie E.; Kennedy, Tabassum; Morgan, Adam; Salamat, Shahriar; Ba?kaya, Mustafa

    2015-01-01

    Background Primary central nervous system post-transplant lymphoproliferative disorder (PCNS-PTLD) is a rare complication following solid organ transplantation (SOT). With increasing rates of SOT, PCNS-PTLD incidence is increasing. Objective Describe the characteristics of PCNS-PTLD patients requiring neurosurgical intervention. Methods From 2000-2011 ten patients with prior SOT underwent biopsy for evaluation of brain lesions and were diagnosed with PCNS-PTLD. Data collected included imaging characteristics, pathology, treatments administered, and survival outcomes. Results All patients had kidney transplantation, and 3 had concurrent pancreas transplantation. Median age at diagnosis was 49 years, with a median of 4.5 years from SOT to diagnosis (range 1.8-11.4 years). Presenting symptoms most often included focal neurologic deficits (n=6), although several patients had non-specific symptoms of headache and altered mental status. Brain lesions were generally multiple (n=7), supratentorial (n=8), and lobar or periventricular in distribution with ring-enhancement. Diagnosis was established by stereotactic (n=4) and open surgical biopsy (n=6). Treatments most frequently administered included reduction of immunosuppression (n=10), dexamethasone (n=10), rituximab (n=8), high-dose methotrexate (n=3), and whole-brain radiotherapy (n=6). Six patients remain alive without PCNS-PTLD relapse, including 4 patients who have sustained remissions beyond 2 years from diagnosis of PCNS-PTLD. Of 4 observed deaths, 1 was related to progressive PCNS-PTLD. Conclusion PCNS-PTLD must be considered in the differential diagnosis of any patient with prior SOT presenting with an intracranial lesion. Histologic diagnosis with brain biopsy is imperative given the risk for opportunistic infections that may have similar imaging findings and presentation. Prognosis is variable, although long-term survival has been reported. PMID:23685504

  1. The radiological spectrum of pulmonary lymphoproliferative disease

    PubMed Central

    Hare, S S; Souza, C A; Bain, G; Seely, J M; Frcpc; Gomes, M M; Quigley, M

    2012-01-01

    Pulmonary lymphoproliferative disorders (LPD) are characterised by abnormal proliferation of indigenous cell lines or infiltration of lung parenchyma by lymphoid cells. They encompass a wide spectrum of focal or diffuse abnormalities, which may be classified as reactive or neoplastic on the basis of cellular morphology and clonality. The spectrum of reactive disorders results primarily from antigenic stimulation of bronchial mucosa-associated lymphoid tissue (MALT) and comprises three main entities: follicular bronchiolitis, lymphoid interstitial pneumonia and (more rarely) nodular lymphoid hyperplasia. Primary parenchymal neoplasms are most commonly extranodal marginal zone lymphomas of MALT origin (MALT lymphomas), followed by diffuse large B-cell lymphomas (DLBCLs) and lymphomatoid granulomatosis (LYG). Secondary lymphomatous parenchymal neoplasms (both Hodgkin and non-Hodgkin lymphomas) are far more prevalent than primary neoplasms. Acquired immune deficiency syndrome (AIDS)-related lymphoma (ARL) and post-transplantation lymphoproliferative disorder (PTLD) may also primarily affect the lung parenchyma. Modern advances in treatments for AIDS and transplant medicine are associated with an increase in the incidence of LPD and have heightened the need to understand the range of imaging appearance of these diseases. The multidetector CT (MDCT) findings of LPD are heterogeneous, thereby reflecting the wide spectrum of clinical manifestations of these entities. Understanding the spectrum of LPD and the various imaging manifestations is crucial because the radiologist is often the first one to suggest the diagnosis and has a pivotal role in differentiating these diseases. The current concepts of LPD are discussed together with a demonstration of the breadth of MDCT patterns within this disease spectrum. PMID:22745203

  2. Mapping the x-linked lymphoproliferative syndrome

    SciTech Connect

    Skare, J.C.; Milunsky, A.; Byron, K.S.; Sullivan, J.L.

    1987-04-01

    The X-linked lymphoproliferative syndrome is triggered by Epstein-Barr virus infection and results in fatal mononucleosis, immunodeficiency, and lymphoproliferative disorders. This study shows that the mutation responsible for X-linked lymphoproliferative syndrome is genetically linked to a restriction fragment length polymorphism detected with the DXS42 probe (from Xq24-q27). The most likely recombination frequency between the loci is 4%, and the associated logarithm of the odds is 5.26. Haplotype analysis using flanking restriction fragment length polymorphism markers indicates that the locus for X-linked lymphoproliferative syndrome is distal to probe DXS42 but proximal to probe DXS99 (from Xq26-q27). It is now possible to predict which members of a family with X-linked lymphoproliferative syndrome are carrier females and to diagnose the syndrome prenatally.

  3. Systemic Epstein-Barr virus-positive T/natural killer-cell lymphoproliferative disorder: a case report and review of literature

    PubMed Central

    Tan, Xia; Liu, Xianling; Hu, Chunhong; Liu, Fuyou; Wu, Fang

    2014-01-01

    Systemic Epstein-Barr virus-positive T/natural killer-cell lymphoproliferative disorder (EBV + LPD) has predominantly been observed among pediatric patients as a life-threatening condition. The present study presents a rare case of EBV + LPD in an adult with good outcome. This patient’s history is more than 2 years and her condition was stable. She received 6 cycles of chemotherapy cyclophosphamide/doxorubicin/vincristine/prednisolone (CHOP). The evaluation was complete remission. The low levels of EBV-DNA in the peripheral blood may have potential benefit factor for the sensitivity to the chemotherapy and good outcome. PMID:25400787

  4. Image findings of monomorphic non-hogdkin lymphoproliferative disorder in a post renal transplant patient diagnosed with fluorine-18 fluorodeoxyglucose-positron emission tomography/computed tomography.

    PubMed

    Kamaleshwaran, Koramadai Karuppusamy; Rajasekar, Thirugnanam; Shibu, Deepu; Radhakrishnan, Edathurthy Kalarikal; Shinto, Ajit Sugunan

    2014-07-01

    Post-transplant lymphoproliferative disorder (PTLD) is a heterogeneous group of lymphoid proliferations caused by immunosuppression after solid organ or bone marrow transplantation. PTLD is categorized by early lesion, polymorphic PTLD and monomorphic PTLD. Fluorine-18 fluorodeoxyglucose-positron emission tomography/computed tomography (F-18 FDG-PET/CT) scans have clinical significance in the evaluation of PTLD following renal transplantation. We report imaging findings of a monomorphic non-Hodgkin lymphoma, post renal transplant seen on FDG PET/CT in a 32-year-old lactating woman. Whole body FDG- ET/CT demonstrated uptake in right external iliac and inguinal lymph nodes. PMID:25210292

  5. Image findings of monomorphic non-hogdkin lymphoproliferative disorder in a post renal transplant patient diagnosed with fluorine-18 fluorodeoxyglucose-positron emission tomography/computed tomography

    PubMed Central

    Kamaleshwaran, Koramadai Karuppusamy; Rajasekar, Thirugnanam; Shibu, Deepu; Radhakrishnan, Edathurthy Kalarikal; Shinto, Ajit Sugunan

    2014-01-01

    Post-transplant lymphoproliferative disorder (PTLD) is a heterogeneous group of lymphoid proliferations caused by immunosuppression after solid organ or bone marrow transplantation. PTLD is categorized by early lesion, polymorphic PTLD and monomorphic PTLD. Fluorine-18 fluorodeoxyglucose-positron emission tomography/computed tomography (F-18 FDG-PET/CT) scans have clinical significance in the evaluation of PTLD following renal transplantation. We report imaging findings of a monomorphic non-Hodgkin lymphoma, post renal transplant seen on FDG PET/CT in a 32-year-old lactating woman. Whole body FDG- ET/CT demonstrated uptake in right external iliac and inguinal lymph nodes. PMID:25210292

  6. FDG PET/CT Findings of the Recurrent Posttransplantation Lymphoproliferative Disorder in a Pediatric Liver Transplant Recipient With Right Leg Pain as the Only Complaint.

    PubMed

    Bai, Xia; Yang, Hua; Zhuang, Hongming

    2015-10-01

    The most commonly observed symptoms of posttransplantation lymphoproliferative disorder (PTLD) after a liver transplantation were diarrhea and fever. Although PTLD can involve bones, bone pain is a rare manifestation of PTLD, much less to say a sole presentation. We report a case of a pediatric patient with recurrent PTLD after liver transplantation, whose only complaint was right tibial pain. FDG PET/CT revealed not only hypermetabolic activity in the right proximal tibia but also in many other parts of the body. Recurrent PTLD was confirmed after bone biopsy. PMID:26098286

  7. Autoimmune Lymphoproliferative Syndrome with Red Cell Aplasia.

    PubMed

    Meena, K R; Bisht, Supriya; Tamaria, K C

    2015-12-01

    Autoimmune Lymphoproliferative Syndrome (ALPS) is a rare inherited disorder of abnormal lymphocyte apoptosis, leading to chronic lymphoproliferation. It presents as lymphadenopathy, hepatosplenomegaly and autoimmune phenomena. Pure red cell aplasia is characterized by normochromic normocytic anemia, reticulocytopenia, and absence of erythroblasts from a normal bone marrow. Only few lymphoproliferative disorders have been associated with erythroid aplasia. The authors are reporting a case of ALPS associated with red cell aplasia in a 7-y-old girl. PMID:25972287

  8. 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

  9. Extranodal large B cell lymphoma of the anterior maxilla. Case report and review of literature.

    PubMed

    Webber, Brian; Webber, Mariel; Keinan, David

    2015-01-01

    In the oral cavity, lymphoproliferative disorders can manifest in various ways, often as an extranodal externalization. In the case presented here, it was a B cell lymphoma originating in the periapical bone of the anterior maxilla. X-ray revealed a periapical radiolucency associated with an intact tooth with no decay, fillings or history of trauma. The tooth tested non-vital. After root canal treatment, an apicoectomy was performed with a biopsy. The most common diagnosis would be of dental etiology. The pathology report revealed a non-Hodgkin's B cell lymphoma. Most often, this disease appears as localized dental or oral pathology. Non-specific signs and symptoms present in association with lymphoproliferative disorders include lymphadenopathy, trismus, pain, swelling, sinusitis, fever, sepsis, prosthetic instability and paresthesia. Early detection results in decreased morbidity and a better prognosis for the patient. PMID:25707167

  10. B-cell overexpression of Bcl-2 cooperates with p21 deficiency for the induction of autoimmunity and lymphomas.

    PubMed

    Santiuste, Ins; Buelta, Luis; Iglesias, Marcos; Genre, Fernanda; Mazorra, Francisco; Izui, Shozo; Merino, Jess; Merino, Ramn

    2010-12-01

    Genetic abnormalities predisposing to autoimmunity generally act in a cooperative manner affecting one or several mechanisms regulating immunological tolerance. In addition, many of these genetic abnormalities are also involved in the development of lymphoproliferative diseases. In the present study, we have determined the possible cooperation between deficiencies in members of the Cip/Kip family of cell cycle regulators (p21(WAF1/Cip1) or p27(kip1)) and the overexpression of human Bcl-2 in B lymphocytes in the induction of autoimmune and lymphoproliferative diseases in non-autoimmune C57BL/6 (B6) mice. Unlike single mutant mice, B6.p21(-/-) mice transgenic for human Bcl-2 in B cells developed a lethal autoimmune syndrome characterized by the production of autoantibodies, the prominent expansion of memory B and CD4(+) T cells and the development of severe glomerular lesions resembling IgA nephropathy. Furthermore, these mice presented a high incidence of B-cell lymphoproliferative disorders. Such genetic cooperation in the induction of autoimmunity was not observed in B6.p27(-/-) mice transgenic for human Bcl-2 in B cells. Altogether, what we have demonstrated here is the existence of preferential interactions among particular regulators of the G(1)/S transition of the cell cycle and B-cell survival in the induction of systemic autoimmune and lymphoproliferative diseases. PMID:20691570

  11. Utility of CD200 immunostaining in the diagnosis of primary mediastinal large B cell lymphoma: comparison with MAL, CD23, and other markers.

    PubMed

    Dorfman, David M; Shahsafaei, Aliakbar; Alonso, Miguel A

    2012-12-01

    CD200, an immunoglobulin superfamily membrane glycoprotein, is expressed in a number of B cell lymphoproliferative disorders, including primary mediastinal large B cell lymphoma, but not diffuse large B cell lymphoma, based on a preliminary study. Here, we compare the expression of CD200 with other markers of primary mediastinal large B cell lymphoma, including MAL and CD23, in formalin-fixed, paraffin-embedded histologic sections from a series of 35 cases of primary mediastinal large B cell lymphoma and 30 cases of diffuse large B cell lymphoma. CD200 exhibits the greatest staining sensitivity of the markers studied: 94%, compared with CD23 (69%), MAL (86%), TRAF (86%), and REL (77%). It exhibits staining specificity of 93%, similar to that of CD23 (93%) and MAL (97%), and greater than that of TRAF (77%) and REL (83%). We conclude that CD200 is a practical and useful marker for the diagnosis of primary mediastinal large B cell lymphoma. PMID:22899296

  12. Chronic Hepatitis C Virus Infection Breaks Tolerance and Drives Polyclonal Expansion of Autoreactive B Cells

    PubMed Central

    Roughan, Jill E.; Reardon, Kathryn M.; Cogburn, Kristin E.; Quendler, Heribert; Pockros, Paul J.

    2012-01-01

    Chronic Hepatitis C virus (HCV) infection has been linked with B cell lymphoproliferative disorders and several autoimmune-related diseases. The mechanisms of how chronic viral infection affects B cell development and predisposes the patients to autoimmune manifestations are poorly understood. In this study, we established an experimental system to probe the B cell responses and characterize the antibodies from chronic-HCV-infected individuals. We identified an unusual polyclonal expansion of the IgM memory B cell subset in some patients. This B cell subset is known to be tightly regulated, and autoreactive cells are eliminated by tolerance mechanisms. Genetic analysis of the immunoglobulin (Ig) heavy chain variable gene (VH) sequences of the expanded cell population showed that the levels of somatic hypermutation (SHM) correlate with the extent of cell expansion in the patients and that the VH genes exhibit signs of antigen-mediated selection. Functional analysis of the cloned B cell receptors demonstrated autoreactivity in some of the expanded IgM memory B cells in the patients which is not found in healthy donors. In summary, this study demonstrated that, in some patients, chronic HCV infection disrupts the tolerance mechanism that normally deletes autoreactive B cells, therefore increasing the risk of developing autoimmune antibodies. Long-term follow-up of this expanded B cell subset within the infected individuals will help determine whether these cells are predictors of more-serious clinical manifestations. PMID:22623650

  13. Association of CLEC16A with human common variable immunodeficiency disorder and role in murine B cells

    PubMed Central

    Li, Jin; Jørgensen, Silje F.; Maggadottir, S. Melkorka; Bakay, Marina; Warnatz, Klaus; Glessner, Joseph; Pandey, Rahul; Salzer, Ulrich; Schmidt, Reinhold E.; Perez, Elena; Resnick, Elena; Goldacker, Sigune; Buchta, Mary; Witte, Torsten; Padyukov, Leonid; Videm, Vibeke; Folseraas, Trine; Atschekzei, Faranaz; Elder, James T.; Nair, Rajan P.; Winkelmann, Juliane; Gieger, Christian; Nöthen, Markus M; Büning, Carsten; Brand, Stephan; Sullivan, Kathleen E.; Orange, Jordan S.; Fevang, Børre; Schreiber, Stefan; Lieb, Wolfgang; Aukrust, Pål; Chapel, Helen; Cunningham-Rundles, Charlotte; Franke, Andre; Karlsen, Tom H.; Grimbacher, Bodo; Hakonarson, Hakon; Hammarström, Lennart; Ellinghaus, Eva

    2015-01-01

    Common variable immunodeficiency disorder (CVID) is the most common symptomatic primary immunodeficiency in adults, characterized by B cell abnormalities and inadequate antibody response. CVID patients have considerable autoimmune comorbidity and we therefore hypothesized that genetic susceptibility to CVID may overlap with autoimmune disorders. Here, in the largest genetic study performed in CVID to date, we compare 778 CVID cases with 10,999 controls across 123,127 single nucleotide polymorphisms (SNPs) on the Immunochip. We identify the first non-HLA genome-wide significant risk locus at CLEC16A (rs17806056, P=2.0×10−9) and confirm the previously reported human leukocyte antigen (HLA) associations on chromosome 6p21 (rs1049225, P =4.8×10−16). Clec16a knock down (KD) mice showed reduced number of B cells and elevated IgM levels compared to controls, suggesting that CLEC16A may be involved in immune regulatory pathways of relevance to CVID. In conclusion, the CLEC16A associations in CVID represent the first robust evidence of non-HLA associations in this immunodeficiency condition. PMID:25891430

  14. Association of CLEC16A with human common variable immunodeficiency disorder and role in murine B cells.

    PubMed

    Li, Jin; Jrgensen, Silje F; Maggadottir, S Melkorka; Bakay, Marina; Warnatz, Klaus; Glessner, Joseph; Pandey, Rahul; Salzer, Ulrich; Schmidt, Reinhold E; Perez, Elena; Resnick, Elena; Goldacker, Sigune; Buchta, Mary; Witte, Torsten; Padyukov, Leonid; Videm, Vibeke; Folseraas, Trine; Atschekzei, Faranaz; Elder, James T; Nair, Rajan P; Winkelmann, Juliane; Gieger, Christian; Nthen, Markus M; Bning, Carsten; Brand, Stephan; Sullivan, Kathleen E; Orange, Jordan S; Fevang, Brre; Schreiber, Stefan; Lieb, Wolfgang; Aukrust, Pl; Chapel, Helen; Cunningham-Rundles, Charlotte; Franke, Andre; Karlsen, Tom H; Grimbacher, Bodo; Hakonarson, Hakon; Hammarstrm, Lennart; Ellinghaus, Eva

    2015-01-01

    Common variable immunodeficiency disorder (CVID) is the most common symptomatic primary immunodeficiency in adults, characterized by B-cell abnormalities and inadequate antibody response. CVID patients have considerable autoimmune comorbidity and we therefore hypothesized that genetic susceptibility to CVID may overlap with autoimmune disorders. Here, in the largest genetic study performed in CVID to date, we compare 778 CVID cases with 10,999 controls across 123,127 single-nucleotide polymorphisms (SNPs) on the Immunochip. We identify the first non-HLA genome-wide significant risk locus at CLEC16A (rs17806056, P=2.0 10(-9)) and confirm the previously reported human leukocyte antigen (HLA) associations on chromosome 6p21 (rs1049225, P=4.8 10(-16)). Clec16a knockdown (KD) mice showed reduced number of B cells and elevated IgM levels compared with controls, suggesting that CLEC16A may be involved in immune regulatory pathways of relevance to CVID. In conclusion, the CLEC16A associations in CVID represent the first robust evidence of non-HLA associations in this immunodeficiency condition. PMID:25891430

  15. 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, Jos 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

  16. Normalized Quantification by Real-Time PCR of Epstein-Barr Virus Load in Patients at Risk for Posttransplant Lymphoproliferative Disorders

    PubMed Central

    Jabs, Wolfram J.; Hennig, Holger; Kittel, Michael; Pethig, Klaus; Smets, Franoise; Bucsky, Peter; Kirchner, Holger; Wagner, Hans J.

    2001-01-01

    The load of Epstein-Barr virus (EBV) in peripheral blood mononuclear cells of transplant recipients represents a predictive parameter for posttransplant lymphoproliferative disorders (PTLD). The aim of our work was to develop a rapid and reliable PCR protocol for the quantification of cell-associated EBV DNA in transplant recipients. In contrast to previous studies, a protocol that facilitated quantification independent of photometric nucleic acid analysis was established. We took advantage of the real-time PCR technology which allows for single-tube coamplification of EBV and genomic C-reactive protein (CRP) DNA. EBV copy numbers were normalized by division by the amount of CRP DNA, with the quotient representing the actual amount of amplifiable genomic DNA per reaction. Coamplification of CRP DNA did not result in a diminished detection limit for EBV. By using the protocol without normalization, EBV copy numbers in 4 out of 10 PTLD patients were within the normal range determined with data for 114 transplant recipients that served as controls. After normalization, however, all of the PTLD patients had a higher viral load than the control population, indicating an increased sensitivity of the assay. Moreover, EBV copy numbers obtained for one patient by conventional quantification and suggestive of relapsing PTLD were within normal range after normalization. We conclude that normalization of PCR signals to coamplified genomic DNA allows a more accurate quantification of cell-bound EBV. PMID:11158107

  17. Outcome of treatment of Epstein-Barr virus-related post-transplant lymphoproliferative disorder in hematopoietic stem cell recipients: a comprehensive review of reported cases.

    PubMed

    Styczynski, J; Einsele, H; Gil, L; Ljungman, P

    2009-10-01

    Post-transplant lymphoproliferative disorder (PTLD) caused by Epstein-Barr virus (EBV) is an important complication in high-risk allogeneic hematopoietic stem cell transplant (HSCT) recipients. Before the current methods of anti-EBV therapy were introduced, the mortality from PTLD after HSCT was >80%. With current approaches the mortality from EBV-PTLD can be significantly reduced. The published literature and meeting abstracts were reviewed to assess the impact of different management strategies against EBV-PTLD. This analysis of reported outcomes indicates that preemptive use of rituximab and EBV-cytotoxic T lymphocytes (CTL) significantly reduced the risk of death due to EBV-PTLD in HSCT recipients with survival rates of 89.7% and 94.1%, respectively. Therapy of established PTLD also reduced the risk of fatal outcome. However, the overall success rates were lower than after preemptive therapy, reaching 63% and 88.2% of total EBV-DNA clearance with rituximab and CTL therapy, respectively. A reduction of immunosuppression and/or donor lymphocyte infusion might also reduce the risk of death due to EBV-PTLD. Although it is difficult to estimate these effects more precisely because of the frequent use of combination therapies, the responses to these modalities can be estimated to be 56.6% and 41.0%, respectively. Finally, chemotherapy seems not to contribute to improved survival of patients with PTLD after HSCT and antiviral agents are not active against PTLD. PMID:19558376

  18. Epstein-Barr Virus-Related Post-Transplantation Lymphoproliferative Disorder after Unmanipulated Human Leukocyte Antigen Haploidentical Hematopoietic Stem Cell Transplantation: Incidence, Risk Factors, Treatment, and Clinical Outcomes.

    PubMed

    Xu, Lan-Ping; Zhang, Chun-Li; Mo, Xiao-Dong; Zhang, Xiao-Hui; Chen, Huan; Han, Wei; Chen, Yu-Hong; Wang, Yu; Yan, Chen-Hua; Wang, Jing-Zhi; Wang, Feng-Rong; Zhao, Ting; Liu, Yan-Rong; Liu, Kai-Yan; Huang, Xiao-Jun

    2015-12-01

    We examined the incidence, risk factors, treatments, and clinical outcomes of post-transplantation lymphoproliferative disorder (PTLD) after unmanipulated haploidentical (haplo) hematopoietic stem cell transplantation (HSCT) in 1184 patients between 2006 and 2012. Age-, transplantation time-, and transplantation duration-matched controls were randomly selected from the same cohort. Forty-five patients experienced PTLD. The median time from HSCT to PTLD occurrence was 61 (range, 33 to 360) days and the 1-year cumulative incidence of total PTLD after haplo-HSCT was 3.0%. In multivariate analysis, a lower absolute count of CD8(+) T lymphocytes at day 30, a lower absolute count of immunoglobulin M at day 30, and cytomegalovirus DNAemia after HSCT were significantly associated with higher risk of PTLD. The 2-year probability of overall survival (OS) after HSCT was 42.8%, which was comparable between the probable PTLD and the proven PTLD patients. Patients who received rituximab-based therapy had significantly better 2-year OS (48.2% versus 13.2%, P= .02). Thus, we were able to identify individuals at a high risk of developing PTLD after unmanipulated haplo-HSCT. Rituximab-based therapy can help to improve the outcomes of PTLD patients. PMID:26253005

  19. Mucosal CD30-Positive T-Cell Lymphoproliferative Disorder Arising in the Oral Cavity Following Dental Implants: Report of the First Case.

    PubMed

    Yoon, Hye-Jung; Choe, Ji-Young; Jeon, Yoon Kyung

    2015-12-01

    Mucosal CD30-positive T-cell lymphoproliferative disorder (CD30+ T-cell LPD) is a novel entity with unique clinicopathological features and an indolent behavior. Here we report the first case of mucosal CD30+ T-cell LPD arising in the oral cavity following dental implant. A 70-year-old woman presented with swelling and redness of the oral mucosa of right maxilla and left mandible surrounding dental implants that had been placed 8 years previously. Radiological examination revealed enhancing oral lesions and multiple cervical lymph nodes. Microscopic examination showed diffuse infiltration of large anaplastic cells with characteristic morphology of hallmark cells described in anaplastic large cell lymphoma. These cells were diffusely positive for CD30, CD3, CD4, CD2, CD5, CD7, TIA-1, and TCR?F1, but negative for CD20, CD8, CD45, EMA, ALK, and Epstein-Barr virus. T-cell monoclonality was detected in a TCR? gene rearrangement study. This a unique case of mucosal CD30+ T-cell LPD with unusual presentation following dental implant. PMID:26261101

  20. HLA-haploidentical stem cell transplantation after removal of ??+ T and B cells in children with nonmalignant disorders.

    PubMed

    Bertaina, Alice; Merli, Pietro; Rutella, Sergio; Pagliara, Daria; Bernardo, Maria Ester; Masetti, Riccardo; Pende, Daniela; Falco, Michela; Handgretinger, Rupert; Moretta, Francesca; Lucarelli, Barbarella; Brescia, Letizia P; Li Pira, Giuseppina; Testi, Manuela; Cancrini, Caterina; Kabbara, Nabil; Carsetti, Rita; Finocchi, Andrea; Moretta, Alessandro; Moretta, Lorenzo; Locatelli, Franco

    2014-07-31

    Twenty-three children with nonmalignant disorders received HLA-haploidentical hematopoietic stem cell transplantation (haplo-HSCT) after ex vivo elimination of ??(+) T cells and CD19(+) B cells. The median number of CD34(+), ??(+)CD3(+), and B cells infused was 16.8 10(6), 40 10(3), and 40 10(3) cells/kg, respectively. No patient received any posttransplantation pharmacologic prophylaxis for graft-versus-host disease (GVHD). All but 4 patients engrafted, these latter being rescued by a second allograft. Three patients experienced skin-only grade 1 to 2 acute GVHD. No patient developed visceral acute or chronic GVHD. Cumulative incidence of transplantation-related mortality was 9.3%. With a median follow-up of 18 months, 21 of 23 children are alive and disease-free, the 2-year probability of disease-free survival being 91.1%. Recovery of ??(+) T cells was prompt, but ??(+) T cells progressively ensued over time. Our data suggest that this novel graft manipulation strategy is safe and effective for haplo-HSCT. This trial was registered at www.clinicaltrials.gov as #NCT01810120. PMID:24869942

  1. Epstein-Barr Virus-Positive T/NK-Cell Lymphoproliferative Disorders Manifested as Gastrointestinal Perforations and Skin Lesions: A Case Report.

    PubMed

    Xiao, Hai-Juan; Li, Ji; Song, Hong-Mei; Li, Zheng-Hong; Dong, Mei; Zhou, Xiao-Ge

    2016-02-01

    Systemic Epstein-Barr virus (EBV)-positive T-cell lymphoproliferative disorders (LPDs) of childhood is a highly aggressive EBV-positive T/natural killer (NK)-cell LPD, which emerges in the background of chronic active EBV infection (CAEBV) or shortly after primary acute EBV infection. The clinical presentations of CAEBV are varied; patients with atypical manifestations are easily misdiagnosed. We described a 14-year-old boy suffering from digestive disorders and intermittent fever for 1 year and 9 months, whose conditions worsened and skin lesions occurred 2 months before hospitalization. He was diagnosed as inflammatory bowel diseases (IBD) and treated accordingly. His other clinical features, hepatosplenomegaly, lymphadenopathy, anemia, hypoalbuminemia, and elevated inflammatory marks, were found in hospitalization. The boy suffered from repeatedly spontaneous intestinal perforations shortly after hospitalization and died of intestinal hemorrhea. The pathological results of intestine and skin both showed EBV-positive T/NK-cell LPD (lymphoma stage).There are rare studies reporting gastrointestinal perforations in EBV-positive T/NK-cell LPD, let alone repeatedly spontaneous perforations. Based on the clinical features and pathological results of this patient, the disease progressed from CAEBV (T-cell type) to systemic EBV-positive T-cell LPD of childhood (lymphoma). Not all the patients with CAEBV could have unusual patterns of anti-EBV antibodies. However, the presence of high EBV loads (EBV-encoded early small ribonucleic acid (RNA) (EBER) in affected tissues and/or EBV deoxyribonucleic acid (DNA) in peripheral blood) is essential for diagnosing CAEBV. Maybe because of his less common clinical features for CAEBV and negative anti-EBV antibodies, the boy was not diagnosed correctly. We should have emphasized the test for EBER or EBV-DNA. Meanwhile, for the IBD patients whose manifestations were not typical, and whose conditions were not improved by suitable therapies against IBD, infectious and malignant diseases should be considered. PMID:26844502

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

    PubMed

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

    2010-10-01

    Plasmacytomas expressing immunoglobulin A are rare and not well characterized. In this study, 9 cases of IgA-positive plasmacytoma presenting in lymph node and 3 in extranodal sites were analyzed by morphology, immunohistochemistry, and polymerase chain reaction examination of immunoglobulin heavy and ? light chain genes. Laboratory features were correlated with clinical findings. There were 7 males and 5 females; age range was 10 to 66 years (median, 32?y). Six of the patients were younger than 30 years of age, 5 of whom had nodal disease. About 67% (6 of 9) of the patients with nodal disease had evidence of immune system dysfunction, including human immunodeficiency virus infection, T-cell deficiency, autoantibodies, arthritis, Sjgren syndrome, and decreased B cells. An IgA M-spike was detected in 6 of 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, nodal 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 ? and ? light chains (ratio 6:6). Clonality was showed in 9 of 12 cases: by polymerase chain reaction 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

  3. Autoimmune and Lymphoproliferative Complications of Common Variable Immunodeficiency.

    PubMed

    Maglione, Paul J

    2016-03-01

    Common variable immunodeficiency (CVID) is frequently complicated by the development of autoimmune and lymphoproliferative diseases. With widespread use of immunoglobulin replacement therapy, autoimmune and lymphoproliferative complications have replaced infection as the major cause of morbidity and mortality in CVID patients. Certain CVID complications, such as bronchiectasis, are likely to be the result of immunodeficiency and are associated with infection susceptibility. However, other complications may result from immune dysregulation rather than immunocompromise. CVID patients develop autoimmunity, lymphoproliferation, and granulomas in association with distinct immunological abnormalities. Mutations in transmembrane activator and CAML interactor, reduction of isotype-switched memory B cells, expansion of CD21 low B cells, heightened interferon signature expression, and retained B cell function are all associated with both autoimmunity and lymphoproliferation in CVID. Further research aimed to better understand that the pathological mechanisms of these shared forms of immune dysregulation may inspire therapies beneficial for multiple CVID complications. PMID:26857017

  4. Epitope distribution in ordered and disordered protein regions. Part B - Ordered regions and disordered binding sites are targets of T- and B-cell immunity.

    PubMed

    Pavlović, Mirjana D; Jandrlić, Davorka R; Mitić, Nenad S

    2014-05-01

    Intrinsically disordered proteins exist in highly flexible conformational states linked to different protein functions. In this work, we have presented evidence that HLA class-I- and class-II-binding T-cell epitopes, experimentally verified in several tumor-associated antigens and nuclear systemic autoantigens, are predominantly located in ordered protein regions or at disorder/order borderlines, defined by the majority of analyzed publicly available disorder predictors. We have also observed the overlapping of secondary structural elements and prevalently hydrophobic regions with T-cell epitopes in Epstein Barr Virus (EBV) nuclear antigen 1 (EBNA-1), cancer/testis antigen MAGE-A4, and Sm-B/B', U1 snRNPA (U1A) and U1-70kDa autoantigens. The results are in accordance with the clustering of the predicted HLA class-I and class-II epitopes in protein parts which encompass the consensus of ordered regions, determined by individual disorder predictors. Some HLA class-II epitopes and linear B-cell epitopes were located near the segments predicted to have elevated crystallographic B factor in EBNA-1, Sm-B/B' and U1 snRNP A proteins, suggesting that protein flexibility could influence the structural availability of epitopes. Naturally processed T-cell epitopes and linear B-cell epitopes could also be found within putative disordered binding sites, determined by "dips" in the prevalently disordered parts of prediction profiles of the majority of disorder predictors, and peaks in ANCHOR-prediction profile. Two minor antigenic regions within EBNA-1, mapped to the residues 58-85 and 398-458, encompassing putative disordered binding sites, contain epitopes connected with anti-Ro 60kDa and anti-Sm B/B' autoimmunity in systemic lupus erythematosus. One of these regions overlaps residues 395-450, identified as the binding site of USP7 (HAUSP), which regulates the EBNA-1 replication function. In Sm-B/B', one of the putative disordered binding sites (residues 114-165) encompasses the T-cell epitope 136-153, while another, residues 200-216, flanks two proline-rich B-cell epitopes (residues 190-198 and 216-222), overlapping the preferred CD2BP2-GYF-binding motif (R/K/G)XXPPGX(R/K), characteristic of splicosomal proteins. We have noticed that the same motif (residues 397-403) is mimicked in EBNA-1 and overlaps epitope 398-404, involved in anti-Sm B/B' autoimmunity. The majority of recognized T- and B-cell epitopes in analyzed autoantigens or tumor-associated antigens appertain to the ordered or transient protein structures. The congruence between certain B- and T-cell epitopes and predicted disordered binding sites or protein-binding eukaryotic motifs in the antigens participating in molecular complexes might influence the capture of antigens, their processing and subsequent presentation and immunodominance. PMID:24726865

  5. Checking whether there is an increased risk of post-transplant lymphoproliferative disorder and other cancers with specific modern immunosuppression regimens in renal transplantation: Protocol for a network meta-analysis of randomized and observational studies

    PubMed Central

    2014-01-01

    Background Patients undergoing renal transplant procedures require multi-agent immunosuppressive regimens both short term (induction phase) and long term (maintenance phase) to minimize the risk of organ rejection. There are several drug classes and agents for immunosuppression. Use of these agents may increase the risk of different harms including not only infections, but also malignancies including post-transplant lymphoproliferative disorder. There is a need to identify which regimens minimize the risk of such outcomes. The objective of this systematic review and network meta-analysis of randomized and observational studies is to explore whether certain modern regimens of immunosuppression used to prevent organ rejection in renal transplant patients are associated with an increased risk of post-transplant lymphoproliferative disorder and other malignancies. Methods/design Modern regimens were defined to be those evaluated in controlled studies beginning in 1990 or later. An electronic literature search of Medline, Embase and the Cochrane Central Register of Controlled Trials has been designed by an experienced information specialist and peer reviewed by a second information specialist. Study selection and data collection will be performed by two reviewers. The outcomes of interest will include post-transplant lymphoproliferative disorder and other incident forms of malignancy occurring in adult renal transplant patients. Network meta-analyses of data from randomized and observational studies will be performed where judged appropriate based on a review of the clinical and methodological features of included studies. A sequential approach to meta-analysis will be used to combine data from different designs. Discussion Our systematic review will include both single-agent and multi-agent modern pharmacotherapy regimens in patients undergoing renal transplantation. It will synthesize malignancy outcomes. Our work will also add to the development of methods for network meta-analysis across study designs to assess treatment safety. Trial registration PROSPERO Registration Number: CRD42013006951 PMID:24559430

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

    PubMed Central

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

    2013-01-01

    Summary Fc receptor-like (FCRL) molecules are preferentially expressed by B lymphocytes and possess tyrosine-based immunoregulatory function. Although they generally inhibit B cell receptor (BCR) 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 BCR activation. Despite this inhibitory property, mounting associations for FCRL3 with autoimmune and lymphoproliferative disorders imply a role for it in promoting B cell pathogenesis. Here we explore its influence on B cell responses to innate Toll-like receptor 9 (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 MAPK 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

  7. Correction of disease related anaemia of B-chronic lymphoproliferative disorders by recombinant human erythropoietin: maintenance is necessary to sustain response.

    PubMed

    Siakantaris, M P; Angelopoulou, M K; Vassilakopoulos, T P; Dimopoulou, M N; Kontopidou, F N; Pangalis, G A

    2000-12-01

    Thirty three B-chronic lymphoproliferative disorder (B-CLD) patients [22 with B-chronic lymphocytic leukemia (B-CLL), 5 with small lymphocytic lymphoma (SLL) and 6 with lymphoplasmacytic lymphoma (LPL)] with anaemia (Ht <32%) of no other cause but their disease, received recombinant human erythropoietin (r-HuEPO). The treatment protocol provided r-HuEPO in a dose of 150 U/kg s.c. thrice weekly for 3 mo. After 1.5 mo of r-HuEPO administration, if response was not satisfactory, r-HuEPO dose escalation was utilised by giving incremental doses of 50 U/kg more than the previous dose up to a maximum dose of 300 U/kg tiw. After maximal response, half of the responding patients discontinued therapy, while the other half received maintenance therapy at a dose of 150 U/kg s.c./w. Oral iron was given throughout the study. Pretreatment EPO levels were determined in all patients. A complete response (CR) was defined when Ht was >38% and a partial response (PR) when there was an increase of the Ht >6% from the initial value was achieved. Sixteen of the 22 B-CLL patients had Rai stage III disease and 6 stage IV, with a median duration of anaemia 27 months (6-38); twelve of them were receiving chlorambucil while the rest were on no treatment. Of the SLL and LPL group, 4 patients had Ann Arbor stage III disease and 7 stage IV with a median duration of anaemia 24 months (5-36); 8 patients were on chlorambucil. Complete response was achieved in 50% of the B-CLL group and 54% of the SLL and LPL group, with an overall response rate of 77% and 81% respectively. All patients on maintenance therapy had a continuous response, while all patients, in whom rHuEPO was discontinued, relapsed. No correlation was found between patients: with low or high pretreatment serum EPO levels; those receiving concomitant therapy or not; those with B-symptoms or not; those with a non-diffuse or diffuse bone marrow infiltration pattern; and with splenomegaly or not. Life quality was significantly improved and no major side effects were encountered. We conclude from our study that r-HuEPO is very effective in correcting disease-related anaemia in B-CLD, resulting in down-staging of Rai stage III patients and that maintenance therapy is necessary. Whether the correction of anaemia improves patients' overall survival, still remains to be seen. PMID:11426615

  8. CD3-CD4+ lymphoid variant of hypereosinophilic syndrome: nodal and extranodal histopathological and immunophenotypic features of a peripheral indolent clonal T-cell lymphoproliferative disorder.

    PubMed

    Lefèvre, Guillaume; Copin, Marie-Christine; Roumier, Christophe; Aubert, Hélène; Avenel-Audran, Martine; Grardel, Nathalie; Poulain, Stéphanie; Staumont-Sallé, Delphine; Seneschal, Julien; Salles, Gilles; Ghomari, Kamel; Terriou, Louis; Leclech, Christian; Morati-Hafsaoui, Chafika; Morschhauser, Franck; Lambotte, Olivier; Ackerman, Félix; Trauet, Jacques; Geffroy, Sandrine; Dumezy, Florent; Capron, Monique; Roche-Lestienne, Catherine; Taieb, Alain; Hatron, Pierre-Yves; Dubucquoi, Sylvain; Hachulla, Eric; Prin, Lionel; Labalette, Myriam; Launay, David; Preudhomme, Claude; Kahn, Jean-Emmanuel

    2015-08-01

    The CD3(-)CD4(+) lymphoid variant of hypereosinophilic syndrome is characterized by hypereosinophilia and clonal circulating CD3(-)CD4(+) T cells. Peripheral T-cell lymphoma has been described during this disease course, and we observed in our cohort of 23 patients 2 cases of angio-immunoblastic T-cell lymphoma. We focus here on histopathological (n=12 patients) and immunophenotypic (n=15) characteristics of CD3(-)CD4(+) lymphoid variant of hypereosinophilic syndrome. Atypical CD4(+) T cells lymphoid infiltrates were found in 10 of 12 CD3(-)CD4(+) L-HES patients, in lymph nodes (n=4 of 4 patients), in skin (n=9 of 9) and other extra-nodal tissues (gut, lacrymal gland, synovium). Lymph nodes displayed infiltrates limited to the interfollicular areas or even an effacement of nodal architecture, associated with proliferation of arborizing high endothelial venules and increased follicular dendritic cell meshwork. Analysis of 2 fresh skin samples confirmed the presence of CD3(-)CD4(+) T cells. Clonal T cells were detected in at least one tissue in 8 patients, including lymph nodes (n=4 of 4): the same clonal T cells were detected in blood and in at least one biopsy, with a maximum delay of 23 years between samples. In the majority of cases, circulating CD3(-)CD4(+) T cells were CD2(hi) (n=9 of 14), CD5(hi) (n=12 of 14), and CD7(-)(n=4 of 14) or CD7(low) (n=10 of 14). Angio-immunoblastic T-cell lymphoma can also present with CD3(-)CD4(+) T cells; despite other common histopathological and immunophenotypic features, CD10 expression and follicular helper T-cell markers were not detected in lymphoid variant of hypereosinophilic syndrome patients, except in both patients who developed angio-immunoblastic T-cell lymphoma, and only at T-cell lymphoma diagnosis. Taken together, persistence of tissular clonal T cells and histopathological features define CD3(-)CD4(+) lymphoid variant of hypereosinophilic syndrome as a peripheral indolent clonal T-cell lymphoproliferative disorder, which should not be confused with angio-immunoblastic T-cell lymphoma. PMID:25682606

  9. Rituximab in Treating Patients Undergoing Donor Peripheral Blood Stem Cell Transplant for Relapsed or Refractory B-cell Lymphoma

    ClinicalTrials.gov

    2015-11-23

    B-cell Adult Acute Lymphoblastic Leukemia; B-cell Childhood Acute Lymphoblastic Leukemia; B-cell Chronic Lymphocytic Leukemia; Childhood Burkitt Lymphoma; Childhood Diffuse Large Cell Lymphoma; Childhood Immunoblastic Large Cell Lymphoma; 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; 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 Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Grade III Lymphomatoid Granulomatosis; Recurrent Adult Hodgkin Lymphoma; Recurrent Adult Immunoblastic Large Cell Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Childhood Acute Lymphoblastic Leukemia; Recurrent Childhood Grade III Lymphomatoid Granulomatosis; Recurrent Childhood Large Cell Lymphoma; Recurrent Childhood Lymphoblastic Lymphoma; Recurrent Childhood Small Noncleaved 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; Recurrent/Refractory Childhood Hodgkin Lymphoma; Refractory Chronic Lymphocytic Leukemia; Refractory Hairy Cell Leukemia; Small Intestine Lymphoma; Splenic Marginal Zone Lymphoma; Testicular Lymphoma; Waldenström Macroglobulinemia

  10. Primary and secondary cutaneous CD30(+) lymphoproliferative disorders: a report from the Dutch Cutaneous Lymphoma Group on the long-term follow-up data of 219 patients and guidelines for diagnosis and treatment.

    PubMed

    Bekkenk, M W; Geelen, F A; van Voorst Vader, P C; Heule, F; Geerts, M L; van Vloten, W A; Meijer, C J; Willemze, R

    2000-06-15

    To evaluate our diagnostic and therapeutic guidelines, clinical and long-term follow-up data of 219 patients with primary or secondary cutaneous CD30(+) lymphoproliferative disorders were evaluated. The study group included 118 patients with lymphomatoid papulosis (LyP; group 1), 79 patients with primary cutaneous CD30(+) large T-cell lymphoma (LTCL; group 2), 11 patients with CD30(+) LTCL and skin and regional lymph node involvement (group 3), and 11 patients with secondary cutaneous CD30(+) LTCL (group 4). Patients with LyP often did not receive any specific treatment, whereas most patients with primary cutaneous CD30(+) LTCL were treated with radiotherapy or excision. All patients with skin-limited disease from groups 1 and 2 who were treated with multiagent chemotherapy had 1 or more skin relapses. The calculated risk for systemic disease within 10 years of diagnosis was 4% for group 1, 16% for group 2, and 20% for group 3 (after initial therapy). Disease-related 5-year-survival rates were 100% (group 1), 96% (group 2), 91% (group 3), and 24% (group 4), respectively. The results confirm the favorable prognoses of these primary cutaneous CD30(+) lymphoproliferative disorders and underscore that LyP and primary cutaneous CD30(+) lymphomas are closely related conditions. They also indicate that CD30(+) LTCL on the skin and in 1 draining lymph node station has a good prognosis similar to that for primary cutaneous CD30(+) LTCL without concurrent lymph node involvement. Multiagent chemotherapy is only indicated for patients with full-blown or developing extracutaneous disease; it is never or rarely indicated for patients with skin-limited CD30(+) lymphomas. (Blood. 2000;95:3653-3661) PMID:10845893

  11. Epstein-Barr virus-induced transformation of B cells for the diagnosis of genetic metabolic disorders--enumerative conditions for cryopreservation.

    PubMed

    Mello, A S; Burin, M G; Michellin, K; Viapiana, M; Giugliani, R; Coelho, J C; Bauer, M E

    2006-02-01

    Epstein-Barr virus (EBV) infection in vitro causes transformation of B cells and generates B lymphoblastoid cell lines (LCLs). These LCLs have been widely used for the diagnostic of several genetic metabolic disorders. However, up to now, efficiency of LCL generation has been based on misleading subjective analysis. In this study, quantitative analyses have been performed to indicate efficiency of B-cell transformation to measuring human lysosomal acid hydrolases associated with: GM1-gangliosidosis type I, Gaucher disease and mucopolysaccharidosis type I. Peripheral blood mononuclear cells were isolated from 13 subjects, and LCLs were produced by culturing them with EBV for 12 days. Activities of the enzymes beta-galactosidase, beta-glucosidase and alpha-iduronidase were measured before and after cryopreservation in liquid nitrogen for 30 days. Efficiency of the B-cell transformation was screened every 4 days by the enumeration of cell proliferation, cell counts and changes in granularity estimated by flow cytometry. We observed the generation of 13 LCLs. Cell transformation was confirmed by the gradual increase of cellular clusters, cell size and granularity. In addition, we determined that the activity of the enzymes mentioned above did not change following cryopreservation. These data suggest that our enumerative approach for screening of EBV-LCLs is efficient for the enzymatic determination of human lysosomal acid hydrolases and may thus replace misleading subjective analyses. PMID:16426420

  12. 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

  13. 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

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

    PubMed Central

    Strati, Paolo

    2015-01-01

    Monoclonal B lymphocytosis (MBL) is defined as the presence of a clonal B-cell population in the peripheral blood with fewer than 5 109/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 0.5 109/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 5 109/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. [Acquired A hemophilia and lymphoproliferative diseases: A literature review].

    PubMed

    Le Cam-Duchez, V

    2015-12-01

    Acquired A haemophilia is a rare but severe autoimmune disease. It is caused by autoantibodies against the coagulation factor VIII. These autoantibodies could have different consequences: no effect, inhibition of factor VIII or factor VIII activity hydrolyzing. In about half of the cases, no cause is associated with the disorder [idiopathic acquired A haemophilia]. But in remaining 50% of the patients, some circumstances could be associated with acquired hemophilia: post-partum, autoimmune disorders, cancer and sometimes malignant blood disorders. The objective of this article was to review the literature about acquired A hemophilia associated with lymphoproliferative diseases. PMID:26481810

  16. Plasmacytoid differentiation of Epstein-Barr virus-transformed B cells in vivo is associated with reduced expression of viral latent genes.

    PubMed Central

    Rochford, R; Hobbs, M V; Garnier, J L; Cooper, N R; Cannon, M J

    1993-01-01

    The Epstein-Barr virus (EBV)-associated B-cell lymphoproliferative disorders that arise in immunosuppressed individuals are considered to resemble EBV-transformed in vitro lymphoblastoid cell lines (LCLs) with a mature activated B-cell phenotype. In this study of human lymphoproliferative disorders in the severe combined immunodeficiency mouse model, however, we demonstrate that EBV-infected tumor cells are not LCL-like but are predominantly plasmacytoid and that this phenotype correlates with reduced expression of EBV latent genes. B-cell tumors developed within 3-6 weeks after injection of LCLs into severe combined immunodeficiency mice. The tumors and the injected LCLs were analyzed by flow cytofluorometry for B-cell differentiation and activation markers and by ribonuclease protection assay for cellular and viral gene expression. No differences in the expression of CD19 and CD21 were observed. However, a decrease in CD23, CD11a (lymphocyte function-associated antigen LFA-1), and CD58 (LFA-3) expression and an increase in CD38 (a plasma-cell-associated antigen), CD54 (intracellular adhesion molecule ICAM-1), and HLA class I in the tumor cells relative to the LCLs was observed. Two-color flow cytofluorometric analysis showed that the predominant population (> 80%) in LCLs was CD23hi/CD38lo and that the major population in LCL-derived tumors was CD23lo/CD38hi. Cell cycle analysis showed that, in contrast to actively cycling LCLs, the majority of tumor cells had exited the cell cycle and were restricted to G0/G1 phase. Finally, and most important, a reduction in mRNA for the EBV latent genes EBV nuclear antigen 2 (EBNA2) and latent membrane protein (LMP1) was observed in the tumors. Images PMID:8380497

  17. Interphase cytogenetics of B-cell chronic lymphocytic leukemia by FISH-technique

    SciTech Connect

    Peddanna, N.; Gogineni, S.K.; Rosenthal, C.J.

    1994-09-01

    Chronic lymphocytic leukemia [CLL] accounts for about 30% of all lymphoproliferative disorders. In over 95% of these cases, the leukemia is caused by B-cells, rarely T-cells. Fifty percent of B-CLL have chromosomal aberrations and of such cases, one-third have trisomy 12. Malignant B-cells have a very low mitotic index and those metaphases that can be analyzed usually represent the normal T-cell population. Retrospectively, we decided to identify the additional chromosome 12 (trisomy 12) directly at interphase by the FISH-technique using centrometric 12 specific alphoid probe (Oncor, Gaithersburg, MD). Preparations were made from 9 patients with B-CLL. All cultures except one failed to produce metaphases for conventional karyotyping. Eighty percent of the cells have two dots (normal cells) over the interphase nuclei while the remaining 20% have three dots (trisomy 12). The clinical implication of trisomy 12 in the pathogenesis of CLL including age, staging and duration of disease, differentials and immunological markers are correlated with interphase cytogenetic data. The loss and/or gain of specific chromosomes in human neoplasia is common and rapid evaluation of such cases should be considered as a routine approach.

  18. EBV Lymphoproliferative Disease after Hematopoietic Stem Cell Transplant

    PubMed Central

    Rouce, Rayne H; Louis, Chrystal U; Heslop, Helen E

    2014-01-01

    PURPOSE OF REVIEW EBV reactivation can cause significant morbidity and mortality after allogeneic hematopoietic stem cell transplant (SCT). Delays in reconstitution of EBV-specific T lymphocyte activity can lead to life-threatening EBV lymphoproliferative disease (EBV-PTLD). This review highlights recent advances in the understanding of pathophysiology, risk factors, diagnosis, and management of EBV viremia and PTLD. RECENT FINDINGS During the past decade, early detection strategies, such as serial measurement of EBV-DNA load, have helped to identify high-risk patients and to diagnose early lymphoproliferation. The most significant advances have come in the form of innovative treatment options, including manipulation of the balance between outgrowing EBV-infected B cells and the EBV cytotoxic T lymphocyte (EBV-CTL) response, and targeting infected B cells with monoclonal antibodies, chemotherapy, unmanipulated donor lymphocytes, and donor or more recently third party EBV-CTLs. Defining criteria for preemptive therapy and remains a challenge. SUMMARY EBV reactivation is a significant complication after SCT. Continued improvements in risk-stratification and treatment options are required to improve the morbidity and mortality caused by EBV associated diseases. Current approaches use Rituximab to deplete B cells or adoptive transfer of EBV-CTL to reconstitute immunity. The availability of rapid EBV specific T cell products offers the possibility of improved outcomes. PMID:25159713

  19. Primary CNS lymphoproliferative disease, mycophenolate and calcineurin inhibitor usage.

    PubMed

    Crane, Genevieve M; Powell, Helen; Kostadinov, Rumen; Rocafort, Patrick Tim; Rifkin, Dena E; Burger, Peter C; Ambinder, Richard F; Swinnen, Lode J; Borowitz, Michael J; Duffield, Amy S

    2015-10-20

    Immunosuppression for solid organ transplantation increases lymphoproliferative disease risk. While central nervous system (CNS) involvement is more rare, we noticed an increase in primary CNS (PCNS) disease. To investigate a potential association with the immunosuppressive regimen we identified all post-transplant lymphoproliferative disease (PTLD) cases diagnosed over a 28-year period at our institution (174 total, 29 PCNS) and all similar cases recorded in a United Network for Organ Sharing-Organ Procurement and Transplant Network (UNOS-OPTN) datafile. While no PCNS cases were diagnosed at our institution between 1986 and 1997, they comprised 37% of PTLD cases diagnosed from 2011-2014. PCNS disease was more often associated with renal vs. other organ transplant, Epstein-Barr virus, large B-cell morphology and mycophenolate mofetil (MMF) as compared to PTLD that did not involve the CNS. Calcineurin inhibitors were protective against PCNS disease when given alone or in combination with MMF. A multivariate analysis of a larger UNOS-OPTN dataset confirmed these findings, where both MMF and lack of calcineurin inhibitor usage were independently associated with risk for development of PCNS PTLD. These findings have significant implications for the transplant community, particularly given the introduction of new regimens lacking calcineurin inhibitors. Further investigation into these associations is warranted. PMID:26460822

  20. Primary CNS lymphoproliferative disease, mycophenolate and calcineurin inhibitor usage

    PubMed Central

    Crane, Genevieve M.; Powell, Helen; Kostadinov, Rumen; Rocafort, Patrick Tim; Rifkin, Dena E.; Burger, Peter C.; Ambinder, Richard F.; Swinnen, Lode J.; Borowitz, Michael J.; Duffield, Amy S.

    2015-01-01

    Immunosuppression for solid organ transplantation increases lymphoproliferative disease risk. While central nervous system (CNS) involvement is more rare, we noticed an increase in primary CNS (PCNS) disease. To investigate a potential association with the immunosuppressive regimen we identified all post-transplant lymphoproliferative disease (PTLD) cases diagnosed over a 28-year period at our institution (174 total, 29 PCNS) and all similar cases recorded in a United Network for Organ Sharing-Organ Procurement and Transplant Network (UNOS-OPTN) data file. While no PCNS cases were diagnosed at our institution between 1986 and 1997, they comprised 37% of PTLD cases diagnosed from 2011–2014. PCNS disease was more often associated with renal vs. other organ transplant, Epstein-Barr virus, large B-cell morphology and mycophenolate mofetil (MMF) as compared to PTLD that did not involve the CNS. Calcineurin inhibitors were protective against PCNS disease when given alone or in combination with MMF. A multivariate analysis of a larger UNOS-OPTN dataset confirmed these findings, where both MMF and lack of calcineurin inhibitor usage were independently associated with risk for development of PCNS PTLD. These findings have significant implications for the transplant community, particularly given the introduction of new regimens lacking calcineurin inhibitors. Further investigation into these associations is warranted. PMID:26460822

  1. Arsenic trioxide induces apoptosis via the mitochondrial pathway by upregulating the expression of Bax and Bim in human B cells.

    PubMed

    Baysan, Abdullah; Yel, Leman; Gollapudi, Sastry; Su, Houfen; Gupta, Sudhir

    2007-02-01

    Arsenic trioxide (As2O3) has been approved for the treatment of acute promyelocytic leukemia (APML) and it is a promising candidate for the treatment of patients with lymphoproliferative disorders, such as relapsed or refractory multiple myeloma and myelodysplastic syndromes. The effects of As2O3 on B cells, specifically which do not express Bcl-2, have not been studied. In this study, we have demonstrated that As2O3, at clinically achievable therapeutic concentrations, induces apoptosis in Bcl-2 negative human B cell line Ramos. As2O3-induced apoptosis is associated with reduced mitochondrial transmembrane potential (delta psi), enhanced generation of intracellular reactive oxygen species (ROS), release of cytochrome c and apoptosis-inducing factor (AIF) from mitochondria into cytoplasm, activation of caspases, and upregulation of Bax and Bim expression. Exogenous glutathione (GSH) reverses the As2O3-induced apoptosis in a dose-dependent manner. Altogether, these data indicate that As2O3 induces apoptosis in B cells, regardless of Bcl-2 expression, via the mitochondrial pathway by enhancing oxidative stress. PMID:17203211

  2. Updated Understanding of Autoimmune Lymphoproliferative Syndrome (ALPS).

    PubMed

    Li, Pu; Huang, Ping; Yang, Ye; Hao, Mu; Peng, Hongwei; Li, Fei

    2016-02-01

    Autoimmune lymphoproliferative syndrome (ALPS), a disorder characterized by immune dysregulation due to disrupted lymphocyte homeostasis, is mainly resulted from the mutations in FAS-mediated apoptotic pathway. In addition, other mutations of the genes such as Fas-ligand (FASLG), Caspase 10 (CASP10) and Caspase 8 (CASP8), NRAS and KRAS have also been observed in a small number of patients with ALPS or ALPS-related disorders. However, approximately 20-30% of patients with ALPS have unidentified defect. Its clinical manifestations observed in multiple family members include unexplained lymphadenopathy, hepatosplenomegaly, autoimmune cytopenias such as thrombocytopenia, neutropenia, and anemia due to excessive production of antibodies by lymphocytes, elevated number of double-negative T (DNT) cells, and increased risk of lymphoma. As a very rare disease, ALPS was first characterized in the early 1990s. More than 300 families with hereditary ALPS have been reported till now; nearly 500 patients from these families have been studied and followed worldwide over the last 20years. ALPS has historically considered as a primary immune defect presenting in early childhood, however, recent studies have shown that it may be more common than previous thought because adult onset presentation is increasingly becoming recognized and more adult ALPS patients are diagnosed. The new genetic and biological insights have improved the understanding of ALPS and a number of targeted therapeutic strategies such as mycophenolate mofetil, sirolimus, and pentostatin have been successfully applied in ALPS patients with promising treatment efficacy. This article comprehensively reviews the clinical and laboratory manifestations, new research advances in the molecular pathogenesis, diagnosis and treatments of this disorder. PMID:25663566

  3. B-Cell-Rich T-Cell Lymphoma Associated with Epstein-Barr Virus-Reactivation and T-Cell Suppression Following Antithymocyte Globulin Therapy in a Patient with Severe Aplastic Anemia.

    PubMed

    Hanaoka, Nobuyoshi; Murata, Shogo; Hosoi, Hiroki; Shimokado, Aiko; Mushino, Toshiki; Kuriyama, Kodai; Hatanaka, Kazuo; Nishikawa, Akinori; Kurimoto, Miwa; Sonoki, Takashi; Muragaki, Yasuteru; Nakakuma, Hideki

    2015-09-23

    B-cell lymphoproliferative disorder (B-LPD) is generally characterized by the proliferation of Epstein-Barr virus (EBV)-infected B lymphocytes. We here report the development of EBV-negative B-LPD associated with EBV-reactivation following antithymocyte globulin (ATG) therapy in a patient with aplastic anemia. The molecular autopsy study showed the sparse EBV-infected clonal T cells could be critically involved in the pathogenesis of EBV-negative oligoclonal B-LPD through cytokine amplification and escape from T-cell surveillances attributable to ATG-based immunosuppressive therapy, leading to an extremely rare B-cell-rich T-cell lymphoma. This report helps in elucidating the complex pathophysiology of intractable B-LPD refractory to rituximab. PMID:26487932

  4. B-Cell-Rich T-Cell Lymphoma Associated with Epstein-Barr Virus-Reactivation and T-Cell Suppression Following Antithymocyte Globulin Therapy in a Patient with Severe Aplastic Anemia

    PubMed Central

    Hanaoka, Nobuyoshi; Murata, Shogo; Hosoi, Hiroki; Shimokado, Aiko; Mushino, Toshiki; Kuriyama, Kodai; Hatanaka, Kazuo; Nishikawa, Akinori; Kurimoto, Miwa; Sonoki, Takashi; Muragaki, Yasuteru; Nakakuma, Hideki

    2015-01-01

    B-cell lymphoproliferative disorder (B-LPD) is generally characterized by the proliferation of Epstein-Barr virus (EBV)-infected B lymphocytes. We here report the development of EBV-negative B-LPD associated with EBV-reactivation following antithymocyte globulin (ATG) therapy in a patient with aplastic anemia. The molecular autopsy study showed the sparse EBV-infected clonal T cells could be critically involved in the pathogenesis of EBV-negative oligoclonal B-LPD through cytokine amplification and escape from T-cell surveillances attributable to ATG-based immunosuppressive therapy, leading to an extremely rare B-cell-rich T-cell lymphoma. This report helps in elucidating the complex pathophysiology of intractable B-LPD refractory to rituximab. PMID:26487932

  5. Alemtuzumab in T-cell lymphoproliferative disorders.

    PubMed

    Dearden, Claire E; Matutes, Estella

    2006-01-01

    The humanized monoclonal antibody alemtuzumab binds to the CD52 antigen, a glycoprotein which is widely expressed on normal and malignant B and T lymphocytes. Recently it has been demonstrated in a number of clinical trials that alemtuzumab has clinical activity in mature T-cell diseases such as T-prolymphocytic leukaemia and cutaneous T-cell lymphoma, inducing responses in up to two thirds of heavily pre-treated relapsed/refractory patients. Response was associated with improved survival. The toxicity profile for the antibody is manageable. The major complications are infusional reactions associated with initial injections, and prolonged lymphopenia associated with reactivation of viruses. Future studies will be directed towards alternative (subcutaneous) routes and schedules of administration, use as first-line therapy, combination strategies, and role of alemtuzumab to purge minimal residual bone-marrow disease prior to stem-cell transplantation. PMID:16997184

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

    PubMed Central

    Nron, Sonia; Darveau, Andr; 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

  7. Regulation of hybridoma B-cell proliferation by immunoglobulin-binding factor.

    PubMed

    Teillaud, J L; Mathiot, C; Amigorena, S; Brunati, S; Moncuit, J; Fridman, W H

    1988-01-01

    Immunoglobulin-binding factors (IBF), which are cytokines able to suppress the immunoglobulin production by normal and transformed B cells, have been tested for their ability to interfere with hybridoma B-cell growth. Coculture experiments performed in soft agar between hybridoma B cells and hybridoma T cells secreting IgG-BF indicated that IgG-BF act as a growth regulatory molecule able to inhibit strongly the development of hybridoma B-cell colonies; this cytostatic effect, which appeared not to be a direct cytotoxic effect, was confirmed when using semi-purified IgG-BF in both soft agar and liquid medium cultures of hybridoma B cells. Thus, IBF appear to act as both immunoregulatory and growth regulatory factors. Some of the molecular consequences of this dual effect and its possible role in certain B-cell lymphoproliferative diseases such as multiple myeloma are discussed. PMID:3263193

  8. B-cell non-Hodgkin lymphoma linked to Coxiella burnetii.

    PubMed

    Melenotte, Cla; Million, Matthieu; Audoly, Gilles; Gorse, Audrey; Dutronc, Herv; Roland, Gauthier; Dekel, Michal; Moreno, Asuncion; Cammilleri, Serge; Carrieri, Maria Patrizia; Protopopescu, Camelia; Ruminy, Philippe; Lepidi, Hubert; Nadel, Bertrand; Mege, Jean-Louis; Xerri, Luc; Raoult, Didier

    2016-01-01

    Bacteria can induce human lymphomas, whereas lymphoproliferative disorders have been described in patients with Q fever. We observed a lymphoma in a patient with Q fever that prompted us to investigate the association between the 2 diseases. We screened 1468 consecutive patients of the 2004 to 2014 French National Referral Center for Q fever database. The standardized incidence ratios (SIRs) of diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) were calculated comparatively to the 2012 Francim Registry. The presence of Coxiella burnetii was tested using immunofluorescence and fluorescence in situ hybridization using a specific 16S ribosomal RNA probe and genomic DNA probe. Seven patients (0.48%) presented mature B-cell lymphoma consisting of 6 DLBCL and 1 FL. An excess risk of DLBCL and FL was found in Q fever patients compared with the general population (SIR [95% confidence interval], 25.4 [11.4-56.4] and 6.7 [0.9-47.9], respectively). C burnetii was detected in CD68(+) macrophages within both lymphoma and lymphadenitis tissues but localization in CD123(+) plasmacytoid dendritic cells (pDCs) was found only in lymphoma tissues. Q fever patients with persistent focalized infection were found more at risk of lymphoma (hazard ratio, 9.35 [1.10-79.4]). Interleukin-10 (IL10) overproduction (P = .0003) was found in patients developing lymphoma. These results suggest that C burnetii should be added to the list of bacteria that promote human B-cell non-Hodgkin lymphoma, possibly by the infection of pDCs and IL10 overproduction. Screening for early lymphoma diagnosis should be considered in the management of patients with Q fever, especially those with persistent focalized infections. PMID:26463422

  9. Activation-induced cytidine deaminase in B cells of hepatits C virus-related cryoglobulinaemic vasculitis.

    PubMed

    Russi, S; Dammacco, F; Sansonno, S; Pavone, F; Sansonno, D

    2015-12-01

    Immunoglobulin variable region heavy chain (IgVH ) somatic gene diversification is instrumental in the transformation process that characterizes hepatitis C virus (HCV)-related B cell lymphoproliferative disorders. However, the extent to which activation-induced cytidine deaminase (AID), an enzyme essential for IgV gene somatic hypermutation (SHM), is active in cryoglobulinaemic vasculitis (CV) remains unclear. AID mRNA expression in the peripheral blood of 102 chronically hepatitis C virus (HCV)-infected patients (58 with and 44 without CV) and 26 healthy subjects was investigated using real-time reverse transcription-polymerase chain reaction (RT-PCR). The features of activation-induced cytidine deaminase (AID) protein and mRNA transcripts were explored in liver tissue biopsies and portal tracts isolated using laser capture microdissection. In chronically HCV-infected patients, AID mRNA expression was almost threefold higher in those with than in those without CV and sevenfold higher than in healthy subjects (median-fold: 6.68 versus 2.54, P = 0.03 and versus 0.95, P = 0.0003). AID transcript levels were significantly higher in polyclonal than in clonally restricted B cell preparations in either CV or non-CV patients (median-fold, 15.0 versus 2.70, P = 0.009 and 3.46 versus 1.58, P = 0.02, respectively). AID gene expression was found to be related negatively to age and virological parameters. AID protein was found in portal tracts containing inflammatory cells that, in several instances, expressed AID mRNA transcripts. Our data indicate that the aberrant expression of AID may reflect continuous B cell activation and sustained survival signals in HCV-related CV patients. PMID:26219420

  10. X-Linked Lymphoproliferative Disease Presenting as Pancytopenia in a 10-Month-Old Boy

    PubMed Central

    Chadha, S. Nicole; Amrol, David

    2010-01-01

    X-linked lymphoproliferative disease, also known as Duncan's syndrome, is a rare genetic disorder that causes exaggerated immune responses to Epstein-Barr virus (EBV) infection and often leads to death. Patient presentation varies but can include signs and symptoms typical of EBV, pancytopenia, and fulminant hepatitis. PMID:20593037

  11. Lymphoproliferative disease in mice infected with murine gammaherpesvirus 68.

    PubMed Central

    Sunil-Chandra, N. P.; Arno, J.; Fazakerley, J.; Nash, A. A.

    1994-01-01

    Murine gammaherpesvirus is a natural pathogen of wild rodents. In the laboratory it establishes an infection of epithelial cells and persists in B lymphocytes in a latent form. Inbred mice chronically infected with the virus develop a lymphoproliferative disease (LPD) similar to that seen in patients infected with Epstein-Barr virus. The frequency of LPD over a period of 3 years was 9% of all infected animals, with 50% of these displaying high grade lymphomas. The incidence of LPD was greatly increased when infected mice were treated with cyclosporin A. The majority of mice used in the experiments were BALB/c, although lymphomas were detected in mice on other genetic backgrounds, ie, CBA and B10Br. Lymphomas were associated with both lymphoid and nonlymphoid tissues (liver, lung, and kidney). In all cases of lymphomas studied thus far, there was a mixed B cell (B220+ve) and T cell (CD3+ve) phenotype. The B cells were light chain restricted, indicative of a clonal origin. Variable numbers of virus genome-positive cells were detected by in situ hybridization in and around the lymphomas. In contrast, no lytic antigen-positive cells were detected, indicating that genome-positive cells were either latently infected or undergoing an abortive infection. These observations suggest that murine gammaherpesvirus-infected mice may be an important model to study the pathogenesis of LPD associated with other gammaherpesviruses, such as Epstein-Barr virus. Images Figure 1 Figure 2 Figure 3 Figure 4 PMID:7943173

  12. Immune Disorder HSCT Protocol

    ClinicalTrials.gov

    2016-01-09

    Immune Deficiency Disorders:; Severe Combined Immunodeficiency; Chronic Granulomatous Disease; X-linked Agammaglobulinemia; Wiskott-Aldrich Syndrome; Hyper-IgM; DiGeorge Syndrome; Chediak-Higashi Syndrome; Common Variable Immune Deficiency; Immune Dysregulatory Disorder:; Hemophagocytic Lymphohistiocytosis; IPEX; Autoimmune Lymphoproliferative Syndrome; X-linked Lymphoproliferative Syndrome

  13. Hunner-Type (Classic) Interstitial Cystitis: A Distinct Inflammatory Disorder Characterized by Pancystitis, with Frequent Expansion of Clonal B-Cells and Epithelial Denudation

    PubMed Central

    Morikawa, Teppei; Kunita, Akiko; Ota, Yasunori; Katoh, Hiroto; Niimi, Aya; Nomiya, Akira; Ishikawa, Shumpei; Goto, Akiteru; Igawa, Yasuhiko; Fukayama, Masashi; Homma, Yukio

    2015-01-01

    Interstitial cystitis (IC) is a chronic bladder disease with urinary frequency, bladder discomfort or bladder pain of unknown etiology. Based on cystoscopic findings, patients with IC are classified as either Hunner-type/classic IC (HIC), presenting with a specific Hunner lesion, or non-Hunner-type IC (NHIC), presenting with no Hunner lesion, but post-hydrodistension mucosal bleeding. Inflammatory cell infiltration, composed predominantly of lymphocytes, plasma cells and epithelial denudation, has in the past been documented as a major pathological IC finding. However, the significance of the pathological evaluation of IC, especially with regard to the difference between HIC and NHIC, has been downplayed in recent years. In this study, we performed immunohistochemical quantification of infiltrating T-lymphocytes, B-lymphocytes and plasma cells, and measured the amount of residual epithelium in urinary bladder biopsy specimens taken from patients with HIC and NHIC, and those with no IC, using image analysis software. In addition, in situ hybridization of the light chains was performed to examine clonal B-cell expansion. Lymphoplasmacytic infiltration was significantly more severe in HIC specimens than in NHIC specimens (P <0.0001). Substantial lymphoplasmacytic inflammation (≥200 cells/mm2) was observed in 93% of HIC specimens, whereas only 8% of NHIC specimens were inflamed. Plasmacytic infiltration was more prominent in HIC specimens compared with NHIC and non-IC cystitis specimens (P <0.005). Furthermore, expansion of light-chain-restricted B-cells was observed in 31% of cases of HIC. The amount of residual epithelium was decreased in HIC specimens compared with NHIC specimens and non-IC cystitis specimens (P <0.0001). These results suggest that NHIC and HIC are distinct pathological entities, with the latter characterized by pancystitis, frequent clonal B-cell expansion and epithelial denudation. An abnormality in the B-cell population may be involved in the pathogenesis of HIC. PMID:26587589

  14. Loss-of-function mutations within the IL-2 inducible kinase ITK in patients with EBV-associated lymphoproliferative diseases.

    PubMed

    Linka, R M; Risse, S L; Bienemann, K; Werner, M; Linka, Y; Krux, F; Synaeve, C; Deenen, R; Ginzel, S; Dvorsky, R; Gombert, M; Halenius, A; Hartig, R; Helminen, M; Fischer, A; Stepensky, P; Vettenranta, K; Khrer, K; Ahmadian, M R; Laws, H-J; Fleckenstein, B; Jumaa, H; Latour, S; Schraven, B; Borkhardt, A

    2012-05-01

    The purpose of this study was the appraisal of the clinical and functional consequences of germline mutations within the gene for the IL-2 inducible T-cell kinase, ITK. Among patients with Epstein-Barr virus-driven lymphoproliferative disorders (EBV-LPD), negative for mutations in SH2D1A and XIAP (n=46), we identified two patients with R29H or D500T,F501L,M503X mutations, respectively. Human wild-type (wt) ITK, but none of the mutants, was able to rescue defective calcium flux in murine Itk(-/-) T cells. Pulse-chase experiments showed that ITK mutations lead to varying reductions of protein half-life from 25 to 69% as compared with wt ITK (107?min). The pleckstrin homology domain of wt ITK binds most prominently to phosphatidylinositol monophosphates (PI(3)P, PI(4)P, PI(5)P) and to lesser extend to its double or triple phosphorylated derivates (PIP2, PIP3), interactions which were dramatically reduced in the patient with the ITK(R29H) mutant. ITK mutations are distributed over the entire protein and include missense, nonsense and indel mutations, reminiscent of the situation in its sister kinase in B cells, Bruton's tyrosine kinase. PMID:22289921

  15. 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

  16. Murine Gammaherpesvirus 68 Reactivation from B Cells Requires IRF4 but Not XBP-1

    PubMed Central

    Matar, Caline G.; Rangaswamy, Udaya Shankari; Wakeman, Brian S.; Iwakoshi, Neal

    2014-01-01

    ABSTRACT Gammaherpesviruses display tropism for B cells and, like all known herpesviruses, exhibit distinct lytic and latent life cycles. One well-established observation among members of the gammaherpesvirus family is the link between viral reactivation from latently infected B cells and plasma cell differentiation. Importantly, a number of studies have identified a potential role for a CREB/ATF family member, X-box binding protein 1 (XBP-1), in trans-activating the immediate early BZLF-1 or BRLF1/gene 50 promoters of Epstein-Barr virus (EBV) and Kaposi's sarcoma-associated herpesvirus (KSHV), respectively. XBP-1 is required for the unfolded protein response and has been identified as a critical transcription factor in plasma cells. Here, we demonstrate that XBP-1 is capable of trans-activating the murine gammaherpesvirus 68 (MHV68) RTA promoter in vitro, consistent with previous observations for EBV and KSHV. However, we show that in vivo there does not appear to be a requirement for XBP-1 expression in B cells for virus reactivation. The MHV68 M2 gene product under some experimental conditions plays an important role in virus reactivation from B cells. M2 has been shown to drive B cell differentiation to plasma cells, as well as interleukin-10 (IL-10) production, both of which are dependent on M2 induction of interferon regulatory factor 4 (IRF4) expression. IRF4 is required for plasma cell differentiation, and consistent with a role for plasma cells in MHV68 reactivation from B cells, we show that IRF4 expression in B cells is required for efficient reactivation of MHV68 from splenocytes. Thus, the latter analyses are consistent with previous studies linking plasma cell differentiation to MHV68 reactivation from B cells. The apparent independence of MHV68 reactivation from XBP-1 expression in plasma cells may reflect redundancy among CREB/ATF family members or the involvement of other plasma cell-specific transcription factors. Regardless, these findings underscore the importance of in vivo studies in assessing the relevance of observations made in tissue culture models. IMPORTANCE All known herpesviruses establish a chronic infection of their respective host, persisting for the life of the individual. A critical feature of these viruses is their ability to reactivate from a quiescent form of infection (latency) and generate progeny virus. In the case of gammaherpesviruses, which are associated with the development of lymphoproliferative disorders, including lymphomas, reactivation from latently infected B lymphocytes occurs upon terminal differentiation of these cells to plasma cellsthe cell type that produces antibodies. A number of studies have linked a plasma cell transcription factor, XBP-1, to the induction of gammaherpesvirus reactivation, and we show here that indeed in tissue culture models this cellular transcription factor can trigger expression of the murine gammaherpesvirus gene involved in driving virus reactivation. However, surprisingly, when we examined the role of XBP-1 in the setting of infection of miceusing mice that lack a functional XBP-1 gene in B cellswe failed to observe a role for XBP-1 in virus reactivation. However, we show that another cellular factor essential for plasma cell differentiation, IRF4, is critical for virus reactivation. Thus, these studies point out the importance of studies in animal models to validate findings from studies carried out in cell lines passaged in vitro. PMID:25078688

  17. Primary Diffuse Large B-Cell Lymphoma of the Liver in a Patient with Sjogren Syndrome

    PubMed Central

    Gorodetskiy, Vadim; Klapper, Wolfram; Probatova, Natalya; Vasilyev, Vladimir

    2016-01-01

    Sjögren's syndrome (SS) has the highest incidence of malignant lymphoproliferative disorders transformation among autoimmune diseases. We present a case of extranodal high grade lymphoma of the liver in a 52-year-old patient with long history of SS. Lymphoma manifested with sharp significant pain in the right hypochondrium, weakness, and profuse night sweats. Contrast-enhanced computed tomography scan (CT-scan) of the abdomen revealed multiple low density foci with homogeneous structure and clear contours in both lobes of the liver. Histologically, proliferation of medium sized lymphoma cells with round-oval and slightly irregular nuclei with fine chromatin was shown. Immunohistochemical and molecular features of the tumors allowed diagnosis of diffuse large B-cell lymphoma (DLBCL). To exclude secondary liver lesion by non-Hodgkin lymphoma, chest and small pelvis CT-scan, endoscopy of upper and lower gastrointestinal tract and study of bone marrow were performed. After 8 cycles of R-CHOP chemotherapy (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone), the complete remission was achieved, which persists after 45 months of follow-up. Primary hepatic lymphomas are extremely rare, and previously only low-grade hepatic lymphomas have been described in SS. To our knowledge, the patient described here represents the first reported case of DLBCL with primary liver involvement in SS. PMID:26998372

  18. Gray zones around diffuse large B cell lymphoma. Conclusions based on the workshop of the XIV meeting of the European Association for Hematopathology and the Society of Hematopathology in Bordeaux, France.

    PubMed

    Quintanilla-Martinez, Leticia; de Jong, Daphne; de Mascarel, Antoine; Hsi, Eric D; Kluin, Philip; Natkunam, Yaso; Parrens, Marie; Pileri, Stefano; Ott, German

    2009-01-01

    The term "gray-zone" lymphoma has been used to denote a group of lymphomas with overlapping histological, biological, and clinical features between various types of lymphomas. It has been used in the context of Hodgkin lymphomas (HL) and non-Hodgkin lymphomas (NHL), including classical HL (CHL), and primary mediastinal large B cell lymphoma, cases with overlapping features between nodular lymphocyte predominant Hodgkin lymphoma and T-cell/histiocyte-rich large B cell lymphoma, CHL, and Epstein-Barr-virus-positive lymphoproliferative disorders, and peripheral T cell lymphomas simulating CHL. A second group of gray-zone lymphomas includes B cell NHL with intermediate features between diffuse large B cell lymphoma and classical Burkitt lymphoma. In order to review controversial issues in gray-zone lymphomas, a joint Workshop of the European Association for Hematopathology and the Society for Hematopathology was held in Bordeaux, France, in September 2008. The panel members reviewed and discussed 145 submitted cases and reached consensus diagnoses. This Workshop summary is focused on the most controversial aspects of gray-zone lymphomas and describes the panel's proposals regarding diagnostic criteria, terminology, and new prognostic and diagnostic parameters. PMID:20309430

  19. B Cells, Antibodies, and More.

    PubMed

    Hoffman, William; Lakkis, Fadi G; Chalasani, Geetha

    2016-01-01

    B cells play a central role in the immunopathogenesis of glomerulonephritides and transplant rejection. B cells secrete antibodies that contribute to tissue injury via multiple mechanisms. In addition, B cells contribute to disease pathogenesis in autoimmunity and alloimmunity by presenting antigens as well as providing costimulation and cytokines to T cells. B cells also play an immunomodulatory role in regulating the immune response by secreting cytokines that inhibit disease onset and/or progression. B cell-targeted approaches for treating immune diseases of the kidney and other organs have gained significant momentum. However, much remains to be understood about B-cell biology in order to determine the timing, duration, and context of optimal therapeutic response to B cell-targeted approaches. In this review, we discuss the multifaceted roles of B cells as enhancers and regulators of immunity with relevance to kidney disease and transplantation. PMID:26700440

  20. Familial Lymphoproliferative Malignancies and Tandem Duplication of NF1 Gene

    PubMed Central

    Fernandes, Gustavo; Souto, Mirela; Costa, Frederico; Oliveira, Edite; Garicochea, Bernardo

    2014-01-01

    Background. Neurofibromatosis type 1 is a genetic disorder caused by loss-of-function mutations in a tumor suppressor gene (NF1) which codifies the protein neurofibromin. The frequent genetic alterations that modify neurofibromin function are deletions and insertions. Duplications are rare and phenotype in patients bearing duplication of NF1 gene is thought to be restricted to developmental abnormalities, with no reference to cancer susceptibility in these patients. We evaluated a patient who presented with few clinical signs of neurofibromatosis type 1 and a conspicuous personal and familiar history of different types of cancer, especially lymphoproliferative malignancies. The coding region of the NF-1 gene was analyzed by real-time polymerase chain reaction and direct sequencing. Multiplex ligation-dependent probe amplification was performed to detect the number of mutant copies. The NF1 gene analysis showed the following alterations: mosaic duplication of NF1, TRAF4, and MYO1D. Fluorescence in situ hybridization using probes (RP5-1002G3 and RP5-92689) flanking NF1 gene in 17q11.2 and CEP17 for 17q11.11.1 was performed. There were three signals (RP5-1002G3conRP5-92689) in the interphases analyzed and two signals (RP5-1002G3conRP5-92689) in 93% of cells. These findings show a tandem duplication of 17q11.2. Conclusion. The case suggests the possibility that NF1 gene duplication may be associated with a phenotype characterized by lymphoproliferative disorders. PMID:25580325

  1. Applied Protein and Molecular Techniques for Characterization of B Cell Neoplasms in Horses.

    PubMed

    Badial, Peres R; Tallmadge, Rebecca L; Miller, Steven; Stokol, Tracy; Richards, Kristy; Borges, Alexandre S; Felippe, M Julia B

    2015-11-01

    Mature B cell neoplasms cover a spectrum of diseases involving lymphoid tissues (lymphoma) or blood (leukemia), with an overlap between these two presentations. Previous studies describing equine lymphoid neoplasias have not included analyses of clonality using molecular techniques. The objective of this study was to use molecular techniques to advance the classification of B cell lymphoproliferative diseases in five adult equine patients with a rare condition of monoclonal gammopathy, B cell leukemia, and concurrent lymphadenopathy (lymphoma/leukemia). The B cell neoplasms were phenotypically characterized by gene and cell surface molecule expression, secreted immunoglobulin (Ig) isotype concentrations, Ig heavy-chain variable (IGHV) region domain sequencing, and spectratyping. All five patients had hyperglobulinemia due to IgG1 or IgG4/7 monoclonal gammopathy. Peripheral blood leukocyte immunophenotyping revealed high proportions of IgG1- or IgG4/7-positive cells and relative T cell lymphopenia. Most leukemic cells lacked the surface B cell markers CD19 and CD21. IGHG1 or IGHG4/7 gene expression was consistent with surface protein expression, and secreted isotype and Ig spectratyping revealed one dominant monoclonal peak. The mRNA expression of the B cell-associated developmental genes EBF1, PAX5, and CD19 was high compared to that of the plasma cell-associated marker CD38. Sequence analysis of the IGHV domain of leukemic cells revealed mutated Igs. In conclusion, the protein and molecular techniques used in this study identified neoplastic cells compatible with a developmental transition between B cell and plasma cell stages, and they can be used for the classification of equine B cell lymphoproliferative disease. PMID:26311245

  2. Restoring balance to B cells in ADA deficiency.

    PubMed

    Luning Prak, Eline T

    2012-06-01

    It is paradoxical that immunodeficiency disorders are associated with autoimmunity. Adenosine deaminase (ADA) deficiency, a cause of X-linked severe combined immunodeficiency (SCID), is a case in point. In this issue of the JCI, Sauer and colleagues investigate the B cell defects in ADA-deficient patients. They demonstrate that ADA patients receiving enzyme replacement therapy had B cell tolerance checkpoint defects. Remarkably, gene therapy with a retrovirus that expresses ADA resulted in the apparent correction of these defects, with normalization of peripheral B cell autoantibody frequencies. In vitro, agents that either block ADA or overexpress adenosine resulted in altered B cell receptor and TLR signaling. Collectively, these data implicate a B cell-intrinsic mechanism for alterations in B cell tolerance in the setting of partial ADA deficiency that is corrected by gene therapy. PMID:22622034

  3. B cells in MS and NMO: pathogenesis and therapy.

    PubMed

    Krumbholz, Markus; Meinl, Edgar

    2014-05-01

    B linage cells are versatile players in multiple sclerosis (MS) and neuromyelitis optica/neuromyelitis optica spectrum disorder (NMO). New potential targets of autoantibodies have been described recently. Pathogenic mechanisms extend further to antigen presentation and cytokine production, which are increasingly recognized as therapeutic targets. In addition to pro-inflammatory effects of B cells, they may act also as anti-inflammatory via production of interleukin (IL)-10, IL-35, and other mechanisms. Definition of regulatory B cell subsets is an ongoing issue. Recent studies have provided evidence for a loss of B cell self-tolerance in MS. An immunogenetic approach demonstrated exchange of B cell clones between CSF and blood. The central nervous system (CNS) of MS patients fosters B cell survival, at least partly via BAFF and APRIL. The unexpected increase of relapses in a trial with a soluble BAFF/APRIL receptor (atacicept) suggests that this system is involved in MS, but with features that are not yet understood. In this review, we further discuss evidence for B cell and Ig contribution to human MS and NMO pathogenesis, pro-inflammatory and regulatory B cell effector functions, impaired B cell immune tolerance, the B cell-fostering microenvironment in the CNS, and B cell-targeted therapeutic interventions for MS and NMO, including CD20 depletion (rituximab, ocrelizumab, and ofatumumab), anti-IL6-R (tocilizumab), complement-blocking (eculizumab), inhibitors of AQP4-Ig binding (aquaporumab, small molecular compounds), and BAFF/BAFF-R-targeting agents. PMID:24832354

  4. Epstein-Barr virus induced hemophagocytic lymphohistiocytosis in X-linked lymphoproliferative disease.

    PubMed

    Sankararaman, Senthilkumar; Riel-Romero, Rosario Maria; Jeroudi, Majed; Gonzalez-Toledo, Eduardo

    2014-04-01

    X-linked lymphoproliferative disease (XLP) is a rare, often fatal genetic disorder characterized by extreme vulnerability to Epstein-Barr virus (EBV). EBV-induced hemophagocytic lymphohistiocytosis (HLH) is a known presentation in XLP. In EBV-induced HLH in XLP, the brain imaging findings in the acute phase include a non specific pattern. In this report, we highlight the magnetic resonance imaging and magnetic resonance spectroscopy findings in a child with EBV induced HLH in XLP. PMID:24966560

  5. Epstein-Barr virus induced hemophagocytic lymphohistiocytosis in X-linked lymphoproliferative disease

    PubMed Central

    Sankararaman, Senthilkumar; Riel-Romero, Rosario Maria; Jeroudi, Majed; Gonzalez-Toledo, Eduardo

    2014-01-01

    X-linked lymphoproliferative disease (XLP) is a rare, often fatal genetic disorder characterized by extreme vulnerability to Epstein-Barr virus (EBV). EBV-induced hemophagocytic lymphohistiocytosis (HLH) is a known presentation in XLP. In EBV-induced HLH in XLP, the brain imaging findings in the acute phase include a non specific pattern. In this report, we highlight the magnetic resonance imaging and magnetic resonance spectroscopy findings in a child with EBV induced HLH in XLP. PMID:24966560

  6. Ibrutinib for B cell malignancies

    PubMed Central

    2014-01-01

    Research over the role of Brutons agammaglobulinemia tyrosine kinase (BTK) in B-lymphocyte development, differentiation, signaling and survival has led to better understanding of the pathogenesis of B-cell malignancies. Down-regulation of BTK activity is an attractive novel strategy for treating patients with B-cell malignancies. Ibrutinib (PCI-32765), a potent inhibitor of BTK induces impressive responses in B-cell malignancies through irreversible bond with cysteine-481 in the active site of BTK (TH/SH1 domain) and inhibits BTK phosphorylation on Tyr223. This review discussed in details the role of BTK in B-cell signaling, molecular interactions between B cell lymphoma/leukemia cells and their microenvironment. Clinical trials of the novel BTK inhibitor, ibrutinib (PCI-32765), in B cell malignancies were summarized. PMID:24472371

  7. B Cells, Antibodies, and More

    PubMed Central

    Hoffman, William; Lakkis, Fadi G.

    2016-01-01

    B cells play a central role in the immunopathogenesis of glomerulonephritides and transplant rejection. B cells secrete antibodies that contribute to tissue injury via multiple mechanisms. In addition, B cells contribute to disease pathogenesis in autoimmunity and alloimmunity by presenting antigens as well as providing costimulation and cytokines to T cells. B cells also play an immunomodulatory role in regulating the immune response by secreting cytokines that inhibit disease onset and/or progression. B cell–targeted approaches for treating immune diseases of the kidney and other organs have gained significant momentum. However, much remains to be understood about B-cell biology in order to determine the timing, duration, and context of optimal therapeutic response to B cell–targeted approaches. In this review, we discuss the multifaceted roles of B cells as enhancers and regulators of immunity with relevance to kidney disease and transplantation. PMID:26700440

  8. Urgent Heart Retransplant in an Adult Patient With Anthracycline-Induced Cardiomyopathy After Diffuse Large B-Cell Lymphoma - Case Report.

    PubMed

    Samardzic, Jure; Skoric, Bosko; Cikes, Maja; Ljubas-Macek, Jana; Baricevic, Zeljko; Milicic, Davor

    2015-12-01

    Heart retransplant is a treatment option for some patients with graft failure. With heart donor short-age, it is important to assess candidates carefully for cardiac retransplant. An adult patient had a successful urgent heart retransplant due to severe toxic cardiomyopathy (anthracycline-induced) after posttransplant lymphoproliferative disease that was a diffuse large B-cell lymphoma. PMID:25654316

  9. Impaired Ig class switch in mice deficient for the X-linked lymphoproliferative disease gene Sap.

    PubMed

    Al-Alem, Umaima; Li, Cuiling; Forey, Nathalie; Relouzat, Francis; Fondanche, Marie-Claude; Tavtigian, Sean V; Wang, Zhao-Qi; Latour, Sylvain; Yin, Luo

    2005-09-15

    X-linked lymphoproliferative disease (XLP) is characterized by abnormal immune responses to Epstein-Barr virus attributed to inactivating mutations of the SAP gene. Previous studies showed immunoglobulin E (IgE) deficiency and low serum IgG levels in Sap-deficient mice before and after viral infections, which are associated with impaired CD4+ T-helper function. In the present work, we find that signaling lymphocytic activation molecule (SLAM)-associated protein (SAP) is expressed in B cells and this expression is down-regulated after stimulation with lipopolysaccharide (LPS) and interleukin 4 (IL-4). We demonstrate that B cells from Sap-deficient mice exhibit reduced IgG and IgA production in vitro. This impairment correlates with decreased circular transcript levels of Ialpha, Igamma2a, Igamma2b, and Igamma3 after stimulation, which indicate a defective Ig switch recombination in Sap-deficient B cells. While XLP is believed to cause defects in T, natural killer T (NKT), and natural killer (NK) cells, our results indicate that B cells are also affected. PMID:15941917

  10. Constitutive autophagy contributes to resistance to TP53-mediated apoptosis in Epstein-Barr virus-positive latency III B-cell lymphoproliferations.

    PubMed

    Pujals, Anas; Favre, Lotitia; Pioche-Durieu, Catherine; Robert, Aude; Meurice, Guillaume; Le Gentil, Marion; Chelouah, Sonia; Martin-Garcia, Nadine; Le Cam, Eric; Guettier, Catherine; Raphal, Martine; Vassilev, Lyubomir T; Gaulard, Philippe; Codogno, Patrice; Lipinski, Marc; Wiels, Jolle

    2015-11-01

    The Epstein-Barr virus (EBV) is associated with various lymphoproliferative disorders and lymphomas. We have previously demonstrated that treating wild-type TP53-expressing B cell lines with the TP53 pathway activator nutlin-3 induced apoptosis in EBV-negative and EBV-positive latency I cells whereas EBV-positive latency III cells remained much more apoptosis-resistant. Here, we report a constitutively high level of autophagy in these resistant cells which express high levels of the proautophagic protein BECN1/Beclin 1 based, at least in part, on the activation of the NFKB signaling pathway by the viral protein LMP1. Following treatment with nutlin-3, several autophagy-stimulating genes were upregulated both in EBV-negative and EBV-positive latency III cells. However the process of autophagy was only triggered in the latter and was associated with an upregulation of SESN1/sestrin 1 and inhibition of MTOR more rapid than in EBV-negative cells. A treatment with chloroquine, an inhibitor of autophagy, potentiated the apoptotic effect of nutlin-3, particularly in those EBV-positive cells which were resistant to apoptosis induced by nutlin-3 alone, thereby showing that autophagy participates in this resistant phenotype. Finally, using immunohistochemical staining, clinical samples from various B cell lymphoproliferations with the EBV-positive latency II or III phenotype were found to harbor a constitutively active autophagy. PMID:26565591

  11. A Novel and Likely Inherited Lymphoproliferative Disease in British Shorthair Kittens.

    PubMed

    Aberdein, D; Munday, J S; Fairley, R A; Vernau, W; Thompson, K G

    2015-11-01

    An unusual lymphoproliferative disease was identified in multiple closely related British Shorthair (BSH) kittens, suggesting an inherited predisposition to disease. Affected kittens typically developed rapidly progressive and marked generalized lymphadenopathy, moderate splenomegaly, and regenerative and likely hemolytic anemia from 6 weeks of age. Microscopic findings were suggestive of multicentric T-cell lymphoma, but additional testing revealed a polyclonal population of CD3+/CD4-/CD8- "double negative" T cells (DNT cells). This is a novel disease presentation with similarities to the human disorder autoimmune lymphoproliferative syndrome (ALPS), a rare inherited disease causing lymphoproliferation and variable manifestations of autoimmunity. The human disease is most commonly due to the presence of Fas gene mutations causing defective lymphocyte apoptosis, and further investigations of both the mode of inheritance and genetic basis for disease in affected cats are currently in progress. PMID:26041772

  12. B Cell Subsets in Atherosclerosis

    PubMed Central

    Perry, Heather M.; Bender, Timothy P.; McNamara, Coleen A.

    2012-01-01

    Atherosclerosis, the underlying cause of heart attacks and strokes, is a chronic inflammatory disease of the artery wall. Immune cells, including lymphocytes modulate atherosclerotic lesion development through interconnected mechanisms. Elegant studies over the past decades have begun to unravel a role for B cells in atherosclerosis. Recent findings provide evidence that B cell effects on atherosclerosis may be subset-dependent. B-1a B cells have been reported to protect from atherosclerosis by secretion of natural IgM antibodies. Conventional B-2 B cells can promote atherosclerosis through less clearly defined mechanism that may involve CD4 T cells. Yet, there may be other populations of B cells within these subsets with different phenotypes altering their impact on atherosclerosis. Additionally, the role of B cell subsets in atherosclerosis may depend on their environmental niche and/or the stage of atherogenesis. This review will highlight key findings in the evolving field of B cells and atherosclerosis and touch on the potential and importance of translating these findings to human disease. PMID:23248624

  13. MicroRNAs, Major Players in B Cells Homeostasis and Function

    PubMed Central

    Danger, Richard; Braza, Faouzi; Giral, Magali; Soulillou, Jean-Paul; Brouard, Sophie

    2014-01-01

    As a main actor in humoral immunity, B cells participate in various antibody-related disorders. However, a deeper understanding of B-cell differentiation and function is needed in order to decipher their immune-modulatory roles, notably with the recent highlighting of regulatory B cells. microRNAs (miRNAs), key factors in various biological and pathological processes, have been shown to be essential for B-cell homeostasis, and therefore understanding their participation in B-cell biology could help identify biomarkers and contribute toward curing B-cell-related immune disorders. This review aims to report studies casting light on the roles played by miRNAs in B-cell lineage and function and B-cell-related immune pathologies. PMID:24653724

  14. Comparison of EBV DNA viral load in whole blood, plasma, B-cells and B-cell culture supernatant.

    PubMed

    Ouedraogo, David Eric; Bollore, Karine; Viljoen, Johannes; Foulongne, Vincent; Reynes, Jacques; Cartron, Guillaume; Vendrell, Jean-Pierre; Van de Perre, Philippe; Tuaillon, Edouard

    2014-05-01

    Epstein-Barr virus (EBV) genome quantitation in whole blood is used widely for therapeutic monitoring of EBV-associated disorders in immunosuppressed individuals and in patients with EBV-associated lymphoma. However, the most appropriate biological material to be used for EBV DNA quantitation remains a subject of debate. This study compare the detection rate and levels of EBV DNA from whole blood, plasma, enriched B-cells, and B-cell short-term culture supernatant using quantitative real-time PCR. Samples were collected from 33 subjects with either HIV infection or B-cell lymphoma. Overall, EBV DNA was detected in 100% of enriched B-cell samples, in 82% of B-cell culture supernatants, in 57% of plasma, and 42% of whole blood samples. A significant correlation for EBV viral load was found between enriched B-cell and B-cell culture supernatant material (ρ = 0.92; P < 0.0001), but no significant correlation existed between EBV DNA levels in whole blood and enriched B-cells (ρ = -0.02; P = 0.89), whole blood and plasma (ρ = 0.24; P = 0.24), or enriched B-cells and plasma (ρ = 0.08; P = 0.77). Testing of enriched B-cells appeared to be the most sensitive method for detection of EBV DNA as well as for exploration of the cellular reservoir. Quantitation of EBV DNA in plasma and B-cell culture supernatant may be of interest to assess EBV reactivation dynamics and response to treatment as well as to decipher EBV host-pathogen interactions in various clinical scenarios. PMID:24265067

  15. How Should We Treat Early Post-Transplant Lymphoproliferative Disease After Heart Transplantation?

    PubMed

    Nitta, Daisuke; Kinugawa, Koichiro; Imamura, Teruhiko; Hatano, Masaru; Ono, Minoru; Nakamura, Fumihiko; Kurokawa, Mineo; Komuro, Issei

    2015-12-01

    Although post-transplant lymphoproliferative disease (PTLD) is one of the major fatal complications encountered several years after heart transplant (HTx), little is known about early-PTLD emerging within the first year. We here describe the rare case of a 24-year-old female patient who suffered from early-PTLD (DLBCL: diffuse large B-cell lymphoma) associated with an Epstein-Barr virus (EBV) infection, that developed around the jejunum at 7 months after HTx. She suffered from acute abdominal peritonitis due to perforation of the jejunum soon after the first chemotherapy. She was treated successfully by emergent partial resection of the jejunum and colostomy after the discontinuation of everolimus (EVL) and successive low-dose chemotherapy under careful monitoring and adjustment of intravenous immunosuppressant including cyclosporine (CyA) and prednisolone to avoid a rejection reaction. Prophylactic strategies for early-PTLD in HTx recipients should be undertaken with caution. PMID:26549285

  16. Diffuse Large B Cell Lymphoma with Extensive Cutaneous Relapse

    PubMed Central

    Malkan, Umit Yavuz; Gunes, Gursel; Yayar, Okan; Demiroglu, Haluk

    2015-01-01

    Herein, we aimed to report a diffuse large B cell lymphoma (DLBCL) case that had extensive cutaneous relapse with no skin involvement previously. A 59-year-old man presented to hospital in April 2014 with fatigue, anorexia, fever, and anemia. Cervical lymph node biopsy revealed CD20+, BCL2+, MUM1+, BCL6+ high grade B lymphoproliferative neoplasm. After FISH investigation, he was diagnosed as DLBCL. He was given 7 cycles of R-CHOP and achieved remission. However, in November 2014, he had emerging skin lesions that cover nearly all of his body. A control PET-CT revealed diffuse cutaneous involvement. CD20+, BCL2+, MUM1+, BCL6+ high grade B cell lymphoma infiltration was detected with skin biopsy. He was diagnosed as relapse lymphoma, so 2 cycles of R-DHAP were given. There was no treatment response; therefore, R-ICE regimen was started. The patient had achieved second complete remission and his skin lesions were completely regressed. The involvement of skin with CD20+ cells after 7 cycles of rituximab therapy favors that there is a rituximab resistant disease which tends to involve the skin. To conclude, DLBCL may relapse extensively with cutaneous involvement and the best treatment option in these patients is salvage chemotherapy followed by autologous peripheral blood stem cell transplantation. PMID:26457084

  17. 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 ...

  18. 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

  19. 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

  20. High-flux hemodialysis after administering high-dose methotrexate in a patient with posttransplant lymphoproliferative disease and impaired renal function.

    PubMed

    Reshetnik, Alexander; Scheurig-Muenkler, Christian; van der Giet, Markus; Tlle, Markus

    2015-11-01

    A young patient develops cerebral posttransplant lymphoproliferative disorder. Despite concurrent significantly impaired transplant kidney function use of add-on high-flux hemodialysis for additional clearance made the administration of high-dose methotrexate feasible in this patient without occurence of acute chronic kidney failure and significant hematological toxicity. PMID:26576275

  1. 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

  2. Cytokine-producing B cells: atranslational view on their roles in human and mouse autoimmune diseases.

    PubMed

    Lino, Andreia C; Drner, Thomas; Bar-Or, Amit; Fillatreau, Simon

    2016-01-01

    B-cell depletion therapy has beneficial effects in autoimmune diseases. This is only partly explained by an elimination of autoantibodies. How does B-cell depletion improve disease? Here, we review preclinical studies showing that B cells can propagate autoimmune disorders through cytokine production. We also highlight clinical observations indicating the relevance of these B-cell functions in human autoimmunity. Abnormalities in B-cell cytokine production have been observed in rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, and systemic lupus erythematosus. In the first two diseases, B-cell depletion erases these abnormalities, and improves disease progression, suggesting a causative role for defective B-cell cytokine expression in disease pathogenesis. However, in the last two disorders, the pathogenic role of B cells and the effect of B-cell depletion on cytokine-producing B cells remain to be clarified. A better characterization of cytokine-expressing human B-cell subsets, and their modulation by B cell-targeted therapies might help understanding both the successes and failures of current B cell-targeted approaches. This may even lead to the development of novel strategies to deplete or amplify selectively pathogenic or protective subsets, respectively, whichmight be more effective than global depletion of the B-cell compartment. PMID:26683150

  3. Anti-CD79 Antibody Induces B cell Anergy That Protects Against Autoimmunity

    PubMed Central

    Hardy, Ian R.; Anceriz, Nadia; Rousseau, Franois; Seefeldt, Matt B.; Hatterer, Eric; Irla, Magali; Buatois, Vanessa; Chatel, Laurence E.; Getahun, Andrew; Fletcher, Ashley; Cons, Laura; Pontini, Guillemette; Hertzberg, Nicole A.; Magistrelli, Giovanni; Malinge, Pauline; Smith, Mia J.; Reith, Walter; Kosco-Vilbois, Marie H.; Ferlin, Walter G.; Cambier, John C.

    2014-01-01

    B cells play a major role in the pathogenesis of many autoimmune disorders including rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis and type I diabetes mellitus, as indicated by the efficacy of B cell-targeted therapies in these diseases. Therapeutic effects of the most commonly used B cell-targeted therapy, anti-CD20 monoclonal antibody, are contingent upon long-term depletion of peripheral B cells. Here, we describe an alternative approach involving the targeting of CD79, the transducer subunit of the B cell antigen receptor. Unlike anti-CD20 mAbs, the protective effects of CD79-targeted mAb are do not require cell depletion, but rather act by inducing an anergic-like state. Thus, we describe a novel B cell-targeted approach predicated on the induction of B cell anergy. PMID:24442438

  4. 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 (Mareks disease virus) or three species of retroviruses [Reticuloendotheliosis virus (REV), Avian leukosis/sarcoma virus, lymphoproliferative disease virus (LPDV)]. Previously, retroviral n...

  5. 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

  6. Primary bone marrow diffuse large B-cell lymphoma accompanying cold agglutinin disease: A case report with review of the literature.

    PubMed

    Yamashita, Tomoko; Ishida, Mitsuaki; Moro, Hiroko; Yumoto, Hirofumi; Uchibayashi, Sachiko; Yoshii, Miyuki; Nakanishi, Ryota; Okuno, Hiroko; Yoshida, Takashi; Okuno, Takafumi; Hodohara, Keiko; Okabe, Hidetoshi

    2014-01-01

    Cold agglutinin disease (CAD) is a well-recognized complication of lymphoproliferative disorders. It has been previously recognized that cases of primary CAD frequently exhibit underlying malignant lymphoma in the bone marrow. Lymphoplasmacytic lymphoma is the most common subtype of malignant lymphoma; however, diffuse large B-cell lymphoma (DLBCL) has also been documented, albeit extremely rare. The current report presents a case of primary bone marrow DLBCL accompanying CAD. A 76-year-old male presented with fever and fatigue. Laboratory tests revealed anemia and elevated bilirubin and cold agglutinins with a titer of 8,192 at 4°C. Bone marrow biopsy demonstrated DLBCL and systemic surveillance failed to detect tumorous lesions or lymphadenopathy. Following R-THP-COP therapy, cold agglutinins titer was markedly decreased (by <4); however, malignant lymphoma relapsed and cold agglutinin levels increased again (4,096). This is the second documented case of primary bone marrow DLBCL accompanying CAD. Previously, malignant lymphoma exclusively involving the bone marrow, namely primary bone marrow lymphoma (PBML), has been recognized as a rare and aggressive subtype. The analyses of the present study revealed that the incidence of hemolytic anemia in primary bone marrow DLBCL may be high compared with conventional DLBCL. Therefore, additional analyses are required to clarify the clinicopathological features of PBML. PMID:24348825

  7. Signal transduction through mu kappa B-cell receptors expressed on pre-B cells is different from that through B-cell receptors on mature B cells.

    PubMed Central

    Nakamura, T; Koyama, M; Yoneyama, A; Higashihara, M; Kawakami, T; Yamamura, H; Sada, K; Okumura, K; Kurokawa, K

    1996-01-01

    We introduced kappa light chain genes into pre-B cells to increase the surface mu HC expression, and established transfectants expressing mature type of B-cell receptors (BCR) on pre-B-cell surfaces. Since the cytoplasmic conformations of the reconstituted BCR and intrinsic pre-B-cell receptor (pre-BCR) are identical, they would be connected with the identical signal transduction pathways in pre-B cells. By using the transfectants, we revealed that the reconstituted BCR on pre-B cells was functionally equivalent to BCR on mature B cells in terms of the induction of intracellular Ca++ mobilization. However, we found that the signal-transduction pathways through BCR on pre-B cells were quantitatively different from those mature B cells in two ways. First, cross-linkage of the reconstituted BCR on pre-B cells induced preferential tyrosine phosphorylation of p120 and p100, which was not observed when BCR on mature B cells was cross-linked. Second, BCR in pre-B cells was physically associated with a larger amount of phosphatidylinositol-3 kinase (PI-3K) than BCR in mature B cells in spite of the fact that both pre-B and B cells expressed a similar amount of PI-3K in cytoplasm. Signals through pre-BCR and BCR are known to cause distinct biological effects in B-cell development. The biochemical features in the downstream of reconstituted BCR on pre-B cells, which we revealed in this study, will be of help in understanding the mechanism of functional differences between pre-BCR and BCR. Images Figure 3 Figure 4 Figure 5 PMID:8881762

  8. Frequent Mutations in SH2D1A (XLP) in Males Presenting With High-Grade Mature B-Cell Neoplasms

    PubMed Central

    Sandlund, J.T.; Shurtleff, S.A.; Onciu, M.; Horwitz, E.; Leung, W.; Howard, V.; Rencher, R.; Conley, M.E.

    2016-01-01

    X-linked lymphoproliferative syndrome (XLP) is caused by mutations in SH2D1A, and is associated with overwhelming infectious mononucleosis, aplastic anemia, hypogammaglobulinemia, and B-cell lymphomas. However, the frequency of SH2D1A mutations in males who present with B NHL is unknown. Five cases of XLP were diagnosed among 158 males presenting with B NHL (approximately 3.2%). Four of the patients had two episodes of B NHL and one had a single episode of B NHL followed by aggressive infectious mononucleosis. Prospective screening for XLP in males with B-cell lymphoma at the time of initial diagnosis should be considered. PMID:23589280

  9. Kras Is Critical for B Cell Lymphopoiesis.

    PubMed

    Chen, Yuhong; Zheng, Yongwei; You, Xiaona; Yu, Mei; Fu, Guoping; Su, Xinlin; Zhou, Fen; Zhu, Wen; Wu, Zhihong; Zhang, Jing; Wen, Renren; Wang, Demin

    2016-02-15

    The three major Ras members, Kras, Hras, and Nras, are highly homologous and individual Ras genes can have distinct biological functions. Embryonic lethality of Kras-deficient mice precludes study of the biological functions of this Ras family member. In this study, we generated and examined mice with hematopoietic-specific deletion of Kras and bone marrow (BM) chimeric mice with B cell-specific targeted deletion of Kras. Hematopoietic-specific deletion of Kras impaired early B cell development at the pre-B cell stage and late B cell maturation, resulting in the reduction of BM pre-, immature, and mature B cells and peripheral follicular, marginal zone, and B1 mature B cells. In contrast, Kras deficiency did not affect T cell development. Studies of BM chimeric mice with B cell-specific deletion of Kras demonstrated that Kras deficiency intrinsically impaired B cell development. Kras deficiency reduced BCR-induced B cell proliferation and survival. Furthermore, Kras deficiency specifically impaired pre-BCR- and BCR-induced activation of the Raf-1/MEK/ERK pathway in pre-B and mature B cells, respectively. Thus, Kras is the unique Ras family member that plays a critical role in early B cell development and late B cell maturation through controlling the Raf-1/MEK/ERK pathway. PMID:26773157

  10. Characterization of immunoglobulin heavy and light chain gene expression in chronic lymphocytic leukemia and related disorders.

    PubMed

    Nakahashi, Hirotaka; Tsukamoto, Norifumi; Hashimoto, Yoko; Koiso, Hiromi; Yokohama, Akihiko; Saitoh, Takayuki; Uchiumi, Hideki; Handa, Hiroshi; Murakami, Hirokazu; Nojima, Yoshihisa; Karasawa, Masamitsu

    2009-04-01

    The incidence of chronic lymphocytic leukemia is low in the Japanese population compared with populations in western countries, suggesting a role for genetic factors in the occurrence of this disease. We have previously shown that chronic lymphocytic leukemia in Japan rarely expresses the immunoglobulin heavy chain variable region (IGHV) 1-69 gene (1 out of 43 patients, 2.3%), which is a gene most commonly expressed in chronic lymphocytic leukemia cases from western countries. In the current study, we extended the previous study by examining immunoglobulin heavy chain and light chain gene expression in 80 Japanese patients with chronic lymphocytic leukemia and in 52 Japanese patients with other leukemic chronic lymphoproliferative disorders. IGHV1-69 gene expression was again quite low in our cohort, found in only two patients: one with chronic lymphocytic leukemia and the other with splenic marginal zone lymphoma. The IGHV4-34 gene was most frequently expressed in chronic lymphocytic leukemia (27.5%), whereas it was rarely found in leukemic chronic lymphoproliferative disorders (7.7%, P = 0.005). There was also a significant difference in the expression of IGLV3-21 between chronic lymphocytic leukemia and leukemic chronic lymphoproliferative disorders (29.4 vs 4.8%, P = 0.018). The IGLV3-21 gene in the majority of chronic lymphocytic leukemia cases was associated with homologous complementarity determining region 3 sequences. Recent studies identified subsets of cases expressing almost identical B-cell receptors. We found that two patients with chronic lymphocytic leukemia and the patient with splenic marginal zone lymphoma expressed IGHV4-39/IGKV1-39 and IGHV1-69/IGKV3-20, respectively, which belong to these subsets. PMID:19220298

  11. VR09 Cell Line: An EBV-Positive Lymphoblastoid Cell Line with In Vivo Characteristics of Diffuse Large B Cell Lymphoma of Activated B-Cell Type

    PubMed Central

    Nichele, Ilaria; Zam, Alberto; Bertolaso, Anna; Bifari, Francesco; Tinelli, Martina; Franchini, Marta; Stradoni, Roberta; Aprili, Fiorenza; Pizzolo, Giovanni; Krampera, Mauro

    2012-01-01

    Background small B-cell neoplasms can show plasmacytic differentiation and may potentially progress to aggressive lymphoma (DLBCL). Epstein-Barr virus (EBV) infection may cause the transformation of malignant cells in vitro. Design and Method we established VR09 cell line with plasmacytic differentiation, obtained from a case of atypical, non-CLL B-cell chronic lymphoproliferative disease with plasmacytic features. We used flow cytometry, immunohistochemistry, polymerase chain reaction, cytogenetic analysis and florescence in situ hybridization in the attempt at thoroughly characterizing the cell line. We showed VR09 tumorigenic potential in vivo, leading to the development of activated DLBCL with plasmacytic features. Results VR09 cells displayed plasmacytic appearance and grew as spherical tumors when inoculated subcutaneously into immunodeficient Rag2?/? ?-chain?/? mice. VR09 cell line and tumors displayed the phenotype of activated stage of B cell maturation, with secretory differentiation (CD19+ CD20+ CD79a+ CD79b+/? CD138+ cyclin D1- Ki67 80% IgM+ IgD+ MUM1+ MNDA+ CD10- CD22+ CD23+ CD43+ K+, ?- Bcl2+ Bcl6-) and they presented episomal EBV genome, chromosome 12 trisomy, lack of c-MYC rearrangement and Myd88 gene mutation, presence of somatic hypermutation in the VH region, and wild-type p53. Conclusion This new EBV-positive cell line may be useful to further characterize in vivo activated DLBCL with plasmacytic features. PMID:23285191

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

    PubMed

    Revel-Vilk, Shoshana; Fischer, Ute; Keller, Brbel; Nabhani, Schafiq; Gmez-Daz, Laura; Rensing-Ehl, Anne; Gombert, Michael; Hnscheid, 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

  13. A New Kid on the Block: IL-10+ Regulatory B Cells and a Possible Role In Psoriasis

    PubMed Central

    Darabi, Kamruz; Jaiswal, Rohit; Hostetler, Sarah G.; Bechtel, Mark A.; Zirwas, Matthew J.; Witman, Patricia

    2009-01-01

    The pivotal role of T cells in the etiology of psoriasis has been elucidated; however, the mechanisms that regulate these T cells are unclear. Recently, it has been shown that an IL-10 producing B cell population may downregulate T cell function and it has been hypothesized that depletion of this B cell population may lead to exacerbation of T-cell mediated autoimmune disease. We present the case of an adolescent male with autoimmune lymphoproliferative syndrome (ALPS) being treated with the anti-CD20 chimeric monoclonal antibody rituximab in addition to intravenous immune globulin (IVIG) for immune thrombocytopenia (ITP) who developed a psoriasiform rash on his hands following mechanical trauma with concomitant severely decreased B cell count. We propose that depletion of the patient's B cells due to rituximab treatment may have led to abrogation of IL-10+ B-cell regulation of T cells. The development of a psoriasiform rash in this predisposed individual may have been triggered by mechanical trauma to his hands (koebnerization). In addition, we believe the patient's rash may have been tempered by concomitant treatment with IVIG, which has been used as treatment in cases of psoriasis. We discuss the immunologic mechanism of psoriasis and the role that a recently described IL-10+ B cell may play in preventing the pathologic process. Further studies are needed to more clearly elucidate this process. PMID:23055903

  14. Expansion of murine gammaherpesvirus latently infected B cells requires T follicular help.

    PubMed

    Collins, Christopher M; Speck, Samuel H

    2014-05-01

    X linked lymphoproliferative disease (XLP) is an inherited immunodeficiency resulting from mutations in the gene encoding the slam associated protein (SAP). One of the defining characteristics of XLP is extreme susceptibility to infection with Epstein-Barr virus (EBV), a gammaherpesvirus belonging to the genus Lymphocryptovirus, often resulting in fatal infectious mononucleosis (FIM). However, infection of SAP deficient mice with the related Murine gammaherpesvirus 68 (MHV68), a gammaherpesvirus in the genus Rhadinovirus, does not recapitulate XLP. Here we show that MHV68 inefficiently establishes latency in B cells in SAP deficient mice due to insufficient CD4 T cell help during the germinal center response. Although MHV68 infected B cells can be found in SAP-deficient mice, significantly fewer of these cells had a germinal center phenotype compared to SAP-sufficient mice. Furthermore, we show that infected germinal center B cells in SAP-deficient mice fail to proliferate. This failure to proliferate resulted in significantly lower viral loads, and likely accounts for the inability of MHV68 to induce a FIM-like syndrome. Finally, inhibiting differentiation of T follicular helper (TFH) cells in SAP-sufficient C57Bl/6 mice resulted in decreased B cell latency, and the magnitude of the TFH response directly correlated with the level of infection in B cells. This requirement for CD4 T cell help during the germinal center reaction by MHV68 is in contrast with EBV, which is thought to be capable of bypassing this requirement by expressing viral proteins that mimic signals provided by TFH cells. In conclusion, the outcome of MHV68 infection in mice in the setting of loss of SAP function is distinct from that observed in SAP-deficient patients infected with EBV, and may identify a fundamental difference between the strategies employed by the rhadinoviruses and lymphocryptoviruses to expand B cell latency during the early phase of infection. PMID:24789087

  15. 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

  16. Antigen-specific memory B cell development.

    PubMed

    McHeyzer-Williams, Louise J; McHeyzer-Williams, Michael G

    2005-01-01

    Helper T (Th) cell-regulated B cell immunity progresses in an ordered cascade of cellular development that culminates in the production of antigen-specific memory B cells. The recognition of peptide MHC class II complexes on activated antigen-presenting cells is critical for effective Th cell selection, clonal expansion, and effector Th cell function development (Phase I). Cognate effector Th cell-B cell interactions then promote the development of either short-lived plasma cells (PCs) or germinal centers (GCs) (Phase II). These GCs expand, diversify, and select high-affinity variants of antigen-specific B cells for entry into the long-lived memory B cell compartment (Phase III). Upon antigen rechallenge, memory B cells rapidly expand and differentiate into PCs under the cognate control of memory Th cells (Phase IV). We review the cellular and molecular regulators of this dynamic process with emphasis on the multiple memory B cell fates that develop in vivo. PMID:15771579

  17. Memory B cells in mouse models.

    PubMed

    Bergmann, B; Grimsholm, O; Thorarinsdottir, K; Ren, W; Jirholt, P; Gjertsson, I; Mårtensson, 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

  18. B cells, BAFF/zTNF4, TACI, and systemic lupus erythematosus

    PubMed Central

    Drner, Thomas; Putterman, Chaim

    2001-01-01

    B cells and B-cell/T-cell collaborations are instrumental in the pathophysiology of systemic lupus erythematosus (SLE). This commentary highlights in particular the newly discovered role of B-cell-activating factor (BAFF; also known as TALL-1, THANK, BlyS, and zTNF4) as a positive regulator of B-cell functions, such as B-cell activation and differentiation. Two members of the tumor necrosis factor(TNF)-receptor superfamily were recently identified as receptors for BAFF on B cells. The interaction between BAFF and its receptors may be important in the pathogenesis of lupus. Advances in our understanding of abnormalities in immune regulation in lupus might provide the opportunity to improve our current therapeutic approaches to this disorder. PMID:11438034

  19. Multiple routes to B-cell memory.

    PubMed

    Good-Jacobson, Kim L; Tarlinton, David M

    2012-07-01

    B-cell memory describes the populations of cells that provide long-term humoral immunity: long-lived antibody-secreting plasma cells that reside mainly in the bone marrow and memory B cells. Interestingly, the memory B-cell population is heterogenous, although the importance of this heterogeneity has been unclear. Recent studies have investigated the formation and function of memory in different settings. In particular, T-independent memory-like cells and T-dependent (TD) IgM memory B cells qualitatively differ from canonical TD class-switched memory B cells; however, these studies suggest that IgM memory cells preserve the memory population over long periods of time. These subsets are evocative of the evolution of the humoral immune response, with memory-like cells appearing before acquisition of germinal centers, suggesting that there are multiple pathways to producing B-cell memory. PMID:22451529

  20. 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

    Mhl, 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

  1. The expanding family of regulatory B cells

    PubMed Central

    Menon, Madhvi

    2015-01-01

    Over the last decade it has become evident that in addition to producing antibody, B cells activate the immune system by producing cytokines and via antigen presentation. In addition, B cells also exhibit immunosuppressive functions via diverse regulatory mechanisms. This subset of B cells, known as regulatory B cells (Bregs), contributes to the maintenance of tolerance, primarily via the production of IL-10. Studies in experimental animal models, as well as in patients with autoimmune diseases, have identified multiple Breg subsets exhibiting diverse mechanisms of immune suppression. In this review, we describe the different Breg subsets identified in mice and humans, and their diverse mechanisms of suppression in different disease settings. PMID:26071023

  2. B-Cell Hematologic Malignancy Vaccination Registry

    ClinicalTrials.gov

    2015-09-15

    Monoclonal Gammopathy of Undetermined Significance; Multiple Myeloma; Waldenstrom Macroglobulinemia; Lymphocytosis; Lymphoma, Non-Hodgkin; B-Cell Chronic Lymphocytic Leukemia; Hematological Malignancies

  3. Reprint of: Environments of B cell development.

    PubMed

    Tsuneto, Motokazu; Kajikhina, Ekaterina; Seiler, Katharina; Reimer, Andreas; Tornack, Julia; Bouquet, Corinne; Simmons, Szandor; Knoll, Marko; Wolf, Ingrid; Tokoyoda, Koji; Hauser, Anja; Hara, Takahiro; Tani-ichi, Shizue; Ikuta, Koichi; Grn, Joachim R; Grtzkau, Andreas; Engels, Niklas; Wienands, Jrgen; Yanagisawa, Yuki; Ohnishi, Kazuo; Melchers, Fritz

    2014-08-01

    B lymphocyte development in the mouse begins with the generation of long-term reconstituting, pluripotent hematopoietic stem cells, over multipotent myeloid/lymphoid progenitors and common lymphoid progenitors to B-lineage committed pro/pre B and pre B cells, which first express pre B cell receptors and then immunoglobulins, B cell receptors, to generate the repertoires of peripheral B cells. This development is influenced and guided by cells of non-hematopoietic and hematopoietic origins. We review here some of the recent developments, and our contributions in this fascinating field of developmental immunology. PMID:24852107

  4. Atacicept: targeting B cells in multiple sclerosis.

    PubMed

    Hartung, Hans-Peter; Kieseier, Bernd C

    2010-07-01

    Multiple sclerosis (MS) has traditionally been considered to be a T-cell-mediated disease. However, there is an increasing body of evidence for the involvement of B cells and autoantibodies in the pathology of this disease, providing a rationale for treatments directed against B cells. In this paper we summarize evidence for the key role of B cells in the immunopathology of MS and review data supporting the use of a novel B-cell targeted therapy, atacicept, in this condition. Atacicept is a human recombinant fusion protein that comprises the binding portion of a receptor for both BLyS (B-Lymphocyte Stimulator) and APRIL (A PRoliferation-Inducing Ligand), two cytokines that have been identified as important regulators of B-cell maturation, function and survival. Atacicept has shown selective effects on cells of the B-cell lineage, acting on mature B cells and blocking plasma cells and late stages of B-cell development while sparing B-cell progenitors and memory cells. The efficacy of atacicept in animal models of autoimmune disease and the biological activity of atacicept in patients with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) has been demonstrated. Clinical studies were initiated to investigate the safety, tolerability and efficacy of atacicept in patients with MS. An unexpected increase in inflammatory activity in one of the trials, however, led to suspension of all atacicept trials in MS. PMID:21179612

  5. Mincle and human B cell function

    PubMed Central

    Kawata, Kazuhito; Illarionov, Petr; Kenny, Thomas; Zhang, Weici; Tsuda, Masanobu; Ando, Yugo; Leung, Patrick; Ansari, Aftab A.; Gershwin, M. Eric

    2012-01-01

    C-type lectin receptors are pattern recognition receptors that are critical for autoimmunity and the immune response. Mincle is a C-type lectin receptor expressed by a variety of antigen presenting cells including macrophages, neutrophils, dendritic cells and B cells; a variety of stimuli including stress are known to induce the expression of Mincle. Mincle is an FcR?-associated activation receptor that senses damaged cells and upon ligation induces activated macrophages to produce inflammatory cytokines. Recently, while several studies have reported that Mincle plays an important role in macrophage responses to fungal infection its function on B cells remains to be defined. In efforts to elucidate the function of Mincle expressed by B cells, we studied the expression of Mincle on subsets of B cells and analyzed cytokines and synthesized immunoglobulin upon ligation of Mincle. The expression of Mincle on CD27?CD19+ nave B cells is significantly higher than CD27+CD19+ memory B cells. The stimulation of TLR9 ligand induced Mincle expression on B cells. Furthermore, co-stimulation of TLR9 and Mincle ligand reduced IgG and IgA production from B cells without a significant change in the inflammatory cytokines TNF?, IL-6, IL-8 and IL-10. Our data identifies Mincle as a potentially critical player in human B cell responses. PMID:22698596

  6. Mincle and human B cell function.

    PubMed

    Kawata, Kazuhito; Illarionov, Petr; Yang, Guo-Xiang; Kenny, Thomas P; Zhang, Weici; Tsuda, Masanobu; Ando, Yugo; Leung, Patrick S C; Ansari, Aftab A; Eric Gershwin, M

    2012-12-01

    C-type lectin receptors are pattern recognition receptors that are critical for autoimmunity and the immune response. Mincle is a C-type lectin receptor expressed by a variety of antigen presenting cells including macrophages, neutrophils, dendritic cells and B cells; a variety of stimuli including stress are known to induce the expression of Mincle. Mincle is an FcR?-associated activation receptor that senses damaged cells and upon ligation induces activated macrophages to produce inflammatory cytokines. Recently, while several studies have reported that Mincle plays an important role in macrophage responses to fungal infection its function on B cells remains to be defined. In efforts to elucidate the function of Mincle expressed by B cells, we studied the expression of Mincle on subsets of B cells and analyzed cytokines and synthesized immunoglobulin upon ligation of Mincle. The expression of Mincle on CD27-CD19(+) nave B cells is significantly higher than CD27 + CD19(+) memory B cells. The stimulation of TLR9 ligand induced Mincle expression on B cells. Furthermore, co-stimulation of TLR9 and Mincle ligand reduced IgG and IgA production from B cells without a significant change in the inflammatory cytokines TNF-?, IL-6, IL-8 and IL-10. Our data identifies Mincle as a potentially critical player in human B cell responses. PMID:22698596

  7. 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

  8. Risk of lymphoproliferative malignancy in celiac patients with a family history of lymphoproliferative malignancy

    PubMed Central

    Ludvigsson, Jonas F; Lebwohl, Benjamin; Rubio-Tapia, Alberto; Murray, Joseph A.; Green, Peter HR; Ekbom, Anders

    2013-01-01

    Background and aims Individuals with celiac disease (CD) are at increased risk of lymphoproliferative malignancy (LPM). We examined if a family history of LPM or any cancer influenced the risk of LPM in individuals with CD. Methods We identified 28,996 individuals with biopsy-verified CD (equal to villous atrophy, Marsh histopathology stage 3), of whom 616 had family history of LPM. Cox regression then estimated hazard ratios (HRs) for LPM in these 616 compared with two control groups. We also examined the risk of LPM in CD individuals with a family history of any cancer (n=8,439). Results During follow-up, 2/616 CD individuals with a family history of LPM, and 235/28,380 CD individuals without a family history of LPM developed LPM themselves. CD individuals with a family history of LPM were not at increased risk of LPM compared to general population controls (HR=1.18; 95%CI=0.27–5.10), or compared to CD individuals without a family history of LPM (adjusted HR=0.31; 95%CI=0.08–1.23). We found no increased risk of LPM in CD individuals with a family history of any cancer. Conclusion This study found no evidence that a family history of LPM or any cancer increases the risk of future LPM in individuals with CD. Despite the large number of study participants, this study is however limited by few positive events due to a low absolute risk of LPM even in individuals with CD. PMID:23440554

  9. 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 β-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 β-glucosylceramide and greatly elevated plasma β-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 β-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

  10. Symptomatic Massive Splenomegaly in Persistent Polyclonal B-cell Lymphocytosis Requiring Splenectomy

    PubMed Central

    Bhagwandin, Shanel B.; Weisenberg, Elliot S.; Ozer, Howard; Maker, Ajay V.

    2015-01-01

    Introduction Persistent polyclonal B-cell lymphocytosis (PPBL) is a rare lymphoproliferative hematological disease characterized by binucleated lymphocytes, CD 19+ CD 5?lymphocytosis, and elevated levels of serum immunoglobulin M (IgM). It can rarely be associated with splenomegaly, though the disease usually remains indolent. Case Presentation We present a case of PPBL in a young man with massive splenomegaly that mimicked isolated splenic lymphoma requiring splenectomy for persistent pain, symptoms, and diagnosis. Discussion Determining the etiology of splenomegaly in these patients is often confounding due to a lack of a tissue diagnosis and the limited morphological and immuno-histochemical features of PPBL, therefore, the presentation remains highly concerning for lymphoma. Conclusion The presentation, surgical treatment, tissue and peripheral blood molecular analysis, and flow cytometry integral to managing these patients and to prevent an assumptive and misleading diagnosis are reviewed. PMID:26693179

  11. Th17 cell-derived IL-17 is dispensable for B cell antibody production.

    PubMed

    Shibui, Akiko; Shimura, Eri; Nambu, Aya; Yamaguchi, Sachiko; Leonard, Warren J; Okumura, Ko; Sugano, Sumio; Sudo, Katsuko; Nakae, Susumu

    2012-07-01

    IL-17, which is preferentially produced by Th17 cells, is important for host defense against pathogens and is also involved in the development of autoimmune and allergic disorders. Antibody (Ab) production was shown to be impaired in IL-17-deficient mice, suggesting that IL-17 may promote B cell activation and direct secretion of Ab. However, the precise role of IL-17 in Ab production by B cells remains unclear. In the present study, we found constitutive expression of IL-17R in murine splenic B cells. Nevertheless, IL-17, IL-17F or IL-25 alone could not induce Ab production by B cells even in the presence of agonistic anti-CD40 Ab. IL-17 also could not affect IFN-?-, IL-4- or TGF-?1-mediated Ig class-switching. Furthermore, in co-cultures of B cells and IL-17(-/-) CD4(+) T cells or IL-17(-/-) Th17 cells, IL-17 deficiency did not influence Ab production by B cells in vitro, suggesting that Th17 cell-derived IL-17 was not required for B cell Ab production through T cell-B cell interaction in vitro. Thus, in vivo, IL-17 may be indirectly involved in Ab production by enhancing production of B cell activator(s) by other immune cells. PMID:22503615

  12. TLR-mediated STAT3 and ERK activation controls IL-10 secretion by human B cells.

    PubMed

    Liu, Bi-Sheng; Cao, Yonghao; Huizinga, Tom W; Hafler, David A; Toes, Rene E M

    2014-07-01

    IL-10-producing B cells have a regulatory effect in various mouse models for immune-mediated disorders via secretion of IL-10, a potent immunoregulatory cytokine. However, currently, the signaling pathways that regulate IL-10 production in B cells are not well understood. Here, we show that TLR signaling, but not BCR activation or CD40 ligation, induces potent production of IL-10 in human B cells. We demonstrate that the activation of STAT3 and ERK is required for TLR-induced IL-10 production by B cells, since inhibition of STAT3 or ERK activation abrogates TLR-induced IL-10 production. We also uncover a novel function of the TLR-MyD88-STAT3 pathway in B cells, namely controlling IL-10 production, in addition to the known role for this pathway in antibody production. Furthermore, IFN-?, a member of the type I IFN family, differentially modulates TLR7/8- and TLR9-activated STAT3 and ERK in B cells, which provides an explanation for our findings that IFN-? enhances TLR7/8-induced, but not TLR9-induced IL-10 production. These results yield insights into the mechanisms by which TLR signaling regulates IL-10 production in B cells and how type I IFN modulates TLR-mediated IL-10 production by B cells, therefore providing potential targets to modulate the function of IL-10-producing B cells. PMID:24737107

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

    PubMed Central

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

    2015-01-01

    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-naïve 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

  14. B-cell malignancies in microRNA Eμ-miR-17~92 transgenic mice.

    PubMed

    Sandhu, Sukhinder K; Fassan, Matteo; Volinia, Stefano; Lovat, Francesca; Balatti, Veronica; Pekarsky, Yuri; Croce, Carlo M

    2013-11-01

    miR-17∼92 is a polycistronic microRNA (miR) cluster (consisting of miR-17, miR-18a, miR-19a, miR-19b, miR-20a, and miR-92a) which frequently is overexpressed in several solid and lymphoid malignancies. Loss- and gain-of-function studies have revealed the role of miR-17∼92 in heart, lung, and B-cell development and in Myc-induced B-cell lymphomas, respectively. Recent studies indicate that overexpression of this locus leads to lymphoproliferation, but no experimental proof that dysregulation of this cluster causes B-cell lymphomas or leukemias is available. To determine whether miR-17∼92- overexpression induces lymphomagenesis/leukemogenesis, we generated a B-cell-specific transgenic mouse model with targeted overexpression of this cluster in B cells. The miR-17∼92 overexpression was driven by the Eµ-enhancer and Ig heavy-chain promoter, and a 3' GFP tag was added to the transgene to track the miR expression. Expression analysis using Northern Blot and quantitative RT-PCR confirmed 2.5- to 25-fold overexpression of all six miRs in the transgenic mice spleens as compared with spleens from wild-type mice. Eµ-miR-17∼92 mice developed B-cell malignancy by the age of 12-18 mo with a penetrance of ∼80% (49% splenic B-cell lymphoproliferative disease, 28% lymphoma). At this stage mice exhibited severe splenomegaly with abnormal B-cell-derived white pulp expansion and enlarged lymph nodes. Interestingly, we found three classes of B-cell lymphomas/leukemias at varying grades of differentiation. These included expansion of CD19(+) and CD5(+) double-positive B cells similar to the aggressive form of human B-cell chronic lymphocytic leukemia, B220(+) CD43(+) B1-cell proliferation, and a CD19(+) aggressive diffuse large B-cell lymphoma-like disease, as assessed by flow cytometry and histopathological analysis. PMID:24145403

  15. New B-cell CD molecules.

    PubMed

    Matesanz-Isabel, Jessica; Sintes, Jordi; Llins, Laia; de Salort, Jose; Lzaro, Adriana; Engel, Pablo

    2011-01-30

    B cells not only play a pivotal role in humoral immunity, but also are involved in a broad spectrum of immune responses, including antigen presentation and T-cell function regulation. The identification of cell-surface CD molecules derived from a series of Human Leukocyte Differentiation Antigens (HLDA) Workshops has been instrumental to the discovery and functional characterization of human B-cell populations. Moreover, many events regulating B-cell development, activation, and effector functions are orchestrated by these cell-surface molecules. During the Ninth HLDA Workshop (HLDA9) eighteen new CDs were allocated to cell-surface molecules expressed on B cells: CD210a (IL10RA), CD215 (IL15RA), CD270 (TNFRSF14), CD307a (FCRL1), CD307b (FCRL2), CD307c (FCRL3), CD307d (FCRL4), CD351 (FCAMR), CD352 (SLAMF6), CD353 (SLAMF8), CD354 (TREM1), CD355 (CRTAM), CD357 (TNFRSF18), CD358 (TNFRSF21), CD360 (IL21RA), CD361 (EVI2B), CD362 (SDC2), and CD363 (S1PR1). Here we present their expression patterns on leukocytes, including T lymphocytes, NK cells, granulocytes, monocytes, plasmacytoid and monocyte-derived dendritic cells, and several B-cell subsets. These new CD molecules are expressed on B cells at various stages of differentiation; from bone marrow precursor pro-B cells to plasma cells. Three of them, CD307a, CD307b and CD307d, exhibit a B-cell restricted expression pattern, whereas the rest are also present on other leukocytes. In this paper we also review the structural characteristics, expression, and function of these new CD molecules. The availability of monoclonal antibodies directed against novel B cell-surface molecules will have broad implications not only for B-cell biology, but also for the development of new diagnostic and therapeutic tools. PMID:20933010

  16. B Cells and Autoantibodies in Multiple Sclerosis

    PubMed Central

    Pröbstel, Anne-Katrin; Sanderson, Nicholas S. R.; Derfuss, Tobias

    2015-01-01

    While over the past decades T cells have been considered key players in the pathogenesis of multiple sclerosis (MS), it has only recently become evident that B cells have a major contributing role. Our understanding of the role of B cells has evolved substantially following the clinical success of B cell-targeting therapies and increasing experimental evidence for significant B cell involvement. Rather than mere antibody-producing cells, it is becoming clear that they are team players with the capacity to prime and regulate T cells, and function both as pro- and anti-inflammatory mediators. However, despite tremendous efforts, the target antigen(s) of B cells in MS have yet to be identified. The first part of this review summarizes the clinical evidence and results from animal studies pointing to the relevance of B cells in the pathogenesis of MS. The second part gives an overview of the currently known potential autoantigen targets. The third part recapitulates and critically appraises the currently available B cell-directed therapies. PMID:26197319

  17. Lack of glucocorticoid-induced leucine zipper (GILZ) deregulates B-cell survival and results in B-cell lymphocytosis in mice.

    PubMed

    Bruscoli, Stefano; Biagioli, Michele; Sorcini, Daniele; Frammartino, Tiziana; Cimino, Monica; Sportoletti, Paolo; Mazzon, Emanuela; Bereshchenko, Oxana; Riccardi, Carlo

    2015-10-01

    Glucocorticoids (GC) are widely used as antiinflammatory/immunosuppressive drugs and antitumor agents in several types of lymphoma and leukemia. Therapeutic doses of GC induce growth-suppressive and cytotoxic effects on various leukocytes including B cells. Molecular mechanisms of GC action include induction of GC target genes. Glucocorticoid-induced leucine zipper (GILZ) is a rapidly, potently, and invariably GC-induced gene. It mediates a number of GC effects, such as control of cell proliferation, differentiation, and apoptosis. Here we show that deletion of GILZ in mice leads to an accumulation of B lymphocytes in the bone marrow, blood, and lymphoid tissues. Gilz knockout (KO) mice develop a progressive nonlethal B lymphocytosis, with expansion of B220(+) cells in the bone marrow and in the periphery, dependent on increased B-cell survival. Decreased B-cell apoptosis in mice lacking GILZ correlates with increased NF-?B transcriptional activity and Bcl-2 expression. B cell-specific gilz KO mice confirmed that the effect of GILZ deletion is B-cell self-intrinsic. These results establish GILZ as an important regulator of B-cell survival and suggest that the deregulation of GILZ expression could be implicated in the pathogenesis of B-cell disorders. PMID:26276664

  18. Dual regulation of IRF4 function in T and B cells is required for the coordination of TB cell interactions and the prevention of autoimmunity

    PubMed Central

    Biswas, Partha S.; Gupta, Sanjay; Stirzaker, Roslynn A.; Kumar, Varsha; Jessberger, Rolf; Lu, Theresa T.; Bhagat, Govind

    2012-01-01

    Effective humoral responses to protein antigens require the precise execution of carefully timed differentiation programs in both T and B cell compartments. Disturbances in this process underlie the pathogenesis of many autoimmune disorders, including systemic lupus erythematosus (SLE). Interferon regulatory factor 4 (IRF4) is induced upon the activation of T and B cells and serves critical functions. In CD4+ T helper cells, IRF4 plays an essential role in the regulation of IL-21 production, whereas in B cells it controls class switch recombination and plasma cell differentiation. IRF4 function in T helper cells can be modulated by its interaction with regulatory protein DEF6, a molecule that shares a high degree of homology with only one other protein, SWAP-70. Here, we demonstrate that on a C57BL/6 background the absence of both DEF6 and SWAP-70 leads to the development of a lupus-like disease in female mice, marked by simultaneous deregulation of CD4+ T cell IL-21 production and increased IL-21 B cell responsiveness. We furthermore show that DEF6 and SWAP-70 are differentially used at distinct stages of B cell differentiation to selectively control the ability of IRF4 to regulate IL-21 responsiveness in a stage-specific manner. Collectively, these data provide novel insights into the mechanisms that normally couple and coordinately regulate T and B cell responses to ensure tight control of productive TB cell interactions. PMID:22370718

  19. Minimal Change Nephrotic Syndrome Associated With Non-Hodgkin Lymphoid Disorders

    PubMed Central

    Kofman, Tomek; Zhang, Shao-Yu; Copie-Bergman, Christiane; Moktefi, Anissa; Raimbourg, Quentin; Francois, Hlne; Karras, Alexandre; Plaisier, Emmanuelle; Painchart, Bernard; Favre, Guillaume; Bertrand, Dominique; Gyan, Emmanuel; Souid, Marc; Roos-Weil, Damien; Desvaux, Dominique; Grimbert, Philippe; Haioun, Corinne; Lang, Philippe; Sahali, Djillali; Audard, Vincent

    2014-01-01

    Abstract Few studies have examined the occurrence of minimal change nephrotic syndrome (MCNS) in patients with non-Hodgkin lymphoma (NHL). We report here a series of 18 patients with MCNS occurring among 13,992 new cases of NHL. We analyzed the clinical and pathologic characteristics of this association, along with the response of patients to treatment, to determine if this association relies on a particular disorder. The most frequent NHLs associated with MCNS were Waldenstrm macroglobulinemia (33.3%), marginal zone B-cell lymphoma (27.8%), and chronic lymphocytic leukemia (22.2%). Other lymphoproliferative disorders included multiple myeloma, mantle cell lymphoma, and peripheral T-cell lymphoma. In 4 patients MCNS occurred before NHL (mean delay, 15 mo), in 10 patients the disorders occurred simultaneously, and in 4 patients MCNS was diagnosed after NHL (mean delay, 25 mo). Circulating monoclonal immunoglobulins were present in 11 patients. A nontumoral interstitial infiltrate was present in renal biopsy specimens from 3 patients without significant renal impairment. Acute kidney injury resulting from tubular lesions or renal hypoperfusion was present in 6 patients. MCNS relapse occurred more frequently in patients treated exclusively by steroid therapy (77.8%) than in those receiving steroids associated with chemotherapy (25%). In conclusion, MCNS occurs preferentially in NHL originating from B cells and requires an aggressive therapeutic approach to reduce the risk of MCNS relapse. PMID:25500704

  20. Ikaros limits follicular B cell activation by regulating B cell receptor signaling pathways.

    PubMed

    Heizmann, Beate; Sellars, MacLean; Macias-Garcia, Alejandra; Chan, Susan; Kastner, Philippe

    2016-02-12

    The Ikaros transcription factor is essential for early B cell development, but its effect on mature B cells is debated. We show that Ikaros is required to limit the response of naive splenic B cells to B cell receptor signals. Ikaros deficient follicular B cells grow larger and enter cell cycle faster after anti-IgM stimulation. Unstimulated mutant B cells show deregulation of positive and negative regulators of signal transduction at the mRNA level, and constitutive phosphorylation of ERK, p38, SYK, BTK, AKT and LYN. Stimulation results in enhanced and prolonged ERK and p38 phosphorylation, followed by hyper-proliferation. Pharmacological inhibition of ERK and p38 abrogates the increased proliferative response of Ikaros deficient cells. These results suggest that Ikaros functions as a negative regulator of follicular B cell activation. PMID:26775846

  1. Genetic errors of the human caspase recruitment domain-B-cell lymphoma 10-mucosa-associated lymphoid tissue lymphoma-translocation gene 1 (CBM) complex: Molecular, immunologic, and clinical heterogeneity.

    PubMed

    Prez de Diego, Rebeca; Snchez-Ramn, Silvia; Lpez-Collazo, Eduardo; Martnez-Barricarte, Rubn; Cubillos-Zapata, Carolina; Ferreira Cerdn, Antonio; Casanova, Jean-Laurent; Puel, Anne

    2015-11-01

    Three members of the caspase recruitment domain (CARD) family of adaptors (CARD9, CARD10, and CARD11) are known to form heterotrimers with B-cell lymphoma 10 (BCL10) and mucosa-associated lymphoid tissue lymphoma-translocation gene 1 (MALT1). These 3 CARD-BCL10-MALT1 (CBM) complexes activate nuclear factor ?B in both the innate and adaptive arms of immunity. Human inherited defects of the 3 components of the CBM complex, including the 2 adaptors CARD9 and CARD11 and the 2 core components BCL10 and MALT1, have recently been reported. Biallelic loss-of-function mutant alleles underlie several different immunologic and clinical phenotypes, which can be assigned to 2 distinct categories. Isolated invasive fungal infections of unclear cellular basis are associated with CARD9 deficiency, whereas a broad range of clinical manifestations, including those characteristic of T- and B-lymphocyte defects, are associated with CARD11, MALT1, and BCL10 deficiencies. Interestingly, human subjects with these mutations have some features in common with the corresponding knockout mice, but other features are different between human subjects and mice. Moreover, germline and somatic gain-of-function mutations of MALT1, BCL10, and CARD11 have also been found in patients with other lymphoproliferative disorders. This broad range of germline and somatic CBM lesions, including loss-of-function and gain-of-function mutations, highlights the contribution of eachof the components of the CBM complex to human immunity. PMID:26277595

  2. 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

  3. The NIK of time for B cells.

    PubMed

    Myles, Arpita; Cancro, Michael P

    2016-03-01

    NF-?B-inducing kinase (NIK) is a key mediator of the noncanonical NF-?B signaling pathway, which is critical for B-cell development and function. Although complete deletion of NIK in mice has been shown to result in defective B cells and impaired secondary lymphoid organogenesis, the consequences of deleting NIK exclusively in B cells have not been determined. In this issue of the European Journal of Immunology, Hahn etal. [Eur. J. Immunol. 2016. 46: 732-741] describe mice in which the NF-?B2 pathway mediator, NIK, is deleted at different points in B-cell lineage differentiation and activation. The results show that the survival of mature peripheral B cells, as well as appropriate kinetics of germinal center reactions, rely on noncanonical NF-?B signaling. These findings confirm and extend prior observations implicating a nonredundant role for NF-?B2 downstream of BAFF signaling via BAFF-R, and prompt assessment of the growing literature regarding the relative roles of BCR and BAFF signals in B-cell homeostasis, as well as the downstream pathways responsible. PMID:26873522

  4. Design of Targeted B Cell Killing Agents

    PubMed Central

    Ponomarenko, Natalia A.; Stremovskiy, Oleg A.; Kozlov, Leonid V.; Bichucher, Anna M.; Dmitriev, Sergey E.; Smirnov, Ivan V.; Shamborant, Olga G.; Balabashin, Dmitry S.; Sashchenko, Lidia P.; Tonevitsky, Alexander G.; Friboulet, Alain; Gabibov, Alexander G.; Deyev, Sergey M.

    2011-01-01

    B cells play an important role in the pathogenesis of both systemic and organ-specific autoimmune diseases. Autoreactive B cells not only produce autoantibodies, but also are capable to efficiently present specific autoantigens to T cells. Furthermore, B cells can secrete proinflammatory cytokines and amplify the vicious process of self-destruction. B cell-directed therapy is a potentially important approach for treatment of various autoimmune diseases. The depletion of B cells by anti-CD20/19 monoclonal antibody Retuximab® used in autoimmune diseases therapy leads to systemic side effects and should be significantly improved. In this study we designed a repertoire of genetically engineered B cell killers that specifically affected one kind of cells carrying a respective B cell receptor. We constructed immunotoxins (ITs), fused with c-myc epitope as a model targeting sequence, based on barnase, Pseudomonas toxin, Shiga-like toxin E.coli and Fc domain of human antibody IgGγ1. C-MYC hybridoma cell line producing anti-c-myc IgG was chosen as a model for targeted cell depletion. C-myc sequence fused with toxins provided addressed delivery of the toxic agent to the target cells. We demonstrated functional activity of designed ITs in vitro and showed recognition of the fusion molecules by antibodies produced by targeted hybridoma. To study specificity of the proposed B cells killing molecules, we tested a set of created ITs ex vivo, using C-MYC and irrelevant hybridoma cell lines. Pseudomonas-containing IT showed one of the highest cytotoxic effects on the model cells, however, possessed promiscuous specificity. Shiga-like toxin construct demonstrated mild both cytotoxicity and specificity. Barnase and Fc-containing ITs revealed excellent balance between their legibility and toxic properties. Moreover, barnase and Fc molecules fused with c-myc epitope were able to selectively deplete c-myc-specific B cells and decrease production of anti-c-myc antibodies in culture of native splenocytes, suggesting their highest therapeutic potential as targeted B cell killing agents. PMID:21677771

  5. Proinflammatory GM-CSF-producing B cells in multiple sclerosis and B cell depletion therapy.

    PubMed

    Li, Rui; Rezk, Ayman; Miyazaki, Yusei; Hilgenberg, Ellen; Touil, Hanane; Shen, Ping; Moore, Craig S; Michel, Laure; Althekair, Faisal; Rajasekharan, Sathy; Gommerman, Jennifer L; Prat, Alexandre; Fillatreau, Simon; Bar-Or, Amit

    2015-10-21

    B cells are not limited to producing protective antibodies; they also perform additional functions relevant to both health and disease. However, the relative contribution of functionally distinct B cell subsets in human disease, the signals that regulate the balance between such subsets, and which of these subsets underlie the benefits of B cell depletion therapy (BCDT) are only partially elucidated. We describe a proinflammatory, granulocyte macrophage-colony stimulating factor (GM-CSF)-expressing human memory B cell subset that is increased in frequency and more readily induced in multiple sclerosis (MS) patients compared to healthy controls. In vitro, GM-CSF-expressing B cells efficiently activated myeloid cells in a GM-CSF-dependent manner, and in vivo, BCDT resulted in a GM-CSF-dependent decrease in proinflammatory myeloid responses of MS patients. A signal transducer and activator of transcription 5 (STAT5)- and STAT6-dependent mechanism was required for B cell GM-CSF production and reciprocally regulated the generation of regulatory IL-10-expressing B cells. STAT5/6 signaling was enhanced in B cells of untreated MS patients compared with healthy controls, and B cells reemerging in patients after BCDT normalized their STAT5/6 signaling as well as their GM-CSF/IL-10 cytokine secretion ratios. The diminished proinflammatory myeloid cell responses observed after BCDT persisted even as new B cells reconstituted. These data implicate a proinflammatory B cell/myeloid cell axis in disease and underscore the rationale for selective targeting of distinct B cell populations in MS and other human autoimmune diseases. PMID:26491076

  6. Adenosine production by human B cells and B cellmediated suppression of activated T cells

    PubMed Central

    Saze, Zenichiro; Schuler, Patrick J.; Hong, Chang-Sook; Cheng, Dongmei; Jackson, Edwin K.

    2013-01-01

    Antibody-independent role of B cells in modulating T-cell responses is incompletely understood. Freshly isolated or cultured B cells isolated from the peripheral blood of 30 normal donors were evaluated for CD39 and CD73 coexpression, the ability to produce adenosine 5?-monophosphate (AMP) and adenosine (ADO) in the presence of exogenous adenosine triphosphate (ATP) as well as A1, A2A, A2B, and A3 adenosine receptor (ADOR) expression. Human circulating B cells coexpress ectonucleotidases CD39 and CD73, hydrolyze exogenous ATP to 5?-AMP and ADO, and express messenger RNA for A1R, A2AR, and A3R. 2-chloroadenosine inhibited B-cell proliferation and cytokine expression, and only A3R selective antagonist restored B-cell functions. This suggested that B cells use the A3R for autocrine signaling and self-regulation. Mediated effects on B-cell growth ADOR antagonists or agonists were tested in carboxyfluorescein diacetate succinimidyl ester assays. In cocultures, resting B cells upregulated functions of CD4+ and CD8+ T cells. However, in vitroactivated B cells downregulated CD73 expression, mainly produced 5?-AMP, and inhibited T-cell proliferation and cytokine production. These B cells acquire the ability to restrict potentially harmful effects of activated T cells. Thus, B cells emerge as a key regulatory component of T cellB cell interactions, and their dual regulatory activity is mediated by the products of ATP hydrolysis, 5?-AMP, and ADO. PMID:23678003

  7. Memory B-cell reconstitution following allogeneic hematopoietic stem cell transplantation is an EBV-associated transformation event

    PubMed Central

    Burns, David M.; Tierney, Rose; Shannon-Lowe, Claire; Croudace, Jo; Inman, Charlotte; Abbotts, Ben; Nagra, Sandeep; Fox, Christopher P.; Chaganti, Sridhar; Craddock, Charles F.; Moss, Paul; Rickinson, Alan B.; Rowe, Martin

    2015-01-01

    Allogeneic stem cell transplantation (allo-HSCT) provides a unique opportunity to track Epstein-Barr virus (EBV) infection in the context of the reconstituting B-cell system. Although many allo-HSCT recipients maintain low or undetectable levels of EBV DNA posttransplant, a significant proportion exhibit elevated and rapidly increasing EBV loads which, if left untreated, may lead to potentially fatal EBV-associated posttransplant lymphoproliferative disease. Intriguingly, this high-level EBV reactivation typically arises in the first 3 months posttransplant, at a time when the peripheral blood contains low numbers of CD27+ memory cells which are the site of EBV persistence in healthy immunocompetent donors. To investigate this apparent paradox, we prospectively monitored EBV levels and B-cell reconstitution in a cohort of allo-HSCT patients for up to 12 months posttransplant. In patients with low or undetectable levels of EBV, the circulating B-cell pool consisted predominantly of transitional and naive cells, with a marked deficiency of CD27+ memory cells which lasted >12 months. However, among patients with high EBV loads, there was a significant increase in both the proportion and number of CD27+ memory B cells. Analysis of sorted CD27+ memory B cells from these patients revealed that this population was preferentially infected with EBV, expressed EBV latent transcripts associated with B-cell growth transformation, had a plasmablastic phenotype, and frequently expressed the proliferation marker Ki-67. These findings suggest that high-level EBV reactivation following allo-HSCT may drive the expansion of latently infected CD27+ B lymphoblasts in the peripheral blood. PMID:26450987

  8. The intestinal B-cell response in celiac disease

    PubMed Central

    Mesin, Luka; Sollid, Ludvig M.; Niro, Roberto Di

    2012-01-01

    The function of intestinal immunity is to provide protection toward pathogens while preserving the composition of the microflora and tolerance to orally fed nutrients. This is achieved via a number of tightly regulated mechanisms including production of IgA antibodies by intestinal plasma cells. Celiac disease is a common gut disorder caused by a dysfunctional immune regulation as signified, among other features, by a massive intestinal IgA autoantibody response. Here we review the current knowledge of this B-cell response and how it is induced, and we discuss key questions to be addressed in future research. PMID:23060888

  9. Syk Tyrosine Kinase Is Critical for B Cell Antibody Responses and Memory B Cell Survival

    PubMed Central

    Ackermann, Jochen A.; Nys, Josquin; Schweighoffer, Edina; McCleary, Scott; Smithers, Nicholas

    2015-01-01

    Signals from the BCR are required for Ag-specific B cell recruitment into the immune response. Binding of Ag to the BCR induces phosphorylation of immune receptor tyrosine-based activation motifs in the cytoplasmic domains of the CD79a and CD79b signaling subunits, which subsequently bind and activate the Syk protein tyrosine kinase. Earlier work with the DT40 chicken B cell leukemia cell line showed that Syk was required to transduce BCR signals to proximal activation events, suggesting that Syk also plays an important role in the activation and differentiation of primary B cells during an immune response. In this study, we show that Syk-deficient primary mouse B cells have a severe defect in BCR-induced activation, proliferation, and survival. Furthermore, we demonstrate that Syk is required for both T-dependent and T-independent Ab responses, and that this requirement is B cell intrinsic. In the absence of Syk, Ag fails to induce differentiation of naive B cells into germinal center B cells and plasma cells. Finally, we show that the survival of existing memory B cells is dependent on Syk. These experiments demonstrate that Syk plays a critical role in multiple aspects of B cell Ab responses. PMID:25862820

  10. Lack of glucocorticoid-induced leucine zipper (GILZ) deregulates B-cell survival and results in B-cell lymphocytosis in mice

    PubMed Central

    Bruscoli, Stefano; Biagioli, Michele; Sorcini, Daniele; Frammartino, Tiziana; Cimino, Monica; Sportoletti, Paolo; Mazzon, Emanuela; Bereshchenko, Oxana

    2015-01-01

    Glucocorticoids (GC) are widely used as antiinflammatory/immunosuppressive drugs and antitumor agents in several types of lymphoma and leukemia. Therapeutic doses of GC induce growth-suppressive and cytotoxic effects on various leukocytes including B cells. Molecular mechanisms of GC action include induction of GC target genes. Glucocorticoid-induced leucine zipper (GILZ) is a rapidly, potently, and invariably GC-induced gene. It mediates a number of GC effects, such as control of cell proliferation, differentiation, and apoptosis. Here we show that deletion of GILZ in mice leads to an accumulation of B lymphocytes in the bone marrow, blood, and lymphoid tissues. Gilz knockout (KO) mice develop a progressive nonlethal B lymphocytosis, with expansion of B220+ cells in the bone marrow and in the periphery, dependent on increased B-cell survival. Decreased B-cell apoptosis in mice lacking GILZ correlates with increased NF-κB transcriptional activity and Bcl-2 expression. B cell–specific gilz KO mice confirmed that the effect of GILZ deletion is B-cell self-intrinsic. These results establish GILZ as an important regulator of B-cell survival and suggest that the deregulation of GILZ expression could be implicated in the pathogenesis of B-cell disorders. PMID:26276664

  11. Receptor Dissociation and B-Cell Activation.

    PubMed

    Yang, Jianying; Reth, Michael

    2016-01-01

    The B-cell antigen receptor (BCR) is one of the most abundant receptors on the surface of B cells with roughly 100,000-200,000 copies per cell. Signaling through the BCR is crucial for the activation and differentiation of B cells. Unlike other receptors, the BCR can be activated by a large set of structurally different ligands, but the molecular mechanism of BCR activation is still a matter of controversy. Although dominant for a long time, the cross-link model (CLM) of BCR activation is not supported by recent studies of the nanoscale organization of the BCR on the surface of resting B cells. In contrast to the prediction of CLM, the numerous BCR complexes on these cells are not randomly distributed monomers but rather form oligomers which reside within membrane confinements. This finding is more in line with the dissociation activation model (DAM), wherein B-cell activation is accompanied by an opening of the auto-inhibited BCR oligomers instead of a cross-linking of the BCR monomers. In this review, we discuss in detail the new findings and their implications for BCR signaling. PMID:26428245

  12. Human norovirus culture in B cells.

    PubMed

    Jones, Melissa K; Grau, Katrina R; Costantini, Veronica; Kolawole, Abimbola O; de Graaf, Miranda; Freiden, Pamela; Graves, Christina L; Koopmans, Marion; Wallet, Shannon M; Tibbetts, Scott A; Schultz-Cherry, Stacey; Wobus, Christiane E; Vinjé, Jan; Karst, Stephanie M

    2015-12-01

    Human noroviruses (HuNoVs) are a leading cause of foodborne disease and severe childhood diarrhea, and they cause a majority of the gastroenteritis outbreaks worldwide. However, the development of effective and long-lasting HuNoV vaccines and therapeutics has been greatly hindered by their uncultivability. We recently demonstrated that a HuNoV replicates in human B cells, and that commensal bacteria serve as a cofactor for this infection. In this protocol, we provide detailed methods for culturing the GII.4-Sydney HuNoV strain directly in human B cells, and in a coculture system in which the virus must cross a confluent epithelial barrier to access underlying B cells. We also describe methods for bacterial stimulation of HuNoV B cell infection and for measuring viral attachment to the surface of B cells. Finally, we highlight variables that contribute to the efficiency of viral replication in this system. Infection assays require 3 d and attachment assays require 3 h. Analysis of infection or attachment samples, including RNA extraction and RT-qPCR, requires ∼6 h. PMID:26513671

  13. Human norovirus culture in B cells

    PubMed Central

    Jones, Melissa K; Grau, Katrina R; Costantini, Veronica; Kolawole, Abimbola O; de Graaf, Miranda; Freiden, Pamela; Graves, Christina L; Koopmans, Marion; Wallet, Shannon M; Tibbetts, Scott A; Schultz-Cherry, Stacey; Wobus, Christiane E; Vinj, Jan; Karst, Stephanie M

    2015-01-01

    Human noroviruses (HunoVs) are a leading cause of foodborne disease and severe childhood diarrhea, and they cause a majority of the gastroenteritis outbreaks worldwide. However, the development of effective and long-lasting HunoV vaccines and therapeutics has been greatly hindered by their uncultivability. We recently demonstrated that a HunoV replicates in human B cells, and that commensal bacteria serve as a cofactor for this infection. In this protocol, we provide detailed methods for culturing the GII.4-sydney HunoV strain directly in human B cells, and in a coculture system in which the virus must cross a confluent epithelial barrier to access underlying B cells. We also describe methods for bacterial stimulation of HunoV B cell infection and for measuring viral attachment to the surface of B cells. Finally, we highlight variables that contribute to the efficiency of viral replication in this system. Infection assays require 3 d and attachment assays require 3 h. analysis of infection or attachment samples, including rna extraction and rt-qpcr, requires ~6 h. PMID:26513671

  14. Altered BCR and TLR signals promote enhanced positive selection of autoreactive transitional B cells in Wiskott-Aldrich syndrome.

    PubMed

    Kolhatkar, Nikita S; Brahmandam, Archana; Thouvenel, Christopher D; Becker-Herman, Shirly; Jacobs, Holly M; Schwartz, Marc A; Allenspach, Eric J; Khim, Socheath; Panigrahi, Anil K; Luning Prak, Eline T; Thrasher, Adrian J; Notarangelo, Luigi D; Candotti, Fabio; Torgerson, Troy R; Sanz, Ignacio; Rawlings, David J

    2015-09-21

    Wiskott-Aldrich syndrome (WAS) is an X-linked immunodeficiency disorder frequently associated with systemic autoimmunity, including autoantibody-mediated cytopenias. WAS protein (WASp)-deficient B cells have increased B cell receptor (BCR) and Toll-like receptor (TLR) signaling, suggesting that these pathways might impact establishment of the mature, naive BCR repertoire. To directly investigate this possibility, we evaluated naive B cell specificity and composition in WASp-deficient mice and WAS subjects (n = 12). High-throughput sequencing and single-cell cloning analysis of the BCR repertoire revealed altered heavy chain usage and enrichment for low-affinity self-reactive specificities in murine marginal zone and human naive B cells. Although negative selection mechanisms including deletion, anergy, and receptor editing were relatively unperturbed, WASp-deficient transitional B cells showed enhanced proliferation in vivo mediated by antigen- and Myd88-dependent signals. Finally, using both BCR sequencing and cell surface analysis with a monoclonal antibody recognizing an intrinsically autoreactive heavy chain, we show enrichment in self-reactive cells specifically at the transitional to naive mature B cell stage in WAS subjects. Our combined data support a model wherein modest alterations in B cell-intrinsic, BCR, and TLR signals in WAS, and likely other autoimmune disorders, are sufficient to alter B cell tolerance via positive selection of self-reactive transitional B cells. PMID:26371186

  15. Alloantigen presentation by B cells: analysis of the requirement for B-cell activation.

    PubMed Central

    Wilson, J L; Cunningham, A C; Kirby, J A

    1995-01-01

    This paper describes a model for investigation of the functional implications of B-cell activation for antigen presentation. Mixed lymphocyte cultures were used to assess the ability of freshly isolated B cells, mitogen-activated B cells and Epstein-Barr virus (EBV)-transformed B-cell lines to stimulate the activation and proliferation of allogeneic T cells under a variety of experimental conditions. It was found that resting B cells presented antigen poorly, while activated cells were highly immunogenic. Paraformaldehyde fixation completely eliminated antigen presentation by resting B cells, despite constitutive expression of class II MHC antigens. However, fixation had little effect on antigen presentation by activated B cells that expressed B7-1 and B7-2 in addition to class II major histocompatibility complex (MHC) molecules. Arrest of B-cell activation by serial fixation after treatment with F(ab')2 fragments of goat anti-human IgM produced cells with variable antigen-presenting capacity. Optimal antigen presentation was observed for cells fixed 72 hr after the initiation of B-cell activation. Although both B7-1 and B7-2 antigen expression increased after B-cell activation, it was found that the rate of T-cell proliferation correlated most closely with B7-2 expression. Stimulation of T cells by fixed activated B lymphocytes could be blocked by antibodies directed at class II MHC molecules, indicating involvement of the T-cell antigen receptor. In addition, T-cell proliferation was inhibited by antibodies specific for B7-1 and B7-2 and by the fusion protein CTLA4-Ig, demonstrating a requirement for CD28 signal transduction. The sole requirement of B7 family expression for antigen presentation by B lymphocytes was shown by demonstration of T-cell stimulation by fixed resting B cells in the presence of CD28 antibody as a source of artificial costimulation. PMID:8550066

  16. 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

  17. B cell suppression in primary glomerular disease.

    PubMed

    Rood, Ilse M; Hofstra, Julia M; Deegens, Jeroen K J; Wetzels, Jack F M

    2014-03-01

    Membranous nephropathy, focal segmental glomerulosclerosis (FSGS), and minimal change disease (MCD) are the most common causes of idiopathic nephrotic syndrome. For many years prednisone, alkylating agents, and calcineurin inhibitors have been the standard of therapy for these patients. More effective or better tolerated treatment modalities are needed. B cell targeted therapy was recently introduced in clinical practice. In this review, we briefly summarize the current standard therapy and discuss the efficacy of B cell targeted therapy in primary glomerular diseases. Observational, short-term studies suggest that rituximab is effective and comparable to standard therapy in maintaining remissions in patients with frequently relapsing or steroid-dependent MCD or FSGS. In contrast, response is limited in patients with steroid-resistant nephrotic syndrome. Rituximab also induces remissions in patients with membranous nephropathy. Controlled clinical trials on kidney endpoints are urgently needed to position B cell targeted therapy in clinical practice. PMID:24602466

  18. 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

  19. Autoimmune lymphoproliferative syndrome due to somatic FAS mutation (ALPS-sFAS) combined with a germline caspase-10 (CASP10) variation.

    PubMed

    Martnez-Feito, Ana; Melero, Josefa; Mora-Daz, Sergio; Rodrguez-Vigil, Carmen; Elduayen, Ramn; Gonzlez-Granado, Luis I; Prez-Mndez, Dolores; Snchez-Zapardiel, Elena; Ruiz-Garca, Raquel; Menchn, Miguela; Daz-Madroero, Josefa; Paz-Artal, Estela; Del Orbe-Barreto, Rafael; Rin, Marta; Allende, Luis M

    2016-01-01

    Autoimmune lymphoproliferative syndrome (ALPS) is a primary immunodeficiency caused by impaired Fas/FasL-mediated apoptosis of lymphocytes and is characterized by chronic nonmalignant or benign lymphoproliferation, autoimmune manifestations and expansion of double negative (DN) T-cells (TCR??+CD4-CD8-). Most cases of ALPS are associated with germline (ALPS-FAS) or somatic (ALPS-sFAS) heterozygous FAS mutations or a combination of both. Here we report three unrelated patients with ALPS-sFAS. Only one of them showed impaired Fas function in PHA-activated T-cells. In this patient, the genetic analysis of the caspase-10 gene (CASP10) identified a heterozygous germline change in exon 9 (c.1337A>G) causing Y446C substitution in the caspase-10 protein. In addition, this patient had a dysregulated T- and B-cell phenotype; circulating lymphocytes showed expansion of T effector memory CD45RA+ (TEMRA) CD4 T-cells, effector memory CD8 T-cells, CD21(low) B-cells and reduced memory switched B-cells. Additionally, this patient showed altered expression in T-cells of several molecules that change during differentiation from nave to effector cells (CD27, CD95, CD57 and perforin). Molecular alterations in genes of the Fas pathway are necessary for the development of ALPS and this syndrome could be influenced by the concurrent effect of other mutations hitting different genes involved in Fas or related pathways. PMID:26323380

  20. [Autoimmune lymphoproliferative syndrome: a case report and literature review].

    PubMed

    Sun, Jia-peng; Lu, Xin-tian; Zhao, Wei-hong; Hua, Ying

    2015-12-18

    We described 1 case of autoimmune lymphoproliferative syndrome (ALPS), first diagnosed in our hospital, and reviewed the recent literature. The 11-month old male patient presented with a history of splenomegaly and hepatomegaly since 1 month after birth. He suffered recurrent infectious diseases including cytomegalovirus infection, parvovirus B19 infection and chronic diarrhea disease. Besides, his symptoms included hemolytic anemia and thrombocytopenia. The laboratory abnormality indicated an expanded population of alpha/beta double-negative T cells (DNTs) (27.18% of lymphocytes, 35.16% of CD3+ T lymphocytes) in peripheral blood, and autoantibodies including antinuclear antibody, double-stranded DNA and rheumatic factor were positive. Hyper gamma globulinemia and positive direct Coombs tests were seen in the patient. His parents were both healthy and denied autoimmune diseases. We identified a heterozygous point mutation in exon 3 of the FAS gene carrying c.309 A>C, resulting in a single base pair substitution in exon 3 of FAS gene which changed the codon of Arg103 to Ser103. Unfortunately, we were unable to obtain the gene results of the child's parents. The patient was treated with glucocorticoids in our hospital and with mycophenolatemofetil in other hospital. And we were informed that his anemia condition relieved through the telephone follow-up, but he still suffered recurrent infections, hepatomegaly and splenomegaly still existed. As we all know ALPS is characterized by defective lymphocyte apoptosis, and thus cause lymphoproliferative disease and autoimmune disease, and increase the risk of lymphoma. It is more likely to be misdiagnosed as other diseases. ALPS should be suspected in the case of chronic lymphadenopathy, splenomegaly and autoimmune features. Flow cytometry approach is helpful for the diagnosis. Immunosuppressive drugs are the necessary treatment. PMID:26679669

  1. FAS Inactivation Releases Unconventional Germinal Center B Cells that Escape Antigen Control and Drive IgE and Autoantibody Production.

    PubMed

    Butt, Danyal; Chan, Tyani D; Bourne, Katherine; Hermes, Jana R; Nguyen, Akira; Statham, Aaron; O'Reilly, Lorraine A; Strasser, Andreas; Price, Susan; Schofield, Peter; Christ, Daniel; Basten, Antony; Ma, Cindy S; Tangye, Stuart G; Phan, Tri Giang; Rao, V Koneti; Brink, Robert

    2015-05-19

    The mechanistic links between genetic variation and autoantibody production in autoimmune disease remain obscure. Autoimmune lymphoproliferative syndrome (ALPS) is caused by inactivating mutations in FAS or FASL, with autoantibodies thought to arise through failure of FAS-mediated removal of self-reactive germinal center (GC) B cells. Here we show that FAS is in fact not required for this process. Instead, FAS inactivation led to accumulation of a population of unconventional GC B cells that underwent somatic hypermutation, survived despite losing antigen reactivity, and differentiated into a large population of plasma cells that included autoantibody-secreting clones. IgE(+) plasma cell numbers, in particular, increased after FAS inactivation and a major cohort of ALPS-affected patients were found to have hyper-IgE. We propose that these previously unidentified cells, designated "rogue GC B cells," are a major driver of autoantibody production and provide a mechanistic explanation for the linked production of IgE and autoantibodies in autoimmune disease. PMID:25979420

  2. 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

  3. Rituximab does not reset defective early B cell tolerance checkpoints.

    PubMed

    Chamberlain, Nicolas; Massad, Christopher; Oe, Tyler; Cantaert, Tineke; Herold, Kevan C; Meffre, Eric

    2016-01-01

    Type 1 diabetes (T1D) patients show abnormalities in early B cell tolerance checkpoints, resulting in the accumulation of large numbers of autoreactive B cells in their blood. Treatment with rituximab, an anti-CD20 mAb that depletes B cells, has been shown to preserve ? cell function in T1D patients and improve other autoimmune diseases, including rheumatoid arthritis and multiple sclerosis. However, it remains largely unknown how anti-B cell therapy thwarts autoimmunity in these pathologies. Here, we analyzed the reactivity of Abs expressed by single, mature naive B cells from 4 patients with T1D before and 52 weeks after treatment to determine whether rituximab resets early B cell tolerance checkpoints. We found that anti-B cell therapy did not alter the frequencies of autoreactive and polyreactive B cells, which remained elevated in the blood of all patients after rituximab treatment. Moreover, the limited proliferative history of autoreactive B cells after treatment revealed that these clones were newly generated B cells and not self-reactive B cells that had escaped depletion and repopulated the periphery through homeostatic expansion. We conclude that anti-B cell therapy may provide a temporary dampening of autoimmune processes through B cell depletion. However, repletion with autoreactive B cells may explain the relapse that occurs in many autoimmune patients after anti-B cell therapy. PMID:26642366

  4. Immune Tolerance Induction to Factor IX through B Cell Gene Transfer: TLR9 Signaling Delineates between Tolerogenic and Immunogenic B Cells

    PubMed Central

    Wang, Xiaomei; Moghimi, Babak; Zolotukhin, Irene; Morel, Laurence M; Cao, Ou; Herzog, Roland W

    2014-01-01

    A subset of patients with severe hemophilia B, the X-linked bleeding disorder resulting from absence of coagulation factor IX (FIX), develop pathogenic antibody responses during replacement therapy. These inhibitors block standard therapy and are often associated with anaphylactic reactions to FIX. Established clinical immune tolerance induction protocols often fail for FIX inhibitors. In a murine model of this immune complication, retrovirally transduced primary B cells expressing FIX antigen fused with immunoglobulin-G heavy chain prevented antibody formation to FIX and was also highly effective in desensitizing animals with preexisting response. In contrast, transplant of B cells that received the identical expression cassette via nucleofection of plasmid vector substantially heightened antibody formation against FIX, a response that could be blocked by toll-like receptor 9 (TLR9) inhibition. While innate responses to TLR4 activation or to retrovirus were minimal in B cells, plasmid DNA activated TLR9, resulting in CpG-dependent NF-?B activation/IL-6 expression and adaptor protein 3 dependent, CpG-independent induction of IFN-I. Neither response was seen in TLR9-deficient B cells. Therefore, TLR9 signaling in B cells, in particular in response to plasmid vector, is highly immunogenic and has to be avoided in design of tolerance protocols. PMID:24609143

  5. 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 4years, 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

  6. Switched-memory B cells remodel B cell receptors within secondary germinal centers

    PubMed Central

    Okitsu, Shinji L.; McHeyzer-Williams, Michael G.

    2015-01-01

    Effective vaccines induce high-affinity memory B cells and durable antibody responses through accelerated mechanisms of natural selection. Secondary changes in antibody repertoires after vaccine boosts suggest progressive B cell receptor (BCR) re-diversification, but underlying mechanisms remain unresolved. Here integrated specificity and function of individual memory B cell progeny reveal ongoing evolution of polyclonal antibody specificities through germinal center (GC) specific transcriptional activity. At the clonal and sub-clonal levels, single cell expression of Cd83 and Pol□ segregates the secondary GC transcriptional program into 4 stages that regulate divergent mechanisms of memory BCR evolution. These studies demonstrate that vaccine boosts re-activate a cyclic program of GC function in switched-memory B cells to remodel existing antibody specificities and enhance durable immune protection. PMID:25642821

  7. Upper airway obstruction and pulmonary abnormalities due to lymphoproliferative disease following bone marrow transplantation in children.

    PubMed

    Fletcher, B D; Heslop, H E; Kaste, S C; Bodner, S

    1998-07-01

    We report three patients who developed severe supraglottic airway obstruction due to Epstein-Barr virus lymphoproliferative disease following allogeneic bone marrow transplantation. In addition to enlarged pharyngeal lymphoid tissue seen in all three patients, two had supraglottic airway narrowing and two developed pulmonary lymphoproliferative disease. They were treated with unmanipulated T cells or EBV-specific cytotoxic T lymphocytes. Life-threatening upper airway obstruction is a radiologically detectable complication of allogeneic bone marrow transplantation in children. PMID:9662565

  8. Characterization of EBV-related Lymphoproliferative Lesions Arising in Donor Lymphocytes of Transplanted Human Tumor Tissues in the NOG Mouse

    PubMed Central

    Fujii, Etsuko; Kato, Atsuhiko; Chen, Yu Jau; Matsubara, Koichi; Ohnishi, Yasuyuki; Suzuki, Masami

    2014-01-01

    Human tumor tissue line models established in the severely immunodeficient NOD.Cg-Prkdcscid Il2rgtm1Sug/Jic (NOD/Shi-scid, IL-2R?null or NOG) mouse are important tools for oncology research. During the establishment process, a lymphoproliferative lesion (LPL) that replaces the original tumor cells in the site of transplantation occurs. In the present study, we studied the impact of the LPL on the establishment process and the characteristics of the lesion, investigated the systemic distribution of the lesion in the mouse, and evaluated the potential of a simple identification method. The incidence of the lesion varied among tumor types, and the lesion was found to be the leading cause of unsuccessful establishment with gastric and colorectal cancer. The lesion consisted of a varying population of proliferating lymphoid cells that expressed CD20. The cells were positive for Epstein-Barr virus (EBV)-related antigens, and EBV DNA was detected. There was systemic distribution of the lesion within the NOG mouse, and the most consistent gross finding was splenomegaly. Additionally, identification of LPL-affected cases was possible by detecting splenomegaly in the 1st and 2nd generation mice at necropsy. From our findings the lesion was judged to arise from EBV-infected B cells originating from the donor, and monitoring splenomegaly at necropsy was thought effective as a simple method for identifying the lesion at an early stage of the establishment process. PMID:25077758

  9. 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

  10. Illuminating vitamin D effects on B cells - the multiple sclerosis perspective.

    PubMed

    Rolf, Linda; Muris, Anne-Hilde; Hupperts, Raymond; Damoiseaux, Jan

    2016-03-01

    Vitamin D is associated with many immune-mediated disorders. In multiple sclerosis (MS) a poor vitamin D status is a major environmental factor associated with disease incidence and severity. The inflammation in MS is primarily T-cell-mediated, but increasing evidence points to an important role for B cells. This has paved the way for investigating vitamin D effects on B cells. In this review we elaborate on vitamin D interactions with antibody production, T-cell-stimulating capacity and regulatory B cells. Although in vitro plasma cell generation and expression of co-stimulatory molecules are inhibited and the function of regulatory B cells is promoted, this is not supported by in vivo data. We speculate that differences might be explained by the B-cell-Epstein-Barr virus interaction in MS, the exquisite role of germinal centres in B-cell biology, and/or in vivo interactions with other hormones and vitamins that interfere with the vitamin D pathways. Further research is warranted to illuminate this tube-versus-body paradox. PMID:26714674

  11. In Senescence, Age-associated B Cells (ABC) Secrete TNF? and Inhibit Survival of B Cell Precursors1

    PubMed Central

    Ratliff, Michelle; Alter, Sarah; Frasca, Daniela; Blomberg, Bonnie B.; Riley, Richard L.

    2013-01-01

    Aged mice exhibit ~ 5-10 fold increases in an ordinarily minor CD21/35? CD23? mature B cell subset termed age-associated B cells (ABC). ABC from old, but not young, mice induce apoptosis in pro-B cells directly through secretion of TNF?. In addition, aged ABC, via TNF?, stimulate bone marrow cells to suppress pro-B cell growth. ABC effects can be prevented by the anti-inflammatory cytokine IL-10. Notably, CD21/35+ CD23+ follicular (FO) splenic and FO-like recirculating bone marrow B cells in both young and aged mice contain a subpopulation which produces IL-10. Unlike young adult FO B cells, old FO B cells also produce TNF?; however, secretion of IL-10 within this B cell population ameliorates the TNF?-mediated effects on B cell precursors. Loss of B cell precursors in the bone marrow of old mice in vivo was significantly associated with increased ABC relative to recirculating FO-like B cells. Adoptive transfer of aged ABC into RAG-2 KO recipients resulted in significant losses of pro-B cells within the bone marrow. These results suggest that alterations in B cell composition during old age, in particular the increase in ABC within the B cell compartments contribute to a pro-inflammatory environment within the bone marrow. This provides a mechanism of inappropriate B cell feedback which promotes down-regulation of B lymphopoiesis in old age. PMID:23410004

  12. Targets for Ibrutinib Beyond B Cell Malignancies.

    PubMed

    Berglf, A; Hamasy, A; Meinke, S; Palma, M; Krstic, A; Mnsson, R; Kimby, E; sterborg, A; Smith, C I E

    2015-09-01

    Ibrutinib (Imbruvica) is an irreversible, potent inhibitor of Bruton's tyrosine kinase (BTK). Over the last few years, ibrutinib has developed from a promising drug candidate to being approved by FDA for the treatment of three B cell malignancies, a truly remarkable feat. Few, if any medicines are monospecific and ibrutinib is no exception; already during ibrutinib's initial characterization, it was found that it could bind also to other kinases. In this review, we discuss the implications of such interactions, which go beyond the selective effect on BTK in B cell malignancies. In certain cases, the outcome of ibrutinib treatment likely results from the combined inhibition of BTK and other kinases, causing additive or synergistic, effects. Conversely, there are also examples when the clinical outcome seems unrelated to inhibition of BTK. Thus, more specifically, adverse effects such as enhanced bleeding or arrhythmias could potentially be explained by different interactions. We also predict that during long-term treatment bone homoeostasis might be affected due to the inhibition of osteoclasts. Moreover, the binding of ibrutinib to molecular targets other than BTK or effects on cells other than B cell-derived malignancies could be beneficial and result in new indications for clinical applications. PMID:26111359

  13. Germinal center B cells and mixed leukocyte reactions

    SciTech Connect

    Monfalcone, A.P.; Kosco, M.H.; Szakal, A.K.; Tew, J.G. )

    1989-09-01

    The present study was undertaken to determine if germinal center (GC) B cells are sufficiently activated to stimulate mixed leukocyte reactions (MLR). Percoll density fractionation and a panning technique with peanut agglutinin (PNA) were used to isolate GC B cells from the lymph nodes of immune mice. The GC B cells were treated with mitomycin C or irradiation and used to stimulate allogeneic or syngeneic splenic T cells in the MLR. Controls included high-density (HD) B cells prepared from spleens of the same mice and HD B cells activated with lipopolysaccharide (LPS) and dextran sulfate. GC B cells bound high amount sof PNA (i.e., PNAhi). Similarly, the LPS-dextran sulfate-activated B cells were PNAhi. Treatment with neuraminidase rendered the PNAlo HD B cells PNAhi. GC B cells and the LPS-dextran sulfate-activated HD B cells stimulated a potent MLR, while the untreated HD B cells did not. However, following neuraminidase treatment, the resulting PNAhi HD B cell population was able to induce an MLR. The PNA marker appeared to be an indicator of stimulatory activity, but incubating the cells with PNA to bind the cell surface ligand did not interfere with the MLR. GC B cells were also capable of stimulating a syngeneic MLR in most experiments although this was not consistently obtained. It appears that germinal centers represent a unique in vivo microenvironment that provides the necessary signals for B cells to become highly effective antigen-presenting cells.

  14. B-Cell-Activating Factor and Autoimmune Myasthenia Gravis

    PubMed Central

    Ragheb, Samia; Lisak, Robert P.

    2011-01-01

    BAFF is a potent B-cell survival factor, and it plays an essential role in B-cell homeostasis and B-cell function in the periphery. Both normal and autoreactive B cells are BAFF dependent; however, excess BAFF promotes the survival, growth, and maturation of autoreactive B cells. When overexpressed, BAFF protects B cells from apoptosis, thereby contributing to autoimmunity. Three independent studies have shown higher BAFF levels in the circulation of MG patients. BAFF may play an important role in the pathogenesis of MG. BAFF antagonists may well provide new treatment options for MG patients, particularly those patients with thymic lymphoid follicular hyperplasia. PMID:22235365

  15. The Ins and Outs of B Cells in Multiple Sclerosis

    PubMed Central

    Blauth, Kevin; Owens, Gregory P.; Bennett, Jeffrey L.

    2015-01-01

    B cells play a central role in multiple sclerosis (MS) pathology. B and plasma cells may contribute to disease activity through multiple mechanisms: antigen presentation, cytokine secretion, or antibody production. Molecular analyses of B cell populations in MS patients have revealed significant overlaps between peripheral lymphoid and clonally expanded central nervous system (CNS) B cell populations, indicating that B cell trafficking may play a critical role in driving MS exacerbations. In this review, we will assess our current knowledge of the mechanisms and pathways governing B cell migration into the CNS and examine evidence for and against a compartmentalized B cell response driving progressive MS pathology. PMID:26594215

  16. Pre-stimulation of CD81 expression by resting B cells increases proliferation following EBV infection, but the overexpression of CD81 induces the apoptosis of EBV-transformed B cells

    PubMed Central

    PARK, GA BIN; KIM, DAEJIN; PARK, SUNG JAE; LEE, HYUN-KYUNG; KIM, JI HYUN; KIM, YEONG SEOK; PARK, SAE-GWANG; CHOI, IN-HAK; YOON, SUNG HO; LEE, YOUN JAE; PAENG, SUNGHWA; HUR, DAE YOUNG

    2015-01-01

    Hepatitis C virus (HCV) E2 protein binds to CD81, which is a component of the B cell co-stimulatory complex. The E2-CD81 interaction leads to B cell proliferation, protein tyrosine phosphorylation and to the hypermutation of immunoglobulin genes. Epidemiological studies have reported a high prevalence of B cell non-Hodgkin lymphoma (NHL) in HCV-positive patients, suggesting a potential association between HCV and Epstein-Barr virus (EBV) in the genesis of B lymphocyte proliferative disorders. In the present study, in order to investigate the association between EBV and HCV in B cells, we created an in vitro EBV-induced B cell transformation model. CD81 was gradually overexpressed during transformation by EBV. B cells isolated from HCV-positive patients grew more rapidly and clumped together earlier than B cells isolated from healthy donors following EBV infection. Pre-stimulation of CD81 expressed by resting B cells with anti-CD81 monoclonal antibody (mAb) or HCV E2 accelerated the generation of lymphoblastoid cell lines (LCLs) by EBV infection. These cells proliferated prominently through the early expression of interleukin-10 and intracellular latent membrane protein (LMP)-l. By contrast, the overexpression of CD81 on EBV-transformed B cells by anti-CD81 mAb or HCV E2 protein induced apoptosis through reactive oxygen species (ROS)-mediated mitochondrial dysfunction. These results suggest that the engagement of CD81 expressed by B cells has differential effects on B cell fate (proliferation or apoptosis) according to EBV infection and the expression level of CD81. PMID:26498453

  17. Pre-stimulation of CD81 expression by resting Bcells increases proliferation following EBV infection, but the overexpression of CD81 induces the apoptosis of EBV-transformed B cells.

    PubMed

    Park, Ga Bin; Kim, Daejin; Park, Sung Jae; Lee, Hyun-Kyung; Kim, Ji Hyun; Kim, Yeong Seok; Park, Sae-Gwang; Choi, In-Hak; Yoon, Sung Ho; Lee, Youn Jae; Paeng, Sunghwa; Hur, Dae Young

    2015-12-01

    HepatitisC virus (HCV)E2 protein binds to CD81, which is a component of the Bcell co-stimulatory complex. The E2-CD81 interaction leads to Bcell proliferation, protein tyrosine phosphorylation and to the hypermutation of immunoglobulin genes. Epidemiological studies have reported a high prevalence of Bcell non-Hodgkin lymphoma(NHL) in HCV-positive patients, suggesting a potential association between HCV and Epstein-Barr virus(EBV) in the genesis of Blymphocyte proliferative disorders. In the present study, in order to investigate the association between EBV and HCV in Bcells, we created an invitro EBV-induced Bcell transformation model. CD81 was gradually overexpressed during transformation by EBV. Bcells isolated from HCV-positive patients grew more rapidly and clumped together earlier than Bcells isolated from healthy donors following EBV infection. Pre-stimulation of CD81 expressed by resting Bcells with anti-CD81 monoclonal antibody(mAb) or HCVE2 accelerated the generation of lymphoblastoid cell lines(LCLs) by EBV infection. These cells proliferated prominently through the early expression of interleukin-10 and intracellular latent membrane protein(LMP)-l. By contrast, the overexpression of CD81 on EBV-transformed Bcells by anti-CD81 mAb or HCVE2 protein induced apoptosis through reactive oxygen species (ROS)-mediated mitochondrial dysfunction. These results suggest that the engagement of CD81 expressed by Bcells has differential effects on Bcell fate (proliferation or apoptosis) according to EBV infection and the expression level of CD81. PMID:26498453

  18. DiGeorge syndrome who developed lymphoproliferative mediastinal mass

    PubMed Central

    Kim, Kyu Yeun; Hur, Ji Ae; Kim, Ki Hwan; Cha, Yoon Jin; Lee, Mi Jung

    2015-01-01

    DiGeorge syndrome is an immunodeficient disease associated with abnormal development of 3rd and 4th pharyngeal pouches. As a hemizygous deletion of chromosome 22q11.2 occurs, various clinical phenotypes are shown with a broad spectrum. Conotruncal cardiac anomalies, hypoplastic thymus, and hypocalcemia are the classic triad of DiGeorge syndrome. As this syndrome is characterized by hypoplastic or aplastic thymus, there are missing thymic shadow on their plain chest x-ray. Immunodeficient patients are traditionally known to be at an increased risk for malignancy, especially lymphoma. We experienced a 7-year-old DiGeorge syndrome patient with mediastinal mass shadow on her plain chest x-ray. She visited Severance Children's Hospital hospital with recurrent pneumonia, and throughout her repeated chest x-ray, there was a mass like shadow on anterior mediastinal area. We did full evaluation including chest computed tomography, chest ultrasonography, and chest magnetic resonance imaging. To rule out malignancy, video assisted thoracoscopic surgery was done. Final diagnosis of the mass which was thought to be malignancy, was lymphoproliferative lesion. PMID:25861334

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

    PubMed Central

    2007-01-01

    Increasing awareness of the importance of aberrant B cell regulation in autoimmunity has driven the clinical development of novel B cell-directed biologic therapies with the potential to treat a range of autoimmune disorders. The first of these drugs—rituximab, a chimeric monoclonal antibody against the B cell-specific surface marker CD20—was recently approved for treating rheumatoid arthritis in patients with an inadequate response to other biologic therapies. The aim of this review is to discuss the potential use of rituximab in the management of other autoimmune disorders. Results from early phase clinical trials indicate that rituximab may provide clinical benefit in systemic lupus erythematosus, Sjögren’s syndrome, vasculitis, and thrombocytopenic purpura. Numerous case reports and several small pilot studies have also been published reporting the use of rituximab in conditions such as myositis, antiphospholipid syndrome, Still’s disease, and multiple sclerosis. In general, the results from these preliminary studies encourage further testing of rituximab therapy in formalized clinical trials. Based on results published to date, it is concluded that rituximab, together with other B cell-directed therapies currently under clinical development, is likely to provide an important new treatment option for a number of these difficult-to-treat autoimmune disorders. PMID:17957371

  20. Systematic Epstein-Barr virus-positive T-cell lymphoproliferative disease presenting as a persistent fever and cough: a case report

    PubMed Central

    2014-01-01

    Introduction Systemic Epstein-Barr virus-positive T-cell lymphoproliferative childhood disease is an extremely rare disorder and classically arises following primary acute or chronic active Epstein-Barr virus infection. It is characterized by clonal proliferation of Epstein-Barr virus-infected T-cells with an activated cytotoxic phenotype. This disease has a rapid clinical course and is more frequent in Asia and South America, with relatively few cases being reported in Western countries. The clinical and pathological features of the disease overlap with other conditions including infectious mononucleosis, chronic active Epstein-Barr virus infection, hemophagocytic lymphohistiocytosis and natural killer cell malignancies. We describe the rare case of systemic Epstein-Barr virus-positive T-cell lymphoproliferative childhood disease in a 16-year-old Malay boy. Case presentation He presented with a six-month history of fever and cough, with pulmonary and mediastinal lymphadenopathy and severe pancytopenia. Medium- to large-sized, CD8+ and Epstein-Barr virus-encoded RNA-positive atypical lymphoid cells were present in the bone marrow aspirate. He subsequently developed fatal virus-associated hemophagocytic syndrome and died due to sepsis and multiorgan failure. Conclusions Although systemic Epstein-Barr virus-positive T-cell lymphoproliferative childhood disease is a disorder which is rarely encountered in clinical practice, our case report underlines the importance of a comprehensive diagnostic approach in the management of this disease. A high level of awareness of the disease throughout the diagnosis process for young patients who present with systemic illness and hemophagocytic syndrome may be of great help for the clinical diagnosis of this disease. PMID:25163591

  1. Dynamics of B cells in germinal centres

    PubMed Central

    De Silva, Nilushi S.; Klein, Ulf

    2015-01-01

    Humoral immunity depends on the germinal centre (GC) reaction during which somatically mutated high-affinity memory B cells and plasma cells are generated. Recent studies have uncovered crucial cues that are required for the formation and the maintenance of GCs and for the selection of high-affinity antibody mutants. In addition, it is now clear that these events are promoted by the dynamic movements of cells within and between GCs. These findings have resolved the complexities of the GC reaction in greater detail than ever before. This Review focuses on these recent advances and discusses their implications for the establishment of humoral immunity. PMID:25656706

  2. B cells regulate anti donor T cell reactivity in transplantation

    PubMed Central

    Valujskikh, Anna

    2015-01-01

    The analyses of indirect T cell responses in patients with antibody-mediated renal transplant injury by Shiu et al. emphasize the complex contribution of B cells in alloimmunity. The data suggest at least three distinct but potentially overlapping consequences of T/B cell interactions: antigen presentation by B cells, alloantibody production, and immune regulation. These multifaceted functions of B cells should be taken into consideration while developing diagnostic tools and therapeutic strategies. PMID:26323072

  3. B-cell anergy: from transgenic models to naturally occurring anergic B cells?

    PubMed Central

    Cambier, John C.; Gauld, Stephen B.; Merrell, Kevin T.; Vilen, Barbara J.

    2013-01-01

    Anergy, a condition in which cells persist in the periphery but are unresponsive to antigen, is responsible for silencing many self-reactive B cells. Loss of anergy is known to contribute to the development of autoimmune diseases, including systemic lupus erythematosus and type 1 diabetes. Multiple transgenic mouse models have enabled the dissection of mechanisms that underlie anergy, and recently, anergic B cells have been identified in the periphery of wild-type mice. Heterogeneity of mechanistic concepts developed using model systems has complicated our understanding of anergy and its biological features. In this Review, we compare and contrast the salient features of anergic B cells with a view to developing unifying mechanistic hypotheses that explain their lifestyles. PMID:17641666

  4. Identification of IFN-γ-producing innate B cells

    PubMed Central

    Bao, Yan; Liu, Xingguang; Han, Chaofeng; Xu, Sheng; Xie, Bin; Zhang, Qian; Gu, Yan; Hou, Jin; Qian, Li; Qian, Cheng; Han, Huanxing; Cao, Xuetao

    2014-01-01

    Although B cells play important roles in the humoral immune response and the regulation of adaptive immunity, B cell subpopulations with unique phenotypes, particularly those with non-classical immune functions, should be further investigated. By challenging mice with Listeria monocytogenes, Escherichia coli, vesicular stomatitis virus and Toll-like receptor ligands, we identified an inducible CD11ahiFcγRIIIhi B cell subpopulation that is significantly expanded and produces high levels of IFN-γ during the early stage of the immune response. This subpopulation of B cells can promote macrophage activation via generating IFN-γ, thereby facilitating the innate immune response against intracellular bacterial infection. As this new subpopulation is of B cell origin and exhibits the phenotypic characteristics of B cells, we designated these cells as IFN-γ-producing innate B cells. Dendritic cells were essential for the inducible generation of these innate B cells from the follicular B cells via CD40L-CD40 ligation. Increased Bruton's tyrosine kinase activation was found to be responsible for the increased activation of non-canonical NF-κB pathway in these innate B cells after CD40 ligation, with the consequent induction of additional IFN-γ production. The identification of this new population of innate B cells may contribute to a better understanding of B cell functions in anti-infection immune responses and immune regulation. PMID:24296781

  5. Activation-Induced Cytidine Deaminase Expression in Human B Cell Precursors Is Essential for Central B Cell Tolerance.

    PubMed

    Cantaert, Tineke; Schickel, Jean-Nicolas; Bannock, Jason M; Ng, Yen-Shing; Massad, Christopher; Oe, Tyler; Wu, Renee; Lavoie, Aubert; Walter, Jolan E; Notarangelo, Luigi D; Al-Herz, Waleed; Kilic, Sara Sebnem; Ochs, Hans D; Nonoyama, Shigeaki; Durandy, Anne; Meffre, Eric

    2015-11-17

    Activation-induced cytidine deaminase (AID), the enzyme-mediating class-switch recombination (CSR) and somatic hypermutation (SHM) of immunoglobulin genes, is essential for the removal of developing autoreactive B cells. How AID mediates central B cell tolerance remains unknown. We report that AID enzymes were produced in a discrete population of immature B cells that expressed recombination-activating gene 2 (RAG2), suggesting that they undergo secondary recombination to edit autoreactive antibodies. However, most AID+ immature B cells lacked anti-apoptotic MCL-1 and were deleted by apoptosis. AID inhibition using lentiviral-encoded short hairpin (sh)RNA in B cells developing in humanized mice resulted in a failure to remove autoreactive clones. Hence, B cell intrinsic AID expression mediates central B cell tolerance potentially through its RAG-coupled genotoxic activity in self-reactive immature B cells. PMID:26546282

  6. Mononeuritis multiplex in a patient with B-cell prolymphocytic leukaemia: a diagnostic challenge

    PubMed Central

    Le Clech, Lenag; Rizcallah, Marie Jeanne; Alavi, Zarrin; Hutin, Pascal

    2013-01-01

    B-cell prolymphocytic leukaemia (BPLL) is a haematological malignancy defined as lymphocytosis and splenomegaly with >55% circulating cells being clonal prolymphocytes of B-cell origin. The evolution of this disease is more aggressive than chronic lymphocytic leukaemia. We reported a case of a 62-year-old man with BPLL who, on treatment, attained cytological, immunophenotypic and complete cytogenetic remission. He subsequently developed an asymmetric sensorimotor neurological disorder, suggestive of lymphomatous infiltration (neurolymphocytosis). Repetition of the MRI and the electromyography was essential for diagnosis. Progressive mononeuritis multiplex in B-cell leukaemias/lymphomas is rare and may be the only presenting symptom of relapsed or progressive disease. Repeat imaging studies based on judicious evaluation of the clinical scenario for exclusion of other causes of neurological symptoms is necessary. This can be challenging in patients with long-standing malignancies who have received multiple courses of chemotherapy and/or radiotherapy. PMID:24000206

  7. B-cell memory against factor VIII.

    PubMed

    Reipert, Birgit M

    2016-03-01

    The development of persistent neutralizing antibodies against factor VIII (FVIII) is the most severe complication in the treatment of congenital hemophilia A patients with FVIII replacement therapies. Recently, we presented data which indicate that neutralizing antibodies are high-affinity antibodies which are mostly of the IgG1 and IgG4 subclasses. However, there are also FVIII-specific antibodies of low to moderate affinity which are found in some patients without neutralizing antibodies and in some healthy individuals. The underlying immune mechanisms which regulate the development of these different populations of FVIII-specific antibodies are poorly understood. In this review, we discuss potential mechanisms for the development of low-affinity and high-affinity antibodies. In particular, we discuss the role of memory B cells which are essential in maintaining long-lasting antibody responses and in driving the rapid anamnestic antibody response after re-exposure to the same antigen. We also present available data on the potential role of FVIII-specific memory B cells in the maintenance of neutralizing antibodies against FVIII. PMID:26780996

  8. IFN-alpha amplifies human naive B cell TLR-9-mediated activation and Ig production.

    PubMed

    Giordani, L; Sanchez, M; Libri, I; Quaranta, M G; Mattioli, B; Viora, M

    2009-08-01

    TLRs are a family of molecules that function as sensors for the detection of pathogens. TLR-9, expressed on B cells and pDCs, recognizes CpG motifs of unmethylated bacterial DNA and plays a role in the development of autoimmunity. The present study was designed to investigate the effects of IFN-alpha in combination with CpG ODN on the activation of CD27(-) naïve B cells and on Ig production. We provide evidence that CpG ODN not only induces a total and T-dependent, specific IgM response by naïve B cells but also their phenotypic differentiation in plasma cells, as demonstrated by the up-regulation of CD38 expression. We found that TLR-9 stimulation with CpG ODN induces IL-1beta, TNF-alpha, IL-10, and IL-6 production. Interestingly, we also found that CpG ODN induces naïve B cell maturation into memory cells, as demonstrated by the induction of CD27, AID mRNA expression, and IgG production. More importantly, our results demonstrate that IFN-alpha amplifies the inductive effect of CpG ODN on naïve B activation and on Ig production through a mechanism involving TLR-9/MyD88-dependent signaling. Moreover, we found that IFN-alpha enhances the frequency of CpG ODN-induced memory B cells. Our results may contribute to clarify the events promoting IFN-alpha-induced amplification of naïve B cell activation via TLR-9 for a better understanding of the pathogenesis of autoimmune disorders and may guide treatments targeting this pathway within B cells. PMID:19401392

  9. The life and death of a B cell.

    PubMed

    Defrance, Thierry; Casamayor-Pallejà, Montserrat; Krammer, Peter H

    2002-01-01

    Regulation of apoptosis in the B cell lineage has implications for homeostasis, quality control of the antibody response, and tolerance. In this chapter we examine the different checkpoints that control life and death decisions of B cells during the antigen-independent and antigen-dependent phases of their development. We discuss the cell death mechanism involved in elimination of unwanted B cells at different stages of their development as well as the signals that trigger or repress the apoptotic process. At the steady state, before or after development of an immune response, B cell apoptosis ensures that the antigen receptor (BCR) on newly produced B cells is functional and does not recognize self-antigens with high avidity. It also ensures that the size of the peripheral B cell compartment remains constant in spite of the continuous input of B cells from the bone marrow. All these processes are controlled by the mitochondrial death pathway and are thus perturbed by overexpression of the antiapoptotic members of the bcl-2 gene family. By contrast, the death receptor pathway plays a prominent role during the antigen-dependent phase of B cell development. Three sets of membrane molecules stand as crucial regulators of B cell survival. First, the BCR which plays a central but ambiguous role. On the one hand, it triggers death of B cells that recognize self-antigens or have been exposed to repeated antigenic stimulations. On the other hand, it promotes survival of the peripheral mature B cell pool and protects activated B cells from CD95-induced killing. Second, the death receptor Fas/CD95 which is instrumental in censoring B cells activated in a bystander fashion at the initiation of the response to T-dependent antigens. It also drives elimination of low-affinity and self-reactive B cell clones that arise through the process of somatic mutations during the germinal center reaction. As such, it contributes to the affinity maturation of the antibody response. Finally, three membrane receptors (TACI, BCMA, and BAFF-R) which bind a newly discovered member of the tumor necrosis factor family named BAFF. BAFF acts specifically on peripheral B cells but its cellular targets seem to be restricted to two splenic B cell populations: (i) transitional immature B cells and (ii) marginal zone B cells, known to be responsible for the response to thymus-independent type 2 antigens. This suggests its possible implication in positive selection of peripheral B cells and in the antibacterial B cell responses. PMID:12374279

  10. Estrogen receptor signal in regulation of B cell activation during diverse immune responses.

    PubMed

    Asaba, Josaine; Bandyopadhyay, Mausumi; Kindy, Mark; Dasgupta, Subhajit

    2015-11-01

    The role of signalling through oestrogen receptors (ERs) in the regulation of B cell activation is an area of growing importance not only in terms protective immunity but also in the determination of the mechanisms of the onset of autoimmune disorders and cancers. The mode of signalling action of this single chain nuclear receptor protein molecule depends on its ability to bind to the promoters of Pax5, HOXC4 and apolipoprotein B RNA-editing enzyme activation-induced cytidine deaminase (AID) genes. ER-mediated transcriptional regulation induces class switch recombination of the immunoglobulin heavy chain variable (VH) to DH-JH genes and somatic hypermutation in developing B cells. The mode of action of ER is associated with BCR-signal pathways that involve the regulator proteins BAFF and APRIL. Additionally, the plasma membrane-bound G protein-coupled oestrogen receptor-1 (GEPR1) directs diverse cell signalling events in B cells that involve the MAPK pathways. These signals are immensely important during progenitor and precursor B cell activation. We have focused our goals on the medicinal aspects of ER-signalling mechanisms and their effects on polyclonal B cell activation. PMID:26299327

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

    PubMed

    Stepanov, A V; Belogurov, 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

  12. Decreased expression of B cell related genes in leukocytes of women with Parkinson's disease

    PubMed Central

    2011-01-01

    Background Parkinson's disease (PD) is a complex disorder caused by genetic, environmental and age-related factors, and it is more prevalent in men. We aimed to identify differentially expressed genes in peripheral blood leukocytes (PBLs) that might be involved in PD pathogenesis. Transcriptomes of 30 female PD-patients and 29 age- and sex-matched controls were profiled using GeneChip Human Exon 1.0 ST Arrays. Samples were from unrelated Ashkenazi individuals, non-carriers of LRRK2 G2019S or GBA founder mutations. Results Differential expression was detected in 115 genes (206 exons), with over-representation of immune response annotations. Thirty genes were related to B cell functions, including the uniquely B cell-expressed IGHM and IGHD, the B cell surface molecules CD19, CD22 and CD79A, and the B cell gene regulator, PAX5. Quantitative-RT-PCR confirmation of these 6 genes in 79 individuals demonstrated decreased expression, mainly in women patients, independent of PD-pharmacotherapy status. Conclusions Our results suggest that the down regulation of genes related to B cell activity reflect the involvement of these cells in PD in Ashkenazi individuals and represents a molecular aspect of gender-specificity in PD. PMID:21943286

  13. B-cell lymphoma 6 and the molecular pathogenesis of diffuse large B-cell lymphoma

    PubMed Central

    Ci, Weimin; Polo, Jose M; Melnick, Ari

    2009-01-01

    Purpose of review The BCL6 transcriptional repressor is the most commonly involved oncogene in B-cell lymphomas. Sustained expression of BCL6 causes malignant transformation of germinal center (GC) B-cells. Understanding the mechanism of action of BCL6 is crucial for the study of how aberrant transcriptional programming leads to lymphomagenesis and development of targeted anti-lymphoma therapy. Recent findings Identification of BCL6 target genes indicate a critical role for BCL6 in facilitating a state of physiological genomic instability required for GC B-cells to undergo affinity maturation, and suggest its contribution to several additional cellular functions. The discovery of several layers of counter-regulatory mechanisms reveals how B-cells can control and fine-tune the potentially lymphomagenic actions of BCL6. From the biochemical standpoint, BCL6 can regulate distinct biological pathways through different cofactors. This observation explains how the biological actions of BCL6 can be physiologically controlled through separate mechanisms and affords the means for improved therapeutic targeting. The fact that patients with BCL6-dependent lymphoma can be identified based on gene signatures suggests that therapeutic trials of BCL6 inhibitors could be personalized to these individuals. Summary BCL6 plays a fundamental role in lymphomagenesis and is an excellent therapeutic target for development of improved anti-lymphoma therapeutic regimens. PMID:18536578

  14. Dengue Virus Directly Stimulates Polyclonal B Cell Activation

    PubMed Central

    Papa, Michelle Premazzi; de Morais, Ana Theresa Silveira; Peçanha, Ligia Maria Torres; de Arruda, Luciana Barros

    2015-01-01

    Dengue infection is associated to vigorous inflammatory response, to a high frequency of activated B cells, and to increased levels of circulating cross-reactive antibodies. We investigated whether direct infection of B cells would promote activation by culturing primary human B lymphocytes from healthy donors with DENV in vitro. B cells were susceptible, but poorly permissive to infection. Even though, primary B cells cultured with DENV induced substantial IgM secretion, which is a hallmark of polyclonal B cell activation. Notably, DENV induced the activation of B cells obtained from either DENV immune or DENV naïve donors, suggesting that it was not dependent on DENV-specific secondary/memory response. B cell stimulation was dependent on activation of MAPK and CD81. B cells cultured with DENV also secreted IL-6 and presented increased expression of CD86 and HLA-DR, which might contribute to B lymphocyte co-stimulatory function. Indeed, PBMCs, but not isolated B cells, secreted high amounts of IgG upon DENV culture, suggesting that interaction with other cell types in vivo might promote Ig isotype switching and IgG secretion from different B cell clones. These findings suggest that activation signaling pathways triggered by DENV interaction with non-specific receptors on B cells might contribute to the exacerbated response observed in dengue patients. PMID:26656738

  15. CNS accumulation of regulatory B cells is VLA-4-dependent

    PubMed Central

    Lehmann-Horn, Klaus; Sagan, Sharon A.; Winger, Ryan C.; Spencer, Collin M.; Bernard, Claude C.A.; Sobel, Raymond A.

    2016-01-01

    Objective: To investigate the role of very late antigen-4 (VLA-4) on regulatory B cells (Breg) in CNS autoimmune disease. Methods: Experimental autoimmune encephalomyelitis (EAE) was induced in mice selectively deficient for VLA-4 on B cells (CD19cre/α4f/f) by immunization with myelin oligodendrocyte glycoprotein (MOG) peptide (p)35–55 or recombinant human (rh) MOG protein. B-cell and T-cell populations were examined by flow cytometry and immunohistochemistry. Breg were evaluated by intracellular IL-10 staining of B cells and, secondly, by coexpression of CD1d and CD5. Results: As previously reported, EAE was less severe in B-cell VLA-4-deficient vs control CD19cre mice when induced by rhMOG, a model that is B-cell-dependent and leads to efficient B-cell activation and antibody production. Paradoxically, B-cell VLA-4-deficient mice developed more severe clinical disease than control mice when EAE was induced with MOG p35-55, a B-cell-independent encephalitogen that does not efficiently activate B cells. Peripheral T-cell and humoral immune responses were not altered in B-cell VLA-4-deficient mice. In MOG p35-55-induced EAE, B-cell VLA-4 deficiency reduced CNS accumulation of B but not T cells. Breg were detected in the CNS of control mice with MOG p35-55-induced EAE. However, more severe EAE in B-cell VLA-4-deficient mice was associated with virtual absence of CNS Breg. Conclusions: Our results demonstrate that CNS accumulation of Breg is VLA-4-dependent and suggest that Breg may contribute to regulation of CNS autoimmunity in situ. These observations underscore the need to choose the appropriate encephalitogen when studying how B cells contribute to pathogenesis or regulation of CNS autoimmunity.

  16. Deregulation of Fas ligand expression as a novel cause of autoimmune lymphoproliferative syndrome-like disease.

    PubMed

    Nabhani, Schafiq; Ginzel, Sebastian; Miskin, Hagit; Revel-Vilk, Shoshana; Harlev, Dan; Fleckenstein, Bernhard; Hnscheid, Andrea; Oommen, Prasad T; Kuhlen, Michaela; Thiele, Ralf; Laws, Hans-Jrgen; Borkhardt, Arndt; Stepensky, Polina; Fischer, Ute

    2015-09-01

    Autoimmune lymphoproliferative syndrome is frequently caused by mutations in genes involved in the Fas death receptor pathway, but for 20-30% of patients the genetic defect is unknown. We observed that treatment of healthy T cells with interleukin-12 induces upregulation of Fas ligand and Fas ligand-dependent apoptosis. Consistently, interleukin-12 could not induce apoptosis in Fas ligand-deficient T cells from patients with autoimmune lymphoproliferative syndrome. We hypothesized that defects in the interleukin-12 signaling pathway may cause a similar phenotype as that caused by mutations of the Fas ligand gene. To test this, we analyzed 20 patients with autoimmune lymphoproliferative syndrome of unknown cause by whole-exome sequencing. We identified a homozygous nonsense mutation (c.698G>A, p.R212*) in the interleukin-12/interleukin-23 receptor-component IL12RB1 in one of these patients. The mutation led to IL12RB1 protein truncation and loss of cell surface expression. Interleukin-12 and -23 signaling was completely abrogated as demonstrated by deficient STAT4 phosphorylation and interferon ? production. Interleukin-12-mediated expression of membrane-bound and soluble Fas ligand was lacking and basal expression was much lower than in healthy controls. The patient presented with the classical symptoms of autoimmune lymphoproliferative syndrome: chronic non-malignant, non-infectious lymphadenopathy, splenomegaly, hepatomegaly, elevated numbers of double-negative T cells, autoimmune cytopenias, and increased levels of vitamin B12 and interleukin-10. Sanger sequencing and whole-exome sequencing excluded the presence of germline or somatic mutations in genes known to be associated with the autoimmune lymphoproliferative syndrome. Our data suggest that deficient regulation of Fas ligand expression by regulators such as the interleukin-12 signaling pathway may be an alternative cause of autoimmune lymphoproliferative syndrome-like disease. PMID:26113417

  17. Deregulation of Fas ligand expression as a novel cause of autoimmune lymphoproliferative syndrome-like disease

    PubMed Central

    Nabhani, Schafiq; Ginzel, Sebastian; Miskin, Hagit; Revel-Vilk, Shoshana; Harlev, Dan; Fleckenstein, Bernhard; Hönscheid, Andrea; Oommen, Prasad T.; Kuhlen, Michaela; Thiele, Ralf; Laws, Hans-Jürgen; Borkhardt, Arndt; Stepensky, Polina; Fischer, Ute

    2015-01-01

    Autoimmune lymphoproliferative syndrome is frequently caused by mutations in genes involved in the Fas death receptor pathway, but for 20–30% of patients the genetic defect is unknown. We observed that treatment of healthy T cells with interleukin-12 induces upregulation of Fas ligand and Fas ligand-dependent apoptosis. Consistently, interleukin-12 could not induce apoptosis in Fas ligand-deficient T cells from patients with autoimmune lymphoproliferative syndrome. We hypothesized that defects in the interleukin-12 signaling pathway may cause a similar phenotype as that caused by mutations of the Fas ligand gene. To test this, we analyzed 20 patients with autoimmune lymphoproliferative syndrome of unknown cause by whole-exome sequencing. We identified a homozygous nonsense mutation (c.698G>A, p.R212*) in the interleukin-12/interleukin-23 receptor-component IL12RB1 in one of these patients. The mutation led to IL12RB1 protein truncation and loss of cell surface expression. Interleukin-12 and -23 signaling was completely abrogated as demonstrated by deficient STAT4 phosphorylation and interferon γ production. Interleukin-12-mediated expression of membrane-bound and soluble Fas ligand was lacking and basal expression was much lower than in healthy controls. The patient presented with the classical symptoms of autoimmune lymphoproliferative syndrome: chronic non-malignant, non-infectious lymphadenopathy, splenomegaly, hepatomegaly, elevated numbers of double-negative T cells, autoimmune cytopenias, and increased levels of vitamin B12 and interleukin-10. Sanger sequencing and whole-exome sequencing excluded the presence of germline or somatic mutations in genes known to be associated with the autoimmune lymphoproliferative syndrome. Our data suggest that deficient regulation of Fas ligand expression by regulators such as the interleukin-12 signaling pathway may be an alternative cause of autoimmune lymphoproliferative syndrome-like disease.

  18. T-cell therapy in the treatment of post-transplant lymphoproliferative disease

    PubMed Central

    Bollard, Catherine M; Rooney, Cliona M; Heslop, Helen E

    2013-01-01

    Post-transplant lymphoproliferative diseases (PTLD) associated with Epstein-Barr virus (EBV) infection often develop after organ and haematopoietic stem-cell transplantation. These lymphoproliferative diseases are tumours that usually express all latent EBV viral proteins, and are therefore amenable to T-cell-based immune therapies, such as donor lymphocyte infusions and the adoptive transfer of EBV-specific cytotoxic T-lymphocytes (CTLs). In this Review, we describe current strategies of T-cell-based therapies to treat PTLD, and describe strategies that improve the feasibility of such treatment. PMID:22801669

  19. Generation and maintenance of mucosal memory B cell responses?

    PubMed

    Vajdy, M

    2006-01-01

    The mucosal immune system comprises B cells that can mount potent antibody responses against a variety of mucosal pathogens. Mucosal B cell responses can play a decisive role in protection against mucosal pathogens. Induction of mucosal B cell responses can be achieved through mucosal vaccination. However, mucosal administration of antigens without the use of adjuvants or delivery systems can lead to tolerance rather than immunity, and thus considerable efforts have been focused on development of effective immunopotentiating adjuvants and delivery systems. However, because the ultimate goal of vaccination is the induction and maintenance of immunological memory, the underlying mechanisms for induction of long-term mucosal B cell memory need to be analyzed for the selection of appropriate adjuvants. Moreover, as the antigen unspecific innate immune system invoked by adjuvants contributes significantly to the development of antigen-specific B cell responses, and presumably B cell memory, optimal interaction of B cells with cellular components of the innate immune system is required. To better understand the mechanisms that lead to the induction of mucosal antibody responses, antibodies against single epitopes from specific B cell clones as opposed to antibodies against large poly proteins from multiple B cell clones can be studied. This review deals with the concept of mucosal B cell memory with special emphasis on efforts to devise effective prophylactic or therapeutic vaccines. PMID:17073644

  20. B cells enhance early innate immune responses during bacterial sepsis.

    PubMed

    Kelly-Scumpia, Kindra M; Scumpia, Philip O; Weinstein, Jason S; Delano, Matthew J; Cuenca, Alex G; Nacionales, Dina C; Wynn, James L; Lee, Pui Y; Kumagai, Yutaro; Efron, Philip A; Akira, Shizuo; Wasserfall, Clive; Atkinson, Mark A; Moldawer, Lyle L

    2011-08-01

    Microbes activate pattern recognition receptors to initiate adaptive immunity. T cells affect early innate inflammatory responses to viral infection, but both activation and suppression have been demonstrated. We identify a novel role for B cells in the early innate immune response during bacterial sepsis. We demonstrate that Rag1(-/-) mice display deficient early inflammatory responses and reduced survival during sepsis. Interestingly, B cell-deficient or anti-CD20 B cell-depleted mice, but not ?/? T cell-deficient mice, display decreased inflammatory cytokine and chemokine production and reduced survival after sepsis. Both treatment of B cell-deficient mice with serum from wild-type (WT) mice and repletion of Rag1(-/-) mice with B cells improves sepsis survival, suggesting antibody-independent and antibody-dependent roles for B cells in the outcome to sepsis. During sepsis, marginal zone and follicular B cells are activated through type I interferon (IFN-I) receptor (IFN-?/? receptor [IFNAR]), and repleting Rag1(-/-) mice with WT, but not IFNAR(-/-), B cells improves IFN-I-dependent and -independent early cytokine responses. Repleting B cell-deficient mice with the IFN-I-dependent chemokine, CXCL10 was also sufficient to improve sepsis survival. This study identifies a novel role for IFN-I-activated B cells in protective early innate immune responses during bacterial sepsis. PMID:21746813

  1. Knockout of Epstein-Barr Virus BPLF1 Retards B-Cell Transformation and Lymphoma Formation in Humanized Mice

    PubMed Central

    Li, Guangming; Montgomery, Stephanie A.; Montgomery, Nathan D.; Su, Lishan; Pagano, Joseph S.

    2015-01-01

    ABSTRACT BPLF1 of Epstein-Barr virus (EBV) is classified as a late lytic cycle protein but is also found in the viral tegument, suggesting its potential involvement at both initial and late stages of viral infection. BPLF1 possesses both deubiquitinating and deneddylating activity located in its N-terminal domain and is involved in processes that affect viral infectivity, viral DNA replication, DNA repair, and immune evasion. A recently constructed EBV BPLF1-knockout (KO) virus was used in conjunction with a humanized mouse model that can be infected with EBV, enabling the first characterization of BPLF1 function in vivo. Results demonstrate that the BPLF1-knockout virus is approximately 90% less infectious than wild-type (WT) virus. Transformation of human B cells, a hallmark of EBV infection, was delayed and reduced with BPLF1-knockout virus. Humanized mice infected with EBV BPLF1-knockout virus showed less weight loss and survived longer than mice infected with equivalent infectious units of WT virus. Additionally, splenic tumors formed in 100% of mice infected with WT EBV but in only 25% of mice infected with BPLF1-KO virus. Morphological features of spleens containing tumors were similar to those in EBV-induced posttransplant lymphoproliferative disease (PTLD) and were almost identical to cases seen in human diffuse large B-cell lymphoma. The presence of EBV genomes was detected in all mice that developed tumors. The results implicate BPLF1 in human B-cell transformation and tumor formation in humanized mice. PMID:26489865

  2. Schistosomes Induce Regulatory Features in Human and Mouse CD1dhi B Cells: Inhibition of Allergic Inflammation by IL-10 and Regulatory T Cells

    PubMed Central

    van der Vlugt, Lucin E. P. M.; Labuda, Lucja A.; Ozir-Fazalalikhan, Arifa; Lievers, Ellen; Gloudemans, Anouk K.; Liu, Kit-Yeng; Barr, Tom A.; Sparwasser, Tim; Boon, Louis; Ngoa, Ulysse Ateba; Feugap, Eliane Ngoune; Adegnika, Ayola A.; Kremsner, Peter G.; Gray, David; Yazdanbakhsh, Maria; Smits, Hermelijn H.

    2012-01-01

    Chronic helminth infections, such as schistosomes, are negatively associated with allergic disorders. Here, using B cell IL-10-deficient mice, Schistosoma mansoni-mediated protection against experimental ovalbumin-induced allergic airway inflammation (AAI) was shown to be specifically dependent on IL-10-producing B cells. To study the organs involved, we transferred B cells from lungs, mesenteric lymph nodes or spleen of OVA-infected mice to recipient OVA-sensitized mice, and showed that both lung and splenic B cells reduced AAI, but only splenic B cells in an IL-10-dependent manner. Although splenic B cell protection was accompanied by elevated levels of pulmonary FoxP3+ regulatory T cells, in vivo ablation of FoxP3+ T cells only moderately restored AAI, indicating an important role for the direct suppressory effect of regulatory B cells. Splenic marginal zone CD1d+ B cells proved to be the responsible splenic B cell subset as they produced high levels of IL-10 and induced FoxP3+ T cells in vitro. Indeed, transfer of CD1d+ MZ-depleted splenic B cells from infected mice restored AAI. Markedly, we found a similarly elevated population of CD1dhi B cells in peripheral blood of Schistosoma haematobium-infected Gabonese children compared to uninfected children and these cells produced elevated levels of IL-10. Importantly, the number of IL-10-producing CD1dhi B cells was reduced after anti-schistosome treatment. This study points out that in both mice and men schistosomes have the capacity to drive the development of IL-10-producing regulatory CD1dhi B cells and furthermore, these are instrumental in reducing experimental allergic inflammation in mice. PMID:22347409

  3. 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

  4. DISSECTING TELEOST B CELL DIFFERENTIATION USING TRANSCRIPTION FACTORS

    PubMed Central

    Zwollo, Patty

    2011-01-01

    B cell developmental pathways in teleost fishes are poorly understood. In the absence of serological reagents, an alternative approach to dissecting teleost B cell development is to use transcription factors that are differentially expressed during B cell development. This review discusses the structure and function of six transcription factors that play essential roles during teleost B cell development: Ikaros, E2A, EBF, Pax5, Blimp1, and XbpI. Research on alternative splicing of both the Ikaros and Pax5 genes in rainbow trout is presented, including their functional significance. An application is discussed that should aid in elucidating teleost B cell development and activation, by using transcription factors as developmental markers in flow cytometric analysis. Possible future studies in teleost B cell development are suggested in the context of gene regulation. Lastly, broader impacts and practical applications are discussed. PMID:21251922

  5. Characterization of the B cell response to Leishmania infection after anti-CD20 B cell depletion

    PubMed Central

    Bockenstedt, Marie M; Boggiatto, Paola M; Jones, Douglas E

    2015-01-01

    Anti-CD20 depletion therapies targeting B cells are commonly used in malignant B cell disease and autoimmune diseases. There are concerns about the ability of B cells to respond to infectious diseases acquired either before or after B cell depletion. There is evidence that the B cell response to existing or acquired viral infections is compromised during treatment, as well as the antibody response to vaccination. Our laboratory has an experimental system using co-infection of C3H mice with both Leishmania major and Leishmania amazonensis that suggests that the B cell response is important to healing infected mice. We tested if anti-CD20 treatment would completely restrict the B cell response to these intracellular pathogens. Infected mice that received anti-CD20 B cell depletion therapy had a significant decrease in CD19+ cells within their lymph nodes and spleens. However, splenic B cells were detected in depleted mice and an antigen-specific antibody response was produced. These results indicate that an antigen-specific B cell response towards intracellular pathogens can be generated during anti-CD20 depletion therapy. PMID:26261496

  6. 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 cellpathogen 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 bacterias internalization. The results substantially underline the functional heterogeneity of B cell subsets in relation to F. tularensis. PMID:26161475

  7. Comparative analyses of B cell populations in trout kidney and mouse bone marrow; establishing B cell signatures

    PubMed Central

    Zwollo, Patty; Mott, Katrina; Barr, Maggie

    2010-01-01

    This study aimed to identify the frequency and distribution of developing B cell populations in the kidney of the rainbow trout, using four molecular B cell markers that are highly conserved between species, including two transcription factors, Pax5 and EBF1, recombination activating gene RAG1, and the immunoglobulin heavy chain mu. Three distinct B cell stages were defined: early developing B cells (CLP, pro-B, and early pre-B cells), late developing B cell (late pre-B, immature B, and mature B cells), and IgM-secreting cells. Developmental stage-specific, combinatorial expression of Pax5, EBF1, RAG1 and immunoglobulin mu was determined in trout anterior kidney cells by flow cytometry. Trout staining patterns were compared to a well-defined primary immune tissue, mouse bone marrow, and using mouse surface markers B220 and CD43. A remarkable level of similarity was uncovered between the primary immune tissues of both species. Subsequent analysis of the entire trout kidney, divided into five contiguous segments K1-K5, revealed a complex pattern of early developing, late developing, and IgM-secreting B cells. Patterns in anterior kidney segment K1 were most similar to those of mouse bone marrow, while the most posterior part of the kidney, K5, had many IgM-secreting cells, but lacked early developing B cells. A potential second B lymphopoiesis site was uncovered in segment K4 of the kidney. The B cell patterns, or B cell signatures described here provide information on the relative abundance of distinct developing B cell populations in the trout kidney, and can be used in future studies on B cell development in other vertebrate species. PMID:20705088

  8. Germline CARD11 mutation in a patient with severe congenital B cell lymphocytosis

    PubMed Central

    Brohl, Andrew S.; Stinson, Jeffrey; Su, Helen C.; Badgett, Thomas; Jennings, Chester D.; Sukumar, Gauthaman; Sindiri, Sivasish; Wang, Wei; Kardava, Lela; Moir, Susan; Dalgard, Clifton L.; Moscow, Jeffrey A.; Snow, Andrew L.; Khan, Javed

    2015-01-01

    Purpose Activating germline mutations in CARD11 have recently been linked to a rare genetic disorder associated with congenital B cell lymphocytosis. We describe a patient with a similar clinical phenotype who had a de novo germline G123D CARD11 mutation. Methods Whole exome sequencing was performed on DNA from the patient and his biological parents. Laboratory studies examined characteristics of the patient’s B and T lymphocytes. A CARD11 cDNA containing the mutation was transfected into a lymphocyte cell line to gain an understanding of its function. RNA sequencing was performed on samples from the patient and from patients with alternate germline CARD11 mutations and differential gene expression analysis was performed. Results The patient had a decade-long history of severe polyclonal B lymphocytosis in the 20,000–90,000 lymphocytes/mm3 range, which was markedly exacerbated by EBV infection and splenectomy at different times. He had a heterozygous germline CARD11 mutation causing a G123D amino acid substitution, which was demonstrated to induce NF-κB activation in unstimulated lymphocytes. In contrast to previous patients with CARD11 mutations, this patient’s B cells exhibited higher expression of several cell cycle progression genes, as well as enhanced proliferation and improved survival following B cell receptor stimulation. Conclusions This is the third reported germline and first de novo CARD11 mutation shown to cause congenital B cell lymphocytosis. The mutation was associated with a dramatically greater lymphocytosis than in previously described cases, disproportionate to the level of constitutive NF-κB activation. However, comparative review of the patient’s clinical history, combined with additional genomic and functional analyses, underscore other important variables that may affect pathophysiology or regulate mutant CARD11 function in B cell proliferation and disease. We now refer to these patients as having BENTA disease (B cell Expansion with NF-κB and T cell Anergy). PMID:25352053

  9. 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

  10. Scrapie Pathogenesis in Subclinically Infected B-Cell-Deficient Mice

    PubMed Central

    Frigg, Rico; Klein, Michael A.; Hegyi, Ivan; Zinkernagel, Rolf M.; Aguzzi, Adriano

    1999-01-01

    Prion infections can present without clinical manifestations. B-cell deficiency may be a model for subclinical transmissible spongiform encephalopathy, since it protects mice from disease upon intraperitoneal administration of scrapie prions; however, a proportion of B-cell-deficient mice accumulate protease-resistant prion protein in their brains. Here, we have characterized this subclinical disease. In addition, we have studied the possibility that a neurotoxic factor secreted by B cells may contribute to pathogenesis. PMID:10516067

  11. Scrapie pathogenesis in subclinically infected B-cell-deficient mice.

    PubMed

    Frigg, R; Klein, M A; Hegyi, I; Zinkernagel, R M; Aguzzi, A

    1999-11-01

    Prion infections can present without clinical manifestations. B-cell deficiency may be a model for subclinical transmissible spongiform encephalopathy, since it protects mice from disease upon intraperitoneal administration of scrapie prions; however, a proportion of B-cell-deficient mice accumulate protease-resistant prion protein in their brains. Here, we have characterized this subclinical disease. In addition, we have studied the possibility that a neurotoxic factor secreted by B cells may contribute to pathogenesis. PMID:10516067

  12. B-Cell Lymphopoiesis Is Regulated by Cathepsin L

    PubMed Central

    Badano, Maria Noel; Camicia, Gabriela Lorena; Lombardi, Gabriela; Maglioco, Andrea; Cabrera, Gabriel; Costa, Hector; Meiss, Roberto Pablo

    2013-01-01

    Cathepsin L (CTSL) is a ubiquitously expressed lysosomal cysteine peptidase with diverse and highly specific functions. The involvement of CTSL in thymic CD4+ T-cell positive selection has been well documented. Using CTSLnkt/nkt mice that lack CTSL activity, we have previously demonstrated that the absence of CTSL activity affects the homeostasis of the T-cell pool by decreasing CD4+ cell thymic production and increasing CD8+ thymocyte production. Herein we investigated the influence of CTSL activity on the homeostasis of peripheral B-cell populations and bone marrow (BM) B-cell maturation. B-cell numbers were increased in lymph nodes (LN), spleen and blood from CTSLnkt/nkt mice. Increases in splenic B-cell numbers were restricted to transitional T1 and T2 cells and to the marginal zone (MZ) cell subpopulation. No alterations in the proliferative or apoptosis levels were detected in peripheral B-cell populations from CTSLnkt/nkt mice. In the BM, the percentage and the absolute number of pre-pro-B, pro-B, pre-B, immature and mature B cells were not altered. However, in vitro and in vivo experiments showed that BM B-cell production was markedly increased in CTSLnkt/nkt mice. Besides, BM B-cell emigration to the spleen was increased in CTSLnkt/nkt mice. Colony-forming unit pre-B (CFU pre-B) assays in the presence of BM stromal cells (SC) and reciprocal BM chimeras revealed that both BM B-cell precursors and SC would contribute to sustain the increased B-cell hematopoiesis in CTSLnkt/nkt mice. Overall, our data clearly demonstrate that CTSL negatively regulates BM B-cell production and output therefore influencing the homeostasis of peripheral B cells. PMID:23585893

  13. Perspectives on fetal derived CD5(+) B1 B cells.

    PubMed

    Hardy, Richard R; Hayakawa, Kyoko

    2015-11-01

    CD5(+) B-cell origins and their predisposition to lymphoma are long-standing issues. Transfer of fetal and adult liver BM Pro-B cells generates B cells with distinct phenotypes: fetal cells generate IgM(high) IgD(low) CD5(+) , whereas adult cells IgM(low) IgD(high) CD5(-) . This suggests a developmental switch in B lymphopoiesis, similar to the switch in erythropoiesis. Comparison of mRNA and miRNA expression in fetal and adult Pro-B cells revealed differential expression of Lin28b mRNA and Let-7 miRNA, providing evidence that this regulatory axis functions in the switch. Recent work has shown that Arid3a is a key transcription factor mediating fetal-type B-cell development. Lin28b-promoted fetal development generates CD5(+) B cells as a consequence of positively selected self-reactivity. CD5(+) B cells play important roles in clearance of apoptotic cells and in protective immune responses, but also pose a risk of progression to leukemia/lymphoma. Differential Lin28b expression in fetal and adult human B-cell precursors showed that human B-cell development may resemble mouse, with self-reactive "innate-like" B cells generated early in life. It remains to be determined whether such human B cells have a higher propensity to leukemic progression. This review describes our recent research with CD5(+) B cells and presents our perspective on their role in disease. PMID:26339791

  14. Utilization of a photoactivatable antigen system to examine B-cell probing termination and the B-cell receptor sorting mechanisms during B-cell activation.

    PubMed

    Wang, Jing; Tang, Shan; Wan, Zhengpeng; Gao, Yiren; Cao, Yiyun; Yi, Junyang; Si, Yanyan; Zhang, Haowen; Liu, Lei; Liu, Wanli

    2016-02-01

    Antigen binding to the B-cell receptor (BCR) induces several responses, resulting in B-cell activation, proliferation, and differentiation. However, it has been difficult to study these responses due to their dynamic, fast, and transient nature. Here, we attempted to solve this problem by developing a controllable trigger point for BCR and antigen recognition through the construction of a photoactivatable antigen, caged 4-hydroxy-3-nitrophenyl acetyl (caged-NP). This photoactivatable antigen system in combination with live cell and single molecule imaging techniques enabled us to illuminate the previously unidentified B-cell probing termination behaviors and the precise BCR sorting mechanisms during B-cell activation. B cells in contact with caged-NP exhibited probing behaviors as defined by the unceasing extension of membrane pseudopods in random directions. Further analyses showed that such probing behaviors are cell intrinsic with strict dependence on F-actin remodeling but not on tonic BCR signaling. B-cell probing behaviors were terminated within 4 s after photoactivation, suggesting that this response was sensitive and specific to BCR engagement. The termination of B-cell probing was concomitant with the accumulation response of the BCRs into the BCR microclusters. We also determined the Brownian diffusion coefficient of BCRs from the same B cells before and after BCR engagement. The analysis of temporally segregated single molecule images of both BCR and major histocompatibility complex class I (MHC-I) demonstrated that antigen binding induced trapping of BCRs into the BCR microclusters is a fundamental mechanism for B cells to acquire antigens. PMID:26764382

  15. Genomic instability resulting from Blm-deficiency compromises development, maintenance, and function of the B cell lineage1

    PubMed Central

    Babbe, Holger; McMenamin, Jennifer; Hobeika, Elias; Wang, Jing; Rodig, Scott J.; Reth, Michael; Leder, Philip

    2009-01-01

    The RecQ family helicase BLM is critically involved in the maintenance of genomic stability and BLM mutation causes the heritable disorder, Blooms syndrome. Affected individuals suffer from a predisposition to a multitude of cancer types and an ill-defined immunodeficiency involving low serum antibody titers. To investigate its role in B cell biology, we inactivated murine Blm specifically in B lymphocytes in vivo. Numbers of developing B lymphoid cells in the bone marrow and mature B cells in the periphery were drastically reduced upon Blm-inactivation. Of the major peripheral B cell subsets, B1a cells were most prominently affected. In the sera of Blm-deficient nave mice, concentrations of all Ig isotypes were low, particularly IgG3. Specific IgG antibody responses upon immunization were poor and mutant B cells exhibited a generally reduced antibody class switch-capacity in vitro. We did not find evidence for a crucial role of Blm in the mechanism of class switch recombination. However, a modest shift towards microhomology-mediated switch junction formation was observed in Blm-deficient B cells. Finally, a cohort of p53-deficient, conditional Blm knockout mice revealed an increased propensity for B cell lymphoma development. Impaired cell cycle progression and survival as well as high rates of chromosomal structural abnormalities in mutant B cell blasts was identified as the basis for the observed effects. Collectively, our data highlight the importance of BLM-dependent genome surveillance for B cell immunity by ensuring proper development and function of the various B cell subsets while counteracting lymphomagenesis. PMID:19109166

  16. 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

  17. 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 β-glucosylceramide 22:0 (βGL1-22) 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 βGL1-22– 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, βGL1-22– 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 βGL1-22– 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

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

    PubMed

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

    2015-02-19

    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 β-glucosylceramide 22:0 (βGL1-22) 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 βGL1-22- 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, βGL1-22- 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 βGL1-22- 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

  19. Involvement of B cells in non-infectious uveitis

    PubMed Central

    Smith, Justine R; Stempel, Andrew J; Bharadwaj, Arpita; Appukuttan, Binoy

    2016-01-01

    Non-infectious uveitis—or intraocular inflammatory disease—causes substantial visual morbidity and reduced quality of life amongst affected individuals. To date, research of pathogenic mechanisms has largely been focused on processes involving T lymphocyte and/or myeloid leukocyte populations. Involvement of B lymphocytes has received relatively little attention. In contrast, B-cell pathobiology is a major field within general immunological research, and large clinical trials have showed that treatments targeting B cells are highly effective for multiple systemic inflammatory diseases. B cells, including the terminally differentiated plasma cell that produces antibody, are found in the human eye in different forms of non-infectious uveitis; in some cases, these cells outnumber other leukocyte subsets. Recent case reports and small case series suggest that B-cell blockade may be therapeutic for patients with non-infectious uveitis. As well as secretion of antibody, B cells may promote intraocular inflammation by presentation of antigen to T cells, production of multiple inflammatory cytokines and support of T-cell survival. B cells may also perform various immunomodulatory activities within the eye. This translational review summarizes the evidence for B-cell involvement in non-infectious uveitis, and considers the potential contributions of B cells to the development and control of the disease. Manipulations of B cells and/or their products are promising new approaches to the treatment of non-infectious uveitis. PMID:26962453

  20. B-cell targeted therapeutics in clinical development.

    PubMed

    Blml, Stephan; McKeever, Kathleen; Ettinger, Rachel; Smolen, Josef; Herbst, Ronald

    2013-01-01

    B lymphocytes are the source of humoral immunity and are thus a critical component of the adaptive immune system. However, B cells can also be pathogenic and the origin of disease. Deregulated B-cell function has been implicated in several autoimmune diseases, including systemic lupus erythematosus, rheumatoid arthritis, and multiple sclerosis. B cells contribute to pathological immune responses through the secretion of cytokines, costimulation of T cells, antigen presentation, and the production of autoantibodies. DNA-and RNA-containing immune complexes can also induce the production of type I interferons, which further promotes the inflammatory response. B-cell depletion with the CD20 antibody rituximab has provided clinical proof of concept that targeting B cells and the humoral response can result in significant benefit to patients. Consequently, the interest in B-cell targeted therapies has greatly increased in recent years and a number of new biologics exploiting various mechanisms are now in clinical development. This review provides an overview on current developments in the area of B-cell targeted therapies by describing molecules and subpopulations that currently offer themselves as therapeutic targets, the different strategies to target B cells currently under investigation as well as an update on the status of novel therapeutics in clinical development. Emerging data from clinical trials are providing critical insight regarding the role of B cells and autoantibodies in various autoimmune conditions and will guide the development of more efficacious therapeutics and better patient selection. PMID:23566679

  1. B-cell-targeted therapies in systemic lupus erythematosus

    PubMed Central

    Chan, Vera Sau-Fong; Tsang, Helen Hoi-Lun; Tam, Rachel Chun-Yee; Lu, Liwei; Lau, Chak-Sing

    2013-01-01

    Autoreactive B cells are one of the key immune cells that have been implicated in the pathogenesis of systemic lupus erythematosus (SLE). In addition to the production of harmful auto-antibodies (auto-Abs), B cells prime autoreactive T cells as antigen-presenting cells and secrete a wide range of pro-inflammatory cytokines that have both autocrine and paracrine effects. Agents that modulate B cells may therefore be of potential therapeutic value. Current strategies include targeting B-cell surface antigens, cytokines that promote B-cell growth and functions, and B- and T-cell interactions. In this article, we review the role of B cells in SLE in animal and human studies, and we examine previous reports that support B-cell modulation as a promising strategy for the treatment of this condition. In addition, we present an update on the clinical trials that have evaluated the therapeutic efficacy and safety of agents that antagonize CD20, CD22 and B-lymphocyte stimulator (BLyS) in human SLE. While the results of many of these studies remain inconclusive, belimumab, a human monoclonal antibody against BLyS, has shown promise and has recently been approved by the US Food and Drug Administration as an indicated therapy for patients with mild to moderate SLE. Undoubtedly, advances in B-cell immunology will continue to lead us to a better understanding of SLE pathogenesis and the development of novel specific therapies that target B cells. PMID:23455017

  2. 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

  3. RHOF PROMOTES MURINE MARGINAL ZONE B CELL DEVELOPMENT

    PubMed Central

    KISHIMOTO, MAYUKO; MATSUDA, TAKENORI; YANASE, SHOUGO; KATSUMI, AKIRA; SUZUKI, NOBUAKI; IKEJIRI, MAKOTO; TAKAGI, AKIRA; IKAWA, MASAHITO; KOJIMA, TETSUHITO; KUNISHIMA, SHINJI; KIYOI, HITOSHI; NAOE, TOMOKI; MATSUSHITA, TADASHI; MARUYAMA, MITSUO

    2014-01-01

    ABSTRACT RhoF is a member of the Rho GTPase family that has been implicated in various cell functions including long filopodia formation, adhesion, and migration of cells. Although RhoF is expressed in lymphoid tissues, the roles of RhoF in B cell development remain largely unclear. On the other hand, other members of the Rho GTPase family, such as Cdc42, RhoA, and Rac, have been intensively studied and are known to be required for B cell development in the bone marrow and spleen. We hypothesized that RhoF is also involved in B cell development. To examine our hypothesis, we analyzed B cell development in RhoF knockout (KO) mice and found a significant reduction in marginal zone (MZ) B cells in the spleen, although T cell development in the thymus and spleen was not affected. Consistent with these results, the width of the MZ B cell region in the spleen was significantly reduced in the RhoF KO mice. However, the antigen-specific antibody titer of IgM and IgG3 after MZ B cell-specific antigen (T cell-independent antigen, type I) stimulation was not affected by RhoF deletion. Furthermore, we demonstrated that RhoF was dispensable for stromal cell-derived factor-1α- and B lymphocyte chemoattractant-induced B cell migration. These results suggest that RhoF promotes MZ B cell development in the spleen. PMID:25741038

  4. Orchestrating B cell lymphopoiesis through interplay of IL-7 receptor and pre-B cell receptor signalling

    PubMed Central

    Clark, Marcus R.; Mandal, Malay; Ochiai, Kyoko; Singh, Harinder

    2014-01-01

    The development of B cells is dependent on the sequential DNA rearrangement of immunoglobulin loci that encode subunits of the B cell receptor. The pathway navigates a crucial checkpoint that ensures expression of a signalling-competent immunoglobulin heavy chain before commitment to rearrangement and expression of an immunoglobulin light chain. The checkpoint segregates proliferation of pre-B cells from immunoglobulin light chain recombination and their differentiation into B cells. Recent advances have revealed the molecular circuitry that controls two rival signalling systems, namely the interleukin-7 (IL-7) receptor and the pre-B cell receptor, to ensure that proliferation and immunoglobulin recombination are mutually exclusive, thereby maintaining genomic integrity during B cell development. PMID:24378843

  5. Clinical consequences of defects in B-cell development.

    PubMed

    Vale, Andre M; Schroeder, Harry W

    2010-04-01

    Abnormalities in humoral immunity typically reflect a generalized or selective failure of effective B-cell development. The developmental processes can be followed through analysis of cell-surface markers, such as IgM, IgD, CD10, CD19, CD20, CD21, and CD38. Early phases of B-cell development are devoted to the creation of immunoglobulin and testing of B-cell antigen receptor signaling. Failure leads to the absence of B cells and immunoglobulin in the blood from birth. As the developing B cells begin to express a surface B-cell receptor, they become subject to negative and positive selection pressures and increasingly depend on survival signals. Defective signaling can lead to selective or generalized hypogammaglobulinemia, even in the presence of normal numbers of B cells. In the secondary lymphoid organs some B cells enter the splenic marginal zone, where preactivated cells lie ready to rapidly respond to T-independent antigens, such as the polysaccharides that coat some microorganisms. Other cells enter the follicle and, with the aid of cognate follicular T cells, divide to help form a germinal center (GC) after their interaction with antigen. In the GC B cells can undergo the processes of class switching and somatic hypermutation. Failure to properly receive T-cell signals can lead to hyper-IgM syndrome. B cells that leave the GC can develop into memory B cells, short-lived plasma cells, or long-lived plasma cells. The latter ultimately migrate back to the bone marrow, where they can continue to produce protective antigen-specific antibodies for decades. PMID:20371392

  6. Stemness of B cell progenitors in multiple myeloma bone marrow

    PubMed Central

    Boucher, Kelly; Parquet, Nancy; Widen, Raymond; Shain, Kenneth; Baz, Rachid; Alsina, Melissa; Koomen, John; Anasetti, Claudio; Dalton, William; Perez, Lia E.

    2012-01-01

    Purpose In myeloma, B cells and plasma cells show a clonal relationship. Clonotypic B cells may represent a tumor-initiating compartment or cancer stem cell responsible for minimal residual disease in myeloma. Experimental Design We report a study of 58 patients with myeloma at time of diagnosis or relapse. B cells in bone marrow were evaluated by multicolor flow cytometry and sorting. Clonality was determined by light chain and/or immunoglobulin chain gene rearrangement PCR. We also determined aldehyde dehydrogenase activity and colony formation growth. Drug sensitivity was tested with conventional and novel agents. Results Marrow CD19+ cells express a light chain identical to plasma cells and are therefore termed light chain restricted (LCR). The LCR B cell mass is small in both newly diagnosed and relapsed patients (?1%). Few marrow LCR B cells (~10%) are CD19+/CD34+, with the rest being more differentiated CD19+/CD34? B cells. Marrow LCR CD19+ B cells exhibit enhanced aldehyde dehydrogenase activity versus healthy controls. Both CD19+/CD34+ and CD19+/CD34? cells showed colony formation activity, with colony growth efficiency optimized when stroma-conditioned medium was used. B cell progenitors showed resistance to melphalan, lenalidomide, and bortezomib. Panobinostat, a histone deacetylase inhibitor, induced apoptosis of LCR B cells and CD138+ cells. LCR B cells are CD117, survivin, and Notch positive. Conclusions We propose that antigen-independent B cell differentiation stages are involved in disease origination and progression in myeloma. Further investigations of myeloma putative stem cell progenitors may lead to novel treatments to eradicate the potential reservoir of minimal residual disease. PMID:22988056

  7. CR2 ligands modulate human B cell activation.

    PubMed

    Bohnsack, J F; Cooper, N R

    1988-10-15

    A considerable body of evidence from this and other laboratories indicates that complement receptor type 2 (CR2) modulates B cell activation and growth. In the present studies we have examined the effects of three different types of CR2 ligands, i.e., monomeric, aggregated, and latex-bound C3dg; mAb to different CR2 epitopes; and UV-inactivated, non-transforming EBV (EBVUV) for their actions on highly purified, high density resting tonsil B cells. Although none of these ligands induced B cells to enter the cell cycle or synergized with either anti-mu or low m.w. B cell growth factor in triggering B cell mitogenesis, aggregated C3dg, latex-bound C3dg, the OKB7 anti-CR2 mAb, and EBVUV-enhanced thymidine incorporation by phorbol ester-activated tonsil B cells. Such enhancement was not T cell or monocyte dependent. The major action of the CR2 ligands thus seems to be to enhance the transition of B cells activated by certain stimuli from the G1 to the S phase of the cell cycle. In contrast to the action of aggregated and latex-bound C3dg, monomeric C3dg was inhibitory for phorbol ester and aggregated C3dg-induced B cell activation. The HB-5 anti-CR2 mAb, which reacts with a different epitope on CR2 from that of OKB7, did not synergize with PMA in B cell activation. These data provide additional evidence for a role for the CR2 in the control of B cell growth and provide a useful model for studying the CR2-mediated signals that affect the growth of B cells. PMID:2459218

  8. B-Cell-Mediated Strategies to Fight Chronic Allograft Rejection

    PubMed Central

    Dalloul, Ali

    2013-01-01

    Solid organs have been transplanted for decades. Since the improvement in graft selection and in medical and surgical procedures, the likelihood of graft function after 1?year is now close to 90%. Nonetheless even well-matched recipients continue to need medications for the rest of their lives hence adverse side effects and enhanced morbidity. Understanding Immune rejection mechanisms, is of increasing importance since the greater use of living-unrelated donors and genetically unmatched individuals. Chronic rejection is devoted to T-cells, however the role of B-cells in rejection has been appreciated recently by the observation that B-cell depletion improve graft survival. By contrast however, B-cells can be beneficial to the grafted tissue. This protective effect is secondary to either the secretion of protective antibodies or the induction of B-cells that restrain excessive inflammatory responses, chiefly by local provision of IL-10, or inhibit effector T-cells by direct cellular interactions. As a proof of concept B-cell-mediated infectious transplantation tolerance could be achieved in animal models, and evidence emerged that the presence of such B-cells in transplanted patients correlate with a favorable outcome. Among these populations, regulatory B-cells constitute a recently described population. These cells may develop as a feedback mechanism to prevent uncontrolled reactivity to antigens and inflammatory stimuli. The difficult task for the clinician, is to quantify the respective ratios and functions of tolerant vs. effector B-cells within a transplanted organ, at a given time point in order to modulate B-cell-directed therapy. Several receptors at the B-cell membrane as well as signaling molecules, can now be targeted for this purpose. Understanding the temporal expansion of regulatory B-cells in grafted patients and the stimuli that activate them will help in the future to implement specific strategies aimed at fighting chronic allograft rejection. PMID:24381571

  9. Btk levels set the threshold for B-cell activation and negative selection of autoreactive B cells in mice.

    PubMed

    Kil, Laurens P; de Bruijn, Marjolein J W; van Nimwegen, Menno; Corneth, Odilia B J; van Hamburg, Jan Piet; Dingjan, Gemma M; Thaiss, Friedrich; Rimmelzwaan, Guus F; Elewaut, Dirk; Delsing, Dianne; van Loo, Pieter Fokko; Hendriks, Rudi W

    2012-04-19

    On antigen binding by the B-cell receptor (BCR), B cells up-regulate protein expression of the key downstream signaling molecule Bruton tyrosine kinase (Btk), but the effects of Btk up-regulation on B-cell function are unknown. Here, we show that transgenic mice overexpressing Btk specifically in B cells spontaneously formed germinal centers and manifested increased plasma cell numbers, leading to antinuclear autoantibody production and systemic lupus erythematosus (SLE)-like autoimmune pathology affecting kidneys, lungs, and salivary glands. Autoimmunity was fully dependent on Btk kinase activity, because Btk inhibitor treatment (PCI-32765) could normalize B-cell activation and differentiation, and because autoantibodies were absent in Btk transgenic mice overexpressing a kinase inactive Btk mutant. B cells overexpressing wild-type Btk were selectively hyperresponsive to BCR stimulation and showed enhanced Ca(2+) influx, nuclear factor (NF)-?B activation, resistance to Fas-mediated apoptosis, and defective elimination of selfreactive B cells in vivo. These findings unravel a crucial role for Btk in setting the threshold for B-cell activation and counterselection of autoreactive B cells, making Btk an attractive therapeutic target in systemic autoimmune disease such as SLE. The finding of in vivo pathology associated with Btk overexpression may have important implications for the development of gene therapy strategies for X-linked agammaglobulinemia, the immunodeficiency associated with mutations in BTK. PMID:22383797

  10. [Acquired angioedema with C1-INH deficiency and accompanying chronic spontaneous urticaria in a patient with chronic lymphatic B cell leukemia].

    PubMed

    Klossowski, N; Braun, S A; von Gruben, V; Losem, C; Plewe, D; Homey, B; Meller, S

    2015-10-01

    Acquired angioedema due to C1 inhibitor deficiency (C1-INH-AAE) is characterized by recurrent edema of the subcutaneous and/or submucosal tissue without wheals and negative family history of angioedema. Here, we present the case of a patient with a chronic lymphatic B cell leukemia who suffered from both C1-INH-AAE and chronic spontaneous urticaria. Oral corticosteroids, antihistamines, and the anti-IgE antibody omalizumab were applied to treat the chronic urticaria in combination with the plasma-derived C1 esterase inhibitor concentrate Berinert® and the bradykinin B2 receptor antagonist icatibant, but the symptoms did not improved significantly. Thus, polychemotherapy targeting the slow-growing lymphoproliferative disease including rituximab was initiated, which resulted in remission of both the urticaria and the angioedema. PMID:26335859

  11. Role and regulation of CD1d in normal and pathological B cells

    PubMed Central

    Chaudhry, Mohammed S.; Karadimitris, Anastasios

    2015-01-01

    CD1d is a non-polymorphic, MHC class I-like molecule, which presents phosphoand glycosphingo-lipid antigens to a subset of CD1d-restricted T cells called invariant NKT (iNKT) cells. This CD1d-iNKT cell axis regulates nearly all aspects of both the innate and adaptive immune response. Expression of CD1d on B cells is suggestive of the ability of these cells to present antigen to and form cognate interactions with iNKT cells. Herein we summarise key evidence regarding the role and regulation of CD1d in normal B cells and in humoral immunity. We then extend the discussion to B cell disorders, with emphasis on autoimmune disease, viral infection and neoplastic transformation of B lineage cells, where CD1d expression can be altered as a mechanism of immune evasion, and can have both diagnostic and prognostic importance. Finally we highlight current and future therapeutic strategies that aim to target the CD1d-iNKT axis in B cells. PMID:25381357

  12. Regulation of B-cell entry into the cell cycle.

    PubMed

    Richards, Sabrina; Watanabe, Chie; Santos, Lorna; Craxton, Andrew; Clark, Edward A

    2008-08-01

    B cells are induced to enter the cell cycle by stimuli including ligation of the B-cell receptor (BCR) complex and Toll-like receptor (TLR) agonists. This review discusses the contribution of several molecules, which act at distinct steps in B-cell activation. The adapter molecule Bam32 (B-lymphocyte adapter of 32 kDa) helps promote BCR-induced cell cycle entry, while the secondary messenger superoxide has the opposite effect. Bam32 and superoxide may fine tune BCR-induced activation by competing for the same limited resources, namely Rac1 and the plasma membrane phospholipid PI(3,4)P(2). The co-receptor CD22 can inhibit BCR-induced proliferation by binding to novel CD22 ligands. Finally, regulators of B-cell survival and death also play roles in B-cell transit through the cell cycle. Caspase 6 negatively regulates CD40- and TLR-dependent G(1) entry, while acting later in the cell cycle to promote S-phase entry. Caspase 6 deficiency predisposes B cells to differentiate rather than proliferate after stimulation. Bim, a pro-apoptotic Bcl-2 family member, exerts a positive regulatory effect on cell cycle entry, which is opposed by Bcl-2. New insights into what regulates B-cell transit through the cell cycle may lead to thoughtful design of highly selective drugs that target pathogenic B cells. PMID:18759927

  13. Suppressive functions of B cells in infectious diseases.

    PubMed

    Shen, Ping; Fillatreau, Simon

    2015-10-01

    B lymphocytes are often essential to successfully control invading pathogens and play a primary role in the protection afforded by successful vaccines through the production of specific antibodies. However, recent studies have highlighted the complex roles of B cells in infectious diseases, showing unexpectedly that some activated B cells limited host defense towards pathogens. This B-cell function involves production of regulatory cytokines including IL-10 and IL-35 and is reminiscent of the regulatory functions of B cells initially defined in autoimmune diseases. It is now known that various types of microbes including bacteria, helminths and viruses can induce IL-10-expressing B cells with inhibitory functions, indicating that this response is a general component of anti-microbial immunity. Interestingly, IL-10-producing B cells induced in the course of some microbial infections can inhibit concurrent immune responses directed towards unrelated antigens in a bystander manner and as a consequence ameliorate the course of autoimmune or allergic diseases. This could explain how some micro-organisms might provide protection from these pathologies, as formulated in the 'hygiene hypothesis'. In this review, we discuss the regulatory functions of B cells in bacterial, parasitic and viral infections, taking into account the phenotype of the B cells implicated, the signals controlling their induction and the cell types targeted by their suppressive activities. PMID:26066008

  14. B Cells: The Old New Players in Reproductive Immunology

    PubMed Central

    Fettke, Franziska; Schumacher, Anne; Costa, Serban-Dan; Zenclussen, Ana Claudia

    2014-01-01

    Reproductive immunology research has long focused on T cell responses to paternal antigens and tolerance mechanisms supporting fetal well-being. The participation of B cells herein was not widely studied. Because of the fascinating immunological uniqueness of pregnancy, it is however to be expected that such pleiotropic cells play a considerable role. In fact, on the one hand B cells contribute toward pregnancy tolerance by secreting the immunomodulatory cytokine IL-10 but on the other hand can seriously harm pregnancy because of their capacity of producing autoantibodies. As for protective B cells, new evidences in mouse models arise suggesting that IL-10 producing B cells, the so-called B10 cells, help in maintaining tolerance toward semi-allogenic fetal antigens. They may be also important to fight danger signals at the fetal-maternal interface as, e.g., in the case of infections with the aim to restore the disrupted fetal tolerance. In human pregnancies, IL-10 producing B cells increase with pregnancy onset but not in the case of spontaneous abortions. In vitro, they are able to suppress TNF-? production by T cells from pregnant individuals. Their generation and functionality will be discussed throughout this review article. B cells can be deleterious to pregnancy as well. Aberrant B cell compartment is associated with obstetric pathologies. In particular, the capacity of B2 cells to produce specific autoantibodies or of B-1a B cells to secrete natural autoantibodies that can turn autoreactive will be discussed herein. PMID:25002862

  15. Leukemia - B-Cell Prolymphocytic Leukemia and Hairy Cell Leukemia

    MedlinePLUS

    ... Chronic lymphocytic leukemia (CLL) Acute myeloid leukemia (AML) Chronic myeloid leukemia (CML) About PLL and HCL There are other, less common types of leukemia, but they are generally subcategories of one ... both of which are types of chronic B-cell leukemia. B cells are a specific ...

  16. DNA breaks early in replication in B cell cancers

    Cancer.gov

    Research by scientists at the NCI has identified a new class of DNA sites in cells that break early in the replication process. They found that these break sites correlate with damage often seen in B cell cancers, such as diffuse large B cell lymphoma.

  17. Subcutaneous Dissemination from an Orbital Diffuse Large B Cell Lymphoma.

    PubMed

    Bains, Sukhdeep; Vidhya, N; Kim, Usha; Shanti, R; Devanand, J

    2015-12-01

    Secondary cutaneous dissemination from an orbital diffuse large B cell lymphoma has not been described before. The authors report an unusual case of anaplastic variant of diffuse large B cell lymphoma which primarily presented in the orbit and during the course of disease had subcutaneous dissemination. PMID:26452055

  18. 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-β), 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-β. To identify gene expression changes and pathways induced by IFN-β 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-β exposure, with over 50 previously unrecognized as IFN-β response genes. Pathways analysis demonstrated that IFN-β affected LCLs in a similar manner to other cell types by activating known IFN-β canonical pathways. Additionally, IFN-β 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-β response genes in primary B cells. In this study new IFN-β 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

  19. Gene expression profiling of the response to interferon beta in Epstein-Barr-transformed and primary B cells of patients with multiple sclerosis.

    PubMed

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

    2014-01-01

    The effects of interferon-beta (IFN-β), 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-β. To identify gene expression changes and pathways induced by IFN-β 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-β exposure, with over 50 previously unrecognized as IFN-β response genes. Pathways analysis demonstrated that IFN-β affected LCLs in a similar manner to other cell types by activating known IFN-β canonical pathways. Additionally, IFN-β 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-β response genes in primary B cells. In this study new IFN-β 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

  20. CD21 -/low B cells: A Snapshot of a Unique B Cell Subset in Health and Disease.

    PubMed

    Thorarinsdottir, K; Camponeschi, A; Gjertsson, I; Mrtensson, I-L

    2015-09-01

    B cells represent one of the cellular components of the immune system that protects the individual from invading pathogens. In response to the invader, these cells differentiate into plasma cells and produce large amounts of antibodies that bind to and eliminate the pathogen. A hallmark of autoimmune diseases is the production of autoantibodies i.e. antibodies that recognize self. Those that are considered pathogenic can damage tissues and organs, either by direct binding or when deposited as immune complexes. For decades, B cells have been considered to play a major role in autoimmune diseases by antibody production. However, as pathogenic autoantibodies appear to derive mainly from T cell dependent responses, T cells have been the focus for many years. The successful treatment of patients with autoimmune diseases with either B cell depletion therapy (rituximab) or inhibition of B cell survival (belimumab), suggested that not only the autoantibodies but also other B cell features are important. This has caused a surge of interest in B cells and their biology resulting in the identification of various subsets e.g. regulatory B cells, several memory B cell subsets etc. Also, in other conditions such as chronic viral infections and primary immunodeficiency, several B cell subsets with unique characteristics have been identified. In this review, we will discuss one of these subsets, a subset that is expanded in conditions characterized by chronic immune stimulation. This B cell subset lacks, or expresses low, surface levels of the complement receptor 2 (CD21) and has therefore been termed CD21(-/low) B cells. PMID:26119182

  1. Molecular Mechanisms of B Cell Antigen Gathering and Endocytosis.

    PubMed

    Hoogeboom, Robbert; Tolar, Pavel

    2016-01-01

    Generation of high-affinity, protective antibodies requires B cell receptor (BCR) signaling, as well as antigen internalization and presentation to helper T cells. B cell antigen internalization is initiated by antigen capture, either from solution or from immune synapses formed on the surface of antigen-presenting cells, and proceeds via clathrin-dependent endocytosis and intracellular routing to late endosomes. Although the components of this pathway are still being discovered, it has become clear that antigen internalization is actively regulated by BCR signaling at multiple steps and, vice versa, that localization of the BCR along the endocytic pathway modulates signaling. Accordingly, defects in BCR internalization or trafficking contribute to enhanced B cell activation in models of autoimmune diseases and in B cell lymphomas. In this review, we discuss how BCR signaling complexes regulate each of the steps of this endocytic process and why defects along this pathway manifest as hyperactive B cell responses in vivo. PMID:26336965

  2. Helper T cell-regulated B cell immunity.

    PubMed

    McHeyzer-Williams, L J; Malherbe, L P; McHeyzer-Williams, M G

    2006-01-01

    In this review, we will discuss the cascade of cellular and molecular events in the immune response to protein antigens that regulate the development of high-affinity B cell memory. The behavior of antigen-experienced pMHCII+ dendritic cells DCs and the dynamics of their interaction with specific T-helper (Th) cells define the first developmental checkpoint for adaptive immunity in vivo. Recent studies provide insight into the basis of Th cell clonal selection and the requirements and consequences of antigen priming in this responsive Th cell compartment. Antigen-specific Th cells expand to become the cognate regulators of effector B cell responses and initiators of the germinal center reaction and memory B cell development. We will discuss the development and role of these diverse mixtures of antigen-specific B cells in the control of B cell memory and long-term humoral immunity that underpin effective protein vaccination. PMID:17048705

  3. B cells and Autoantibodies: Complex Roles in CNS Injury

    PubMed Central

    Ankeny, Daniel P.; Popovich, Phillip G.

    2010-01-01

    Emerging data indicate that traumatic injury to the brain or spinal cord activates B lymphocytes, culminating in the production of antibodies specific for antigens found within and outside the central nervous system (CNS). In this article, we summarize what is known about the effects of CNS injury on B cells. We outline the potential mechanisms for CNS trauma-induced B cell activation and discuss the potential consequences of these injury-induced B cell responses. Based on recent data, we hypothesize that a subset of autoimmune B cell responses initiated by CNS injury are pathogenic and that targeted inhibition of B cells could improve recovery in brain and spinal cord injured patients. PMID:20691635

  4. Novel Pharmacotherapies for B-Cell Lymphomas and Leukemias.

    PubMed

    Tees, Michael T; Sokol, Lubomir

    2016-01-01

    Novel pharmacotherapeutic agents were recently approved for treatment of low-grade B-cell neoplasms, and many other agents are under investigation. Several agents have demonstrated impressive activity in targeting malignant B-cell processes and specific pathways, all with the potential to expand our ability to effectively treat B-cell malignancies. The inhibitors of several cell regulatory proteins, including Bruton tyrosine kinase (Btk), phosphoinositide 3-kinase (PI3-K), B-cell lymphoma/leukemia-2 (Bcl-2), and histone deacetylases, as well as immunomodulatory agents are a few of the many pharmacotherapeutic agents under study. A comprehensive review and assessment is presented of the current pharmacotherapies under investigation targeting B-cell lymphomas and leukemias. PMID:25549076

  5. Role of B cells in common variable immune deficiency

    PubMed Central

    Ahn, Sam; Cunningham-Rundles, Charlotte

    2010-01-01

    Common variable immune deficiency is a heterogeneous immune deficiency characterized by reduced serum immunoglobulins and a lack of antibodies. As the name implies, B-cell defects are variably defective. In particular, peripheral blood isotype-switched CD27+ memory B cells are reduced in number and have been the basis of several classification schemes. A lack of these B cells has been associated with selected clinical conditions, including immune cytopenias, splenomegaly, granulomatous disease and lymphadenopathy. Genetic defects in ICOS, CD19 and TACI have been described. In addition to defects in the production or survival of memory B cells, in most subjects, B cells have defects in Toll-like receptor signaling. PMID:20477641

  6. Thymic B Cells and Central T Cell Tolerance.

    PubMed

    Yamano, Tomoyoshi; Steinert, Madlen; Klein, Ludger

    2015-01-01

    Central T cell tolerance is believed to be mainly induced by thymic dendritic cells and medullary thymic epithelial cells. The thymus also harbors substantial numbers of B cells. These may arise though intrathymic B lymphopoiesis or immigration from the bloodstream. Importantly, and in contrast to resting "mainstream" B cells in the periphery, thymic B cells display elevated levels of MHC class II and constitutively express CD80. Arguably, their most unexpected feature is the expression of autoimmune regulator. These unique features of thymic B cells result from a licensing process that involves cross-talk with CD4 single-positive T cells and CD40 signaling. Together, these recent findings suggest that B cells play a more prominent role as thymic APCs than previously appreciated. PMID:26257742

  7. BCR and co-receptor crosstalk facilitate the positive selection of self-reactive transitional B cells.

    PubMed

    Metzler, Genita; Kolhatkar, Nikita S; Rawlings, David J

    2015-12-01

    The establishment of a diverse B cell repertoire requires fine-tuning of antigen receptor selection during development in order to permit sufficient diversity while reducing the potential for autoimmunity. In this review, we highlight recent studies demonstrating the central role of the B cell antigen receptor (BCR), in coordination with other key pro-survival signals mediated by CD40, BAFF-R, TACI and/or TLRs, in regulating both negative and positive selection of autoreactive B cells. In particular, we show how altered antigen or co-stimulatory signaling can facilitate positive selection of transitional B cells with self-reactive BCRs, ultimately leading to their entry into the mature, naive B cell compartment. We propose a model wherein altered receptor signals (due to inherited genetic changes) leads: first, to enhanced positive selection of autoreactive cells into the nave B cell repertoire; subsequently, to an increased probability of pathogenic germinal center responses in individuals with a broad range of autoimmune disorders. PMID:26605835

  8. 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

  9. ATM deficiency promotes development of murine B-cell lymphomas that resemble diffuse large B-cell lymphoma in humans.

    PubMed

    Hathcock, Karen S; Padilla-Nash, Hesed M; Camps, Jordi; Shin, Dong-Mi; Triner, Daniel; Shaffer, Arthur L; Maul, Robert W; Steinberg, Seth M; Gearhart, Patricia J; Staudt, Louis M; Morse, Herbert C; Ried, Thomas; Hodes, Richard J

    2015-11-12

    The serine-threonine kinase ataxia-telangiectasia mutated (ATM) plays a central role in maintaining genomic integrity. In mice, ATM deficiency is exclusively associated with T-cell lymphoma development, whereas B-cell tumors predominate in human ataxia-telangiectasia patients. We demonstrate in this study that when T cells are removed as targets for lymphomagenesis and as mediators of immune surveillance, ATM-deficient mice exclusively develop early-onset immunoglobulin M(+) B-cell lymphomas that do not transplant to immunocompetent mice and that histologically and genetically resemble the activated B cell-like (ABC) subset of human diffuse large B-cell lymphoma (DLBCL). These B-cell lymphomas show considerable chromosomal instability and a recurrent genomic amplification of a 4.48-Mb region on chromosome 18 that contains Malt1 and is orthologous to a region similarly amplified in human ABC DLBCL. Of importance, amplification of Malt1 in these lymphomas correlates with their dependence on nuclear factor (NF)-?B, MALT1, and B-cell receptor (BCR) signaling for survival, paralleling human ABC DLBCL. Further, like some human ABC DLBCLs, these mouse B-cell lymphomas also exhibit constitutive BCR-dependent NF-?B activation. This study reveals that ATM protects against development of B-cell lymphomas that model human ABC DLBCL and identifies a potential role for T cells in preventing the emergence of these tumors. PMID:26400962

  10. Common patterns of B cell perturbation and expanded V4-34 immunoglobulin gene usage in autoimmunity and infection.

    PubMed

    Mockridge, C Ian; Rahman, Anisur; Buchan, Sarah; Hamblin, Terry; Isenberg, David A; Stevenson, Freda K; Potter, Kathleen N

    2004-02-01

    Features of the lymphocyte population in systemic lupus erythematosus (SLE) include a disordered B cell profile and production of autoantibodies. An additional distinctive perturbation is the overexpression of V4-34-encoded serum immunoglobulins (Ig). A similar rise in V4-34-encoded Ig occurs in normal subjects following infection with certain herpesviruses, and is found in Epstein-Barr virus (EBV)-associated infectious mononucleosis (IM). To assess common and distinctive features of B cells in patients with SLE and IM, we compared the B cell profile and V4-34 gene involvement in patients with SLE and IM. B cell profiles from patients with IM paralleled those of patients with SLE, showing a differential loss of nave and memory B cells and the maintenance of plasmablast/early plasma cells. Class-switched V4-34-encoded IgG from plasmablast/early plasma cells was evident both in patients with SLE and IM and revealed common features of oligoclonal expansions with most having undergone somatic hypermutation. It has been proposed that, in healthy individuals, expression of the V4-34 gene is specifically censored prior to isotype switch as a control on autoreactivity. If so, censoring is bypassed following EBV infection, after which equilibrium is restored. Continuing high serum levels in SLE may arise either by disordered regulation, or by subclinical reactivation of endogenous virus. PMID:15115306

  11. Conditional inactivation of p53 in mature B cells promotes generation of nongerminal center-derived B-cell lymphomas

    PubMed Central

    Gostissa, Monica; Bianco, Julia M.; Malkin, Daniel J.; Kutok, Jeffery L.; Rodig, Scott J.; Morse, Herbert C.; Bassing, Craig H.; Alt, Frederick W.

    2013-01-01

    The p53 tumor suppressor exerts a central role in protecting cells from oncogenic transformation. Accordingly, the p53 gene is mutated in a large number of human cancers. In mice, germ-line inactivation of p53 confers strong predisposition to development of different types of malignancies, but the early onset of thymic lymphomas in the majority of the animals prevents detailed studies of tumorigenesis in other tissues. Here, we use the Cre/Lox approach to inactivate p53 in mature B cells in mice (referred to as CP B cells) and find that such p53 inactivation results in the routine development of IgM-positive CP peripheral B-cell lymphomas. The CP lymphomas generally appear to arise, even in mice subjected to immunization protocols to activate germinal center reaction, from naive B cells that had not undergone immunoglobulin (Ig) heavy chain gene class switching or somatic hypermutation. In contrast to thymic lymphomas that arise in p53-deficient mice, which generally lack clonal translocations, nearly all analyzed CP B-cell tumors carried clonal translocations. However, in contrast to spontaneous translocations in other mouse B-cell tumor models, CP B-cell tumor translocations were not recurrent and did not involve Ig loci. Therefore, CP tumors might provide models for human lymphomas lacking Ig translocations, such as splenic marginal zone B-cell lymphoma or Waldenstrom macroglobulinemia. Our studies indicate that deletion of p53 is sufficient to trigger transformation of mature B cells and support the notion that p53 deficiency may allow accumulation of oncogenic translocations in B cells. PMID:23382223

  12. The Relationship between B-cell Epitope and Mimotope Sequences.

    PubMed

    Zhang, Chunhua; Li, Yunyun; Tang, Weina; Zhou, Zhiguo; Sun, Pingping; Ma, Zhiqiang

    2016-01-01

    B-cell epitope is a group of residues which is on the surface of an antigen. It invokes humoral responses. Locating B-cell epitope is important for effective vaccine design, and the development of diagnostic reagents. Mimotope-based B-cell epitope prediction method is a kind of conformational B-cell epitope prediction, and the core idea of the method is mapping the mimotope sequences which are obtained from a random phage display library. However, current mimotope-based B-cell epitope prediction methods cannot maintain a high degree of satisfaction in the circumstances of employing only mimotope sequences. In this study, we did a multi-perspective analysis on parameters for conformational B-cell epitopes and characteristics between epitope and mimotope on a benchmark datasets which contains 67 mimotope sets, corresponding to 40 unique complex structures. In these 67 cases, there are 25 antigen-antibody complexes and 42 protein-protein interactions. We analyzed the two parts separately. The results showed the mimotope sequences do have some epitope features, but there are also some epitope properties that mimotope sequences do not contain. In addition, the numbers of epitope segments with different lengths were obviously different between the antigen-antibody complexes and the protein-protein interactions. This study reflects how similar do mimotope sequence and genuine epitopes have; and evaluates existing mimotope-based B-cell epitope prediction methods from a novel viewpoint. PMID:26715528

  13. Phenotypic Approaches to Identify Inhibitors of B Cell Activation.

    PubMed

    Rex, Elizabeth B; Kim, Suzie; Wiener, Jake; Rao, Navin L; Milla, Marcos E; DiSepio, Daniel

    2015-08-01

    An EPIC label-free phenotypic platform was developed to explore B cell receptor (BCR) and CD40R-mediated B cell activation. The phenotypic assay measured the association of RL non-Hodgkin's lymphoma B cells expressing lymphocyte function-associated antigen 1 (LFA-1) to intercellular adhesion molecule 1 (ICAM-1)-coated EPIC plates. Anti-IgM (immunoglobulin M) mediated BCR activation elicited a response that was blocked by LFA-1/ICAM-1 specific inhibitors and a panel of Bruton's tyrosine kinase (BTK) inhibitors. LFA-1/ICAM-1 association was further increased on coapplication of anti-IgM and mega CD40L when compared to individual application of either. Anti-IgM, mega CD40L, or the combination of both displayed distinct kinetic profiles that were inhibited by treatment with a BTK inhibitor. We also established a FLIPR-based assay to measure B cell activation in Ramos Burkitt's lymphoma B cells and an RL cell line. Anti-IgM-mediated BCR activation elicited a robust calcium response that was inhibited by a panel of BTK inhibitors. Conversely, CD40R activation did not elicit a calcium response in the FLIPR assay. Compared to the FLIPR, the EPIC assay has the propensity to identify inhibitors of both BCR and CD40R-mediated B cell activation and may provide more pharmacological depth or novel mechanisms of action for inhibition of B cell activation. PMID:25948491

  14. BTK Signaling in B Cell Differentiation and Autoimmunity.

    PubMed

    Corneth, Odilia B J; Klein Wolterink, Roel G J; Hendriks, Rudi W

    2016-01-01

    Since the original identification of Bruton's tyrosine kinase (BTK) as the gene defective in the primary immunodeficiency X-linked agammaglobulinemia (XLA) in 1993, our knowledge on the physiological function of BTK has expanded impressively. In this review, we focus on the role of BTK during B cell differentiation in vivo, both in the regulation of expansion and in the developmental progression of pre-B cells in the bone marrow and as a crucial signal transducer of signals downstream of the IgM or IgG B cell antigen receptor (BCR) in mature B cells governing proliferation, survival, and differentiation. In particular, we highlight BTK function in B cells in the context of host defense and autoimmunity. Small-molecule inhibitors of BTK have very recently shown impressive anti-tumor activity in clinical studies in patients with various B cell malignancies. Since promising effects of BTK inhibition were also seen in experimental animal models for lupus and rheumatoid arthritis, BTK may be a good target for controlling autoreactive B cells in patients with systemic autoimmune disease. PMID:26341110

  15. B cell fate decisions following influenza virus infection

    PubMed Central

    Rothaeusler, Kristina; Baumgarth, Nicole

    2010-01-01

    Summary Rapidly induced, specific antibodies generated in extrafollicular foci are important components of early immune protection to influenza virus. The signal(s) that prompt B cells to participate in extrafollicular rather than germinal center responses are incompletely understood. To study the regulation of early B cell differentiation events following influenza infection, we exploited earlier findings of a strong contribution of C12 idiotype-expressing B cells to the primary hemagglutinin (HA)-specific response against influenza A/PR/8/34. Using an idiotype-specific mAb to C12 and labeled-HA, in conjunction with multicolor flow cytometry, we followed the fate of C12Id-expressing influenza HA-specific B cells in wildtype BALB/c mice, requiring neither genetic manipulation nor adoptive cell transfer. Our studies demonstrate that HA-specific C12Id+ B cells are phenotypically indistinguishable from follicular B cells. While they induced both extrafollicular and germinal center responses, extrafollicular responses were strongly predominant. Provision of increased HA-specific T cell help increased the magnitude of the extrafollicular response, but did not shift the C12Id+ response towards germinal center formation. Collectively the data are consistent with the hypothesis that B cell fate-determination following activation is a stochastic process in which infection-induced innate signals might drive the preferential expansion of the early extrafollicular response. PMID:19946883

  16. Phenotypic Approaches to Identify Inhibitors of B Cell Activation

    PubMed Central

    Kim, Suzie; Wiener, Jake; Rao, Navin L.; Milla, Marcos E.; DiSepio, Daniel

    2015-01-01

    An EPIC label-free phenotypic platform was developed to explore B cell receptor (BCR) and CD40R-mediated B cell activation. The phenotypic assay measured the association of RL non-Hodgkins lymphoma B cells expressing lymphocyte function-associated antigen 1 (LFA-1) to intercellular adhesion molecule 1 (ICAM-1)-coated EPIC plates. Anti-IgM (immunoglobulin M) mediated BCR activation elicited a response that was blocked by LFA-1/ICAM-1 specific inhibitors and a panel of Brutons tyrosine kinase (BTK) inhibitors. LFA-1/ICAM-1 association was further increased on coapplication of anti-IgM and mega CD40L when compared to individual application of either. Anti-IgM, mega CD40L, or the combination of both displayed distinct kinetic profiles that were inhibited by treatment with a BTK inhibitor. We also established a FLIPR-based assay to measure B cell activation in Ramos Burkitts lymphoma B cells and an RL cell line. Anti-IgM-mediated BCR activation elicited a robust calcium response that was inhibited by a panel of BTK inhibitors. Conversely, CD40R activation did not elicit a calcium response in the FLIPR assay. Compared to the FLIPR, the EPIC assay has the propensity to identify inhibitors of both BCR and CD40R-mediated B cell activation and may provide more pharmacological depth or novel mechanisms of action for inhibition of B cell activation. PMID:25948491

  17. Salmonella induces PD-L1 expression in B cells.

    PubMed

    Lopez-Medina, Marcela; Perez-Lopez, Araceli; Alpuche-Aranda, Celia; Ortiz-Navarrete, Vianney

    2015-10-01

    Salmonella persists for a long time in B cells; however, the mechanism(s) through which infected B cells avoid effector CD8 T cell responses has not been characterized. In this study, we show that Salmonella infects and survives within all B1 and B2 cell subpopulations. B cells are infected with a Salmonella typhimurium strain expressing an ovalbumin (OVA) peptide (SIINFEKL) to evaluate whether B cells process and present Salmonella antigens in the context of MHC-I molecules. Our data showed that OVA peptides are presented by MHC class I K(b)-restricted molecules and the presented antigen is generated through proteasomal degradation and vacuolar processing. In addition, Salmonella-infected B cells express co-stimulatory molecules such as CD40, CD80, and CD86 as well as inhibitory molecules such as PD-L1. Thus, the cross-presentation of Salmonella antigens and the expression of activation molecules suggest that infected B cells are able to prime and activate specific CD8(+) T cells. However, the Salmonella infection-stimulated expression of PD-L1 suggests that the PD-1/PD-L1 pathway may be involved in turning off the cytotoxic effector response during Salmonella persistent infection, thereby allowing B cells to become a reservoir for the bacteria. PMID:26292028

  18. B Cells in Chronic Graft versus Host Disease

    PubMed Central

    Sarantopoulos, Stefanie; Blazar, Bruce R.; Cutler, Corey; Ritz, Jerome

    2015-01-01

    Chronic graft versus host disease (cGVHD) continues to be a common complication of allogeneic hematopoietic stem cell transplantation (HSCT). Unlike acute GVHD, which is mediated almost entirely by donor T cells, the immune pathology of cGVHD is more complex and donor B cells have also been found to play an important role. Recent studies from several laboratories have enhanced our understanding of how donor B cells contribute to this clinical syndrome and this has led to new therapeutic opportunities. Here, Dr. Sarantopoulos reviews some of the important mechanisms responsible for persistent B cell activation and loss of B cell tolerance in patients with cGVHD. Dr. Blazar describes recent studies in preclinical models that have identified novel B cell directed agents that may be effective for prevention or treatment of cGVHD. Some B cell directed therapies have already been tested in patients with cGVHD and Dr. Cutler reviews the results of these studies documenting the potential efficacy of this approach. Supported by studies mechanistic studies in patients and preclinical models, new B cell directed therapies for cGVHD will now be evaluated in clinical trials. PMID:25452031

  19. T-cell and B-cell immunity in celiac disease.

    PubMed

    du Pr, M Fleur; Sollid, Ludvig M

    2015-06-01

    Celiac disease is an inflammatory disorder with leukocyte infiltration and changes of tissue architecture of the small intestine. The condition develops in genetically susceptible individuals as the result of an inappropriate immune response to gluten proteins of wheat, barley and rye. The clinical manifestations and the histological changes normalize when gluten is eliminated from the diet. CD4(+) T cells that recognize gluten peptides bound to predisposing HLA-DQ molecules play a key role in the pathogenesis. These T cells recognize better gluten peptides that are deamidated, and this posttranslational modification is mediated by the enzyme transglutaminase 2 (TG2). Another hallmark of celiac disease is the production of antibodies to gluten as well as to TG2. A role for B cells in celiac disease pathogenesis is receiving increased recognition. This review will discuss the main discoveries in the field of T-cell and B-cell biology of celiac disease. PMID:26060106

  20. Predicting linear B-cell epitopes using string kernels.

    PubMed

    El-Manzalawy, Yasser; Dobbs, Drena; Honavar, Vasant

    2008-01-01

    The identification and characterization of B-cell epitopes play an important role in vaccine design, immunodiagnostic tests, and antibody production. Therefore, computational tools for reliably predicting linear B-cell epitopes are highly desirable. We evaluated Support Vector Machine (SVM) classifiers trained utilizing five different kernel methods using fivefold cross-validation on a homology-reduced data set of 701 linear B-cell epitopes, extracted from Bcipep database, and 701 non-epitopes, randomly extracted from SwissProt sequences. Based on the results of our computational experiments, we propose BCPred, a novel method for predicting linear B-cell epitopes using the subsequence kernel. We show that the predictive performance of BCPred (AUC = 0.758) outperforms 11 SVM-based classifiers developed and evaluated in our experiments as well as our implementation of AAP (AUC = 0.7), a recently proposed method for predicting linear B-cell epitopes using amino acid pair antigenicity. Furthermore, we compared BCPred with AAP and ABCPred, a method that uses recurrent neural networks, using two data sets of unique B-cell epitopes that had been previously used to evaluate ABCPred. Analysis of the data sets used and the results of this comparison show that conclusions about the relative performance of different B-cell epitope prediction methods drawn on the basis of experiments using data sets of unique B-cell epitopes are likely to yield overly optimistic estimates of performance of evaluated methods. This argues for the use of carefully homology-reduced data sets in comparing B-cell epitope prediction methods to avoid misleading conclusions about how different methods compare to each other. Our homology-reduced data set and implementations of BCPred as well as the APP method are publicly available through our web-based server, BCPREDS, at: http://ailab.cs.iastate.edu/bcpreds/. PMID:18496882

  1. Alcohol Affects the Late Differentiation of Progenitor B Cells

    PubMed Central

    Wang, Hao; Zhou, Huijuan; Mahler, Simon; Chervenak, Robert; Wolcott, Michael

    2011-01-01

    Aims: Previous studies show that alcohol exposure can affect the differentiation of progenitor B cells. Before final commitment to a B lineage, progenitor B cells usually undergo several important stages. However, it is still unclear whether alcohol alters B cell differentiation at which stages. The aim of this study was to determine which stage(s) of progenitor cell differentiation are affected by alcohol and to elucidate the mechanism(s) responsible for the effect of alcohol on B cell differentiation. Methods: Oligoclonal-neonatal-progenitor (ONP) cells from bone marrow cells of 2-week-old mice were cultured under different conditions in vitro with or without the exposure of 100 mM alcohol. Phenotype analysis was performed at different time points and expression levels of transcription factors (TFs) and cytokine receptors were measured quantitatively and kinetically. Results: After 3 days in vitro culture, ONP cells differentiated into two populations: B220−CD11b− and B220−CD11b+ cells. B220−CD11b− cells can further differentiate into B lineage cells only with the support of B220−CD11b+ cells. Cells exposed to 100 mM of alcohol during the first 3 days of culture showed no statistically significant difference in B cell formation after 12 days compared with the control group. However, cells exposed to alcohol from Day 4 till the end of culture yield very few B cells. Expression levels of TFs and cytokine receptors were down-regulated kinetically among ONP cells co-cultured with the addition of 100 mM alcohol. Conclusions: Alcohol affects the ONP cell differentiation into B lineage at a late stage. Alcohol also down-regulates the expression level of TFs and cytokine receptors resulting in the impairment of B cell differentiation. PMID:21098503

  2. Primary Diffuse Large B-cell Lymphoma involving the Mandible.

    PubMed

    Alshahrani, Faleh Ali A; Aljabab, Abdulsalam S; Motabi, Ibraheem Hm; Alrashed, Abdullah; Anil, Sukumaran

    2015-10-01

    Lymphomas of the oral cavity are rare and typically present as intraosseous lesions that are most commonly diffuse large B-cell type. Diffuse large B-cell lymphoma (DLBCL) is an aggressive B-cell lymphoma histologically characterized by diffuse proliferation of large neoplastic B-lymphoid cells with a nuclear size equal to or exceeding normal histiocytic nuclei. A case of DLBCL of the mandible in an 18 years old male patient is presented. This report discusses this rare malignancy, including clinical presentation, histopathologic features, immunologic profile, treatment and prognosis. Though lymphoma of mandible is rare, it must be considered in differential diagnosis of swellings arising in the region. PMID:26581467

  3. Immunopathology of B-cell lymphomas induced in C57BL/6 mice by dualtropic murine leukemia virus (MuLV)

    SciTech Connect

    Pattengale, P.K.; Taylor, C.R.; Twomey, P.; Hill, S.; Jonasson, J.; Beardsley, T.; Haas, M.

    1982-06-01

    Combined clinicopathologic and immunomorphologic evidence is presented that would indicate that a murine leukemia virus (MuLV) with the dualtropic host range is capable of producing a clinically malignant lesion composed of immunoblasts and associated plasma cells in C57BL/6 mice. This process, morphologically diagnosed as an immunoblastic lymphoma of B cells using standard histopathologic criteria, was found to be distinctly polyclonal with regard to immunoglobulin (Ig) isotype when analyzed for both surface and cytoplasmic Ig. Further studies demonstrated that this clinicopathologically malignant, dualtropic MuLV-induced, polyclonal immunoblastic lymphoma of B cells in C57BL/6 mice was normal diploid and unable to be successfully transplanted to nonimmunosuppressed syngeneic recipients. Although all serum heavy and light chain components were found to be progressively elevated as the tumor load increased, the polyclonal increase in serum immunoglobulins was most pronounced for mu heavy and kappa light chains (ie, mu greater than gamma 2A greater than alpha greater than gamma 2B greater than gamma 1; kappa greater than lamba). The dissociation of clinicopathologic and biologic criteria for malignancy in the presently described dualtropic (RadLV) MuLV-induced B-cell lesion is sharply contrasted with the thymotropic (RadLV), MuLV-induced T-cell lymphoblastic lymphoma in C57BL/6 mice. This process is also a clinicopathologically malignant lesion but, when one uses biologic criteria, is found to be distinctly monoclonal, aneuploid, and easily transplanted to nonimmunosuppressed syngeneic recipients. The close clinicopathologic and biologic similarities of the dualtropic MuLV-induced animal model to corresponding human B-cell lymphoproliferative diseases are stressed.

  4. Reprint of: B cell elimination in systemic lupus erythematosus. Clin. Immunol. 146(2) 90-103.

    PubMed

    Furtado, João; Isenberg, David A

    2013-09-01

    Systemic lupus erythematosus (SLE) is an autoimmune disorder with a worldwide distribution, potentially life-threatening with considerable morbidity. The elimination of pathogenic B cells has emerged as a rational therapeutic option. Many open label studies have reported encouraging results in which clinical and serological remission have invariably been described, often enabling the reduction of steroid and immunosuppressive treatment. However, the results from randomized controlled studies have been disappointing and several questions remain to be answered. In this review we will focus on results of B cell direct depletion in the treatment of patients with systemic lupus erythematosus. PMID:23642318

  5. Why do human B cells secrete granzyme B? Insights into a novel B-cell differentiation pathway

    PubMed Central

    Hagn, Magdalena; Jahrsdrfer, Bernd

    2012-01-01

    B cells are generally believed to operate as producers of high affinity antibodies to defend the body against microorganisms, whereas cellular cytotoxicity is considered as an exclusive prerogative of natural killer (NK) cells and cytotoxic T lymphocytes (CTLs). In conflict with this dogma, recent studies have demonstrated that the combination of interleukin-21 (IL-21) and B-cell receptor (BCR) stimulation enables B cells to produce and secrete the active form of the cytotoxic serine protease granzyme B (GrB). Although the production of GrB by B cells is not accompanied by that of perforin as in the case of many other GrB-secreting cells, recent findings suggest GrB secretion by B cells may play a significant role in early antiviral immune responses, in the regulation of autoimmune responses, and in cancer immunosurveillance. Here, we discuss in detail how GrB-secreting B cells may influence a variety of immune processes. A better understanding of the role that GrB-secreting B cells are playing in the immune system may allow for the development and improvement of novel immunotherapeutic approaches against infectious, autoimmune and malignant diseases. PMID:23243600

  6. ATM deficiency promotes development of murine B-cell lymphomas that resemble diffuse large B-cell lymphoma in humans

    PubMed Central

    Hathcock, Karen S.; Padilla-Nash, Hesed M.; Camps, Jordi; Shin, Dong-Mi; Triner, Daniel; Shaffer, Arthur L.; Maul, Robert W.; Steinberg, Seth M.; Gearhart, Patricia J.; Staudt, Louis M.; Morse, Herbert C.; Ried, Thomas

    2015-01-01

    The serine-threonine kinase ataxia-telangiectasia mutated (ATM) plays a central role in maintaining genomic integrity. In mice, ATM deficiency is exclusively associated with T-cell lymphoma development, whereas B-cell tumors predominate in human ataxia-telangiectasia patients. We demonstrate in this study that when T cells are removed as targets for lymphomagenesis and as mediators of immune surveillance, ATM-deficient mice exclusively develop early-onset immunoglobulin M+ B-cell lymphomas that do not transplant to immunocompetent mice and that histologically and genetically resemble the activated B cell–like (ABC) subset of human diffuse large B-cell lymphoma (DLBCL). These B-cell lymphomas show considerable chromosomal instability and a recurrent genomic amplification of a 4.48-Mb region on chromosome 18 that contains Malt1 and is orthologous to a region similarly amplified in human ABC DLBCL. Of importance, amplification of Malt1 in these lymphomas correlates with their dependence on nuclear factor (NF)-κB, MALT1, and B-cell receptor (BCR) signaling for survival, paralleling human ABC DLBCL. Further, like some human ABC DLBCLs, these mouse B-cell lymphomas also exhibit constitutive BCR-dependent NF-κB activation. This study reveals that ATM protects against development of B-cell lymphomas that model human ABC DLBCL and identifies a potential role for T cells in preventing the emergence of these tumors. PMID:26400962

  7. Impairment of neutrophil chemotaxis by serum from patients with chronic lymphoproliferative disease.

    PubMed Central

    Jayaswal, U; Roper, S; Roath, S

    1983-01-01

    The sera of 74 individuals with chronic lymphoproliferative disease were screened for the presence of inhibitory activity against neutrophil chemotaxis. This was present in more than half the patients with IgA myeloma and Hodgkin's disease but was less common in chronic lymphocytic leukaemia, lymphocytic lymphoma and non-IgA paraproteinaemia. Heating the sera prior to testing frequently enhanced inhibitory activity particularly in myeloma and lymphoma. PMID:6833512

  8. Diffuse Large B-Cell Lymphoma Version 1.2016.

    PubMed

    Zelenetz, Andrew D; Gordon, Leo I; Wierda, William G; Abramson, Jeremy S; Advani, Ranjana H; Andreadis, C Babis; Bartlett, Nancy; Byrd, John C; Fayad, Luis E; Fisher, Richard I; Glenn, Martha J; Habermann, Thomas M; Lee Harris, Nancy; Hernandez-Ilizaliturri, Francisco; Hoppe, Richard T; Horwitz, Steven M; Kaminski, Mark S; Kelsey, Christopher R; Kim, Youn H; Krivacic, Susan; LaCasce, Ann S; Lunning, Matthew; Nademanee, Auayporn; Porcu, Pierluigi; Press, Oliver; Rabinovitch, Rachel; Reddy, Nishitha; Reid, Erin; Roberts, Kenneth; Saad, Ayman A; Sokol, Lubomir; Swinnen, Lode J; Vose, Julie M; Yahalom, Joachim; Zafar, Nadeem; Dwyer, Mary; Sundar, Hema

    2016-02-01

    Diffuse large B-cell lymphomas (DLBCL) are now considered a heterogeneous group of distinct molecular subtypes (germinal center B-cell DLBCL, activated B-cell DLBCL, and primary mediastinal large B-cell lymphoma (PMBL) with varied natural history and response to therapy. In addition, a subset of patients with DLBCL have concurrent MYC and/or BCL2 gene rearrangements (double-hit lymphomas; DHL) and others have a dual expression of both MYC and BCL2 proteins (double-expressing DLBCL; DEL). The standard of care for the treatment of patients with PMBL, DHL, or DEL has not been established. Adequate immunophenotyping and molecular testing (in selected circumstances) are necessary for the accurate diagnosis of different subtypes of DLBCL. The NCCN Guidelines included in this issue, part of the NCCN Guidelines for non-Hodgkin's lymphomas, address the diagnosis and management of DLBCL and its subtypes. PMID:26850490

  9. 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.

  10. BAFF suppresses IL-15 expression in B cells.

    PubMed

    Ma, Ning; Xing, Chen; Xiao, He; He, Youdi; Han, Gencheng; Chen, Guojiang; Hou, Chunmei; Marrero, Bernadette; Wang, Yujuan; Zhang, Shengquan; Shen, Beifen; Li, Yan; Wang, Renxi

    2014-05-01

    Clinical trials have shown that BAFF inhibitors do not reduce memory B cell levels but can reduce the number of mature B cells. It remains uncertain whether BAFF affects memory-maintaining cytokines such as IL-15. We found that BAFF suppressed IL-15 expression in B cells from lupus-like or experimental allergic encephalomyelitis mice. When BAFF was blocked with atacicept-IgG, IL-15 expression was upregulated in lupus-like or experimental allergic encephalomyelitis mice. Finally, we showed that BAFF suppressed IL-15 expression in transitional 2 B cells by reducing Foxo1 expression and inducing Foxo1 phosphorylation. This study suggests that BAFF suppresses IL-15 expression in autoimmune diseases, and this opens up the possible opportunity for the clinical application of BAFF- and IL-15-specific therapeutic agents. PMID:24670802

  11. B-cell receptor pathobiology and targeting in NHL.

    PubMed

    Macias-Perez, Ines M; Flinn, Ian W

    2012-10-01

    B-cell receptor signaling plays varied and critical roles in B-cell development, homeostasis and disease. The key players of the pathway and its many signaling modulators have been identified as well as some of the mechanisms by which the pathway is regulated. With the increased incidence of non-Hodgkin's lymphoma in recent years, there is a clear clinical need for novel agents to offer new options in resistant disease to potentially improve outcomes in curative settings. With the tremendous insight gained in the last 2 decades from basic science research, our understanding of the pathobiology of the B-cell receptor is leading to the discovery and clinical development of many new therapeutic targets such as Syk, Bruton's tyrosine kinase, and phosphatidylinositol 3-kinase. This review will emphasize contemporary and salient findings on novel agents targeting the B-cell receptor signaling pathway for the treatment of non-Hodgkin's lymphoma. PMID:22865093

  12. Why do B cells mutate their immunoglobulin receptors?

    PubMed

    Longo, Nancy S; Lipsky, Peter E

    2006-08-01

    B cells have the unique ability to acquire large numbers of point mutations in the variable segment of rearranged immunoglobulin (Ig) genes during a germinal center reaction. It is broadly accepted that somatic hypermutation (SHM) and affinity maturation are required to generate memory B cells and to produce antibodies capable of accomplishing the host defense functions of the humoral component of the adaptive immune system. However, several studies illustrate that low-avidity interactions between antigen and the B-cell receptor can induce deletion, receptor editing and a T-dependent immune response, suggesting that the high-avidity binding of antigen is not essential. If enhanced antigen binding is not essential for immune responses, what is the purpose of SHM? An alternative benefit of SHM might be to enhance the ability of B cells to track antigens expressed by rapidly mutating microorganisms. PMID:16809065

  13. 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.

  14. B cell-directed therapies in multiple sclerosis.

    PubMed

    Gasperi, Christiane; Stüve, Olaf; Hemmer, Bernhard

    2016-02-01

    Multiple sclerosis (MS) is a chronic inflammatory neurological disease of the CNS that goes along with demyelination and neurodegeneration. It is probably caused by an autoimmune response against the CNS, which emerges from the interplay of genetic and environmental factors. Although major progress has been made in the treatment of MS, it is still the leading cause for acquired nontraumatic neurological disability in young adults. Several therapeutic agents have been approved for the treatment of relapsing-remitting MS (RRMS), aiming at the reduction of relapses and a delay in disability progression. Three therapeutic monoclonal antibodies targeting CD20-positive B cells (rituximab, ocrelizumab and ofatumumab) were investigated in MRI-based Phase II and Phase III trials in RRMS, providing consistent evidence for a disease-ameliorating effect of B cell depleting therapies in MS. Here, we discuss the role of B cells and review current and future therapeutic approaches to target B cells in MS. PMID:26782316

  15. Long Noncoding RNA Expression during Human B-Cell Development

    PubMed Central

    Petri, Andreas; Dybkær, Karen; Bøgsted, Martin; Thrue, Charlotte Albæk; Hagedorn, Peter H.; Schmitz, Alexander; Bødker, Julie Støve; Johnsen, Hans Erik; Kauppinen, Sakari

    2015-01-01

    Long noncoding RNAs (lncRNAs) have emerged as important regulators of diverse cellular processes, but their roles in the developing immune system are poorly understood. In this study, we analysed lncRNA expression during human B-cell development by array-based expression profiling of eleven distinct flow-sorted B-cell subsets, comprising pre-B1, pre-B2, immature, naive, memory, and plasma cells from bone marrow biopsies (n = 7), and naive, centroblast, centrocyte, memory, and plasmablast cells from tonsil tissue samples (n = 6), respectively. A remapping strategy was used to assign the array probes to 37630 gene-level probe sets, reflecting recent updates in genomic and transcriptomic databases, which enabled expression profiling of 19579 long noncoding RNAs, comprising 3947 antisense RNAs, 5277 lincRNAs, 7625 pseudogenes, and 2730 additional lncRNAs. As a first step towards inferring the functions of the identified lncRNAs in developing B-cells, we analysed their co-expression with well-characterized protein-coding genes, a method known as “guilt by association”. By using weighted gene co-expression network analysis, we identified 272 lincRNAs, 471 antisense RNAs, 376 pseudogene RNAs, and 64 lncRNAs within seven sub-networks associated with distinct stages of B-cell development, such as early B-cell development, B-cell proliferation, affinity maturation of antibody, and terminal differentiation. These data provide an important resource for future studies on the functions of lncRNAs in development of the adaptive immune response, and the pathogenesis of B-cell malignancies that originate from distinct B-cell subpopulations. PMID:26394393

  16. Long Noncoding RNA Expression during Human B-Cell Development.

    PubMed

    Petri, Andreas; Dybkr, Karen; Bgsted, Martin; Thrue, Charlotte Albk; Hagedorn, Peter H; Schmitz, Alexander; Bdker, Julie Stve; Johnsen, Hans Erik; Kauppinen, Sakari

    2015-01-01

    Long noncoding RNAs (lncRNAs) have emerged as important regulators of diverse cellular processes, but their roles in the developing immune system are poorly understood. In this study, we analysed lncRNA expression during human B-cell development by array-based expression profiling of eleven distinct flow-sorted B-cell subsets, comprising pre-B1, pre-B2, immature, naive, memory, and plasma cells from bone marrow biopsies (n = 7), and naive, centroblast, centrocyte, memory, and plasmablast cells from tonsil tissue samples (n = 6), respectively. A remapping strategy was used to assign the array probes to 37630 gene-level probe sets, reflecting recent updates in genomic and transcriptomic databases, which enabled expression profiling of 19579 long noncoding RNAs, comprising 3947 antisense RNAs, 5277 lincRNAs, 7625 pseudogenes, and 2730 additional lncRNAs. As a first step towards inferring the functions of the identified lncRNAs in developing B-cells, we analysed their co-expression with well-characterized protein-coding genes, a method known as "guilt by association". By using weighted gene co-expression network analysis, we identified 272 lincRNAs, 471 antisense RNAs, 376 pseudogene RNAs, and 64 lncRNAs within seven sub-networks associated with distinct stages of B-cell development, such as early B-cell development, B-cell proliferation, affinity maturation of antibody, and terminal differentiation. These data provide an important resource for future studies on the functions of lncRNAs in development of the adaptive immune response, and the pathogenesis of B-cell malignancies that originate from distinct B-cell subpopulations. PMID:26394393

  17. ?? T Cells Shape Preimmune Peripheral B Cell Populations.

    PubMed

    Huang, Yafei; Getahun, Andrew; Heiser, Ryan A; Detanico, Thiago O; Aviszus, Katja; Kirchenbaum, Greg A; Casper, Tamara L; Huang, Chunjian; Aydintug, M Kemal; Carding, Simon R; Ikuta, Koichi; Huang, Hua; Wysocki, Lawrence J; Cambier, John C; O'Brien, Rebecca L; Born, Willi K

    2016-01-01

    We previously reported that selective ablation of certain ?? T cell subsets, rather than removal of all ?? T cells, strongly affects serum Ab levels in nonimmunized mice. This type of manipulation also changed T cells, including residual ?? T cells, revealing some interdependence of ?? T cell populations. For example, in mice lacking V?4(+) and V?6(+) ?? T cells (B6.TCR-V?4(-/-)/6(-/-)), we observed expanded V?1(+) cells, which changed in composition and activation and produced more IL-4 upon stimulation in vitro, increased IL-4 production by ?? T cells as well as spontaneous germinal center formation in the spleen, and elevated serum Ig and autoantibodies. We therefore examined B cell populations in this and other ??-deficient mouse strains. Whereas immature bone marrow B cells remained largely unchanged, peripheral B cells underwent several changes. Specifically, transitional and mature B cells in the spleen of B6.TCR-V?4(-/-)/6(-/-) mice and other peripheral B cell populations were diminished, most of all splenic marginal zone (MZ) B cells. However, relative frequencies and absolute numbers of Ab-producing cells, as well as serum levels of Abs, IL-4, and BAFF, were increased. Cell transfers confirmed that these changes are directly dependent on the altered ?? T cells in this strain and on their enhanced potential of producing IL-4. Further evidence suggests the possibility of direct interactions between ?? T cells and B cells in the splenic MZ. Taken together, these data demonstrate the capability of ?? T cells of modulating size and productivity of preimmune peripheral B cell populations. PMID:26582947

  18. Cyclosporine inhibition of a murine B cell lymphoma.

    PubMed

    Pisetsky, D S; Haughton, G

    1986-03-01

    The effect of cyclosporine (CsA) on the CH12 murine B cell lymphoma was investigated to determine whether sensitivity to this agent is retained by malignant B cells. This tumour produces an antibody to bromelain-treated red blood cells and may represent transformation of a B cell with certain activation properties associated with early resting B cells. In in vitro cultures, the growth and proliferation of CH12 were inhibited by CsA in concentrations of 0.1-1.0 microgram/ml; these levels were ineffective against non-lymphoid tumours, although some non-specific cell toxicity was noted at higher levels. IgM antibody production, as measured by enzyme-linked immunosorbent assay (ELISA), was inhibited over the same range. CH12 cells stimulated by lipopolysaccharide, however, were less sensitive to CsA than untreated cells. These studies indicate that malignant B cells may be sensitive to CsA, perhaps reflecting their derivation from a functionally distinct B cell population with enhanced drug sensitivity. PMID:3486733

  19. B-Cell Mediated Pathogenesis of ANCA-Mediated Vasculitis

    PubMed Central

    Jennette, J. Charles; Falk, Ronald J.

    2014-01-01

    B cells and their progeny that produce and release anti-neutrophil cytoplasmic autoantibodies (ANCA) are the primary cause for an aggressive form of necrotizing small vessel vasculitis. Cytoplasmic ANCA antigens are released at the surface and in the microenvironment of cytokine-primed neutrophils. Binding of ANCA to ANCA antigens activates neutrophils by both Fc receptor engagement and direct Fab2 binding to antigen on the cell surface. ANCA-activated neutrophils release factors that induce alternative complement pathway activation, which establishes a potent inflammatory amplification loop that causes severe necrotizing vascular inflammation. The origin of the ANCA autoimmune response is unknown but appears to involve genetically determined HLA specificities that allow the autoimmune response to develop. One putative immunogenic mechanisms begins with an immune response to a peptide that is complementary to the autoantigen and evolves through an anti-idiotypic network to produce autoantibodies to the autoantigen. Another putative immunogenic mechanism begins with an immune response to a microbe-derived molecular mimic of the autoantigen resulting in antibodies that cross-react with the autoantigen. Release of neutrophil extracellular traps, apoptosis and increased granule protein expression of ANCA antigens may facilitate the initiation of an ANCA autoimmune response, augment established pathogenic ANCA production, or both. The ANCA B cell autoimmune response is facilitated by quantitatively and qualitatively impaired T cell and B cell suppression, and by release from activated neutrophils of B cell activating factors that enhance B cell proliferation and retard B cell apoptosis. PMID:24777746

  20. Development and function of murine B cells lacking RANK.

    PubMed

    Perlot, Thomas; Penninger, Josef M

    2012-02-01

    RANKL-RANK signaling regulates numerous physiologic processes such as bone remodeling, lymph node organogenesis, central thermoregulation, and formation of a lactating mammary gland in pregnancy. Recently, a receptor activator of NF-?B ligand (RANKL)-blocking Ab has been approved for human use in potentially millions of osteoporosis and cancer patients. However, germline deficiencies in RANKL or receptor activator of NF-?B (RANK) also lead to strong B cell defects in mice and human patients, suggesting that RANKL-RANK inhibition could interfere with B cell physiology and thereby trigger immunologic side-effects. To address this key question--that is, whether RANKL-RANK signaling affects B cell physiology directly or the observed defects are secondary because of the severe osteopetrosis--we generated B cell-specific RANK knockout mice. We show that B cells deficient for RANK undergo normal development and do not show any obvious defects in Ab secretion, class switch recombination, or somatic hypermutation. Our data indicate that ablation of the RANKL-RANK pathway has no direct adverse effect on B cell physiology. PMID:22219325

  1. B cells mediate chronic allograft rejection independently of antibody production

    PubMed Central

    Zeng, Qiang; Ng, Yue-Harn; Singh, Tripti; Jiang, Ke; Sheriff, Khaleefathullah A.; Ippolito, Renee; Zahalka, Salwa; Li, Qi; Randhawa, Parmjeet; Hoffman, Rosemary A.; Ramaswami, Balathiripurasundari; Lund, Frances E.; Chalasani, Geetha

    2014-01-01

    Chronic rejection is the primary cause of long-term failure of transplanted organs and is often viewed as an antibody-dependent process. Chronic rejection, however, is also observed in mice and humans with no detectable circulating alloantibodies, suggesting that antibody-independent pathways may also contribute to pathogenesis of transplant rejection. Here, we have provided direct evidence that chronic rejection of vascularized heart allografts occurs in the complete absence of antibodies, but requires the presence of B cells. Mice that were deficient for antibodies but not B cells experienced the same chronic allograft vasculopathy (CAV), which is a pathognomonic feature of chronic rejection, as WT mice; however, mice that were deficient for both B cells and antibodies were protected from CAV. B cells contributed to CAV by supporting splenic lymphoid architecture, T cell cytokine production, and infiltration of T cells into graft vessels. In chimeric mice, in which B cells were present but could not present antigen, both T cell responses and CAV were markedly reduced. These findings establish that chronic rejection can occur in the complete absence of antibodies and that B cells contribute to this process by supporting T cell responses through antigen presentation and maintenance of lymphoid architecture. PMID:24509079

  2. B cells are critical for autoimmune pathology in Scurfy mice.

    PubMed

    Aschermann, Susanne; Lehmann, Christian H K; Mihai, Sidonia; Schett, Georg; Dudziak, Diana; Nimmerjahn, Falk

    2013-11-19

    Impaired regulatory T-cell function results in a severe chronic autoimmune disease affecting multiple organs in Scurfy mice and humans with the immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome. Previous studies have shown that T helper cells but not cytotoxic T cells are critical for the disease pathology. Whether this T-cell subset is responsible directly for tissue inflammation or rather indirectly via the interaction with B cells or myeloid cells is largely unknown. To study this and to identify potential therapeutic targets for this lethal disease we investigated the contribution of B cells to this complex autoimmune phenotype. We show that B cells and the production of autoantibodies plays a major role for skin, liver, lung, and kidney inflammation and therapeutic depletion of B cells resulted in reduced tissue pathology and in prolonged survival. In contrast, the absence of B cells did not impact systemic T-cell activation and hyperreactivity, indicating that autoantibody production by B cells may be a major factor for the autoimmune pathology in mice deficient for regulatory T cells. PMID:24194550

  3. The role of B cells in systemic sclerosis

    PubMed Central

    Kraaij, Marina D; van Laar, Jacob M

    2008-01-01

    Systemic sclerosis (SSc) is a connective disease characterized by features of autoimmunity, vasculopathy, inflammation, and fibrosis. The disease typically starts with Raynauds phenomenon, followed by skin thickening in the extremities due to inflammation and fibrosis. Fibrosis results from excessive collagen production by fibroblasts, which constitutes the final common pathway of complex cellular interactions including B cells. Several studies have indicated that B cells may play a role in SSc. Lesional skin infiltrates from SSc patients consist of a variety of cells, including eosinophils, neutrophils, lymphocytes, plasma cells, and macrophages. Autoantibodies of several specificities are present in the serum of SSc patients of which antitopoisomerase 1 is the most common, and evidence has been gathered for a potential pathogenic role of some autoantibodies, eg, anti-PDGF antibodies. The blood of SSc patients contains an increased proportion of nave B cells but a decreased proportion of memory B cells. Furthermore, serum levels of interleukin-6, an important pro-inflammatory cytokine, have been shown to correlate with skin fibrosis. Animal models of SSc have provided more in-depth information on the role of B lymphocytes, eg, through disruption of B cell function. In this review we will discuss the evidence that B cells are involved in the pathogenesis of SSc. PMID:19707370

  4. Cyclosporine inhibition of a murine B cell lymphoma.

    PubMed Central

    Pisetsky, D S; Haughton, G

    1986-01-01

    The effect of cyclosporine (CsA) on the CH12 murine B cell lymphoma was investigated to determine whether sensitivity to this agent is retained by malignant B cells. This tumour produces an antibody to bromelain-treated red blood cells and may represent transformation of a B cell with certain activation properties associated with early resting B cells. In in vitro cultures, the growth and proliferation of CH12 were inhibited by CsA in concentrations of 0.1-1.0 microgram/ml; these levels were ineffective against non-lymphoid tumours, although some non-specific cell toxicity was noted at higher levels. IgM antibody production, as measured by enzyme-linked immunosorbent assay (ELISA), was inhibited over the same range. CH12 cells stimulated by lipopolysaccharide, however, were less sensitive to CsA than untreated cells. These studies indicate that malignant B cells may be sensitive to CsA, perhaps reflecting their derivation from a functionally distinct B cell population with enhanced drug sensitivity. PMID:3486733

  5. B cells with regulatory properties in transplantation tolerance

    PubMed Central

    Durand, Justine; Chiffoleau, Elise

    2015-01-01

    Induction of tolerance remains a major goal in transplantation. Indeed, despite potent immunosuppression, chronic rejection is still a real problem in transplantation. The humoral response is an important mediator of chronic rejection, and numerous strategies have been developed to target either B cells or plasma cells. However, the use of anti-CD20 therapy has highlighted the beneficial role of subpopulation of B cells, termed regulatory B cells. These cells have been characterized mainly in mice models of auto-immune diseases but emerging literature suggests their role in graft tolerance in transplantation. Regulatory B cells seem to be induced following inflammation to restrain excessive response. Different phenotypes of regulatory B cells have been described and are functional at various differentiation steps from immature to plasma cells. These cells act by multiple mechanisms such as secretion of immuno-suppressive cytokines interleukin-10 (IL-10) or IL-35, cytotoxicity, expression of inhibitory receptors or by secretion of non-inflammatory antibodies. Better characterization of the development, phenotype and mode of action of these cells seems urgent to develop novel approaches to manipulate the different B cell subsets and the response to the graft in a clinical setting. PMID:26722647

  6. Cutaneous primary B-cell lymphomas: from diagnosis to treatment.

    PubMed

    Lima, Margarida

    2015-10-01

    AbstractPrimary cutaneous B-cell lymphomas are a heterogeneous group of mature B-cells neoplasms with tropism for the skin, whose biology and clinical course differ significantly from the equivalent nodal lymphomas. The most indolent forms comprise the primary cutaneous marginal zone and follicle center B-cell lymphomas that despite the excellent prognosis have cutaneous recurrences very commonly. The most aggressive forms include the primary cutaneous large B-cell lymphomas, consisting in two major groups: the leg type, with poor prognosis, and others, the latter representing a heterogeneous group of lymphomas from which specific entities are supposed to be individualized over time, such as intravascular large B-cell lymphomas. Treatment may include surgical excision, radiotherapy, antibiotics, corticosteroids, interferon, monoclonal antibodies and chemotherapy, depending on the type of lymphoma and on the type and location of the skin lesions. In subtypes with good prognosis is contraindicated overtreatment and in those associated with a worse prognosis the recommended therapy relies on CHOP-like regimens associated with rituximab, assisted or not with local radiotherapy. We review the primary cutaneous B-cell lymphomas, remembering the diagnostic criteria, differential diagnosis, classification, and prognostic factors and presenting the available therapies. PMID:26560215

  7. B cells with regulatory properties in transplantation tolerance.

    PubMed

    Durand, Justine; Chiffoleau, Elise

    2015-12-24

    Induction of tolerance remains a major goal in transplantation. Indeed, despite potent immunosuppression, chronic rejection is still a real problem in transplantation. The humoral response is an important mediator of chronic rejection, and numerous strategies have been developed to target either B cells or plasma cells. However, the use of anti-CD20 therapy has highlighted the beneficial role of subpopulation of B cells, termed regulatory B cells. These cells have been characterized mainly in mice models of auto-immune diseases but emerging literature suggests their role in graft tolerance in transplantation. Regulatory B cells seem to be induced following inflammation to restrain excessive response. Different phenotypes of regulatory B cells have been described and are functional at various differentiation steps from immature to plasma cells. These cells act by multiple mechanisms such as secretion of immuno-suppressive cytokines interleukin-10 (IL-10) or IL-35, cytotoxicity, expression of inhibitory receptors or by secretion of non-inflammatory antibodies. Better characterization of the development, phenotype and mode of action of these cells seems urgent to develop novel approaches to manipulate the different B cell subsets and the response to the graft in a clinical setting. PMID:26722647

  8. Cutaneous primary B-cell lymphomas: from diagnosis to treatment*

    PubMed Central

    Lima, Margarida

    2015-01-01

    Primary cutaneous B-cell lymphomas are a heterogeneous group of mature B-cells neoplasms with tropism for the skin, whose biology and clinical course differ significantly from the equivalent nodal lymphomas. The most indolent forms comprise the primary cutaneous marginal zone and follicle center B-cell lymphomas that despite the excellent prognosis have cutaneous recurrences very commonly. The most aggressive forms include the primary cutaneous large B-cell lymphomas, consisting in two major groups: the leg type, with poor prognosis, and others, the latter representing a heterogeneous group of lymphomas from which specific entities are supposed to be individualized over time, such as intravascular large B-cell lymphomas. Treatment may include surgical excision, radiotherapy, antibiotics, corticosteroids, interferon, monoclonal antibodies and chemotherapy, depending on the type of lymphoma and on the type and location of the skin lesions. In subtypes with good prognosis is contraindicated overtreatment and in those associated with a worse prognosis the recommended therapy relies on CHOP-like regimens associated with rituximab, assisted or not with local radiotherapy. We review the primary cutaneous B-cell lymphomas, remembering the diagnostic criteria, differential diagnosis, classification, and prognostic factors and presenting the available therapies. PMID:26560215

  9. Characterization of a presecretory phase in B-cell differentiation.

    PubMed Central

    King, L B; Corley, R B

    1989-01-01

    We have identified and characterized an inducible in vitro subclone of the CH12 B-cell lymphoma, CH12-LBK, which appears to represent a transitional phase in the B-cell differentiation pathway. This phase, which we call the "presecretory" phase, falls between replicating B cells that are not secreting antibodies and B cells that secrete antibody at a high rate. Presecretory cells are characterized by abundant steady-state levels of immunoglobulin and joining (J) chain transcripts and of protein but low levels of mouse mammary tumor virus envelope transcripts and low rates of immunoglobulin secretion. Additional stimulation is required for presecretory cells to differentiate into cells that secrete antibodies at a high rate. The existence of cells with this phenotype suggests that high-level expression of immunoglobulin and J-chain protein does not necessarily commit a B cell to polymerize and secrete multimeric immunoglobulin. Rather, other gene products, expressed after immunoglobulin and J-chain transcripts have been upregulated late in B-cell differentiation, appear responsible for inducing high rates of antibody secretion. Images PMID:2495536

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

    PubMed Central

    Kastritis, Efstathios; Owen, Roger G.; Kyle, Robert A.; Landgren, Ola; Morra, Enrica; Leleu, Xavier; Garca-Sanz, Ramn; Munshi, Nikhil; Anderson, Kenneth C.; Terpos, Evangelos; Ghobrial, Irene M.; Morel, Pierre; Maloney, David; Rummel, Mathias; Leblond, Vronique; 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

    Waldenstrm 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

  11. Toll-like receptor 9 and interferon-? receptor signaling suppress the B-cell fate of uncommitted progenitors in mice.

    PubMed

    Baratono, Sheena R; Chu, Niansheng; Richman, Lee P; Behrens, Edward M

    2015-05-01

    Systemic inflammatory response syndrome describes a heterogeneous group of cytokine storm disorders, with different immunogens and cytokines leading to variations in organ pathology. The severe inflammation generated by the cytokine storm results in widespread organ pathology including alterations in T- and B-lymphocyte counts. This study explores the roles of TLR9 and IFN-?R stimulation in decreasing T- and B-cell lymphopoiesis in a mouse model of hyperinflammation. We demonstrate that early B-cell lymphopoiesis is severely compromised during TLR9- and IFN-?-driven hyperinflammation from the Ly-6D(+) common lymphoid progenitor stage onwards with different effects inhibiting development at multiple stages. We show that TLR9 signaling directly decreases in vitro B-cell yields while increasing T-cell yields. IFN-? also directly inhibits B-cell and T-cell differentiation in vitro as well as when induced by TLR9 in vivo. Microarray and RT-PCR analysis of Ly-6D(-) common lymphoid progenitors point to HOXa9 and EBF-1 as transcription factors altered by TLR9-induced inflammation. Our work demonstrates both cellular and molecular targets that lead to diminished B-cell lymphopoiesis in sustained TLR9- and IFN-?-driven inflammation that may be relevant in a number of infectious and autoimmune/inflammatory settings. PMID:25639361

  12. Primary intestinal diffuse large B-cell lymphoma forming multiple lymphomatous polyposis.

    PubMed

    Barut, Figen; Kandem?r, Nilfer Onak; Karakaya, Kemal; Kkten, Neslihan; Ozdamar, Skru O?uz

    2011-06-01

    Multifocal and skip involvement is quite a rare developmental pattern for primary gastrointestinal lymphomas. A 25-year-old male patient with diffuse large B-cell lymphoma of the small intestine, with macroscopic features and clinical aspects imitating Crohn's disease and attracting attention with cobblestone-like appearance, is presented herein together with the clinical and pathological features.Multiple ulcerated lesions were also observed infiltrating the serosa with polypoid appearance, 2.5 cm in largest diameter, within the resected jejunoileal specimen, which displayed patchy, healthy-appearing mucosal areas. In microscopic examination, a tumoral infiltration was observed comprised of pleomorphic, atypical lymphoid cells with abundant eosinophilic cytoplasm, marked nucleoli and vesicular nuclei. A B-cell phenotype immunoreaction was observed by vimentin, LCA, CD20, and CD79a in those atypical cells. The diagnosis of the case was diffuse large B-cell lymphoma.The possibility of the presence of this disorder, although rare, is emphasized here for patients applying to the hospital with the signs and symptoms of Crohn's disease. PMID:21805425

  13. Epstein-Barr virus in patients with immunodeficiency disorders.

    PubMed

    Okano, M

    2001-09-01

    The Epstein-Barr virus (EBV), one of eight known human herpesviruses, causes a wide spectrum of diseases under certain conditions. In particular, in the setting of immunodeficiency, which includes primary or secondary/acquired immunodeficiencies, they have been increasingly reported. The major clinical phenotype is the EBV genome-positive lymphoproliferative disorder, which ranges from benign lymphoproliferation to malignant lymphoma with cytogenetic alterations. Severe or fatal infectious mononucleosis may develop in some patients with immunodeficiencies such as X-linked lymphoproliferative disease. PMID:11669496

  14. De novo cancers and post-transplant lymphoproliferative disorder in adult liver transplantation.

    PubMed

    Aseni, Paolo; Vertemati, Maurizio; De Carlis, Luciano; Sansalone, Cosimo Vincenzo; Bonacina, Edgardo; Minola, Ernesto; Oreste, Pierluigi; Vizzotto, Laura; Rondinara, Gianfranco

    2006-11-01

    De novo cancer is one of the most serious complications after organ transplantation. Chronic immunosuppression, viral agents, pretransplant chronic alcohol-induced and other addictive behavior-induced injury are important conditions associated with the development of de novo cancers in solid organ transplants. The aim of the study was to evaluate types and clinical course of de novo cancers in adult liver transplant recipients. Data regarding 502 adult patients who underwent to 554 liver transplantations have been collected. Sex, age at transplantation, immunosuppressive regimen, time from transplantation to diagnosis of cancer, cancer type, surgical and non-surgical treatments and follow-up time have been analyzed as well as acute rejection episodes and viral status. Thirty patients developed 31 de novo cancers. The predominant tumors were carcinoma of the skin, lymphomas and Kaposi's sarcoma. Kaposi's sarcoma and lung cancer were associated with greater mortality. In lymphomas and Kaposi's sarcoma, a high rate of graft involvement was observed. In liver transplant recipients, de novo cancers demand strategies focusing on prophylactic and careful long-term screening protocols. Lymphomas and Kaposi's sarcoma should be ruled out in all patients with clinical manifestations of chronic biliary obstruction. PMID:17040297

  15. Epstein-Barr virus (EBV)-positive sporadic burkitt lymphoma: an age-related lymphoproliferative disorder?

    PubMed

    Satou, Akira; Asano, Naoko; Nakazawa, Atsuko; Osumi, Tomoo; Tsurusawa, Masahito; Ishiguro, Atsushi; Elsayed, Ahmed Ali; Nakamura, Naoya; Ohshima, Koichi; Kinoshita, Tomohiro; Nakamura, Shigeo

    2015-02-01

    Epstein-Barr virus (EBV) is detected in 20% to 30% of sporadic Burkitt lymphoma (sBL). However, only a few studies of EBV-positive (EBV) sBL have been reported, and its characteristics still remain controversial. To highlight the features of EBV sBL, we compared the clinicopathologic characteristics of 33 cases of EBV and 117 cases of EBV-negative (EBV) sBL in Japan. EBV sBL showed significantly higher age distribution (median, 42 vs. 13 y; P<0.0001) and higher frequency of patients older than 50 years (48% vs. 16%, P<0.0001). We also revealed the difference of the involved sites. The EBV group showed significantly higher incidence of involvement of tonsil (P=0.027), adrenal gland (P=0.011), and cervical lymph node (P=0.040). In addition, the EBV group tended to have higher incidence of nodal involvement (P=0.078) and involvement of para-aorta lymph node (P=0.084) and heart (P=0.050). In contrast, the gastrointestinal tract was less frequently affected in EBV sBL (P=0.024). In addition, the less positivity for MUM1 (P=0.020) of EBV sBL was highlighted. These results indicate that biological behavior and pathogenesis of EBV sBL might be different from those of EBV sBL. Our results demonstrate that EBV sBL has an aspect of age-related disease and is a distinct clinicopathologic subtype, which should be distinguished from EBV sBL. PMID:25321330

  16. Safety and Tolerability Study of PCI-32765 in B Cell Lymphoma and Chronic Lymphocytic Leukemia

    ClinicalTrials.gov

    2016-01-19

    B-cell Chronic Lymphocytic Leukemia; Small Lymphocytic Lymphoma; Diffuse Well-differentiated Lymphocytic Lymphoma; B Cell Lymphoma; Follicular Lymphoma,; Mantle Cell Lymphoma; Non-Hodgkin's Lymphoma; Waldenstrom Macroglobulinemia; Burkitt Lymphoma; B-Cell Diffuse Lymphoma

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

    SciTech Connect

    Ma, Juan; Usui, Yoshihiko; Department of Ophthalmology, Tokyo Medical University, 6-7-1 Nishi-shinjuku-ku, Tokyo 160-0023 ; Takeda, Kazuyoshi; Harada, Norihiro; Department of Respiratory Medicine, Juntendo University, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421; Research Institute for Diseases of Old Ages, Juntendo University, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421 ; Yagita, Hideo; Okumura, Ko; Akiba, Hisaya

    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.

  18. The B-cell development in tonsillar lymphoid follicles.

    PubMed

    Brandtzaeg, P

    1996-01-01

    The palatine tonsils, and particularly the nasopharyngeal tonsil (adenoid), may be functionally comparable to nasal-associated lymphoid tissue in rodents. Primary follicles occur in human tonsils at 16 weeks' gestation, and formation of germinal centres (GC) takes place shortly after birth. The GC arise in T-cell-dependent B-cell responses and are associated with: i) clonal expansion; ii) somatic hypermutation in immunoglobulin variable (Ig V)-region genes; iii) positive selection of B cells based on affinity for antigen; iv) differentiation to memory B cells and plasma cells; and v) induction of the J-chain gene. The follicular dendritic cells (FDC) of GC retain native antigen which stimulates growth of B-cell blasts and hypermutation of their Ig V genes. The resulting centrocytes die by apoptosis unless they are selected by antigen. Cognate interaction between CD4+ helper T cells and B cells is important to promote downstream switching of the heavy chain constant (CH) genes. In human tonsillar GC this process normally gives rise mainly to IgG (55%-72%) and IgA (13%-18%) immunocytes, both isotypes normally being partially associated with J-chain expression (36% and 29%, respectively). Because J chain is a key peptide in secretory IgA, tonsillar GC may contribute precursor cells to mucosal effector sites. Thus, mucosal immunity can be induced in the airways by nasal immunization, and the level of nasopharyngeal and salivary secretory IgA is decreased after adenotonsillectomy. PMID:9082810

  19. The Role of Latently Infected B Cells in CNS Autoimmunity.

    PubMed

    Mrquez, Ana Citlali; Horwitz, Marc Steven

    2015-01-01

    The onset of multiple sclerosis (MS) is caused by both genetic and environmental factors. Among the environmental factors, it is believed that previous infection with Epstein-Barr virus (EBV) may contribute in the development of MS. EBV has been associated with other autoimmune diseases, such as systemic lupus erythematous, and cancers like Burkitt's lymphoma. EBV establishes a life-long latency in B cells with occasional reactivation of the virus throughout the individual's life. The role played by B cells in MS pathology has been largely studied, yet is not clearly understood. In MS patients, Rituximab, a novel treatment that targets CD20(+) B cells, has proven to have successful results in diminishing the number of relapses in remitting relapsing MS; however, the mechanism of how this drug acts has not been clearly established. In this review, we analyze the evidence of how B cells latently infected with EBV might be altering the immune system response and helping in the development of MS. We will also discuss how animal models, such as experimental autoimmune encephalomyelitis (EAE) and murine gammaherpesvirus-68 (?HV-68), can be used as powerful tools in the study of the relationship between EBV, MS, and B cells. PMID:26579121

  20. B cells as effectors and regulators of autoimmunity.

    PubMed

    Mario, Eliana; Grey, Shane T

    2012-08-01

    A classic understanding of the interplay between B and T cell components of the immune system that drive autoimmunity, where B cells provide an effector function, is represented by systemic lupus erythematosus (SLE), an autoimmune condition characterised by the production of auto-antibodies. In SLE, CD4+T cells provide cognate help to self-reactive B cells, which in turn produce pathogenic auto-antibodies (1). Thus, B cells act as effectors by producing auto-antibody aided by T cell help such that B and T cell interactions are unidirectional. However, this paradigm of B and T cell interactions is challenged by new clinical data demonstrating that B cell depletion is effective for T cell mediated autoimmune diseases including type I diabetes mellitus (T1D) (2), rheumatoid arthritis (3), and multiple sclerosis (4). These clinical data indicate a model whereby B cells can influence the developing autoimmune T cell response, and therefore act as effectors, in ways that extend beyond the production of autoantibody (5). In this review by largely focusing on type I diabetes we will develop a hypothesis that bi-directional B and T interactions control the course of autoimmunity. PMID:22432804

  1. Regulation of germinal center B-cell differentiation.

    PubMed

    Zhang, Yang; Garcia-Ibanez, Laura; Toellner, Kai-Michael

    2016-03-01

    Germinal centers (GC) are the main sites where antigen-activated B-cell clones expand and undergo immunoglobulin gene hypermutation and selection. Iterations of this process will lead to affinity maturation, replicating Darwinian evolution on the cellular level. GC B-cell selection can lead to four different outcomes: further expansion and evolution, apoptosis (non-selection), or output from the GC with differentiation into memory B cells or plasma cells. T-helper cells in GC have been shown to have a central role in regulating B-cell selection by sensing the density of major histocompatibility complex (MHC):peptide antigen complexes. Antigen is provided on follicular dendritic cells in the form of immune complex. Antibody on these immune complexes regulates antigen accessibility by shielding antigen from B-cell receptor access. Replacement of antibody on immune complexes by antibody generated from GC-derived plasma cell output will gradually reduce the availability of antigen. This antibody feedback can lead to a situation where a slow rise in selection stringency caused by a changing environment leads to directional evolution toward higher affinity antibody. PMID:26864101

  2. B-cell antigen-receptor signalling in lymphocyte development

    PubMed Central

    Wang, Leo D; Clark, Marcus R

    2003-01-01

    Signalling through the B-cell antigen receptor (BCR) is required throughout B-cell development and peripheral maturation. Targeted disruption of BCR components or downstream effectors indicates that specific signalling mechanisms are preferentially required for central B-cell development, peripheral maturation and repertoire selection. Additionally, the avidity and the context in which antigen is encountered determine both cell fate and differentiation in the periphery. Although the signalling and receptor components required at each stage have been largely elucidated, the molecular mechanisms through which specific signalling are evoked at each stage are still obscure. In particular, it is not known how the pre-BCR initiates the signals required for normal development or how immature B cells regulate the signalling pathways that determine cell fate. In this review, we will summarize the recent studies that have defined the molecules required for B-cell development and maturation as well as the theories on how signals may be regulated at each stage. PMID:14632637

  3. The Role of Latently Infected B Cells in CNS Autoimmunity

    PubMed Central

    Márquez, Ana Citlali; Horwitz, Marc Steven

    2015-01-01

    The onset of multiple sclerosis (MS) is caused by both genetic and environmental factors. Among the environmental factors, it is believed that previous infection with Epstein–Barr virus (EBV) may contribute in the development of MS. EBV has been associated with other autoimmune diseases, such as systemic lupus erythematous, and cancers like Burkitt’s lymphoma. EBV establishes a life-long latency in B cells with occasional reactivation of the virus throughout the individual’s life. The role played by B cells in MS pathology has been largely studied, yet is not clearly understood. In MS patients, Rituximab, a novel treatment that targets CD20+ B cells, has proven to have successful results in diminishing the number of relapses in remitting relapsing MS; however, the mechanism of how this drug acts has not been clearly established. In this review, we analyze the evidence of how B cells latently infected with EBV might be altering the immune system response and helping in the development of MS. We will also discuss how animal models, such as experimental autoimmune encephalomyelitis (EAE) and murine gammaherpesvirus-68 (γHV-68), can be used as powerful tools in the study of the relationship between EBV, MS, and B cells. PMID:26579121

  4. B-cell depletion in the treatment of lupus nephritis.

    PubMed

    Gregersen, Jon W; Jayne, David R W

    2012-09-01

    Systemic lupus erythematosus (SLE) is a systemic autoimmune disease that is clinically heterogeneous and affects multiple organs. Lupus nephritis is the most frequent severe manifestation of SLE. Conventional immunosuppressive therapy has increased the life expectancy of patients diagnosed with lupus nephritis, but only 70-80% of patients respond to this treatment and its adverse effects are considerable. B cells are central to the pathogenesis of SLE and are, therefore, an attractive therapeutic target. B-cell depletion has been used successfully to treat other autoimmune diseases, such as rheumatoid arthritis and antineutrophil cytoplasmic antibody-associated vasculitis, and many case reports and small nonrandomized trials of B-cell-depleting agents in patients with lupus nephritis have reported positive results. By contrast, two large placebo-controlled trials designed to investigate the efficacy of the B-cell-depleting agents rituximab and ocrelizumab as a treatment for lupus nephritis, failed to meet their primary efficacy end points (LUNAR and BELONG, respectively). This Review discusses the current evidence on the use of B-cell depletion in the treatment of lupus nephritis, which is derived from case studies and clinical trials including a total of over 800 patients. PMID:22801948

  5. 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.

  6. Characterization of phenotypically distinct B-cell subsets and receptor-stimulated mitogen-activated protein kinase activation in human cord blood B cells.

    PubMed

    Ha, Yun Jung; Mun, Yeung-Chul; Seong, Chu-Myong; Lee, Jong Ran

    2008-12-01

    Human cord blood (CB) is a valuable source of hematopoietic stem cells, but clinical reports have indicated slow recovery of B-cell development and function after CB transplantation. To investigate the basis of these B-cell defects in reconstitution, we characterized B cells purified from CB. We compared B-cell receptor activation and B-cell subsets in CB, bone marrow (BM), and peripheral blood (PB). We found that in CB B cells activation of extracellular signal-regulated kinase (ERK) and p38 following ligation of CD40 but not of the B-cell antigen receptor (BCR) was inefficient. The patterns of expression of CD5, CD34, and CD40 in the B-cell population of CB were similar to those in PB rather than in BM. The B cells in CB contained an increased proportion of B cells expressing a high level of CD24 and a low proportion of B cells expressing CD27, pointing to the presence of circulating CD24high immature transitional and CD27(-) naive B cells. CD40-mediated activation of ERK and p38 was also minimal in these B cells of CB. These findings may account for the functional defects of B cells in transplanted CB. PMID:18725396

  7. Transamination of 3-phenylpyruvate in pancreatic B-cell mitochondria.

    PubMed

    Lenzen, S; Rustenbeck, I; Panten, U

    1984-02-25

    High aminotransferase activities catalyzing the reaction between L-glutamate and the aromatic ketomonocarboxylic acid, 3-phenylpyruvate, were observed in the mitochondria from pancreatic B-cells. At very low concentrations of 3-phenylpyruvate, L-glutamine was an effective amino group donor. The aminotransferase activities for the aliphatic ketomonocarboxylic acids, pyruvate and 2-ketoisovalerate, were lower in B-cell mitochondria. High rates of transamination of 2-ketoisocaproate with L-glutamine were observed and may be an important prerequisite for the insulin secretory potency of this 2-keto acid. Since B-cell mitochondria are well supplied with L-glutamine and L-glutamate, 3-phenylpyruvate-induced 2-ketoglutarate production may explain the insulin secretory potency of 3-phenylpyruvate which is not a fuel for pancreatic islet cells. PMID:6142039

  8. 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

  9. Mannose 6 phosphorylation of lysosomal enzymes controls B cell functions

    PubMed Central

    Schweizer, Michaela; Kollmann, Katrin; Schumacher, Vala; Muschol, Nicole; Tolosa, Eva; Mittrcker, Hans-Willi

    2015-01-01

    Antigen processing and presentation and cytotoxic targeting depend on the activities of several lysosomal enzymes that require mannose 6-phosphate (M6P) sorting signals for efficient intracellular transport and localization. In this paper, we show that mice deficient in the formation of M6P residues exhibit significant loss of cathepsin proteases in B cells, leading to lysosomal dysfunction with accumulation of storage material, impaired antigen processing and presentation, and subsequent defects in B cell maturation and antibody production. The targeting of lysosomal and granular enzymes lacking M6P residues is less affected in dendritic cells and T cells and sufficient for maintenance of degradative and lytic functions. M6P deficiency also impairs serum immunoglobulin levels and antibody responses to vaccination in patients. Our data demonstrate the critical role of M6P-dependent transport routes for B cell functions in vivo and humoral immunity in mice and human. PMID:25601403

  10. Expression of Tac antigen in B cell lymphomas.

    PubMed Central

    Laurent, G; Al Saati, T; Olive, D; Laurent, J C; Poncelet, P; Delsol, G

    1986-01-01

    In a series of 55 cases of B cell derived non-Hodgkin's lymphoma the reactivity of two distinct anti-Tac monoclonal antibodies was examined using a sensitive immunoperoxidase technique on cryostat sections. Eighteen out of the thirty-five cases of B cell lymphomas of low or intermediate grade of malignancy were found to be reactive while six out of 20 cases of high-grade malignancy lymphomas showed a positive immunostaining. No correlation was found between anti-Tac reactivity and surface immunoglobulin phenotype, T65 antigen, or calla expression. These findings showed that IL2 receptor expression is not restricted to activated T cells, and raise the question of the possible role of IL2 in the regulation of malignant B cell clone expansion. Images Fig. 1 Fig. 2 PMID:3024885

  11. Dataset of transcriptional landscape of B cell early activation.

    PubMed

    Garruss, Alexander S; Fowler, Trent

    2015-09-01

    Signaling via B cell receptors (BCR) and Toll-like receptors (TLRs) result in activation of B cells with distinct physiological outcomes, but transcriptional regulatory mechanisms that drive activation and distinguish these pathways remain unknown. At early time points after BCR and TLR ligand exposure, 0.5 and 2h, RNA-seq was performed allowing observations on rapid transcriptional changes. At 2h, ChIP-seq was performed to allow observations on important regulatory mechanisms potentially driving transcriptional change. The dataset includes RNA-seq, ChIP-seq of control (Input), RNA Pol II, H3K4me3, H3K27me3, and a separate RNA-seq for miRNA expression, which can be found at Gene Expression Omnibus Dataset GSE61608. Here, we provide details on the experimental and analysis methods used to obtain and analyze this dataset and to examine the transcriptional landscape of B cell early activation. PMID:26484262

  12. 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

  13. EB virus induction is associated with B-cell maturation.

    PubMed Central

    Crawford, D H; Ando, I

    1986-01-01

    EB virus genome-carrying B-cell lines have been double-stained for B-cell activation or maturation antigens and viral antigens using indirect immunofluorescence. The vast majority of cells express activation antigens, whereas the plasma cell antigen PC1 is present on only a few cells. Staining for this antigen doubles with staining for EB viral capsid antigen. Thus it marks cells in the virus replicative cycle, and these cells are negative for the EB virus nuclear antigen EBNA. We suggest that within EB virus genome-carrying B-cell lines the maturation of a few cells to the stage of expression of plasma-cell markers leads to the loss of EBNA expression and consequent loss of the immortalized state of the cell. This would allow completion of the lytic cycle with the production of virus particles and cell death. The implications of these findings are discussed. Images Figure 1 Figure 2 PMID:3025081

  14. 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

  15. Evolution of B-cell malignancy; Pre-B-cell leukemia resulting from MYC activation in a B-cell neoplasm with a rearranged BCL2 gene

    SciTech Connect

    Gauwerky, C.E.; Haluska, F.G.; Tsujimoto, Y.; Nowell, P.C.; Croce, C.M. )

    1988-11-01

    The authors have analyzed the molecular genetics of the breakpoints involved in the t(8;14) and t(14;18) translocations of an acute pre-B-cell leukemia from a patient with a history of follicular lymphoma. In this patient's leukemic cells, the breakpoint of the t(14;18) translocation occurred in the major breakpoint-cluster region of the BCL2 gene and became linked to the J{sub H}4 joining-region gene segment of the immunoglobulin heavy-chain locus on the 14q+ chromosome as previously observed in follicular lymphoma. An N region and heptamer and nonamer signal sequences indicated that this translocation occurred as a mistake in V{sub H}-D{sub H}-J{sub H} joining (where V{sub H} and D{sub H} are the variable and diversity segments). In the t(8;14) translocation, the breakpoint was located immediately 5' of the first exon of the MYC protooncogene, which was juxtaposed with the C{gamma}2 constant gene segment of the second 14q+ chromosome. The finding of repeated sequences typical of switch regions suggested that this translocation occurred during heavy-chain isotype switching, resulting in progression to pre-B-cell leukemia with both the 5(8;14) and the t(14;18) translocations. The terminal deoxynucleotidyltransferase-positive phenotype of the patient's leukemic cells further suggests that the pre-B-cell leukemia was derived from a pre-B cell carrying a t(14;18) translocation in the original follicular lymphoma. The polymerase chain reaction method was then used to identify cancer cells in the bone marrow of the patient.

  16. Antigen Receptor Signals Rescue B Cells From TLR Tolerance

    PubMed Central

    Poovassery, Jayakumar S.; Vanden Bush, Tony J.; Bishop, Gail A.

    2009-01-01

    Interactions between innate and adaptive immune receptors are critical for an optimal immune response, but the role played by antigen receptors in modulating innate receptor functions is less clear. TLRs are a family of pattern recognition receptors that play crucial roles in detecting microbial pathogens and subsequent development of immune responses. However, chronic stimulation through TLRs render immune cells hyporesponsive to subsequent stimulation with TLR ligands; a phenomenon known as TLR tolerance, well characterized in myeloid cells. However, it has not been studied in detail in B lymphocytes. In addition to the BCR, B cells express almost all known TLRs and respond robustly to many TLR ligands. Thus, B cells may receive signals through both TLRs and BCR during an infection and may respond differently to TLR stimulation than myeloid cells. We tested this possibility by stimulating repeatedly through either TLR alone or through both TLR and BCR. Prestimulation through TLR7 resulted in reduced B cell proliferation, cytokine production and IgM secretion upon subsequent TLR7 restimulation. The hyporesponsiveness to TLR7 restimulation was associated with reduced NF-?B and MAP kinase activation and defective c-Jun phosphorylation. However, simultaneous BCR signaling prevented or reversed TLR7 tolerance in both mouse and human B cells. Importantly, BCR signaling also rescued B cells from TLR7-mediated TLR9 tolerance. Additionally, the reversal of TLR7-mediated JNK activation was dependent on phosphatidylinositol 3-kinase activation. Together these results present a novel mechanism to prevent and reverse TLR tolerance in B cells. PMID:19648281

  17. Transcription factors regulating B cell fate in the germinal centre.

    PubMed

    Recaldin, T; Fear, D J

    2016-01-01

    Diversification of the antibody repertoire is essential for the normal operation of the vertebrate adaptive immune system. Following antigen encounter, B cells are activated, proliferate rapidly and undergo two diversification events; somatic hypermutation (followed by selection), which enhances the affinity of the antibody for its cognate antigen, and class-switch recombination, which alters the effector functions of the antibody to adapt the response to the challenge faced. B cells must then differentiate into antibody-secreting plasma cells or long-lived memory B cells. These activities take place in specialized immunological environments called germinal centres, usually located in the secondary lymphoid organs. To complete the germinal centre activities successfully, a B cell adopts a transcriptional programme that allows it to migrate to specific sites within the germinal centre, proliferate, modify its DNA recombination and repair pathways, alter its apoptotic potential and finally undergo terminal differentiation. To co-ordinate these processes, B cells employ a number of 'master regulator' transcription factors which mediate wholesale transcriptomic changes. These master transcription factors are mutually antagonistic and form a complex regulatory network to maintain distinct gene expression programs. Within this network, multiple points of positive and negative feedback ensure the expression of the 'master regulators', augmented by a number of 'secondary' factors that reinforce these networks and sense the progress of the immune response. In this review we will discuss the different activities B cells must undertake to mount a successful T cell-dependent immune response and describe how a regulatory network of transcription factors controls these processes. PMID:26352785

  18. Clostridium butyricum in combination with specific immunotherapy converts antigen-specific B cells to regulatory B cells in asthmatic patients.

    PubMed

    Liao, Hong-Ying; Tao, Li; Zhao, Jian; Qin, Jie; Zeng, Gu-Cheng; Cai, Song-Wang; Li, Yun; Zhang, Jian; Chen, Hui-Guo

    2016-01-01

    The effect of antigen specific immunotherapy (SIT) on asthma is supposed to be improved. Published data indicate that administration of probiotics alleviates allergic diseases. B cells play important roles in the pathogenesis of allergic diseases. This study aims to modulate antigen specific B cell property by the administration of Clostridium butyrate (CB) in combination with SIT. The results showed that after a 3-month treatment, the total asthma clinical score and serum specific IgE were improved in the patients treated with SIT, which was further improved in those treated with both SIT and CB, but not in those treated with CB alone. Treatment with SIT and CB increased p300 and STAT3 activation, up regulated the IL-10 gene transcription and increased the frequency of peripheral antigen specific B cells. In conclusion, administration with SIT in combination with CB converts Der p 1 specific B cells to regulatory B cells in asthma patients allergic to Der p 1. The data suggest a potential therapeutic remedy in the treatment of allergic diseases. PMID:26857726

  19. Clostridium butyricum in combination with specific immunotherapy converts antigen-specific B cells to regulatory B cells in asthmatic patients

    PubMed Central

    Liao, Hong-Ying; Tao, Li; Zhao, Jian; Qin, Jie; Zeng, Gu-Cheng; Cai, Song-Wang; Li, Yun; Zhang, Jian; Chen, Hui-Guo

    2016-01-01

    The effect of antigen specific immunotherapy (SIT) on asthma is supposed to be improved. Published data indicate that administration of probiotics alleviates allergic diseases. B cells play important roles in the pathogenesis of allergic diseases. This study aims to modulate antigen specific B cell property by the administration of Clostridium butyrate (CB) in combination with SIT. The results showed that after a 3-month treatment, the total asthma clinical score and serum specific IgE were improved in the patients treated with SIT, which was further improved in those treated with both SIT and CB, but not in those treated with CB alone. Treatment with SIT and CB increased p300 and STAT3 activation, up regulated the IL-10 gene transcription and increased the frequency of peripheral antigen specific B cells. In conclusion, administration with SIT in combination with CB converts Der p 1 specific B cells to regulatory B cells in asthma patients allergic to Der p 1. The data suggest a potential therapeutic remedy in the treatment of allergic diseases. PMID:26857726

  20. High-efficiency Generation of Multiple Short Noncoding RNA in B-cells and B-cell-derived Extracellular Vesicles.

    PubMed

    Almanza, Gonzalo; Zanetti, Maurizio

    2015-01-01

    Short noncoding (snc)RNAs are important new players in the landscape of biologics with therapeutic potential. Recently, we reported on a new method for the synthesis and delivery of snc RNA in B-cells transfected with plasmid DNA. Here using the same approach, we demonstrate that B-cells can be programmed for the enforced biogenesis and synchronous release of multiple sncRNAs. Our data show that this goal is feasible and that multiple sncRNA are released in the extracellular compartment in amounts comparable to those from B-cells programmed to express and secrete one scnRNA only. Furthermore, we found that the cargo of extracellular vescicles (EVs) isolated from programmed B-cells is remarkably enriched for multiple sncRNA. On average, we found that the content of multiple sncRNAs in EVs is 3.6 copynumber/EV. Collectively, we demonstrate that B-cells can be easily programmed toward the synthesis and release of multiple sncRNAs, including sncRNA-laden EVs, efficiently and specifically. PMID:26670278

  1. The LRF transcription factor regulates mature B cell development and the germinal center response in mice

    PubMed Central

    Sakurai, Nagisa; Maeda, Manami; Lee, Sung-Uk; Ishikawa, Yuichi; Li, Min; Williams, John C.; Wang, Lisheng; Su, Leila; Suzuki, Mai; Saito, Toshiki I.; Chiba, Shigeru; Casola, Stefano; Yagita, Hideo; Teruya-Feldstein, Julie; Tsuzuki, Shinobu; Bhatia, Ravi; Maeda, Takahiro

    2011-01-01

    B cells play a central role in immune system function. Deregulation of normal B cell maturation can lead to the development of autoimmune syndromes as well as B cell malignancies. Elucidation of the molecular features of normal B cell development is important for the development of new target therapies for autoimmune diseases and B cell malignancies. Employing B cellspecific conditional knockout mice, we have demonstrated here that the transcription factor leukemia/lymphoma-related factor (LRF) forms an obligate dimer in B cells and regulates mature B cell lineage fate and humoral immune responses via distinctive mechanisms. Moreover, LRF inactivation in transformed B cells attenuated their growth rate. These studies identify what we believe to be a new key factor for mature B cell development and provide a rationale for targeting LRF dimers for the treatment of autoimmune diseases and B cell malignancies. PMID:21646720

  2. Primary B-cell malignant lymphoma of the lung.

    PubMed

    Canver, C C

    1993-10-01

    A 52-year-old asymptomatic man was evaluated for two right lung lesions discovered on a chest roentgenogram during a routine physical examination. A computed tomographic scan revealed the absence of mediastinal nodal involvement. Guided-needle aspiration cytology was inconclusive. A subsequent right thoracotomy was necessary to perform biopsy of these masses, which proved to be B-cell malignant lymphomas of the lung. This case represents a rare example of a primary low-grade B-cell pulmonary lymphoma of mucosa-associated lymphoid tissue, with its distinct clinicopathologic features. PMID:8215676

  3. Diagnosis and Management of Cutaneous B-cell Lymphoma.

    PubMed

    Pinter-Brown, Lauren C

    2015-10-01

    The diagnosis of primary cutaneous B-cell lymphoma (CBCL) requires that the search for a more widespread lymphoma has been negative. The clinical presentation, outlook, and treatment options of the common types of CBCLs, with emphasis on differences or similarities to their nodal counterparts, are discussed. Treatment may range from observation to topical therapies to systemic therapies, depending on the histology, degree and area of skin involvement, patient performance, and comorbidities. Rare lymphomas, such as intravascular large B-cell lymphoma and Epstein-Barr virus-positive cutaneous lymphoproliferations that are associated with immunodeficiency, are also briefly described. PMID:26433853

  4. Heterogeneity in the differentiation and function of memory B cells.

    PubMed

    Taylor, Justin J; Jenkins, Marc K; Pape, Kathryn A

    2012-12-01

    Vaccines that induce neutralizing antibodies have led to the eradication of small pox and have severely reduced the prevalence of many other infections. However, even the most successful vaccines do not induce protective antibodies in all individuals, and can fail to induce lifelong immunity. A key to remedying these shortcomings may lie in a better understanding of long-lived memory B cells. Recent studies have revealed novel insights into the differentiation and function of these cells, and have shown that the memory B cell pool is much more heterogeneous than previously appreciated. PMID:22920843

  5. Emerging treatment options for B-cell lymphomas.

    PubMed

    Zelenetz, Andrew D

    2015-05-01

    As targeted therapy in B-cell lymphomas rapidly expands beyond anti-CD20 monoclonal antibodies, many newer types of agents are in various stages of development. During his presentation at the NCCN 20th Annual Conference, Dr. Andrew D. Zelenetz explored many of them, including the newer immunoconjugates, the Bruton's tyrosine kinase inhibitor ibrutinib, agents targeting apoptosis such as venetoclax (ABT-199), the immunomodulator lenalidomide, and novel immune checkpoint inhibitors such as nivolumab. To improve outcomes in patients with B-cell lymphomas, these therapies either target the tumor cells and their pathways or focus on the microenvironment and immune modulation. PMID:25995425

  6. Rituximab-induced Cytokine Storm in the Absence of Overt Lymphoproliferative Disease.

    PubMed

    Williams, Mark; Khalid, Tasneem; Hughes, Stephen; Bonney, Denise; Wynn, Robert

    2016-01-01

    Rituximab is a monoclonal antibody that first demonstrated efficacy in the treatment of lymphoma but has since seen a dramatic growth in its use for other conditions. Cytokine release syndrome (CRS) is a rare but potentially fatal complication of rituximab infusion that has been described in patients with bulky lymphoproliferative disease. Here we report a convincing case of CRS occurring in a patient with no demonstrable lymphoproliferation. This case has implications for our understanding of the pathogenesis of CRS, our attempts to define an at-risk population and the design of future monoclonal antibodies. PMID:26583621

  7. Hepatitis C virus-associated neurocognitive and neuropsychiatric disorders: Advances in 2015.

    PubMed

    Monaco, Salvatore; Mariotto, Sara; Ferrari, Sergio; Calabrese, Massimiliano; Zanusso, Gianluigi; Gajofatto, Alberto; Sansonno, Domenico; Dammacco, Franco

    2015-11-14

    Since its identification in 1989, hepatitis C virus (HCV) has emerged as a worldwide health problem with roughly 185 million chronic infections, representing individuals at high risk of developing cirrhosis and liver cancer. In addition to being a frequent cause of morbidity and mortality due to liver disease, HCV has emerged as an important trigger of lymphoproliferative disorders, owing to its lymphotropism, and of a wide spectrum of extra-hepatic manifestations (HCV-EHMs) affecting different organ systems. The most frequently observed HCV-EHMs include mixed cryoglobulinemia and cryoglobulinemic vasculitis, B-cell non-Hodgkin's lymphoma, nephropathies, thyreopathies, type 2 diabetes mellitus, cardiovascular diseases, and several neurological conditions. In addition, neuropsychiatric disorders and neurocognitive dysfunction are reported in nearly 50% of patients with chronic HCV infection, which are independent of the severity of liver disease or HCV replication rates. Fatigue, sleep disturbance, depression and reduced quality of life are commonly associated with neurocognitive alterations in patients with non-cirrhotic chronic HCV infection, regardless of the stage of liver fibrosis and the infecting genotype. These manifestations, which are the topic of this review, typically occur in the absence of structural brain damage or signal abnormalities on conventional brain magnetic resonance imaging (MRI), although metabolic and microstructural changes can be detected by in vivo proton magnetic resonance spectroscopy, perfusion-weighted and diffusion tensor MRI, and neurophysiological tests of cognitive processing. Several lines of evidence, including comparative and longitudinal neuropsychological assessments in patients achieving spontaneous or treatment-induced viral clearance, support a major pathogenic role for HCV in neuropsychiatric and neurocognitive disorders. PMID:26576086

  8. Hepatitis C virus-associated neurocognitive and neuropsychiatric disorders: Advances in 2015

    PubMed Central

    Monaco, Salvatore; Mariotto, Sara; Ferrari, Sergio; Calabrese, Massimiliano; Zanusso, Gianluigi; Gajofatto, Alberto; Sansonno, Domenico; Dammacco, Franco

    2015-01-01

    Since its identification in 1989, hepatitis C virus (HCV) has emerged as a worldwide health problem with roughly 185 million chronic infections, representing individuals at high risk of developing cirrhosis and liver cancer. In addition to being a frequent cause of morbidity and mortality due to liver disease, HCV has emerged as an important trigger of lymphoproliferative disorders, owing to its lymphotropism, and of a wide spectrum of extra-hepatic manifestations (HCV-EHMs) affecting different organ systems. The most frequently observed HCV-EHMs include mixed cryoglobulinemia and cryoglobulinemic vasculitis, B-cell non-Hodgkin’s lymphoma, nephropathies, thyreopathies, type 2 diabetes mellitus, cardiovascular diseases, and several neurological conditions. In addition, neuropsychiatric disorders and neurocognitive dysfunction are reported in nearly 50% of patients with chronic HCV infection, which are independent of the severity of liver disease or HCV replication rates. Fatigue, sleep disturbance, depression and reduced quality of life are commonly associated with neurocognitive alterations in patients with non-cirrhotic chronic HCV infection, regardless of the stage of liver fibrosis and the infecting genotype. These manifestations, which are the topic of this review, typically occur in the absence of structural brain damage or signal abnormalities on conventional brain magnetic resonance imaging (MRI), although metabolic and microstructural changes can be detected by in vivo proton magnetic resonance spectroscopy, perfusion-weighted and diffusion tensor MRI, and neurophysiological tests of cognitive processing. Several lines of evidence, including comparative and longitudinal neuropsychological assessments in patients achieving spontaneous or treatment-induced viral clearance, support a major pathogenic role for HCV in neuropsychiatric and neurocognitive disorders. PMID:26576086

  9. The molecular pathogenesis of B-cell non-Hodgkin lymphoma.

    PubMed

    Blombery, Piers A; Wall, Meaghan; Seymour, John F

    2015-10-01

    The B-cell non-Hodgkin lymphomas (B-NHL) are a diverse group of haematological malignancies which arise from the mature B-lymphocyte compartment. Recently, our understanding of the molecular pathogenesis of these disorders has greatly increased due to technological advances such as high-throughput DNA sequencing techniques. A paradigm of B-NHL pathogenesis has emerged where the normal genetic processes that are central to generating B-cell receptor diversity (somatic hypermutation and class switch/VDJ recombination) also drive the genesis of large-scale, chromosomal-level genetic lesions and smaller-scale gene-level mutations to produce the malignant phenotypes observed. Whilst a significant degree of genetic heterogeneity exists within each B-NHL subtype, the genetic lesions present within each subtype show a degree of convergence on common intracellular signalling, epigenetic and cell cycle pathways. This convergence gives an insight into the key oncogenic drivers of specific B-NHL subtypes and potential targets for therapeutic intervention. This review covers the current understanding of the causative genetic processes of B-NHL, the associated driving molecular lesions and the implications of these findings for the treatment of this group of disorders. PMID:25996166

  10. Does B cell receptor signaling in chronic lymphocytic leukaemia cells differ from that in other B cell types?

    PubMed

    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

  11. 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

  12. Internalization of B cell and pre-B cell receptors is regulated by tyrosine kinase and phosphatase activities.

    PubMed

    Salamero, J; Fougereau, M; Seckinger, P

    1995-10-01

    Prior to the expression of the B cell antigen receptor, the mu heavy chain associates with two non-polymorphic polypeptides, lambda like and VpreB, which form a pseudo-light chain complex in pre-B cells and pre-B cell lines. Surface expression of the so-called pre-B cell receptor (pre-BCR) occurs only in the presence of Ig alpha and Ig beta, known to be involved both in B cell antigen receptor (BCR) signaling and trafficking. Although the pre-BCR organization is consistent with an efficient transport to the cell surface, most of the newly synthesized receptor remains within the cells, and so far, no data are available concerning the rate of exit from the endoplasmic reticulum. Using the human pre-B cell line Nalm-6, we found that only a small fraction (2%) of newly synthesized pre-BCR is transported to the cell surface within 4-6 h after synthesis, where it is constitutively re-internalized. Membrane Ig-heavy chain cross-linking induced internalization of surface pre-BCR within a few minutes, and the mechanisms underlying endocytosis were analyzed by immunofluorescence and confocal microscopy. Preincubation of the cells with either genistein or orthovanadate, which inhibit, respectively, tyrosine kinases and tyrosine phosphatases, blocked pre-BCR internalization in a dose-dependent manner, indicating that both activities are required for endocytosis. BCR internalization was also inhibited in a reversible manner by the drugs. In contrast, neither drug affected the size of the steady-state pool of internalized transferrin receptors. Thus, our data show that tyrosine phosphorylation and dephosphorylation are both required for cross-linking-induced pre-BCR and BCR internalization. PMID:7589068

  13. Decreased production of interleukin-10 and transforming growth factor-? in Toll-like receptor-activated intestinal B cells in SAMP1/Yit mice

    PubMed Central

    Mishima, Yoshiyuki; Ishihara, Shunji; Aziz, Md Monowar; Oka, Akihiko; Kusunoki, Ryusaku; Otani, Aya; Tada, Yasumasa; Li, Yong-Yu; Moriyama, Ichiro; Oshima, Naoki; Yuki, Takafumi; Amano, Yuji; Matsumoto, Satoshi; Kinoshita, Yoshikazu

    2010-01-01

    A unique subset of B cells expressing interleukin-10 (IL-10) and transforming growth factor-? (TGF-?) plays an essential role in preventing inflammation and autoimmunity. We investigated the presence of this cell subset in intestines and its role in the pathogenesis of ileitis using SAMP1/Yit and age-matched control AKR/J mice. Mononuclear cells were isolated from mesenteric lymph nodes (MLNs) and the expressions of B220, CD1d, CD5, Toll-like receptor 4 (TLR4) and TLR9 in isolated cells were analysed. Purified B cells were stimulated with lipopolysaccharide (LPS) or CpG-DNA, then IL-10 and TGF-?1 expressions were examined by enzyme immunoassay and flow cytometry. Production of IL-1? by TLR-mediated macrophages co-cultured with or without purified MLN B cells from SAMP1/Yit and AKR/J mice was evaluated. In addition, interferon-? (IFN-?) production in intestinal T cells co-cultured with MLN B cells were also assessed in SAMP1/Yit and AKR/J strains. The production levels of IL-10 and TGF-?1 stimulated by LPS and CpG-DNA were significantly lower in B cells separated from MLNs from the SAMP1/Yit strain. B cells expressing IL-10 and TGF-?1 were mainly located in a population characterized by the cell surface marker CD1d+. Interleukin-1? production by TLR-activated macrophages co-cultured with MLN B cells from SAMP1/Yit mice was significantly higher than that of those from AKR/J mice. Interestingly, IFN-? production by T cells was noted only when they were co-cultured with SAMP1/Yit but not the AKR/J B cells. These results are the first to show that disorders of regulatory B-cell function under innate immune activation may cause disease pathogenesis in a murine model of Crohn's disease. PMID:20561083

  14. Impact of Gastrointestinal Bacillus anthracis Infection on Hepatic B Cells.

    PubMed

    Colliou, Natacha; Sahay, Bikash; Zadeh, Mojgan; Owen, Jennifer L; Mohamadzadeh, Mansour

    2015-09-01

    Ingestion of Bacillus anthracis results in rapid gastrointestinal (GI) infection, known as GI anthrax. We previously showed that during GI anthrax, there is swift deterioration of intestinal barrier function leading to translocation of gut-associated bacteria into systemic circulation. Additionally, we described dysfunction in colonic B cells. In concordance with our previous studies, here, we report early migration of the Sterne strain of B. anthracis along with other gut-resident bacteria into the infected murine liver. Additionally, despite a global decrease in the B cell population, we observed an increase in both B-1a and marginal zone (MZ)-like B cells. Both of these cell types are capable of producing immunoglobulins against common pathogens and commensals, which act as a general antibody barrier before an antigen-specific antibody response. Accumulation of these cells in the liver was associated with an increase in chemokine expression. These data suggest that the presence of Sterne and other commensals in the liver trigger migration of MZ-like B cells from the spleen to the liver to neutralize systemic spread. Further research is required to evaluate the possible cause of their failure to clear the infection within the liver, including the potential role of dysfunctional mitogen-activated protein kinase (MAPK) signaling. PMID:26402706

  15. 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...

  16. Do Follicular Dendritic Cells Regulate Lupus-specific B Cells?

    PubMed Central

    Heesters, Balthasar A.; Das, Abhishek; Chatterjee, Priyadarshini; Carroll, Michael C.

    2014-01-01

    The factors that allow self-reactive B cells to escape negative selection and become activated remain poorly defined. In this review we describe recently published results in which a B cell receptor-knock-in mouse strain specific for nucleolar self-antigens was bred with mice deficient in complement C4 and discuss the implications for the lupus field. Absence of C4 leads to a breakdown in the elimination of autoreactive B cell clones at the transitional stage. This is characterized by a relative increase in their response to a range of stimuli, entrance into follicles and a greater propensity to form self-reactive germinal centers. In this review, a model is proposed in which, in the absence of complement C4, inappropriate clearance of apoptotic debris promotes chronic activation of myeloid cells and follicular dendritic cells, resulting in secretion of Type I interferon. This allows for the maturation and activation of self-reactive B cell clones leading to increased spontaneous formation of germinal centers and subsequent generation of autoantibodies. PMID:24636642

  17. Multiple Regulatory Mechanisms Control B-1 B Cell Activation

    PubMed Central

    Sindhava, Vishal J.; Bondada, Subbarao

    2012-01-01

    B-1 cells constitute a unique subset of B cells identified in several species including mice and humans. B-1 cells are further subdivided into B-1a and B-1b subsets as the former but not the later express CD5. The B-1a subset contributes to innate type of immune responses while the B-1b B cell subset contributes to adaptive responses. B-1 cell responses to B cell receptor (BCR) as well as Toll-like receptor (TLR) ligation are tightly regulated due to the cross-reactivity of antigen specific receptors on B-1 cells to self-antigens. B-1 cells are elevated in several autoimmune diseases. CD5 plays a major role in down regulation of BCR responses in the B-1a cell subset. Reduced amplification of BCR induced signals via CD19 and autoregulation of BCR and TLR responses by B-1 cell produced IL-10 appear to have a role in regulation of both B-1a and B-1b B cell responses. Siglec G receptors and Lyn kinase also regulate B-1 cell responses but their differential role in the two B-1 cell subsets is unknown. PMID:23251136

  18. The histological classification of diffuse large B-cell lymphomas.

    PubMed

    Xie, Yi; Pittaluga, Stefania; Jaffe, Elaine S

    2015-04-01

    Diffuse large B-cell lymphomas (DLBCLs) are aggressive B-cell neoplasms with considerable clinical, biologic, and pathologic diversity, in part reflecting the functional diversity of the B-cell system and multiple pathways of transformation. In recent years, the advent of new high-throughput genomic technologies has provided new insights into the biology of DLBCL, leading to the identification of distinct molecular identities and novel pathogenetic pathways. This increasing complexity had led to an expanding number of entities in the World Health Organization classification. Using a multi-modality approach, the updated 2008 classification delineated some new subgroups, including DLBCLs associated with particular age groups or specific anatomic sites, as well as two borderline categories (tumors at the interface between classical Hodgkin lymphoma and DLBCL as well as between Burkitt lymphoma and DLBCL). This article reviews the histopathologic features of the various aggressive B-cell lymphoma subtypes included in the 2008 classification, with emphasis on some of the new entities as well as areas of diagnostic challenge. PMID:25805585

  19. The Memory Function of the B Cell Antigen Receptor.

    PubMed

    Wienands, Jrgen; Engels, Niklas

    2016-01-01

    Activated B lymphocytes preserve their antigen experience by differentiating into long-lived pools of antibody-secreting plasma cells or various types of memory B cells (MBCs). The former population constantly produces serum immunoglobulins with sufficient specificity and affinity to thwart infections with recurrent pathogens. By contrast, memory B cell populations retain their antigen receptors on the cell surface and hence need pathogen-induced differentiation steps before they can actively contribute to host defense. The terminal differentiation of MBCs into antibody-secreting plasma cells is hallmarked by the absence of the lag phase characteristic for primary antibody responses. Moreover, secondary antibody responses are predominantly driven by MBCs that bear an antigen receptor of the IgG class on their surface although IgM-positive memory populations exist as well. These fundamental principles of B cell memory were enigmatic for decades. Only recently, we have begun to understand the underlying mechanisms. This review summarizes our current understanding of how different subpopulations of MBCs are generated during primary immune responses and how their functional heterogeneity on antigen recall is controlled by different signaling capabilities of B cell antigen receptor (BCR) isotypes and by the nature of the antigen. PMID:26362935

  20. Impact of Gastrointestinal Bacillus anthracis Infection on Hepatic B Cells

    PubMed Central

    Colliou, Natacha; Sahay, Bikash; Zadeh, Mojgan; Owen, Jennifer L.; Mohamadzadeh, Mansour

    2015-01-01

    Ingestion of Bacillus anthracis results in rapid gastrointestinal (GI) infection, known as GI anthrax. We previously showed that during GI anthrax, there is swift deterioration of intestinal barrier function leading to translocation of gut-associated bacteria into systemic circulation. Additionally, we described dysfunction in colonic B cells. In concordance with our previous studies, here, we report early migration of the Sterne strain of B. anthracis along with other gut-resident bacteria into the infected murine liver. Additionally, despite a global decrease in the B cell population, we observed an increase in both B-1a and marginal zone (MZ)-like B cells. Both of these cell types are capable of producing immunoglobulins against common pathogens and commensals, which act as a general antibody barrier before an antigen-specific antibody response. Accumulation of these cells in the liver was associated with an increase in chemokine expression. These data suggest that the presence of Sterne and other commensals in the liver trigger migration of MZ-like B cells from the spleen to the liver to neutralize systemic spread. Further research is required to evaluate the possible cause of their failure to clear the infection within the liver, including the potential role of dysfunctional mitogen-activated protein kinase (MAPK) signaling. PMID:26402706

  1. Developing novel strategies to target B-cell malignancies.

    PubMed

    Fowler, Nathan; Oki, Yasuhiro

    2013-01-01

    In the past several years we have seen the identification and validation of several key pathways that drive malignant B-cell development. In addition, the effect nonmalignant effector cells within the immune microenvironment have on tumor survival, proliferation, and possibly chemotherapy resistance is increasingly understood. Although there is still much to be learned, this improved understanding combined with rapid advances in medicinal chemistry focusing on structure-based drug design have resulted in a shift in the development of new agents away from traditional chemotherapy to more selective agents targeting key cellular pathways. Examples of "hot" new therapeutic targets include the B-cell receptor signaling pathway, PI3K/mTOR/AKT pathway, histone deacetylases (HDAC), regulators of apoptosis such as the BCL-2 family, the proteasome, and cell-cell interactions within the tumor environment. Many drugs that target specific agents in early clinical development have demonstrated activity in various subtypes of lymphoma and leukemia. Monoclonal and conjugated antibodies targeting cell surface proteins such as CD19, CD22, CD37, and different epitopes of CD20 have also shown promise in relapsed B-cell malignancies and are rapidly moving into efficacy studies. This review will focus on a few of the new nonantibody-based targeted agents in development, their respective pathways, and their activity in various B-cell malignancies. PMID:23714549

  2. Ibrutinib Before and After Stem Cell Transplant in Treating Patients With Relapsed or Refractory Diffuse Large B-cell Lymphoma

    ClinicalTrials.gov

    2015-12-14

    B-Cell Lymphoma, Unclassifiable, With Features Intermediate Between Diffuse Large B-Cell Lymphoma and Burkitt Lymphoma; Recurrent Diffuse Large B-Cell Lymphoma; Refractory Diffuse Large B-Cell Lymphoma

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

    PubMed Central

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

    2015-01-01

    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

  4. B cell autophagy mediates TLR7-dependent autoimmunity and inflammation.

    PubMed

    Weindel, Chi G; Richey, Lauren J; Bolland, Silvia; Mehta, Abhiruchi J; Kearney, John F; Huber, Brigitte T

    2015-01-01

    Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease, defined by loss of B cell self-tolerance that results in production of antinuclear antibodies (ANA) and chronic inflammation. While the initiating events in lupus development are not well defined, overexpression of the RNA-recognizing toll-like receptor (TLR)7 has been linked to SLE in humans and mice. We postulated that autophagy plays an essential role in TLR7 activation of B cells for the induction of SLE by delivering RNA ligands to the endosomes, where this innate immune receptor resides. To test this hypothesis, we compared SLE development in Tlr7 transgenic (Tg) mice with or without B cell-specific ablation of autophagy (Cd19-Cre Atg5(f/f)). We observed that in the absence of B cell autophagy the 2 hallmarks of SLE, ANA and inflammation, were eliminated, thus curing these mice of lupus. This was also evident in the significantly extended survival of the autophagy-deficient mice compared to Tlr7.1 Tg mice. Furthermore, glomerulonephritis was ameliorated, and the serum levels of inflammatory cytokines in the knockout (KO) mice were indistinguishable from those of control mice. These data provide direct evidence that B cells require TLR7-dependent priming through an autophagy-dependent mechanism before autoimmunity is induced, thereafter involving many cell types. Surprisingly, hyper-IgM production persisted in Tlr7.1 Tg mice in the absence of autophagy, likely involving a different activation pathway than the production of autoantibodies. Furthermore, these mice still presented with anemia, but responded with a striking increase in extramedullary hematopoiesis (EMH), possibly due to the absence of pro-inflammatory cytokines. PMID:26120731

  5. Epstein Barr virus-associated lymphoproliferative diseases: the virus as a therapeutic target.

    PubMed

    Tse, Eric; Kwong, Yok-Lam

    2015-01-01

    Epstein Barr virus (EBV)-associated lymphoproliferative diseases (LPDs) express all EBV latent antigens (type III latency) in immunodeficient patients and limited antigens (type I and II latencies) in immunocompetent patients. Post-transplantation lymphoproliferative disease (PTLD) is the prototype exhibiting type III EBV latency. Although EBV antigens are highly immunogenic, PTLD cell proliferation remains unchecked because of the underlying immunosuppression. The restoration of anti-EBV immunity by EBV-specific T cells of either autologous or allogeneic origin has been shown to be safe and effective in PTLDs. Cellular therapy can be improved by establishing a bank of human leukocyte antigen-characterized allogeneic EBV-specific T cells. In EBV+ LPDs exhibiting type I and II latencies, the use of EBV-specific T cells is more limited, although the safety and efficacy of this therapy have also been demonstrated. The therapeutic role of EBV-specific T cells in EBV+ LPDs needs to be critically reappraised with the advent of monoclonal antibodies and other targeted therapy. Another strategy involves the use of epigenetic approaches to induce EBV to undergo lytic proliferation when expression of the viral thymidine kinase renders host tumor cells susceptible to the cytotoxic effects of ganciclovir. Finally, the prophylactic use of antiviral drugs to prevent EBV reactivation may decrease the occurrence of EBV+ LPDs. PMID:25613733

  6. 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

  7. 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.

    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.

  8. The oncoprotein LMO2 is expressed in normal germinal-center B cells and in human B-cell lymphomas

    PubMed Central

    Natkunam, Yasodha; Zhao, Shuchun; Mason, David Y.; Chen, Jun; Taidi, Behnaz; Jones, Margaret; Hammer, Anne S.; Hamilton Dutoit, Stephen; Lossos, Izidore S.; Levy, Ronald

    2007-01-01

    We previously developed a multivariate model based on the RNA expression of 6 genes (LMO2, BCL6, FN1, CCND2, SCYA3, and BCL2) that predicts survival in diffuse large B-cell lymphoma (DLBCL) patients. Since LMO2 emerged as the strongest predictor of superior outcome, we generated a monoclonal anti-LMO2 antibody in order to study its tissue expression pattern. Immunohistologic analysis of over 1200 normal and neoplastic tissue and cell lines showed that LMO2 protein is expressed as a nuclear marker in normal germinal-center (GC) B cells and GC-derived B-cell lines and in a subset of GC-derived B-cell lymphomas. LMO2 was also expressed in erythroid and myeloid precursors and in megakaryocytes and also in lymphoblastic and acute myeloid leukemias. It was rarely expressed in mature T, natural killer (NK), and plasma cell neoplasms and was absent from nonhematolymphoid tissues except for endothelial cells. Hierarchical cluster analysis of immunohistologic data in DLBCL demonstrated that the expression profile of the LMO2 protein was similar to that of other GC-associated proteins (HGAL, BCL6, and CD10) but different from that of non-GC proteins (MUM1/IRF4 and BCL2). Our results warrant inclusion of LMO2 in multivariate analyses to construct a clinically applicable immunohistologic algorithm for predicting survival in patients with DLBCL. PMID:17038524

  9. The oncoprotein LMO2 is expressed in normal germinal-center B cells and in human B-cell lymphomas.

    PubMed

    Natkunam, Yasodha; Zhao, Shuchun; Mason, David Y; Chen, Jun; Taidi, Behnaz; Jones, Margaret; Hammer, Anne S; Hamilton Dutoit, Stephen; Lossos, Izidore S; Levy, Ronald

    2007-02-15

    We previously developed a multivariate model based on the RNA expression of 6 genes (LMO2, BCL6, FN1, CCND2, SCYA3, and BCL2) that predicts survival in diffuse large B-cell lymphoma (DLBCL) patients. Since LMO2 emerged as the strongest predictor of superior outcome, we generated a monoclonal anti-LMO2 antibody in order to study its tissue expression pattern. Immunohistologic analysis of over 1200 normal and neoplastic tissue and cell lines showed that LMO2 protein is expressed as a nuclear marker in normal germinal-center (GC) B cells and GC-derived B-cell lines and in a subset of GC-derived B-cell lymphomas. LMO2 was also expressed in erythroid and myeloid precursors and in megakaryocytes and also in lymphoblastic and acute myeloid leukemias. It was rarely expressed in mature T, natural killer (NK), and plasma cell neoplasms and was absent from nonhematolymphoid tissues except for endothelial cells. Hierarchical cluster analysis of immunohistologic data in DLBCL demonstrated that the expression profile of the LMO2 protein was similar to that of other GC-associated proteins (HGAL, BCL6, and CD10) but different from that of non-GC proteins (MUM1/IRF4 and BCL2). Our results warrant inclusion of LMO2 in multivariate analyses to construct a clinically applicable immunohistologic algorithm for predicting survival in patients with DLBCL. PMID:17038524

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

    PubMed Central

    Rodrguez-Cortez, Virginia C.; del Pino-Molina, Lucia; Rodrguez-Ubreva, Javier; Ciudad, Laura; Gmez-Cabrero, David; Company, Carlos; Urquiza, Jos M.; Tegnr, Jesper; Rodrguez-Gallego, Carlos; Lpez-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

  11. 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

  12. Bone biopsy in haematological disorders.

    PubMed Central

    Burkhardt, R; Frisch, B; Bartl, R

    1982-01-01

    Bone marrow biopsies are now widely used in the investigation and follow-up of many diseases. Semi-thin sections of 8216 undecalcified biopsies of patients with haematological disorders were studied. Observations were made on the cytopenias and the myelodysplastic syndromes, the acute leukaemias the myeloproliferative disorders, Hodgkin's disease and the malignant lymphomas including multiple myeloma, hairy cell leukaemia and angioimmunoblastic lymphadenopathy. Bone marrow biopsies are essential for the differential diagnosis of most cytopenias and for the early recognition of fibrosis which most frequently occurred as a consequence of megakaryocytic proliferation in the myeloproliferative disorders. Different patterns of bone marrow involvement were found in the lymphoproliferative disorders and both their type and extent constituted factors of prognostic significance. A survey of the literature is given and the conclusion is drawn that bone marrow biopsies provide indispensible information for the diagnostic evaluation and the follow-up of patients with haematological disorders. Images PMID:7040489

  13. CD5 Is Dissociated from the B-Cell Receptor in B Cells from Bovine Leukemia Virus-Infected, Persistently Lymphocytotic Cattle: Consequences to B-Cell Receptor-Mediated Apoptosis

    PubMed Central

    Cantor, Glenn H.; Pritchard, Suzanne M.; Dequiedt, Franck; Willems, Luc; Kettmann, Richard; Davis, William C.

    2001-01-01

    Bovine leukemia virus (BLV), a retrovirus related to human T-cell leukemia virus types 1 and 2, can induce persistent nonneoplastic expansion of the CD5+ B-cell population, termed persistent lymphocytosis (PL). As in human CD5+ B cells, we report here that CD5 was physically associated with the B-cell receptor (BCR) in normal bovine CD5+ B cells. In contrast, in CD5+ B cells from BLV-infected PL cattle, CD5 was dissociated from the BCR. In B cells from PL cattle, apoptosis decreased when cells were stimulated with antibody to surface immunoglobulin M (sIgM), while in B cells from uninfected cattle, apoptosis increased after sIgM stimulation. The functional significance of the CD5-BCR association was suggested by experimental dissociation of the CD5-BCR interaction by cross-linking of CD5. This caused CD5+ B cells from uninfected animals to decrease apoptosis when stimulated with anti-sIgM. In contrast, in CD5+ B cells from PL animals, in which CD5 was already dissociated from the BCR, there was no statistically significant change in apoptosis when CD5 was cross-linked and the cells were stimulated with anti-sIgM. Disruption of CD5-BCR interactions and subsequent decreased apoptosis and increased survival in antigenically stimulated B cells may be a mechanism of BLV-induced PL. PMID:11160667

  14. Local B cells and IgE production in the oesophageal mucosa in eosinophilic oesophagitis

    PubMed Central

    Vicario, M; Blanchard, C; Stringer, K F; Collins, M H; Mingler, M K; Ahrens, A; Putnam, P E; Abonia, J P; Santos, J; Rothenberg, M E

    2010-01-01

    Background: Eosinophilic oesophagitis (EO) is an emerging yet increasingly prevalent disorder characterised by a dense and selective eosinophilic infiltration of the oesophageal wall. While EO is considered an atopic disease primarily triggered by food antigens, disparities between standard allergen testing and clinical responses to exclusion diets suggest the participation of distinct antigen-specific immunoglobulin E (IgE) in the pathophysiology of EO. Aim: To find evidence for a local IgE response. Methods: Endoscopic biopsies of the distal oesophagus of atopic and non-atopic EO and control individuals (CTL) were processed for immunohistochemistry and immunofluorescence to assess the presence of B cells, mast cells, and IgE-bearing cells. Oesophageal RNA was analysed for the expression of genes involved in B cell activation, class switch recombination to IgE and IgE production, including germline transcripts (GLTs), activation-induced cytidine deaminase (AID), IgE heavy chain (C?) and mature IgE mRNA using polymerase chain reaction and microarray analysis. Results: Regardless of atopy, EO showed increased density of B cells (p<0.05) and of IgE-bounded mast cells compared to CTL. Both EO and CTL expressed ?GLT, ?GLT, ?4GLT, AID, C? and IgE mRNA. However, the frequency of expression of total GLTs (p?=?0.002), ?GLT (p?=?0.024), and C? (p?=?0.0003) was significantly higher in EO than in CTL, independent of the atopic status. Conclusion: These results support the heretofore unproven occurrence of both local immunoglobulin class switching to IgE and IgE production in the oesophageal mucosa of EO patients. Sensitisation and activation of mast cells involving local IgE may therefore critically contribute to disease pathogenesis. PMID:19528036

  15. DNA Microarray Gene Expression Profile of Marginal Zone versus Follicular B cells and Idiotype Positive Marginal Zone B cells Before and After Immunization with Streptococcus pneumoniae 1

    PubMed Central

    Liu, Jiabin; Behrens, Timothy W.; Kearney, John F.

    2014-01-01

    Marginal Zone (MZ) B cells play an important role in the clearance of blood-borne bacterial infections via rapid T-independent IgM responses. We have previously demonstrated that MZ B cells respond rapidly and robustly to bacterial particulates. To determine the MZ-specific genes that are expressed to allow for this response, MZ and Follicular (FO) B cells were sort-purified and analyzed via DNA microarray analysis. We identified 181 genes that were significantly different between the two B cell populations. 99 genes were more highly expressed in MZ B cells while 82 genes were more highly expressed in FO B cells. To further understand the molecular mechanisms by which MZ B cells respond so rapidly to bacterial challenge, idiotype positive and negative MZ B cells were sort-purified before (0 hour) or after (1 hour) i.v. immunization with heat killed Streptococcus pneumoniae, R36A, and analyzed via DNA microarray analysis. We identified genes specifically up regulated or down regulated at 1 hour following immunization in the idiotype positive MZ B cells. These results give insight into the gene expression pattern in resting MZ vs. FO B cells and the specific regulation of gene expression in antigen-specific MZ B cells following interaction with antigen. PMID:18453586

  16. Infections, B cell receptor activation and autoimmunity: different check-point impairments lead to autoimmunity, clonal B cell expansion and fibrosis in different immunological settings.

    PubMed

    Ferraccioli, Gianfranco; Tolusso, Barbara

    2007-12-01

    B cells as autoantibody producing cells are major players in several autoimmune chronic inflammatory diseases (ACIDs). In some particular settings (i.e. Sjogren's syndrome, rheumatoid arthritis), the activated B cells could undergo malignant clonal expansion. Chronic infections by lymphotropic viruses (hepatitis C virus, Epstein Barr Virus, Herpes 6 and 8 viruses) could amplify the activation process by inducing antiapoptotic signals that lead to a longer survival of B cell subsets. This might then lead, through multiple oncogenic events, to benign first and malignant thereafter clonal B cell expansion. Understanding how the B cell are activated, how the B cell receptor activation can be maintained under control, which check-points could be deregulated and lead to a persistent activation is of crucial importance in benign and malignant diseases. The evidence suggests that the B cells faulty check-points are different in chronic lymphocytic leukaemia, in cryoglobulinemia, rheumatoid arthritis, systemic lupus erythematosus and systemic sclerosis. PMID:18035319

  17. Plasma-cell-predominant B-cell pseudolymphoma.

    PubMed

    Nervi, Stephen J; Schwartz, R A

    2008-01-01

    A 46-year-old woman with no history of foreign travel presented to the New Jersey Medical School Dermatology Clinic in July, 2007, with pruritic ulcerating facial masses that had been present since October, 2006. Clinical and histopathologic findings were most consistent with a diagnosis of cutaneous plasma cell predominant B cell pseudolymphoma. An extensive search using special stains for an etiologic organism was negative. The term cutaneous pseudolymphoma has been coined to describe the accumulation of either T or B cell lymphocytes in the skin that is caused by a nonmalignant stimulus and encompasses several different terms depending on etiology. In cases of cutaneous pseudolymphoma where a cause is identified, treatment entails removing the underlying causative agent. Idiopathic cases tend to be recalcitrant to treatment. PMID:19061611

  18. 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

  19. 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

  20. Memory in the B-cell compartment: antibody affinity maturation.

    PubMed

    Neuberger, M S; Ehrenstein, M R; Rada, C; Sale, J; Batista, F D; Williams, G; Milstein, C

    2000-03-29

    In the humoral arm of the immune system, the memory response is not only more quickly elicited and of greater magnitude than the primary response, but it is also different in quality. In the recall response to antigen, the antibodies produced are of higher affinity and of different isotype (typically immunoglobulin G rather than immunoglobulin M). This maturation rests on the antigen dependence of B-cell maturation and is effected by programmed genetic modifications of the immunoglobulin gene loci. Here we consider how the B-cell response to antigen depends on the affinity of the antigen receptor interaction. We also compare and draw parallels between the two processes, which underpin the generation of secondary-response antibodies: V gene somatic hypermutation and immunoglobulin heavy-chain class switching. PMID:10794054

  1. B-cell precursors in early chicken embryos.

    PubMed Central

    Lebacq, A M; Ritter, M A

    1979-01-01

    The ontogeny of B-cell precursors in chicken embryos from day 3 of incubation onwards has been studied. Purified antibodies to chicken Ig L, gamma, mu, alpha chains were used in a sensitive indirect immunofluorescence assayed on fixed cell smears and wax-embedded tissue sections; the location and morphology of immunoglobulin positive (Ig+) cells were determined either in phase contrast or after histological staining. Lymphoid cells containing small amounts of cytoplasmic immunoglobulin were found in 3 day and older embryonic yolk sac, 11 and 12 day blood, 11, 12 and 13 day bursal mesenchyme. cIg+ large basophilic cells were first seen in 14 day bursal follicles. It is concluded that cells enter the embryonic bursa at different developmental stages: some appear to be uncommitted stem cells, whilst others have already commenced B-cell maturation in an extra-bursal site. Images Figure 1 Figure 2 PMID:381171

  2. 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

  3. B-cell Homeostasis in Chronic Hepatitis C Virus-Related Mixed Cryoglobulinemia is Maintained Through Naïve B-cell Apoptosis

    PubMed Central

    Holz, Lauren E.; Yoon, Joo Chun; Raghuraman, Sukanya; Moir, Susan; Sneller, Michael C.; Rehermann, Barbara

    2012-01-01

    Mixed cryoglobulinemia (MC) is the most common extrahepatic manifestation of chronic hepatitis C virus (HCV) infection. Although the formation of inflammation-triggering immune complexes is driven by clonal expansions of autoreactive B-cells we paradoxically found total B-cell numbers reduced in HCV-infected patients with MC. HCV patients with MC (n=17) also displayed a reduced number and a reduced frequency of naïve B-cells compared to HCV-infected patients without MC (n=19), HBV-infected patients (n=10) and uninfected controls (n=50). This was due to an increased sensitivity of naïve B-cells to apoptosis resulting in a reduction in the size of the naïve B-cell subset. In addition, four-fold expansion and skewing (lower T1/T2-ratio) of the immature B-cell subset was noted in MC patients suggesting that apoptosis of naïve B-cells triggered the release of B-cell precursors from the bone marrow in an attempt to maintain normal B-cell numbers. Following treatment of MC with the B-cell-depleting antibody Rituximab, the size of all B-cell subsets, the T1/T2-ratio and cyroglobulin levels normalized. Cryoglobulin levels correlated with in vivo proliferation of T2 B-cells, suggesting a link between the skewing of the T1/T2-ratio and the formation of immune complexes. Conclusion This study provides insight into the mechanisms maintaining B-cell homeostasis in HCV-induced MC, and the ability of Rituximab therapy to restore normal B-cell compartments. PMID:22556016

  4. Early alterations of B cells in patients with septic shock

    PubMed Central

    2013-01-01

    Introduction It has recently been proposed that B lymphocytes are involved in sepsis pathogenesis. The goal of this study is to investigate potential abnormalities in a subset distribution and activation of circulating B lymphocytes in patients with septic shock. Methods This observational prospective study was conducted in a medical-surgical ICU. All patients with septic shock were eligible for inclusion. B-cell phenotypes (CD19+CD69+, CD19+CD23+, CD19+CD5+, CD19+CD80, CD19+CD86+, CD19+CD40 and CD19+CD95+) were assessed by quantitative flow cytometry upon admission to the ICU and 3, 7, 14 and 28 d later. Results Fifty-two patients were included. Thirty-six healthy volunteers matched for age and sex were used as controls. The patients had lymphopenia that was maintained during 28 d of follow-up. In patients with septic shock who died, the percentage of CD19+CD23+ was lower during the 7 d of follow-up than it was in survival patients. Moreover, the percentage of CD80+ and CD95+ expression on B cells was higher in patients who died than in survivors. Receiver operating characteristic curve analysis showed that a CD19+CD23+ value of 64.6% at ICU admission enabled discrimination between survivors and nonsurvivors with a sensitivity of 90.9% and a specificity of 80.0% (P = 0.0001). Conclusions Patients with septic shock who survive and those who don't have different patterns of abnormalities in circulating B lymphocytes. At ICU admission, a low percentage of CD23+ and a high of CD80+ and CD95+ on B cells were associated with increased mortality of patients with septic shock. Moreover, a drop in circulating B cells persisted during 28 d of ICU follow-up. PMID:23721745

  5. Molecular characterization of primary mediastinal B cell lymphoma.

    PubMed Central

    Tsang, P.; Cesarman, E.; Chadburn, A.; Liu, Y. F.; Knowles, D. M.

    1996-01-01

    Primary mediastinal B cell lymphoma (PMBL) is a diffuse large B cell lymphoma (DLCL) postulated to arise from noncirculating thymic B lymphocytes. Because of its distinctive clinical and morphological features and putative unique cellular origin, PMBL is generally considered a distinct clinicopathological entity. Little is known, however, about the molecular characteristics of PMBL. Therefore, we analyzed 16 PMBLs for molecular alterations involving the bcl-1, bcl-2, bcl-6, c-myc, H-ras, K-ras, N-ras, and p53 genes and for Epstein-Barr virus infection, which are commonly involved in lymphoid neoplasia. Employing a combination of Southern blotting and/or polymerase chain reaction and single-strand conformation polymorphism assays, we detected genetic alterations in 7 of the 16 (44%) PMBLs. Whereas the bcl-6 gene is rearranged in up to 45% of DLCLs, rearrangement of the bcl-6 gene was detected in only 1 of these 16 (6%) PMBLS. Point mutations of the 5' noncoding region of the c-myc gene were demonstrated in 3 other cases (19%), although c-myc gene rearrangements were not seen by Southern blotting. Missense point mutations of the p53 gene were identified in 3 additional PMBLs (19%). Alterations of the bcl-1, bcl-2, or ras genes and evidence of Epstein-Barr virus infection were not observed. In conclusion, a variety of molecular lesions occur in PMBLs and may be involved in their pathogenesis. This molecular genetic pattern bears little resemblance to that known for other B cell malignancies, including DLCL. In particular, the infrequent occurrence of bcl-6 gene rearrangement in PMBLs distinguishes them from other DLCLs of B cell origin, suggesting that PMBLs do not represent a distinct subtype of DLCL. Images Figure 1 Figure 2 Figure 3 Figure 4 PMID:8669486

  6. Akt and mTOR in B Cell Activation and Differentiation

    PubMed Central

    Limon, Jose J.; Fruman, David A.

    2012-01-01

    Activation of phosphoinositide 3-kinase (PI3K) is required for B cell proliferation and survival. PI3K signaling also controls key aspects of B cell differentiation. Upon engagement of the B cell receptor (BCR), PI3K activation promotes Ca2+ mobilization and activation of NFκB-dependent transcription, events which are essential for B cell proliferation. PI3K also initiates a distinct signaling pathway involving the Akt and mTOR serine/threonine kinases. It has been generally assumed that activation of Akt and mTOR downstream of PI3K is essential for B cell function. However, Akt and mTOR have complex roles in B cell fate decisions and suppression of this pathway can enhance certain B cell responses while repressing others. In this review we will discuss genetic and pharmacological studies of Akt and mTOR function in normal B cells, and in malignancies of B cell origin. PMID:22888331

  7. A crucial role for B cells in neuroinvasive scrapie.

    PubMed

    Klein, M A; Frigg, R; Flechsig, E; Raeber, A J; Kalinke, U; Bluethmann, H; Bootz, F; Suter, M; Zinkernagel, R M; Aguzzi, A

    Although prion proteins are most efficiently propagated through intracerebral inoculation, peripheral administration has caused the diseases kuru, iatrogenic Creutzfeldt-Jakob disease (CJD), bovine spongiform encephalopathy (BSE) and new-variant CJD. The development of neurological disease after peripheral inoculation depends on prion expansion within cells of the lymphoreticular system. Here we investigate the identity of these cells by using a panel of immune-deficient mice inoculated with prions intraperitoneally: we found that defects affecting only T lymphocytes had no apparent effect, but that all mutations that disrupted the differentiation and response of B lymphocytes prevented the development of clinical scrapie. As an absence of B cells and of antibodies correlates with severe defects in follicular dendritic cells, a lack of any of these three components may prevent the development of clinical scrapie. However, we found that scrapie developed after peripheral inoculation in mice expressing immunoglobulins that were exclusively of the M subclass and without detectable specificity for the normal form of the prion PrPC, and in mice which had differentiated B cells but no functional follicular dendritic cells. We conclude that differentiated B cells are crucial for neuroinvasion by scrapie, regardless of the specificity of their receptors. PMID:9414161

  8. Immortalized B lymphocytes produce B-cell growth factor.

    PubMed

    Gordon, J; Ley, S C; Melamed, M D; English, L S; Hughes-Jones, N C

    The activation, clonal expansion and terminal differentiation of small resting B lymphocytes primed by an antigen (or antibodies to its receptors) appear to follow an orderly developmental sequence triggered at each stage by distinct soluble cytokines, primarily produced by T lymphocytes. For man, the only known B-cell mitogen independent of accessory cells for its action is the Epstein-Barr virus (EBV). Lymphocytes transformed by EBV are released from the usual constraints on B-cell growth, proliferating continuously in the absence of any exogenous cytokine. The resultant cell lines are of special interest as they possess certain features compatible with a preneoplastic state of Burkitt's lymphoma, one of two human cancers with which the virus is intimately associated. We report here that following EBV-transformation, B lymphoblasts release a soluble factor which mimics the B-cell stimulatory product(s) of mitogen-conditioned T lymphocytes. Furthermore, the virally-transformed cells utilize this activity to sustain their own growth. The ectopic production of an otherwise normal growth factor may represent a critical event in the malignant evolution of human lymphomas harbouring the EBV genome. PMID:6610833

  9. Genetics and diffuse large B-Cell lymphoma.

    PubMed

    Niroula, Rabin; Butera, James

    2015-11-01

    Diffuse large B-Cell lymphoma (DLBCL) is one of the most common and aggressive subtypes of non-Hodgkin's lymphoma (NHL). Gene expression profiling (GEP) studies have identified at least two distinct molecular subtypes of DLBCL termed as germinal center B-cell (GCB) and activated B-cell (ABC). These molecular subtypes represent lymphomas that are driven by very different intracellular oncogenic signaling pathways which have prognostic value and could potentially be exploited for therapeutic benefit in future. There are other oncogenes, namely BCL-2, BCL-6 and MYC, which have been associated with the pathogenesis of DLBCL. Concurrent presence of two oncogenes is present in about 5% of DLBCL and it is termed "double hit lymphoma" (DHL). DHL are associated with an aggressive clinical course and do not respond well to the standard DLBCL immune-chemotherapy regimen, RCHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone). Other aggressive therapeutic approaches including autologous bone marrow transplant have not shown any survival benefit in this subgroup of DLBCL patients. New strategies in development to address this resistance in DHL include the regimen DA-EPOCH-R (dose adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin and rituximab). Recent studies have shown increased sensitivity of DHL to DA-EPOCH-R chemotherapy and will likely be the new standard of care in this subset of DLBCL patients in the future. PMID:26517251

  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. Practical guidelines for B-cell receptor repertoire sequencing analysis.

    PubMed

    Yaari, Gur; Kleinstein, Steven H

    2015-01-01

    High-throughput sequencing of B-cell immunoglobulin repertoires is increasingly being applied to gain insights into the adaptive immune response in healthy individuals and in those with a wide range of diseases. Recent applications include the study of autoimmunity, infection, allergy, cancer and aging. As sequencing technologies continue to improve, these repertoire sequencing experiments are producing ever larger datasets, with tens- to hundreds-of-millions of sequences. These data require specialized bioinformatics pipelines to be analyzed effectively. Numerous methods and tools have been developed to handle different steps of the analysis, and integrated software suites have recently been made available. However, the field has yet to converge on a standard pipeline for data processing and analysis. Common file formats for data sharing are also lacking. Here we provide a set of practical guidelines for B-cell receptor repertoire sequencing analysis, starting from raw sequencing reads and proceeding through pre-processing, determination of population structure, and analysis of repertoire properties. These include methods for unique molecular identifiers and sequencing error correction, V(D)J assignment and detection of novel alleles, clonal assignment, lineage tree construction, somatic hypermutation modeling, selection analysis, and analysis of stereotyped or convergent responses. The guidelines presented here highlight the major steps involved in the analysis of B-cell repertoire sequencing data, along with recommendations on how to avoid common pitfalls. PMID:26589402

  12. Adaptive Response of T and B Cells in Atherosclerosis.

    PubMed

    Ketelhuth, Daniel F J; Hansson, Gran K

    2016-02-19

    Atherosclerosis is a chronic inflammatory disease that is initiated by the retention and accumulation of cholesterol-containing lipoproteins, particularly low-density lipoprotein, in the artery wall. In the arterial intima, lipoprotein components that are generated through oxidative, lipolytic, and proteolytic activities lead to the formation of several danger-associated molecular patterns, which can activate innate immune cells as well as vascular cells. Moreover, self- and non-self-antigens, such as apolipoprotein B-100 and heat shock proteins, can contribute to vascular inflammation by triggering the response of T and B cells locally. This process can influence the initiation, progression, and stability of plaques. Substantial clinical and experimental data support that the modulation of adaptive immune system may be used for treating and preventing atherosclerosis. This may lead to the development of more selective and less harmful interventions, while keeping host defense mechanisms against infections and tumors intact. Approaches such as vaccination might become a realistic option for cardiovascular disease, especially if they can elicit regulatory T and B cells and the secretion of atheroprotective antibodies. Nevertheless, difficulties in translating certain experimental data into new clinical therapies remain a challenge. In this review, we discuss important studies on the function of T- and B-cell immunity in atherosclerosis and their manipulation to develop novel therapeutic strategies against cardiovascular disease. PMID:26892965

  13. Current status of immunotherapy in B cell malignancies.

    PubMed

    Kofler, D M; Mayr, C; Wendtner, C-M

    2006-10-01

    Conventional treatment of hematologic malignancies mainly consists of chemotherapeutic agents or a combination of both, chemotherapy and monoclonal antibodies. Despite recent advances, chemotherapeutic treatments often remain unsatisfying due to severe side effects and incomplete long-term remission. Therefore the evaluation of novel therapeutic options is of great interest. B cell malignancies, in particularly follicular lymphomas, chronic lymphocytic leukemia and multiple myeloma, represent the most immune-responsive types of all human cancer. Several immunotherapeutic strategies are presently employed to combat these B-cell malignancies. Active immunotherapies include vaccination strategies with dendritic cells (DCs) and genetically-modified tumor cell preparations as well as DNA and protein vaccination. Most of these vaccines target the tumor-specific immunoglobulin idiotype and have already demonstrated some anti-lymphoma activity in early phase clinical trials while their definitive impact is evaluated in ongoing phase III randomized trials. In contrast to these active immunizations, T cells transduced with chimeric antigen receptors and donor leukocyte infusions (DLI) represent adoptive (passive) immunotherapies. Recent advances of gene transduction technologies enabled improvement of immunotherapeutic strategies based on genetic modification of malignant cells or adoptive T cells. Current early phase clinical trials are investigating the potential of these innovative approaches. At the moment it remains unclear if the novel immunotherapeutic strategies will be able to play a similar role in the treatment of B cell malignancies than the already established antibody-based immunotherapy. PMID:17073599

  14. B-cell-depleting therapy in systemic lupus erythematosus.

    PubMed

    Ramos-Casals, Manuel; Sanz, Iñaki; Bosch, Xavier; Stone, John H; Khamashta, Munther A

    2012-04-01

    The emergence of a new class of agents (B-cell-depleting therapies) has opened a new era in the therapeutic approach to systemic lupus erythematosus, with belimumab being the first drug licensed for use in systemic lupus erythematosus in more than 50 years. Four agents deserve specific mention: rituximab, ocrelizumab, epratuzumab, and belimumab. Controlled trials have shown negative results for rituximab, promising results for epratuzumab, and positive results for belimumab. Despite these negative results, rituximab is the most-used agent in patients who do not respond or are intolerant to standard therapy and those with life-threatening presentations. B-cell-depleting agents should not be used in patients with mild disease and should be tailored according to individual patient characteristics, including ethnicity, organ involvement, and the immunological profile. Forthcoming studies of B-cell-directed strategies, particularly data from investigations of off-label rituximab use and postmarketing studies of belimumab, will provide new insights into the utility of these treatments in the routine management of patients with systemic lupus erythematosus. PMID:22444096

  15. Effect of Multiple Sclerosis Disease-Modifying Therapies on B Cells and Humoral Immunity.

    PubMed

    Longbrake, Erin E; Cross, Anne H

    2016-02-01

    The unequivocal success of B-cell-depleting agents in reducing magnetic resonance imaging and clinical activity in therapeutic trials indicates that B cells play a vital role in mediating the clinical course of relapsing multiple sclerosis (MS). Although no agent that specifically targets B cells has yet been approved for clinical use, all existing disease-modifying therapies (DMTs) for MS modulate B-cell immunity to some degree. This review examines the effects of MS DMTs on B-cell immunity. Most MS DMTs induced a relative decrease in circulating memory B cells with concomitant expansion of circulating B-cell precursors and/or naive B cells. B-cell function was also altered; most DMTs induced B-cell production of the anti-inflammatory cytokine interleukin 10 while inhibiting B-cell expression of proinflammatory cytokines. The commonalities in the effects of approved DMTs on B-cell phenotype and function among treated patients with MS are striking and suggest that effects on B cells underlie part of their efficacy. More complete understanding of how the existing DMTs modulate B-cell immunity may identify future targets for therapeutic intervention. PMID:26720195

  16. Activated mast cells promote differentiation of B cells into effector cells.

    PubMed

    Palm, Anna-Karin E; Garcia-Faroldi, Gianni; Lundberg, Marcus; Pejler, Gunnar; Kleinau, Sandra

    2016-01-01

    Based on the known accumulation of mast cells (MCs) in B cell-dependent inflammatory diseases, including rheumatoid arthritis, we hypothesized that MCs directly modulate B cells. We show here that degranulated, and to a lesser extent nave or IgE-sensitized, MCs activate both nave and B cell receptor-activated B cells. This was shown by increased proliferation, blast formation, and expression of CD19, MHC class II and CD86 in the B cells. Further, MCs stimulated the secretion of IgM and IgG in IgM(+) B cells, indicating that MCs can induce class-switch recombination in B cells. We also show that coculture of MCs with B cells promotes surface expression of L-selectin, a homing receptor, on the B cells. The effects of MCs on B cells were partly dependent on cell-cell contact and both follicular and marginal zone B cells could be activated by MCs. Our findings suggest that degranulated MCs support optimal activation of B cells, a finding that is in line with in vivo studies showing that MCs frequently degranulate in the context of B-cell driven pathologies such as arthritis. Together, our findings show that MCs have the capacity to differentiate B cells to effector cells. PMID:26847186

  17. Decreased Frequency of Intestinal Regulatory CD5+ B Cells in Colonic Inflammation

    PubMed Central

    Mishima, Yoshiyuki; Ishihara, Shunji; Oka, Akihiko; Fukuba, Nobuhiko; Oshima, Naoki; Sonoyama, Hiroki; Yamashita, Noritsugu; Tada, Yasumasa; Kusunoki, Ryusaku; Moriyama, Ichiro; Yuki, Takafumi; Kawashima, Kousaku; Kinoshita, Yoshikazu

    2016-01-01

    Background CD5+ B cells are a type of regulatory immune cells, though the involvement of this B cell subset in intestinal inflammation and immune regulation is not fully understood. Methods We examined the distribution of CD5+ B cells in various mouse organs. Expression levels of CD11b, IgM, and toll-like receptor (TLR)-4 and -9 in B cells were evaluated. In vitro, TLR-stimulated IL-10 production by colonic lamina propria (LP) CD5+ and CD5- B cells was measured. In vivo, mice with acute or chronic dextran sulfate sodium (DSS)-induced colonic injury were examined, and the frequency of colonic LP CD5+ B cells in those was assessed by flow cytometry. Results The expression level of TLR9 was higher in colonic LP CD5+ B cells as compared to CD5- B cells. Colonic LP CD5+ B cells produced greater amounts of IL-10 following stimulation with TLR ligands, especially TLR9, as compared with the LP CD5- B cells. Acute intestinal inflammation transiently decreased the frequency of colonic LP CD5+ B cells, while chronic inflammation induced a persistent decrease in colonic LP CD5+ B cells and led to a CD5- B cell-dominant condition. Conclusion A persistent altered mucosal B cell population caused by chronic gut inflammation may be involved in the pathogenesis of inflammatory bowel diseases. PMID:26727001

  18. Activated mast cells promote differentiation of B cells into effector cells

    PubMed Central

    Palm, Anna-Karin E.; Garcia-Faroldi, Gianni; Lundberg, Marcus; Pejler, Gunnar; Kleinau, Sandra

    2016-01-01

    Based on the known accumulation of mast cells (MCs) in B cell-dependent inflammatory diseases, including rheumatoid arthritis, we hypothesized that MCs directly modulate B cells. We show here that degranulated, and to a lesser extent naïve or IgE-sensitized, MCs activate both naïve and B cell receptor-activated B cells. This was shown by increased proliferation, blast formation, and expression of CD19, MHC class II and CD86 in the B cells. Further, MCs stimulated the secretion of IgM and IgG in IgM+ B cells, indicating that MCs can induce class-switch recombination in B cells. We also show that coculture of MCs with B cells promotes surface expression of L-selectin, a homing receptor, on the B cells. The effects of MCs on B cells were partly dependent on cell-cell contact and both follicular and marginal zone B cells could be activated by MCs. Our findings suggest that degranulated MCs support optimal activation of B cells, a finding that is in line with in vivo studies showing that MCs frequently degranulate in the context of B-cell driven pathologies such as arthritis. Together, our findings show that MCs have the capacity to differentiate B cells to effector cells. PMID:26847186

  19. 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

  20. Establishment of Murine Gammaherpesvirus Latency in B Cells Is Not a Stochastic Event

    PubMed Central

    Fontinha, Diana; Marques, Sofia; Simas, J. Pedro

    2014-01-01

    Murid ?-herpesvirus-4 (MuHV-4) promotes polyclonal B cell activation and establishes latency in memory B cells via unclear mechanisms. We aimed at exploring whether B cell receptor specificity plays a role in B cell susceptibility to viral latency and how this is related to B cell activation. We first observed that MuHV-4-specific B cells represent a minority of the latent population, and to better understand the influence of the virus on non-MuHV-4 specific B cells we used the SWHEL mouse model, which produce hen egg lysozyme (HEL)-specific B cells. By tracking HEL+ and HEL? B cells, we showed that in vivo latency was restricted to HEL? B cells while the two populations were equally sensitive to the virus in vitro. Moreover, MuHV-4 induced two waves of B cell activation. While the first wave was characterized by a general B cell activation, as shown by HEL+ and HEL? B cells expansion and upregulation of CD69 expression, the second wave was restricted to the HEL? population, which acquired germinal center (GC) and plasma cell phenotypes. Antigenic stimulation of HEL+ B cells led to the development of HEL+ GC B cells where latent infection remained undetectable, indicating that MuHV-4 does not benefit from acute B cell responses to establish latency in non-virus specific B cells but relies on other mechanisms of the humoral response. These data support a model in which the establishment of latency in B cells by ?-herpesviruses is not stochastic in terms of BCR specificity and is tightly linked to the formation of GCs. PMID:25079788

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

    SciTech Connect

    Hong, J.X.; Wilson, G.L.; Fox, C.H.; Kehrl, J.H. )

    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.

  2. Differential impact of Toll-like receptor signaling on distinct B cell subpopulations

    PubMed Central

    Meyer-Bahlburg, Almut; Rawlings, David J.

    2013-01-01

    B cells exhibit a range of functional responses following TLR engagement including immunoglobulin and cytokine production, proliferation, antigen presentation and migration. However, B cell intrinsic TLR responses appear to be precisely programmed based upon the developmental stage of the cell. B cell subpopulations classified as innate immune cells including marginal zone and B-1 B cells exhibit robust responses to TLR stimulation. In contrast, activation of other B cell subsets is constrained via a variety of developmentally regulated events. In this review we provide an overview of TLR responses in murine and human B cells and specifically highlight patterns of TLR expression and developmentally regulated functional responses. PMID:22201817

  3. Pathogen manipulation of B cells: the best defence is a good offence.

    PubMed

    Nothelfer, Katharina; Sansonetti, Philippe J; Phalipon, Armelle

    2015-03-01

    B cells have long been regarded as simple antibody production units, but are now becoming known as key players in both adaptive and innate immune responses. However, several bacteria, viruses and parasites have evolved the ability to manipulate B cell functions to modulate immune responses. Pathogens can affect B cells indirectly, by attacking innate immune cells and altering the cytokine environment, and can also target B cel