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Sample records for aggressive b-cell malignancy

  1. 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

  2. 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

  3. B-cell markers in malignant B-cell lymphoma with scleroderma-like manifestation.

    PubMed

    Van Joost, T; Stolz, E; Blog, F B; Van der Kwast, T H; Vuzevski, V D; Van Dongen, J M

    1984-12-01

    A case is described of malignant B-cell lymphoma with scleroderma-like manifestation. Using different monoclonals as B-cell markers the tumor appeared to be positive for surface immunoglobulins (SmIg) and for B2-antigen, but negative for intracytoplasmic immunoglobulin (CIg), BA2- and FMC7-antigens. Therefore, the tumor could be determined as a highly differentiated Sm-positive early B-cell type of B-cell lymphoma. In this clinically rare manifestation of cutaneous B-cell lymphoma aspects of the cell morphology and of cellular mediated immunity are briefly discussed.

  4. A B-Cell Superantigen Induces the Apoptosis of Murine and Human Malignant B Cells

    PubMed Central

    Lorenzo, Daniela; Duarte, Alejandra; Mundiñano, Juliana; Berguer, Paula; Nepomnaschy, Irene; Piazzon, Isabel

    2016-01-01

    B-cell superantigens (Sags) bind to conserved sites of the VH or VL regions of immunoglobulin molecules outside their complementarity-determining regions causing the apoptosis of normal cognate B cells. No attempts to investigate whether B-cell Sags are able to induce the apoptosis of cognate malignant B cells were reported. In the present study we show that protein L (PpL), secreted by Finegoldia magna, a B-cell Sag which interacts with κ+ bearing cells, induces the apoptosis of murine and human κ+ lymphoma B cells both in vitro and in vivo. Apoptosis was not altered by caspase-8 inhibitor. No alterations in the levels of Bid, Fas and Fas-L were found suggesting that PpL does not activate the extrinsic pathway of apoptosis. The involvement of the intrinsic pathway was clearly indicated by: i) alterations in mitochondrial membrane potential (ΔΨm) both in murine and human lymphoma cells exposed to PpL; ii) decreased levels of apoptosis in the presence of caspase-9 inhibitor; iii) significant increases of Bim and Bax protein levels and downregulation of Bcl-2; iv) the translocation from the cytoplasm to the mitochondria of Bax and Bim pro-apoptotic proteins and its inhibition by caspase-9 inhibitor but not by caspase-8 inhibitor and v) the translocation of Bcl-2 protein from the mitochondria to the cytosol and its inhibition by caspase-9 inhibitor but not by caspase-8 inhibitor. The possibility of a therapeutic use of Sags in lymphoma/leukemia B cell malignancies is discussed. PMID:27603942

  5. A B-Cell Superantigen Induces the Apoptosis of Murine and Human Malignant B Cells.

    PubMed

    Lorenzo, Daniela; Duarte, Alejandra; Mundiñano, Juliana; Berguer, Paula; Nepomnaschy, Irene; Piazzon, Isabel

    2016-01-01

    B-cell superantigens (Sags) bind to conserved sites of the VH or VL regions of immunoglobulin molecules outside their complementarity-determining regions causing the apoptosis of normal cognate B cells. No attempts to investigate whether B-cell Sags are able to induce the apoptosis of cognate malignant B cells were reported. In the present study we show that protein L (PpL), secreted by Finegoldia magna, a B-cell Sag which interacts with κ+ bearing cells, induces the apoptosis of murine and human κ+ lymphoma B cells both in vitro and in vivo. Apoptosis was not altered by caspase-8 inhibitor. No alterations in the levels of Bid, Fas and Fas-L were found suggesting that PpL does not activate the extrinsic pathway of apoptosis. The involvement of the intrinsic pathway was clearly indicated by: i) alterations in mitochondrial membrane potential (ΔΨm) both in murine and human lymphoma cells exposed to PpL; ii) decreased levels of apoptosis in the presence of caspase-9 inhibitor; iii) significant increases of Bim and Bax protein levels and downregulation of Bcl-2; iv) the translocation from the cytoplasm to the mitochondria of Bax and Bim pro-apoptotic proteins and its inhibition by caspase-9 inhibitor but not by caspase-8 inhibitor and v) the translocation of Bcl-2 protein from the mitochondria to the cytosol and its inhibition by caspase-9 inhibitor but not by caspase-8 inhibitor. The possibility of a therapeutic use of Sags in lymphoma/leukemia B cell malignancies is discussed. PMID:27603942

  6. Cell of origin associated classification of B-cell malignancies by gene signatures of the normal B-cell hierarchy.

    PubMed

    Johnsen, Hans Erik; Bergkvist, Kim Steve; Schmitz, Alexander; Kjeldsen, Malene Krag; Hansen, Steen Møller; Gaihede, Michael; Nørgaard, Martin Agge; Bæch, John; Grønholdt, Marie-Louise; Jensen, Frank Svendsen; Johansen, Preben; Bødker, Julie Støve; Bøgsted, Martin; Dybkær, Karen

    2014-06-01

    Recent findings have suggested biological classification of B-cell malignancies as exemplified by the "activated B-cell-like" (ABC), the "germinal-center B-cell-like" (GCB) and primary mediastinal B-cell lymphoma (PMBL) subtypes of diffuse large B-cell lymphoma and "recurrent translocation and cyclin D" (TC) classification of multiple myeloma. Biological classification of B-cell derived cancers may be refined by a direct and systematic strategy where identification and characterization of normal B-cell differentiation subsets are used to define the cancer cell of origin phenotype. Here we propose a strategy combining multiparametric flow cytometry, global gene expression profiling and biostatistical modeling to generate B-cell subset specific gene signatures from sorted normal human immature, naive, germinal centrocytes and centroblasts, post-germinal memory B-cells, plasmablasts and plasma cells from available lymphoid tissues including lymph nodes, tonsils, thymus, peripheral blood and bone marrow. This strategy will provide an accurate image of the stage of differentiation, which prospectively can be used to classify any B-cell malignancy and eventually purify tumor cells. This report briefly describes the current models of the normal B-cell subset differentiation in multiple tissues and the pathogenesis of malignancies originating from the normal germinal B-cell hierarchy. PMID:23998255

  7. Adhesive interactions regulate transcriptional diversity in malignant B cells.

    PubMed

    Nadav-Dagan, Liat; Shay, Tal; Dezorella, Nili; Naparstek, Elizabeth; Domany, Eytan; Katz, Ben-Zion; Geiger, Benjamin

    2010-04-01

    The genetic profiling of B-cell malignancies is rapidly expanding, providing important information on the tumorigenic potential, response to treatment, and clinical outcome of these diseases. However, the relative contributions of inherent gene expression versus microenvironmental effects are poorly understood. The regulation of gene expression programs by means of adhesive interactions was studied here in ARH-77 human malignant B-cell variants, derived from the same cell line by selective adhesion to a fibronectin matrix. The populations included cells that adhere to fibronectin and are highly tumorigenic (designated "type A" cells) and cells that fail to adhere to fibronectin and fail to develop tumors in vivo ("type F" cells). To identify genes directly affected by cell adhesion to fibronectin, type A cells deprived of an adhesive substrate (designated "AF cells") were also examined. Bioinformatic analyses revealed a remarkable correlation between cell adhesion and both B-cell differentiation state and the expression of multiple myeloma (MM)-associated genes. The highly adherent type A cells expressed higher levels of NFkappaB-regulated genes, many of them associated with MM. Moreover, we found that the transcription of several MM-related proto-oncogenes is stimulated by adhesion to fibronectin. In contrast, type F cells, which display poor adhesive and tumorigenic properties, expressed genes associated with higher levels of B-cell differentiation. Our findings indicate that B-cell differentiation, as manifested by gene expression profiles, is attenuated by cell adhesion to fibronectin, leading to upregulation of specific genes known to be associated with the pathogenesis of MM.

  8. Immunomodulatory nonablative conditioning regimen for B-cell lymphoid malignancies

    PubMed Central

    Chinratanalab, Wichai; Reddy, Nishitha; Greer, John P.; Morgan, David; Engelhardt, Brian; Kassim, Adetola; Brandt, Stephen J.; Jagasia, Madan; Goodman, Stacey; Savani, Bipin N.

    2013-01-01

    Twenty-six patients with recurrent CD20+ B-cell lymphoid malignancies received fludarabine, cyclophosphamide, and rituximab–based nonablative conditioning followed by either matched related (n = 18) or unrelated (n = 8) donor allogeneic stem cell transplantation (allo-SCT) between March 2008 and May 2011. Median age of patients at transplantation was 59 years (range, 41–64 years). At diagnosis, 20 (77%) had stage IV disease; 23 (88%) received ≥3 regimens, 14 (54%) received ≥4 regimens, and 4 (15%) had earlier autologous-SCT. All patients had either chemosensitive or stable disease and nine (35%) were in complete remission before transplantation. At the time of analysis, 17 patients were alive with an estimated 2-year overall survival and progression-free survival rate of 63% and nonrelapse mortality of 25%. Grade II to IV acute graft-vs-host-disease occurred in 8 (31%) and chronic graft-vs-host-disease in 6 (23%) patients (extensive, n = 3). Causes of death include progressive disease in four, acute graft-vs-host-disease in two (both after receiving donor lymphocyte infusion for mixed chimerism with residual disease), infection in one, and other (e.g., substance abuse, leukoencephalopathy) in two. Six patients required rehospitalization within 100 days of SCT (mean = 10 days; range, 3–18 days). Our data support fludarabine, cyclophosphamide, and rituximab–based nonablative conditioning allo-SCT in CD20+ B-cell lymphoid malignancies and it is time to compare this regimen with an alternative reduced-intensity conditioning regimen in B-cell malignancies. PMID:22269114

  9. Epiglottic diffuse B-cell malignant lymphoma: A case report

    PubMed Central

    CHANG, HUNG-MIN; LI, CHIUNG-CHON; TSAI, STELLA CHIN-SHAW; TSAO, TANG-YI

    2016-01-01

    A 55-year-old male patient was admitted to our department with complaints of dysphagia and throat soreness for 2 months. A tumor of the left epiglottis, with an irregular surface, was identified by video laryngoscopy. The diagnosis of malignant lymphoma was confirmed by biopsy during laryngomicrosurgery. The atypical diffuse lymphocytic lymphoma was positive for CD20 and Bcl-2, and negative for CD3, CD10 and Bcl-1. The diagnosis was diffuse large B-cell malignant lymphoma. The patient was treated with eight cycles of rituximab with cyclophosphamide + doxorubicin + vincristine + prednisolone (R-CHOP regimen). This is a rare case of extranodal non-Hodgkin lymphoma occurring in the epiglottis. PMID:26870358

  10. B-cell receptor signaling inhibitors for treatment of autoimmune inflammatory diseases and B-cell malignancies.

    PubMed

    Puri, Kamal D; Di Paolo, Julie A; Gold, Michael R

    2013-08-01

    B-cell receptor (BCR) signaling is essential for normal B-cell development, selection, survival, proliferation, and differentiation into antibody-secreting cells. Similarly, this pathway plays a key role in the pathogenesis of multiple B-cell malignancies. Genetic and pharmacological approaches have established an important role for the Spleen tyrosine kinase (Syk), Bruton's tyrosine kinase (Btk), and phosphatidylinositol 3-kinase isoform p110delta (PI3Kδ) in coupling the BCR and other BCRs to B-cell survival, migration, and activation. In the past few years, several small-molecule inhibitory drugs that target PI3Kδ, Btk, and Syk have been developed and shown to have efficacy in clinical trials for the treatment of several types of B-cell malignancies. Emerging preclinical data have also shown a critical role of BCR signaling in the activation and function of self-reactive B cells that contribute to autoimmune diseases. Because BCR signaling plays a major role in both B-cell-mediated autoimmune inflammation and B-cell malignancies, inhibition of this pathway may represent a promising new strategy for treating these diseases. This review summarizes recent achievements in the mechanism of action, pharmacological properties, and clinical activity and toxicity of these BCR signaling inhibitors, with a focus on their emerging role in treating lymphoid malignancies and autoimmune disorders.

  11. Tumor microenvironment (TME)-driven immune suppression in B cell malignancy.

    PubMed

    Nicholas, Nicole S; Apollonio, Benedetta; Ramsay, Alan G

    2016-03-01

    Immune checkpoint blockade antibodies and immunomodulatory drugs can unleash anti-tumor T cell immunity and mediate durable cancer regressions. However, only a fraction of patients currently respond to immunotherapy. Lymphoid malignancies are known to have clinically exploitable immune sensitivity and their intrinsic lymphoid tumor-microenvironment (TME) should make them natural targets for immunotherapy. However, accumulating evidence is showing that malignant cells engage in novel associations/interdependencies with reprogrammed immune and stromal cells in the TME that provide crucial contributions to the licencing of tumour progression and immune evasion (suppression of antitumor immune responses). In this review, we outline TME-driven contributions to the licencing of immune evasion mechanisms including the expression and activity of the immune checkpoint network, focussing on two types of B cell malignancy: indolent chronic lymphocytic leukemia (CLL) and aggressive diffuse large B-cell lymphoma (DLBCL). We also highlight recent therapeutic strategies to re-educate the TME to have anti-tumorigenic effects. This article is part of a Special Issue entitled: Tumor Microenvironment Regulation of Cancer Cell Survival, Metastasis, Inflammation, and Immune Surveillance edited by Peter Ruvolo and Gregg L. Semenza.

  12. Ultrasonographic features of aggressive primary thyroid diffuse B-cell lymphoma: A report of two cases

    PubMed Central

    HU, GUOBING; ZHU, XIANGMING

    2016-01-01

    Primary thyroid lymphoma (PTL) is a relatively rare malignant tumor. Aggressive PTL is extremely rare, and there is limited literature regarding the imaging features of PTL with invasion into adjacent structures, including internal jugular vein, muscles, esophagus, trachea and carotid artery. In addition, the ultrasonographic features of the cases presented in the current report differ from those reported in previous studies. In the present study, two cases of PTL, who presented to The First Affiliated Hospital of Wannan Medical College (Wuhu, China) with a short history of a rapidly growing mass in the front of their neck, are reported. Both patients had undergone ultrasound examination, and the subsequent histopathological and immunohistochemical examinations confirmed that the two masses were primary diffuse large B-cell lymphoma. The ultrasonographic findings of these two cases are discussed in the present report. PMID:27073503

  13. Targeted Therapies in Adult B-Cell Malignancies

    PubMed Central

    Rossi, Jean-François

    2015-01-01

    B-lymphocytes are programmed for the production of immunoglobulin (Ig) after antigen presentation, in the context of T-lymphocyte control within lymphoid organs. During this differentiation/activation process, B-lymphocytes exhibit different restricted or common surface markers, activation of cellular pathways that regulate cell cycle, metabolism, proteasome activity, and protein synthesis. All molecules involved in these different cellular mechanisms are potent therapeutic targets. Nowadays, due to the progress of the biology, more and more targeted drugs are identified, a situation that is correlated with an extended field of the targeted therapy. The full knowledge of the cellular machinery and cell-cell communication allows making the best choice to treat patients, in the context of personalized medicine. Also, focus should not be restricted to the immediate effects observed as clinical endpoints, that is, response rate, survival markers with conventional statistical methods, but it should consider the prediction of different clinical consequences due to other collateral drug targets, based on new methodologies. This means that new reflection and new bioclinical follow-up have to be monitored, particularly with the new drugs used with success in B-cell malignancies. This review discussed the principal aspects of such evident bioclinical progress. PMID:26425544

  14. Oncogenic Properties of Apoptotic Tumor Cells in Aggressive B Cell Lymphoma

    PubMed Central

    Ford, Catriona A.; Petrova, Sofia; Pound, John D.; Voss, Jorine J.L.P.; Melville, Lynsey; Paterson, Margaret; Farnworth, Sarah L.; Gallimore, Awen M.; Cuff, Simone; Wheadon, Helen; Dobbin, Edwina; Ogden, Carol Anne; Dumitriu, Ingrid E.; Dunbar, Donald R.; Murray, Paul G.; Ruckerl, Dominik; Allen, Judith E.; Hume, David A.; van Rooijen, Nico; Goodlad, John R.; Freeman, Tom C.; Gregory, Christopher D.

    2015-01-01

    Summary Background Cells undergoing apoptosis are known to modulate their tissue microenvironments. By acting on phagocytes, notably macrophages, apoptotic cells inhibit immunological and inflammatory responses and promote trophic signaling pathways. Paradoxically, because of their potential to cause death of tumor cells and thereby militate against malignant disease progression, both apoptosis and tumor-associated macrophages (TAMs) are often associated with poor prognosis in cancer. We hypothesized that, in progression of malignant disease, constitutive loss of a fraction of the tumor cell population through apoptosis could yield tumor-promoting effects. Results Here, we demonstrate that apoptotic tumor cells promote coordinated tumor growth, angiogenesis, and accumulation of TAMs in aggressive B cell lymphomas. Through unbiased “in situ transcriptomics” analysis—gene expression profiling of laser-captured TAMs to establish their activation signature in situ—we show that these cells are activated to signal via multiple tumor-promoting reparatory, trophic, angiogenic, tissue remodeling, and anti-inflammatory pathways. Our results also suggest that apoptotic lymphoma cells help drive this signature. Furthermore, we demonstrate that, upon induction of apoptosis, lymphoma cells not only activate expression of the tumor-promoting matrix metalloproteinases MMP2 and MMP12 in macrophages but also express and process these MMPs directly. Finally, using a model of malignant melanoma, we show that the oncogenic potential of apoptotic tumor cells extends beyond lymphoma. Conclusions In addition to its profound tumor-suppressive role, apoptosis can potentiate cancer progression. These results have important implications for understanding the fundamental biology of cell death, its roles in malignant disease, and the broader consequences of apoptosis-inducing anti-cancer therapy. PMID:25702581

  15. MicroRNAs in B-cells: from normal differentiation to treatment of malignancies

    PubMed Central

    Marques, Sara Correia; Laursen, Maria Bach; Bødker, Julie Støve; Kjeldsen, Malene Krag; Falgreen, Steffen; Schmitz, Alexander; Bøgsted, Martin; Johnsen, Hans Erik; Dybkaer, Karen

    2015-01-01

    MicroRNAs (miRNAs) are small non-coding RNAs that play important post-transcriptional regulatory roles in a wide range of biological processes. They are fundamental to the normal development of cells, and evidence suggests that the deregulation of specific miRNAs is involved in malignant transformation due to their function as oncogenes or tumor suppressors. We know that miRNAs are involved in the development of normal B-cells and that different B-cell subsets express specific miRNA profiles according to their degree of differentiation. B-cell-derived malignancies contain transcription signatures reminiscent of their cell of origin. Therefore, we believe that normal and malignant B-cells share features of regulatory networks controlling differentiation and the ability to respond to treatment. The involvement of miRNAs in these processes makes them good biomarker candidates. B-cell malignancies are highly prevalent, and the poor overall survival of patients with these malignancies demands an improvement in stratification according to prognosis and therapy response, wherein we believe miRNAs may be of great importance. We have critically reviewed the literature, and here we sum up the findings of miRNA studies in hematological cancers, from the development and progression of the disease to the response to treatment, with a particular emphasis on B-cell malignancies. PMID:25622103

  16. SAR3419: an anti-CD19-Maytansinoid Immunoconjugate for the treatment of B-cell malignancies.

    PubMed

    Blanc, Veronique; Bousseau, Anne; Caron, Anne; Carrez, Chantal; Lutz, Robert J; Lambert, John M

    2011-10-15

    SAR3419 is a novel anti-CD19 humanized monoclonal antibody conjugated to a maytansine derivate through a cleavable linker for the treatment of B-cell malignancies. SAR3419 combines the strengths of a high-potency tubulin inhibitor and the exquisite B-cell selectivity of an anti-CD19 antibody. The internalization and processing of SAR3419, following its binding at the surface of CD19-positive human lymphoma cell lines and xenograft models, release active metabolites that trigger cell-cycle arrest and apoptosis, leading to cell death and tumor regression. SAR3419 has also been shown to be active in different lymphoma xenograft models, including aggressive diffuse large B-cell lymphoma, resulting in complete regressions and tumor-free survival. In these models, the activity of SAR3419 compared favorably with rituximab and lymphoma standard of care chemotherapy. Two phase I trials with 2 different schedules of SAR3419 as a single agent were conducted in refractory/relapsed B-cell non-Hodgkin lymphoma. Activity was reported in both schedules, in heavily pretreated patients of both follicular and diffuse large B-cell lymphoma subtypes, with a notable lack of significant hematological toxicity, validating SAR3419 as an effective antibody-drug conjugate and opening opportunities in the future. Numerous B-cell-specific anti-CD19 biologics are available to treat B-cell non-Hodgkin lymphoma, and early phase I results obtained with SAR3419 suggest that it is a promising candidate for further development in this disease. In addition, thanks to the broad expression of CD19, SAR3419 may provide treatment options for B-cell leukemias that are often CD20-negative. PMID:22003072

  17. Signaling Proteins and Transcription Factors in Normal and Malignant Early B Cell Development

    PubMed Central

    Pérez-Vera, Patricia; Reyes-León, Adriana; Fuentes-Pananá, Ezequiel M.

    2011-01-01

    B cell development starts in bone marrow with the commitment of hematopoietic progenitors to the B cell lineage. In murine models, the IL-7 and preBCR receptors, and the signaling pathways and transcription factors that they regulate, control commitment and maintenance along the B cell pathway. E2A, EBF1, PAX5, and Ikaros are among the most important transcription factors controlling early development and thereby conditioning mice homeostatic B cell lymphopoiesis. Importantly, their gain or loss of function often results in malignant development in humans, supporting conserved roles for these transcription factors. B cell acute lymphoblastic leukemia is the most common cause of pediatric cancer, and it is characterized by unpaired early B cell development resulting from genetic lesions in these critical signaling pathways and transcription factors. Fine mapping of these genetic abnormalities is allowing more specific treatments, more accurately predicting risk profiles for this disease, and improving survival rates. PMID:22046564

  18. Signaling proteins and transcription factors in normal and malignant early B cell development.

    PubMed

    Pérez-Vera, Patricia; Reyes-León, Adriana; Fuentes-Pananá, Ezequiel M

    2011-01-01

    B cell development starts in bone marrow with the commitment of hematopoietic progenitors to the B cell lineage. In murine models, the IL-7 and preBCR receptors, and the signaling pathways and transcription factors that they regulate, control commitment and maintenance along the B cell pathway. E2A, EBF1, PAX5, and Ikaros are among the most important transcription factors controlling early development and thereby conditioning mice homeostatic B cell lymphopoiesis. Importantly, their gain or loss of function often results in malignant development in humans, supporting conserved roles for these transcription factors. B cell acute lymphoblastic leukemia is the most common cause of pediatric cancer, and it is characterized by unpaired early B cell development resulting from genetic lesions in these critical signaling pathways and transcription factors. Fine mapping of these genetic abnormalities is allowing more specific treatments, more accurately predicting risk profiles for this disease, and improving survival rates.

  19. Malignant transformation of aggressive osteoblastoma to ostesarcoma.

    PubMed

    Görgün, Ömer; Salduz, Ahmet; Kebudi, Rejin; Özger, Harzem; Bilgiç, Bilge

    2016-08-01

    Osteoblastoma is a rare, bone-forming tumor, characterized by osteoid and woven bone production. A 13-year-old boy patient presented to our clinic with complaint of pain in his left proximal tibia. We performed curettage and bone grafting for the lesion diagnosed as osteoblastoma. Two years later, the patient admitted to the hospital with a mass in the same region which was diagnosed by biopsy to be osteosarcoma. Patient was performed reconstruction operation with local resection and mega prosthesis. Fourteen months after termination of chemotherapy, lung metastasis developed and the patient died consequently. In this article, we reported a patient with aggressive osteoblastoma of the left proximal tibia which recurred as an osteosarcoma and discussed the difficulties in the histopathological diagnosis and management of these patients. As some other cases in the literature, our case indicates that osteoblastomas may undergo malignant transformation. PMID:27499324

  20. Primary Malignant B-cell Lymphoma of the Epididymis

    PubMed Central

    Suh, Jungyo; Jeong, Hyeon; Kim, Young A.

    2015-01-01

    Primary epididymal lymphomas are very rare condition, only 6 case report was published. In 4 of them, initial presentation was non-tender, continuous growth of testis. It can be misdiagnosed with epididymitis, 5 of them was treated by antibiotics before surgery. One patients treated by surgery another 5 makes neoadjuvant therapy, 2 of radiotherapy 3 of chemotherapy. Only one man died after treatment. This case is about 54-year male patients, diagnosed by diffuse large B-cell lymphoma, who treated by surgery and neoadjuvant chemotherapy combined with radiotherapy. PMID:26793572

  1. Gaucher disease and comorbidities: B-cell malignancy and parkinsonism.

    PubMed

    Cox, Timothy M; Rosenbloom, Barry E; Barker, Roger A

    2015-07-01

    Data emerging from the International Collaborative Gaucher Group (ICGG) Gaucher Registry together with other contemporary clinical surveys have revealed a close association between Gaucher disease and non-Hodgkin's B-cell lymphoma and myeloma and Gaucher disease and Parkinson's disease. Several possible explanations for increased B-cell proliferation and neoplasia in Gaucher disease have been proposed, including the possible influence of sphingosine (derived from the extra lysosomal metabolism of glucosylceramide), gene modifiers, splenectomy and immune system deregulation induced by cytokines, chemokines, and hydrolases released from Gaucher cells. Parkinson's disease is frequently seen in the otherwise-healthy relatives of Gaucher disease patients leading to the finding that GBA mutations represent a genetic risk factor for Parkinson's disease. The mechanism of the association between GBA mutations and Parkinson's disease has yet to be elucidated but the pathogenesis appears distinct from that of Gaucher disease. Several pathogenic pathways have been proposed including lysosomal and/or mitochondrial dysfunction. The effect of Gaucher disease specific therapies on the incidence of cancer or Parkinson's disease are not clear and will likely be evaluated in future ICGG Gaucher Registry studies. PMID:26096744

  2. Loss of SIRT3 Provides Growth Advantage for B Cell Malignancies.

    PubMed

    Yu, Wei; Denu, Ryan A; Krautkramer, Kimberly A; Grindle, Kreg M; Yang, David T; Asimakopoulos, Fotis; Hematti, Peiman; Denu, John M

    2016-02-12

    B cell malignancies comprise a diverse group of cancers that proliferate in lymph nodes, bone marrow, and peripheral blood. SIRT3 (sirtuin 3) is the major deacetylase within the mitochondrial matrix that promotes aerobic metabolism and controls reactive oxygen species (ROS) by deacetylating and activating isocitrate dehydrogenase 2 (IDH2) and superoxide dismutase 2 (SOD2). There is controversy as to whether SIRT3 acts as an oncogene or a tumor suppressor, and here we investigated its role in B cell malignancies. In mantle cell lymphoma patient samples, we found that lower SIRT3 protein expression was associated with worse overall survival. Further, SIRT3 protein expression was reduced in chronic lymphocytic leukemia primary samples and malignant B cell lines compared to primary B cells from healthy donors. This lower level of expression correlated with hyperacetylation of IDH2 and SOD2 mitochondrial proteins, lowered enzymatic activities, and higher ROS levels. Overexpression of SIRT3 decreased proliferation and diminished the Warburg-like phenotype in SIRT3-deficient cell lines, and this effect is largely dependent on deacetylation of IDH2 and SOD2. Lastly, depletion of SIRT3 from malignant B cell lines resulted in greater susceptibility to treatment with an ROS scavenger but did not result in greater sensitivity to inhibition of the hypoxia-inducible factor-1α pathway, suggesting that loss of SIRT3 increases proliferation via ROS-dependent but hypoxia-inducible factor-1α-independent mechanisms. Our study suggests that SIRT3 acts as a tumor suppressor in B cell malignancies, and activating the SIRT3 pathway might represent a novel therapeutic approach for treating B cell malignancies. PMID:26631723

  3. Targeting the B cell receptor signaling pathway in B lymphoid malignancies

    PubMed Central

    Buchner, Maike; Müschen, Markus

    2014-01-01

    PURPOSE OF REVIEW Normal B cells that failed to productively rearrange immunoglobulin V region genes, encoding a functional B cell receptor (BCR) are destined to die. Likewise, the majority of B cell malignancies remain dependent on functional BCR signaling, while in some subtypes BCR expression is missing and, apparently, counterselected. Here we summarize recent the experimental evidence for the importance of BCR signaling and clinical concepts to target the BCR pathway in B cell leukemia and lymphoma. RECENT FINDINGS While the dependency on pre-BCR signaling in pre-B acute lymphoblastic leukemia (ALL) seems to be limited to few ALL subtypes (e.g. TCF3-PBX1), most mature B cell lymphomas rely on BCR signaling provided by different stimuli e.g. tonic B cell signaling, chronic (auto)-antigen exposure, and self-binding properties of the BCR. The finding that in chronic lymphocytic leukemia (CLL), BCRs bind to an epitope on the BCR itself unravels a novel concept for CLL pathogenesis. SUMMARY Targeting of the B cell receptor tyrosine kinases SYK, BTK, and PI3K achieve promising clinical responses in various mature B cell malignancies and might also be useful in defined subsets of ALL. However, further understanding of the BCR signal integration in the different disease groups are required to accurately predict, which groups of patients will benefit from BCR pathway-inhibition. PMID:24811161

  4. Development of a Malignancy-Associated Proteomic Signature for Diffuse Large B-Cell Lymphoma

    PubMed Central

    Romesser, Paul B.; Perlman, David H.; Faller, Douglas V.; Costello, Catherine E.; McComb, Mark E.; Denis, Gerald V.

    2009-01-01

    The extreme pathological diversity of non-Hodgkin’s lymphomas has made their accurate histological assessment difficult. New diagnostics and treatment modalities are urgently needed for these lymphomas, particularly in drug development for cancer-specific targets. Previously, we showed that a subset of B cell lymphoma, diffuse large B cell lymphoma, may be characterized by two major, orthogonal axes of gene expression: one set of transcripts that is differentially expressed between resting and proliferating, nonmalignant cells (ie, a “proliferative signature”) and another set that is expressed only in proliferating malignant cells (ie, a “cancer signature”). A differential proteomic analysis of B cell proliferative states, similar to previous transcriptional profiling analyses, holds great promise either to reveal novel factors that participate in lymphomagenesis or to define biomarkers of onset or progression. Here, we use a murine model of diffuse large B cell lymphoma to conduct unbiased two-dimensional gel electrophoresis and mass spectrometry-based comparative proteomic analyses of malignant proliferating B cells and tissue-matched, normal resting, or normal proliferating cells. We show that the expression patterns of particular proteins or isoforms across these states fall into eight specific trends that provide a framework to identify malignancy-associated biomarkers and potential drug targets, a signature proteome. Our results support the central hypothesis that clusters of proteins of known function represent a panel of expression markers uniquely associated with malignancy and not normal proliferation. PMID:19498000

  5. Modulation of B-cell receptor and microenvironment signaling by a guanine exchange factor in B-cell malignancies

    PubMed Central

    Liao, Wei; Sharma, Sanjai

    2016-01-01

    Objective: Chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL) cells over-express a guanine exchange factor (GEF), Rasgrf-1. This GEF increases active Ras as it catalyzes the removal of GDP from Ras so that GTP can bind and activate Ras. This study aims to study the mechanism of action of Rasgrf-1 in B-cell malignancies. Methods: N-terminus truncated Rasgrf-1 variants have a higher GEF activity as compared to the full-length transcript therefore a MCL cell line with stable over-expression of truncated Rasgrf-1 was established. The B-cell receptor (BCR) and chemokine signaling pathways were compared in the Rasgrf-1 over-expressing and a control transfected cell line. Results: Cells over-expressing truncated form of Rasgrf-1 have a higher proliferative rate as compared to control transfected cells. BCR was activated by lower concentrations of anti-IgM antibody in Rasgrf-1 over-expressing cells as compared to control cells indicating that these cells are more sensitive to BCR signaling. BCR signaling also phosphorylates Rasgrf-1 that further increases its GEF function and amplifies BCR signaling. This activation of Rasgrf-1 in over-expressing cells resulted in a higher expression of phospho-ERK, AKT, BTK and PKC-alpha as compared to control cells. Besides BCR, Rasgrf-1 over-expressing cells were also more sensitive to microenvironment stimuli as determined by resistance to apoptosis, chemotaxis and ERK pathway activation. Conclusions: This GEF protein sensitizes B-cells to BCR and chemokine mediated signaling and also upregulates a number of other signaling pathways which promotes growth and survival of these cells. PMID:27458535

  6. miR-155 as a Biomarker in B-Cell Malignancies

    PubMed Central

    Due, Hanne; Svendsen, Pernille; Bødker, Julie Støve; Schmitz, Alexander; Bøgsted, Martin; Johnsen, Hans Erik; El-Galaly, Tarec Christoffer; Roug, Anne Stidsholt; Dybkær, Karen

    2016-01-01

    MicroRNAs have the potential to be useful biomarkers in the development of individualized treatment since they are easy to detect, are relatively stable during sample handling, and are important determinants of cellular processes controlling pathogenesis, progression, and response to treatment of several types of cancers including B-cell malignancies. miR-155 is an oncomiR with a crucial role in tumor initiation and development of several B-cell malignancies. The present review elucidates the potential of miR-155 as a diagnostic, prognostic, or predictive biomarker in B-cell malignancies using a systematic search strategy to identify relevant literature. miR-155 was upregulated in several malignancies compared to nonmalignant controls and overexpression of miR-155 was further associated with poor prognosis. Elevated expression of miR-155 shows potential as a diagnostic and prognostic biomarker in diffuse large B-cell lymphoma and chronic lymphocytic leukemia. Additionally, in vitro and in vivo studies suggest miR-155 as an efficient therapeutic target, supporting its oncogenic function. The use of inhibiting anti-miR structures indicates promising potential as novel anticancer therapeutics. Reports from 53 studies prove that miR-155 has the potential to be a molecular tool in personalized medicine. PMID:27294145

  7. Bruton's Tyrosine Kinase: From X-Linked Agammaglobulinemia Toward Targeted Therapy for B-Cell Malignancies

    PubMed Central

    Ponader, Sabine; Burger, Jan A.

    2014-01-01

    Discovery of Bruton's tyrosine kinase (BTK) mutations as the cause for X-linked agammaglobulinemia was a milestone in understanding the genetic basis of primary immunodeficiencies. Since then, studies have highlighted the critical role of this enzyme in B-cell development and function, and particularly in B-cell receptor signaling. Because its deletion affects mostly B cells, BTK has become an attractive therapeutic target in autoimmune disorders and B-cell malignancies. Ibrutinib (PCI-32765) is the most advanced BTK inhibitor in clinical testing, with ongoing phase III clinical trials in patients with chronic lymphocytic leukemia and mantle-cell lymphoma. In this article, we discuss key discoveries related to BTK and clinically relevant aspects of BTK inhibitors, and we provide an outlook into clinical development and open questions regarding BTK inhibitor therapy. PMID:24778403

  8. B-cell receptor signalling and its crosstalk with other pathways in normal and malignant cells.

    PubMed

    Seda, Vaclav; Mraz, Marek

    2015-03-01

    The physiology of B cells is intimately connected with the function of their B-cell receptor (BCR). B-cell lymphomas frequently (dys)regulate BCR signalling and thus take advantage of this pre-existing pathway for B-cell proliferation and survival. This has recently been underscored by clinical trials demonstrating that small molecules (fosfamatinib, ibrutinib, idelalisib) inhibiting BCR-associated kinases (SYK, BTK, PI3K) have an encouraging clinical effect. Here we describe the current knowledge of the specific aspects of BCR signalling in diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, chronic lymphocytic leukaemia (CLL) and normal B cells. Multiple factors can contribute to BCR pathway (dys)regulation in these malignancies and the activation of 'chronic' or 'tonic' BCR signalling. In lymphoma B cells, the balance of initiation, amplitude and duration of BCR activation can be influenced by a specific immunoglobulin structure, the expression and mutations of adaptor molecules (like GAB1, BLNK, GRB2, CARD11), the activity of kinases (like LYN, SYK, PI3K) or phosphatases (like SHIP-1, SHP-1 and PTEN) and levels of microRNAs. We also discuss the crosstalk of BCR with other signalling pathways (NF-κB, adhesion through integrins, migration and chemokine signalling) to emphasise that the 'BCR inhibitors' target multiple pathways interconnected with BCR, which might explain some of their clinical activity.

  9. Agonist-Mediated Activation of STING Induces Apoptosis in Malignant B Cells.

    PubMed

    Tang, Chih-Hang Anthony; Zundell, Joseph A; Ranatunga, Sujeewa; Lin, Cindy; Nefedova, Yulia; Del Valle, Juan R; Hu, Chih-Chi Andrew

    2016-04-15

    Endoplasmic reticulum (ER) stress responses through the IRE-1/XBP-1 pathway are required for the function of STING (TMEM173), an ER-resident transmembrane protein critical for cytoplasmic DNA sensing, IFN production, and cancer control. Here we show that the IRE-1/XBP-1 pathway functions downstream of STING and that STING agonists selectively trigger mitochondria-mediated apoptosis in normal and malignant B cells. Upon stimulation, STING was degraded less efficiently in B cells, implying that prolonged activation of STING can lead to apoptosis. Transient activation of the IRE-1/XBP-1 pathway partially protected agonist-stimulated malignant B cells from undergoing apoptosis. In Eμ-TCL1 mice with chronic lymphocytic leukemia, injection of the STING agonist 3'3'-cGAMP induced apoptosis and tumor regression. Similarly efficacious effects were elicited by 3'3'-cGAMP injection in syngeneic or immunodeficient mice grafted with multiple myeloma. Thus, in addition to their established ability to boost antitumoral immune responses, STING agonists can also directly eradicate malignant B cells. Cancer Res; 76(8); 2137-52. ©2016 AACR. PMID:26951929

  10. Burkitt's lymphoma is a malignancy of mature B cells expressing somatically mutated V region genes.

    PubMed Central

    Klein, U.; Klein, G.; Ehlin-Henriksson, B.; Rajewsky, K.; Küppers, R.

    1995-01-01

    BACKGROUND: The developmental stage from which stems the malignant B cell population in Burkitt's lymphoma (BL) is unclear. An approach to answering this question is provided by the sequence analysis of rear-ranged immunoglobulin (Ig) variable region (V) genes from BL for evidence of somatic mutations, together with a phenotypic characterization. As somatic hypermutation of Ig V region genes occurs in germinal center B cells, somatically mutated Ig genes are found in germinal center B cells and their descendents. MATERIALS AND METHODS: Rearranged V kappa region genes from 10 kappa-expressing sporadic and endemic BL-derived cell lines (9 IgM and 1 IgG positive) and three kappa-expressing endemic BL biopsy specimens were amplified by polymerase chain reaction and sequenced. In addition, VH region gene sequences from these cell lines were determined. RESULTS: All BL cell lines and the three biopsy specimens carried somatically mutated V region genes. The average mutation frequency of rearranged V kappa genes from eight BL cell lines established from sporadic BL was 1.8%. A higher frequency (6%) was found in five endemic cases (three biopsy specimens and two BL cell lines). CONCLUSIONS: The detection of somatic mutations in the rearranged V region genes suggests that both sporadic and endemic BL represent a B-cell malignancy originating from germinal center B cells or their descendants. Interestingly, the mutation frequency detected in sporadic BL is in a range similar to that characteristic for IgM-expressing B cells in the human peripheral blood and for mu chain-expressing germinal center B cells, whereas the mutation frequency found in endemic BL is significantly higher. PMID:8529116

  11. Biology and clinical application of CAR T cells for B cell malignancies.

    PubMed

    Davila, Marco L; Sadelain, Michel

    2016-07-01

    Chimeric antigen receptor (CAR)-modified T cells have generated broad interest in oncology following a series of dramatic clinical successes in patients with chemorefractory B cell malignancies. CAR therapy now appears to be on the cusp of regulatory approval as a cell-based immunotherapy. We review here the T cell biology and cell engineering research that led to the development of second generation CARs, the selection of CD19 as a CAR target, and the preclinical studies in animal models that laid the foundation for clinical trials targeting CD19+ malignancies. We further summarize the status of CD19 CAR clinical therapy for non-Hodgkin lymphoma and B cell acute lymphoblastic leukemia, including their efficacy, toxicities (cytokine release syndrome, neurotoxicity and B cell aplasia) and current management in humans. We conclude with an overview of recent pre-clinical advances in CAR design that argues favorably for the advancement of CAR therapy to tackle other hematological malignancies as well as solid tumors. PMID:27262700

  12. Combinatorial targeting of nuclear export and translation of RNA inhibits aggressive B-cell lymphomas

    PubMed Central

    Culjkovic-Kraljacic, Biljana; Fernando, Tharu M.; Marullo, Rossella; Calvo-Vidal, Nieves; Verma, Akanksha; Yang, ShaoNing; Tabbò, Fabrizio; Gaudiano, Marcello; Zahreddine, Hiba; Goldstein, Rebecca L.; Patel, Jayeshkumar; Taldone, Tony; Chiosis, Gabriela; Ladetto, Marco; Ghione, Paola; Machiorlatti, Rodolfo; Elemento, Olivier; Inghirami, Giorgio; Melnick, Ari; Borden, Katherine L. B.

    2016-01-01

    Aggressive double- and triple-hit (DH/TH) diffuse large B-cell lymphomas (DLBCLs) feature activation of Hsp90 stress pathways. Herein, we show that Hsp90 controls posttranscriptional dynamics of key messenger RNA (mRNA) species including those encoding BCL6, MYC, and BCL2. Using a proteomics approach, we found that Hsp90 binds to and maintains activity of eIF4E. eIF4E drives nuclear export and translation of BCL6, MYC, and BCL2 mRNA. eIF4E RNA-immunoprecipitation sequencing in DLBCL suggests that nuclear eIF4E controls an extended program that includes B-cell receptor signaling, cellular metabolism, and epigenetic regulation. Accordingly, eIF4E was required for survival of DLBCL including the most aggressive subtypes, DH/TH lymphomas. Indeed, eIF4E inhibition induces tumor regression in cell line and patient-derived tumorgrafts of TH-DLBCL, even in the presence of elevated Hsp90 activity. Targeting Hsp90 is typically limited by counterregulatory elevation of Hsp70B, which induces resistance to Hsp90 inhibitors. Surprisingly, we identify Hsp70 mRNA as an eIF4E target. In this way, eIF4E inhibition can overcome drug resistance to Hsp90 inhibitors. Accordingly, rational combinatorial inhibition of eIF4E and Hsp90 inhibitors resulted in cooperative antilymphoma activity in DH/TH DLBCL in vitro and in vivo. PMID:26603836

  13. CD4-positive diffuse large B-cell lymphoma: A variant with aggressive clinical potential

    PubMed Central

    Hussaini, Mohammad O; Kreisel, Friederike H; Hassan, Anjum; Nguyen, TuDung T; Frater, John L

    2016-01-01

    CD4 expression is rare in diffuse large B-cell lymphoma (DLBCL), with 4 previously reported cases. Its significance is uncertain. We report five patients with CD4+ DLBCL and one CD4+ primary mediastinal large B-cell lymphoma. Cases were identified by searching the electronic database of the department; each was reviewed. Average age was 56 years. Neoplastic cells expressed CD20 (5/6 tested cases). BCL2/BCL6 expression were seen in 3/3 tested cases, suggesting a germinal center origin. Additionally, expression of T-cell antigens CD2 and CD5 was noted in 2/2 and CD7 in 1/1 tested case. CD3 was negative in all. Lymph nodes were commonly involved (67%). Patients received chemotherapy +/- radiation (6/6) and bone marrow transplant (2/6). Average survival was 44.2 mo. CD4 expression in DLBCL raises questions of lineage commitment. CD4+ DLBCL is rare; care should be exercised not to diagnose these as T-cell lymphomas. A subset behaves aggressively. PMID:27679780

  14. CD4-positive diffuse large B-cell lymphoma: A variant with aggressive clinical potential.

    PubMed

    Hussaini, Mohammad O; Kreisel, Friederike H; Hassan, Anjum; Nguyen, TuDung T; Frater, John L

    2016-09-26

    CD4 expression is rare in diffuse large B-cell lymphoma (DLBCL), with 4 previously reported cases. Its significance is uncertain. We report five patients with CD4(+) DLBCL and one CD4(+) primary mediastinal large B-cell lymphoma. Cases were identified by searching the electronic database of the department; each was reviewed. Average age was 56 years. Neoplastic cells expressed CD20 (5/6 tested cases). BCL2/BCL6 expression were seen in 3/3 tested cases, suggesting a germinal center origin. Additionally, expression of T-cell antigens CD2 and CD5 was noted in 2/2 and CD7 in 1/1 tested case. CD3 was negative in all. Lymph nodes were commonly involved (67%). Patients received chemotherapy +/- radiation (6/6) and bone marrow transplant (2/6). Average survival was 44.2 mo. CD4 expression in DLBCL raises questions of lineage commitment. CD4(+) DLBCL is rare; care should be exercised not to diagnose these as T-cell lymphomas. A subset behaves aggressively. PMID:27679780

  15. CD4-positive diffuse large B-cell lymphoma: A variant with aggressive clinical potential

    PubMed Central

    Hussaini, Mohammad O; Kreisel, Friederike H; Hassan, Anjum; Nguyen, TuDung T; Frater, John L

    2016-01-01

    CD4 expression is rare in diffuse large B-cell lymphoma (DLBCL), with 4 previously reported cases. Its significance is uncertain. We report five patients with CD4+ DLBCL and one CD4+ primary mediastinal large B-cell lymphoma. Cases were identified by searching the electronic database of the department; each was reviewed. Average age was 56 years. Neoplastic cells expressed CD20 (5/6 tested cases). BCL2/BCL6 expression were seen in 3/3 tested cases, suggesting a germinal center origin. Additionally, expression of T-cell antigens CD2 and CD5 was noted in 2/2 and CD7 in 1/1 tested case. CD3 was negative in all. Lymph nodes were commonly involved (67%). Patients received chemotherapy +/- radiation (6/6) and bone marrow transplant (2/6). Average survival was 44.2 mo. CD4 expression in DLBCL raises questions of lineage commitment. CD4+ DLBCL is rare; care should be exercised not to diagnose these as T-cell lymphomas. A subset behaves aggressively.

  16. Absence of tissue factor is characteristic of lymphoid malignancies of both T- and B-cell origin

    PubMed Central

    Cesarman-Maus, Gabriela; Braggio, Esteban; Lome-Maldonado, Carmen; Morales-Leyte, Ana Lilia; Fonseca, Rafael

    2014-01-01

    Summary Background Thrombosis is a marker of poor prognosis in individuals with solid tumors. The expression of tissue factor (TF) on the cell surface membrane of malignant cells is a pivotal molecular link between activation of coagulation, angiogenesis, metastasis, aggressive tumor behavior and poor survival. Interestingly, thrombosis is associated with shortened survival in solid, but not in lymphoid neoplasias. Objectives We sought to study whether the lack of impact of thrombosis on survival in lymphoid neoplasias could be due to a lack of tumor-derived TF expression. Methods We analyzed TF gene (F3) expression in lymphoid (N=114), myeloid (N=49) and solid tumor (N=856) cell lines using the publicly available dataset from the Broad-Novartis Cancer Cell Line Encyclopedia (http://www.broadinstitute.org/ccle/home), and in 90 patient-derived lymphoma samples. TF protein expression was studied by immunohistochemistry (IHC). Results In sharp contrast to wide F3 expression in solid tumors (74.2%), F3 was absent in all low and high grade T- and B-cell lymphomas, and in most myeloid tumors, except for select acute myeloid leukemias with monocytic component. IHC confirmed the absence of TF protein in all indolent and high-grade B-cell (0/90) and T-cell (0/20) lymphomas, and acute leukemias (0/11). Conclusions We show that TF in lymphomas does not derive from the malignant cells, since these do not express either F3 or TF protein. Therefore, it is unlikely that thrombosis in patients with lymphoid neoplasms is secondary to tumor-derived tissue factor. PMID:24491425

  17. Unusually Aggressive Primary Testicular Diffuse Large B Cell Lymphoma with Post Therapy Extensive Metastasis.

    PubMed

    Goel, Shalini; Sachdev, Ritesh; Mohapatra, Ishani; Gajendra, Smeeta; Gupta, Sunil

    2016-07-01

    Primary Testicular Lymphoma (PTL) is a rare intermediate to high grade tumour, diffuse large cell being the most common type. Unlike nodal Diffuse Large B-Cell Lymphoma (DLBCL), testicular DLBCL has a less aggressive course and better prognosis. Metastasis is uncommon in testicular DLBCL. Commonly involved sites are contralateral testes, Waldeyer's ring, skin, lung, Central Nervous System (CNS) and prostate, however the kidneys, liver, bone marrow, pleura and bones are more rarely involved. We report a case of testicular DLBCL which has metastasized to skin and bone marrow with an aggressive clinical course in a year, in-spite of combined modality of therapy given to the patient. Bone marrow infiltration is common and well documented with nodal DLBCL, however there is no published literature for simultaneous bone marrow and skin infiltration in testicular DLBCL till date. Other large studies done in the west have shown that distinct metastasis is usually common but the median progression-free survival is usually in years. This case stresses on shorter period of progression after standard treatment protocol in this part of the world, thus highlighting the need for other extensive studies to define specific treatment protocol for testicular DLBCL. PMID:27630854

  18. Unusually Aggressive Primary Testicular Diffuse Large B Cell Lymphoma with Post Therapy Extensive Metastasis

    PubMed Central

    Goel, Shalini; Mohapatra, Ishani; Gajendra, Smeeta; Gupta, Sunil

    2016-01-01

    Primary Testicular Lymphoma (PTL) is a rare intermediate to high grade tumour, diffuse large cell being the most common type. Unlike nodal Diffuse Large B-Cell Lymphoma (DLBCL), testicular DLBCL has a less aggressive course and better prognosis. Metastasis is uncommon in testicular DLBCL. Commonly involved sites are contralateral testes, Waldeyer’s ring, skin, lung, Central Nervous System (CNS) and prostate, however the kidneys, liver, bone marrow, pleura and bones are more rarely involved. We report a case of testicular DLBCL which has metastasized to skin and bone marrow with an aggressive clinical course in a year, in-spite of combined modality of therapy given to the patient. Bone marrow infiltration is common and well documented with nodal DLBCL, however there is no published literature for simultaneous bone marrow and skin infiltration in testicular DLBCL till date. Other large studies done in the west have shown that distinct metastasis is usually common but the median progression-free survival is usually in years. This case stresses on shorter period of progression after standard treatment protocol in this part of the world, thus highlighting the need for other extensive studies to define specific treatment protocol for testicular DLBCL.

  19. Unusually Aggressive Primary Testicular Diffuse Large B Cell Lymphoma with Post Therapy Extensive Metastasis

    PubMed Central

    Goel, Shalini; Mohapatra, Ishani; Gajendra, Smeeta; Gupta, Sunil

    2016-01-01

    Primary Testicular Lymphoma (PTL) is a rare intermediate to high grade tumour, diffuse large cell being the most common type. Unlike nodal Diffuse Large B-Cell Lymphoma (DLBCL), testicular DLBCL has a less aggressive course and better prognosis. Metastasis is uncommon in testicular DLBCL. Commonly involved sites are contralateral testes, Waldeyer’s ring, skin, lung, Central Nervous System (CNS) and prostate, however the kidneys, liver, bone marrow, pleura and bones are more rarely involved. We report a case of testicular DLBCL which has metastasized to skin and bone marrow with an aggressive clinical course in a year, in-spite of combined modality of therapy given to the patient. Bone marrow infiltration is common and well documented with nodal DLBCL, however there is no published literature for simultaneous bone marrow and skin infiltration in testicular DLBCL till date. Other large studies done in the west have shown that distinct metastasis is usually common but the median progression-free survival is usually in years. This case stresses on shorter period of progression after standard treatment protocol in this part of the world, thus highlighting the need for other extensive studies to define specific treatment protocol for testicular DLBCL. PMID:27630854

  20. Clinicopathological features of aggressive B-cell lymphomas including B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell and Burkitt lymphomas: a study of 44 patients from Argentina.

    PubMed

    Bürgesser, María Virginia; Gualco, Gabriela; Diller, Ana; Natkunam, Yasodha; Bacchi, Carlos E

    2013-06-01

    Aggressive B-cell lymphomas incorporate a wide spectrum of lymphomas that pose challenges in diagnosis as well as treatment. We evaluated the clinicopathological features of 44 patients with aggressive B-cell lymphomas which were classified into 3 groups based on the World Health Organization 2008 classification as follows: including 30 cases of diffuse large B-cell lymphoma (DLBCL), 8 cases of Burkitt lymphoma (BL) and 6 cases of B-cell lymphoma, unclassifiable, with features intermediate between Burkitt lymphoma and diffuse large B-cell lymphoma (BCLU). Male predominance was observed in BL and BCLU groups and the mean age varied from 29 years in BL, 61 years in DLBCL and 70 years in BCLU. Patients with BCLU presented at more advanced stages and had a higher international prognostic index. By immunohistochemistry, they shared characteristics of both BL (including more frequent expression of SOX11) and DLBCL. FISH analyses showed three cases with more than one rearrangement: one MYC/BCL2 and two BCL2/BCL6, in addition to which one case with BCL2/IGH translocation and another with MYC rearrangement were also detected. The mean follow-up survival time of BCLU was 6.6 months, which was significantly shorter in comparison to DLBCL (31 months) and BL (30 months), respectively. The importance of recognizing this BCLU group relies on its different clinical course, poor prognosis and shorter survival than DLBCL and BL. An accurate diagnosis is critical for risk stratification and to improve therapeutic approaches and outcomes.

  1. The phosphoinositide 3-kinase signaling pathway in normal and malignant B cells: activation mechanisms, regulation and impact on cellular functions.

    PubMed

    Pauls, Samantha D; Lafarge, Sandrine T; Landego, Ivan; Zhang, Tingting; Marshall, Aaron J

    2012-01-01

    The phosphoinositide 3-kinase (PI3K) pathway is a central signal transduction axis controlling normal B cell homeostasis and activation in humoral immunity. The p110δ PI3K catalytic subunit has emerged as a critical mediator of multiple B cell functions. The activity of this pathway is regulated at multiple levels, with inositol phosphatases PTEN and SHIP both playing critical roles. When deregulated, the PI3K pathway can contribute to B cell malignancies and autoantibody production. This review summarizes current knowledge on key mechanisms that activate and regulate the PI3K pathway and influence normal B cell functional responses including the development of B cell subsets, antigen presentation, immunoglobulin isotype switch, germinal center responses, and maintenance of B cell anergy. We also discuss PI3K pathway alterations reported in select B cell malignancies and highlight studies indicating the functional significance of this pathway in malignant B cell survival and growth within tissue microenvironments. Finally, we comment on early clinical trial results, which support PI3K inhibition as a promising treatment of chronic lymphocytic leukemia.

  2. Role of the tumor microenvironment in mature B-cell lymphoid malignancies

    PubMed Central

    Fowler, Nathan H.; Cheah, Chan Yoon; Gascoyne, Randy D.; Gribben, John; Neelapu, Sattva S.; Ghia, Paolo; Bollard, Catherine; Ansell, Stephen; Curran, Michael; Wilson, Wyndham H.; O’Brien, Susan; Grant, Cliona; Little, Richard; Zenz, Thorsten; Nastoupil, Loretta J.; Dunleavy, Kieron

    2016-01-01

    The tumor microenvironment is the cellular and molecular environment in which the tumor exists and with which it continuously interacts. In B-cell lymphomas, this microenvironment is intriguing in that it plays critical roles in the regulation of tumor cell survival and proliferation, fostering immune escape as well as the development of treatment resistance. The purpose of this review is to summarize the proceedings of the Second Annual Summit on the Immune Microenvironment in Hematologic Malignancies that took place on September 11–12, 2014 in Dublin, Ireland. We provide a timely overview of the composition and biological relevance of the cellular and molecular microenvironment interface and discuss the role of interactions between the microenvironment and neoplastic cells in a variety of B-cell lymphomas. In addition, we focus on various novel therapeutic strategies that target the tumor microenvironment, including agents that modulate B-cell receptor pathways and immune-checkpoints, chimeric antigen receptor T cells and immunomodulatory agents. PMID:27132279

  3. AT9283, a novel aurora kinase inhibitor, suppresses tumor growth in aggressive B-cell lymphomas.

    PubMed

    Qi, Wenqing; Liu, Xiaobing; Cooke, Laurence S; Persky, Daniel O; Miller, Thomas P; Squires, Matthew; Mahadevan, Daruka

    2012-06-15

    Aurora kinases are oncogenic serine/threonine kinases that play key roles in regulating the mitotic phase of the eukaryotic cell cycle. Auroras are overexpressed in numerous tumors including B-cell non-Hodgkin's lymphomas and are validated oncology targets. AT9283, a pan-aurora inhibitor inhibited growth and survival of multiple solid tumors in vitro and in vivo. In this study, we demonstrated that AT9283 had potent activity against Aurora B in a variety of aggressive B-(non-Hodgkin lymphoma) B-NHL cell lines. Cells treated with AT9283 exhibited endoreduplication confirming the mechanism of action of an Aurora B inhibitor. Also, treatment of B-NHL cell lines with AT9283 induced apoptosis in a dose and time dependent manner and inhibited cell proliferation with an IC(50) < 1 μM. It is well known that inhibition of auroras (A or B) synergistically enhances the effects of microtubule targeting agents such as taxanes and vinca alkaloids to induce antiproliferation and apoptosis. We evaluated whether AT9283 in combination with docetaxel is more efficient in inducing apoptosis than AT9283 or docetaxel alone. At very low doses (5 nM) apoptosis was doubled in the combination (23%) compared to AT9283 or docetaxel alone (10%). A mouse xenograft model of mantle cell lymphoma demonstrated that AT9283 at 15 mg/kg and docetaxel (10 mg/kg) alone had modest anti-tumor activity. However, AT9283 at 20 mg/kg and AT9283 (15 or 20 mg/kg) plus docetaxel (10 mg/kg) demonstrated a statistically significant tumor growth inhibition and enhanced survival. Together, our results suggest that AT9283 plus docetaxel may represent a novel therapeutic strategy in B-cell NHL and warrant early phase clinical trial evaluation. PMID:21796626

  4. AT9283, a novel aurora kinase inhibitor, suppresses tumor growth in aggressive B-cell lymphomas.

    PubMed

    Qi, Wenqing; Liu, Xiaobing; Cooke, Laurence S; Persky, Daniel O; Miller, Thomas P; Squires, Matthew; Mahadevan, Daruka

    2012-06-15

    Aurora kinases are oncogenic serine/threonine kinases that play key roles in regulating the mitotic phase of the eukaryotic cell cycle. Auroras are overexpressed in numerous tumors including B-cell non-Hodgkin's lymphomas and are validated oncology targets. AT9283, a pan-aurora inhibitor inhibited growth and survival of multiple solid tumors in vitro and in vivo. In this study, we demonstrated that AT9283 had potent activity against Aurora B in a variety of aggressive B-(non-Hodgkin lymphoma) B-NHL cell lines. Cells treated with AT9283 exhibited endoreduplication confirming the mechanism of action of an Aurora B inhibitor. Also, treatment of B-NHL cell lines with AT9283 induced apoptosis in a dose and time dependent manner and inhibited cell proliferation with an IC(50) < 1 μM. It is well known that inhibition of auroras (A or B) synergistically enhances the effects of microtubule targeting agents such as taxanes and vinca alkaloids to induce antiproliferation and apoptosis. We evaluated whether AT9283 in combination with docetaxel is more efficient in inducing apoptosis than AT9283 or docetaxel alone. At very low doses (5 nM) apoptosis was doubled in the combination (23%) compared to AT9283 or docetaxel alone (10%). A mouse xenograft model of mantle cell lymphoma demonstrated that AT9283 at 15 mg/kg and docetaxel (10 mg/kg) alone had modest anti-tumor activity. However, AT9283 at 20 mg/kg and AT9283 (15 or 20 mg/kg) plus docetaxel (10 mg/kg) demonstrated a statistically significant tumor growth inhibition and enhanced survival. Together, our results suggest that AT9283 plus docetaxel may represent a novel therapeutic strategy in B-cell NHL and warrant early phase clinical trial evaluation.

  5. Stromal niche communalities underscore the contribution of the matricellular protein SPARC to B-cell development and lymphoid malignancies.

    PubMed

    Sangaletti, Sabina; Tripodo, Claudio; Portararo, Paola; Dugo, Matteo; Vitali, Caterina; Botti, Laura; Guarnotta, Carla; Cappetti, Barbara; Gulino, Alessandro; Torselli, Ilaria; Casalini, Patrizia; Chiodoni, Claudia; Colombo, Mario P

    2014-01-01

    Neoplastic B-cell clones commonly arise within secondary lymphoid organs (SLO). However, during disease progression, lymphomatous cells may also colonize the bone marrow (BM), where they localize within specialized stromal niches, namely the osteoblastic and the vascular niche, according to their germinal center- or extra-follicular-derivation, respectively. We hypothesized the existence of common stromal motifs in BM and SLO B-cell lymphoid niches involved in licensing normal B-cell development as well as in fostering transformed B lymphoid cells. Thus, we tested the expression of prototypical mesenchymal stromal cell (MSC) markers and regulatory matricellular proteins in human BM and SLO under physiologically unperturbed conditions and during B-cell lymphoma occurrence. We identified common stromal features in the BM osteoblastic niche and SLO germinal center (GC) microenvironments, traits that were also enriched within BM infiltrates of GC-associated B-cell lymphomas, suggesting that stromal programs involved in central and peripheral B-cell lymphopoiesis are also involved in malignant B-cell nurturing. Among factors co-expressed by stromal elements within these different specialized niches, we identified the pleiotropic matricellular protein secreted protein acidic and rich in cysteine (SPARC). The actual role of stromal SPARC in normal B-cell lymphopoiesis, investigated in Sparc(-/-) mice and BM chimeras retaining the Sparc(-/-) genotype in host stroma, demonstrated defective BM and splenic B-cell lymphopoiesis. Moreover, in the Trp53 knockout (KO) lymphoma model, p53(-/-)/Sparc(-/-) double-KO mice displayed impaired spontaneous splenic B-cell lymphomagenesis and reduced neoplastic clone BM infiltration in comparison with their p53(-/-)/Sparc(+/+) counterparts. Our results are among the first to demonstrate the existence of common stromal programs regulating both the BM osteoblastic niche and the SLO GC lymphopoietic functions potentially fostering the genesis

  6. Stromal niche communalities underscore the contribution of the matricellular protein SPARC to B-cell development and lymphoid malignancies.

    PubMed

    Sangaletti, Sabina; Tripodo, Claudio; Portararo, Paola; Dugo, Matteo; Vitali, Caterina; Botti, Laura; Guarnotta, Carla; Cappetti, Barbara; Gulino, Alessandro; Torselli, Ilaria; Casalini, Patrizia; Chiodoni, Claudia; Colombo, Mario P

    2014-01-01

    Neoplastic B-cell clones commonly arise within secondary lymphoid organs (SLO). However, during disease progression, lymphomatous cells may also colonize the bone marrow (BM), where they localize within specialized stromal niches, namely the osteoblastic and the vascular niche, according to their germinal center- or extra-follicular-derivation, respectively. We hypothesized the existence of common stromal motifs in BM and SLO B-cell lymphoid niches involved in licensing normal B-cell development as well as in fostering transformed B lymphoid cells. Thus, we tested the expression of prototypical mesenchymal stromal cell (MSC) markers and regulatory matricellular proteins in human BM and SLO under physiologically unperturbed conditions and during B-cell lymphoma occurrence. We identified common stromal features in the BM osteoblastic niche and SLO germinal center (GC) microenvironments, traits that were also enriched within BM infiltrates of GC-associated B-cell lymphomas, suggesting that stromal programs involved in central and peripheral B-cell lymphopoiesis are also involved in malignant B-cell nurturing. Among factors co-expressed by stromal elements within these different specialized niches, we identified the pleiotropic matricellular protein secreted protein acidic and rich in cysteine (SPARC). The actual role of stromal SPARC in normal B-cell lymphopoiesis, investigated in Sparc(-/-) mice and BM chimeras retaining the Sparc(-/-) genotype in host stroma, demonstrated defective BM and splenic B-cell lymphopoiesis. Moreover, in the Trp53 knockout (KO) lymphoma model, p53(-/-)/Sparc(-/-) double-KO mice displayed impaired spontaneous splenic B-cell lymphomagenesis and reduced neoplastic clone BM infiltration in comparison with their p53(-/-)/Sparc(+/+) counterparts. Our results are among the first to demonstrate the existence of common stromal programs regulating both the BM osteoblastic niche and the SLO GC lymphopoietic functions potentially fostering the genesis

  7. Aggression: the dominant psychological response in children with malignant disease.

    PubMed

    Kvist, S B; Rajantie, J; Kvist, M; Siimes, M A

    1991-06-01

    During the 11-yr. period of 1976 to 1986 leukemia or lymphoma treatment at the Children's Hospital, University of Helsinki was electively discontinued for the children in 90 different families. Of the 53 (59%) patients (mean age 6.4 yr. at diagnosis and 12.8 yr. at completion of questionnaires) who agreed to participate in the present study, 48 had acute lymphoblastic leukemia and five nonHodgkin lymphoma. Patients' and parents' impressions of the patients' psychological reactions during patients' prior chemotherapy were evaluated on parental and self-ratings. Also, knowledge of and presumed causes of the malignancy were studied. Patients' reactions of aggression, depression, eating disorders, hypersensitivity, phobic anxiety, death anxiety, and night terror were examined using factor analysis. Aggression, in the form of irritation and anger, was displayed more often by girls than by boys. Patients of families suffering from stress were prone to exhibit aggression in the form of mood changes, irritation, and anger. Patients with disease-related knowledge, as opposed to those less well informed, were less depressed. Discrepancies between parents' and patients' thoughts about the origin of the malignancy were noted.

  8. Global gene expression changes of in vitro stimulated human transformed germinal centre B cells as surrogate for oncogenic pathway activation in individual aggressive B cell lymphomas

    PubMed Central

    2012-01-01

    Background Aggressive Non-Hodgkin lymphomas (NHL) are a group of lymphomas derived from germinal centre B cells which display a heterogeneous pattern of oncogenic pathway activation. We postulate that specific immune response associated signalling, affecting gene transcription networks, may be associated with the activation of different oncogenic pathways in aggressive Non-Hodgkin lymphomas (NHL). Methodology The B cell receptor (BCR), CD40, B-cell activating factor (BAFF)-receptors and Interleukin (IL) 21 receptor and Toll like receptor 4 (TLR4) were stimulated in human transformed germinal centre B cells by treatment with anti IgM F(ab)2-fragments, CD40L, BAFF, IL21 and LPS respectively. The changes in gene expression following the activation of Jak/STAT, NF-кB, MAPK, Ca2+ and PI3K signalling triggered by these stimuli was assessed using microarray analysis. The expression of top 100 genes which had a change in gene expression following stimulation was investigated in gene expression profiles of patients with Aggressive non-Hodgkin Lymphoma (NHL). Results αIgM stimulation led to the largest number of changes in gene expression, affecting overall 6596 genes. While CD40L stimulation changed the expression of 1194 genes and IL21 stimulation affected 902 genes, only 283 and 129 genes were modulated by lipopolysaccharide or BAFF receptor stimulation, respectively. Interestingly, genes associated with a Burkitt-like phenotype, such as MYC, BCL6 or LEF1, were affected by αIgM. Unique and shared gene expression was delineated. NHL-patients were sorted according to their similarity in the expression of TOP100 affected genes to stimulated transformed germinal centre B cells The αIgM gene module discriminated individual DLBCL in a similar manner to CD40L or IL21 gene modules. DLBCLs with low module activation often carry chromosomal MYC aberrations. DLBCLs with high module activation show strong expression of genes involved in cell-cell communication, immune responses

  9. Switch-mediated activation and retargeting of CAR-T cells for B-cell malignancies.

    PubMed

    Rodgers, David T; Mazagova, Magdalena; Hampton, Eric N; Cao, Yu; Ramadoss, Nitya S; Hardy, Ian R; Schulman, Andrew; Du, Juanjuan; Wang, Feng; Singer, Oded; Ma, Jennifer; Nunez, Vanessa; Shen, Jiayin; Woods, Ashley K; Wright, Timothy M; Schultz, Peter G; Kim, Chan Hyuk; Young, Travis S

    2016-01-26

    Chimeric antigen receptor T (CAR-T) cell therapy has produced impressive results in clinical trials for B-cell malignancies. However, safety concerns related to the inability to control CAR-T cells once infused into the patient remain a significant challenge. Here we report the engineering of recombinant antibody-based bifunctional switches that consist of a tumor antigen-specific Fab molecule engrafted with a peptide neo-epitope, which is bound exclusively by a peptide-specific switchable CAR-T cell (sCAR-T). The switch redirects the activity of the bio-orthogonal sCAR-T cells through the selective formation of immunological synapses, in which the sCAR-T cell, switch, and target cell interact in a structurally defined and temporally controlled manner. Optimized switches specific for CD19 controlled the activity, tissue-homing, cytokine release, and phenotype of sCAR-T cells in a dose-titratable manner in a Nalm-6 xenograft rodent model of B-cell leukemia. The sCAR-T-cell dosing regimen could be tuned to provide efficacy comparable to the corresponding conventional CART-19, but with lower cytokine levels, thereby offering a method of mitigating cytokine release syndrome in clinical translation. Furthermore, we demonstrate that this methodology is readily adaptable to targeting CD20 on cancer cells using the same sCAR-T cell, suggesting that this approach may be broadly applicable to heterogeneous and resistant tumor populations, as well as other liquid and solid tumor antigens. PMID:26759369

  10. Switch-mediated activation and retargeting of CAR-T cells for B-cell malignancies

    PubMed Central

    Rodgers, David T.; Mazagova, Magdalena; Hampton, Eric N.; Cao, Yu; Ramadoss, Nitya S.; Hardy, Ian R.; Schulman, Andrew; Du, Juanjuan; Wang, Feng; Singer, Oded; Ma, Jennifer; Nunez, Vanessa; Shen, Jiayin; Woods, Ashley K.; Wright, Timothy M.; Schultz, Peter G.; Kim, Chan Hyuk; Young, Travis S.

    2016-01-01

    Chimeric antigen receptor T (CAR-T) cell therapy has produced impressive results in clinical trials for B-cell malignancies. However, safety concerns related to the inability to control CAR-T cells once infused into the patient remain a significant challenge. Here we report the engineering of recombinant antibody-based bifunctional switches that consist of a tumor antigen-specific Fab molecule engrafted with a peptide neo-epitope, which is bound exclusively by a peptide-specific switchable CAR-T cell (sCAR-T). The switch redirects the activity of the bio-orthogonal sCAR-T cells through the selective formation of immunological synapses, in which the sCAR-T cell, switch, and target cell interact in a structurally defined and temporally controlled manner. Optimized switches specific for CD19 controlled the activity, tissue-homing, cytokine release, and phenotype of sCAR-T cells in a dose-titratable manner in a Nalm-6 xenograft rodent model of B-cell leukemia. The sCAR–T-cell dosing regimen could be tuned to provide efficacy comparable to the corresponding conventional CART-19, but with lower cytokine levels, thereby offering a method of mitigating cytokine release syndrome in clinical translation. Furthermore, we demonstrate that this methodology is readily adaptable to targeting CD20 on cancer cells using the same sCAR-T cell, suggesting that this approach may be broadly applicable to heterogeneous and resistant tumor populations, as well as other liquid and solid tumor antigens. PMID:26759369

  11. Molecular sequelae of histone deacetylase inhibition in human malignant B cells.

    PubMed

    Mitsiades, Nicholas; Mitsiades, Constantine S; Richardson, Paul G; McMullan, Ciaran; Poulaki, Vassiliki; Fanourakis, Galinos; Schlossman, Robert; Chauhan, Dharminder; Munshi, Nikhil C; Hideshima, Teru; Richon, Victoria M; Marks, Paul A; Anderson, Kenneth C

    2003-05-15

    Histone acetylation modulates gene expression, cellular differentiation, and survival and is regulated by the opposing activities of histone acetyltransferases (HATs) and histone deacetylases (HDACs). HDAC inhibition results in accumulation of acetylated nucleosomal histones and induces differentiation and/or apoptosis in transformed cells. In this study, we characterized the effect of suberoylanilide hydroxamic acid (SAHA), the prototype of a series of hydroxamic acid-based HDAC inhibitors, in cell lines and patient cells from B-cell malignancies, including multiple myeloma (MM) and related disorders. SAHA induced apoptosis in all tumor cells tested, with increased p21 and p53 protein levels and dephosphorylation of Rb. We also detected cleavage of Bid, suggesting a role for Bcl-2 family members in regulation of SAHA-induced cell death. Transfection of Bcl-2 cDNA into MM.1S cells completely abrogated SAHA-induced apoptosis, confirming its protective role. SAHA did not induce cleavage of caspase-8, -9, or -3 in MM.1S cells during the early phase of apoptosis, and the pan-caspase inhibitor ZVAD-FMK did not protect against SAHA. Conversely, poly(ADP)ribose polymerase (PARP) was cleaved in a pattern indicative of calpain activation, and the calpain inhibitor calpeptin abrogated SAHA-induced cell death. Importantly, SAHA sensitized MM.1S cells to death receptor-mediated apoptosis and inhibited the secretion of interleukin 6 (IL-6) induced in bone marrow stromal cells (BMSCs) by binding of MM cells, suggesting that it can overcome cell adhesion-mediated drug resistance. Our studies delineate the mechanisms whereby HDAC inhibitors mediate anti-MM activity and overcome drug resistance in the BM milieu and provide the framework for clinical evaluation of SAHA, which is bioavailable, well tolerated, and bioactive after oral administration, to improve patient outcome.

  12. Application of J-Aggregate Monolayers in Silica Encapsulated SERS Nanoprobes for Immunophenotyping of B-cell Malignancies

    NASA Astrophysics Data System (ADS)

    Song, Byron

    Immunophenotyping is indispensable in studying B-cell malignancies as the cell surface markers on malignant cells provide critical information for the diagnosis, treatment decisions and prognosis of the disease. Surface Enhanced Raman Spectroscopy (SERS) nanoprobes as an alternative optical label have been explored as they may overcome limitations of fluorescent labels through their naturally sharper spectral bands and resistance to photobleaching. In this project, we demonstrate the successful labelling of lymphoma cells with rituximab-anti-CD20 functionalized silica-encapsulated J-aggregate SERS gold nanoparticles -- these particles represent the brightest of their kind thus far. Additionally, we demonstrate that the Raman signal on cells labelled with our particles is not affected by treatment with two hematological stains: hematoxylin and methylene blue; although two others: Giemsa and eosin mask the Raman spectra with intense fluorescence. These results support the potential of simultaneously using hematological stains with SERS nanoprobes for visualizing B-cells.

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

    PubMed Central

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

    2014-01-01

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

  14. Evidence that the B lymphocyte proliferating in B-CLL and in other B-cell malignancies is frequently committed to production of natural autoantibodies.

    PubMed

    Dighiero, G; Borche, L

    1990-01-01

    Autoreactive B-cells constitute a substantial part of B-cell repertoire. They frequently secrete polyspecific natural autoantibodies which are the expression of germinal genes. During recent years, considerable evidence has accumulated indicating that autoreactive B-cells frequently undergo malignant transformation. This evidence arose from the study of monoclonal immunoglobulins (MIgs) and from recent studies of chronic lymphocytic leukemia (CLL) and non Hodgkin lymphoma (NHL) B lymphocytes. The present review, includes two sections. The first one reviews evidence supporting the idea that autoreactive B-cells constitute a substantial part of autoreactive B-cell repertoire. The second one is devoted to review evidence favouring the view that this autoreactive B-cell repertoire is frequently involved in B-cell malignancies.

  15. BET Inhibition Induces Apoptosis in Aggressive B-Cell Lymphoma via Epigenetic Regulation of BCL-2 Family Members.

    PubMed

    Hogg, Simon J; Newbold, Andrea; Vervoort, Stephin J; Cluse, Leonie A; Martin, Benjamin P; Gregory, Gareth P; Lefebure, Marcus; Vidacs, Eva; Tothill, Richard W; Bradner, James E; Shortt, Jake; Johnstone, Ricky W

    2016-09-01

    Targeting BET bromodomain proteins using small molecules is an emerging anticancer strategy with clinical evaluation of at least six inhibitors now underway. Although MYC downregulation was initially proposed as a key mechanistic property of BET inhibitors, recent evidence suggests that additional antitumor activities are important. Using the Eμ-Myc model of B-cell lymphoma, we demonstrate that BET inhibition with JQ1 is a potent inducer of p53-independent apoptosis that occurs in the absence of effects on Myc gene expression. JQ1 skews the expression of proapoptotic (Bim) and antiapoptotic (BCL-2/BCL-xL) BCL-2 family members to directly engage the mitochondrial apoptotic pathway. Consistent with this, Bim knockout or Bcl-2 overexpression inhibited apoptosis induction by JQ1. We identified lymphomas that were either intrinsically resistant to JQ1-mediated death or acquired resistance following in vivo exposure. Strikingly, in both instances BCL-2 was strongly upregulated and was concomitant with activation of RAS pathways. Eμ-Myc lymphomas engineered to express activated Nras upregulated BCL-2 and acquired a JQ1 resistance phenotype. These studies provide important information on mechanisms of apoptosis induction and resistance to BET-inhibition, while providing further rationale for the translation of BET inhibitors in aggressive B-cell lymphomas. Mol Cancer Ther; 15(9); 2030-41. ©2016 AACR. PMID:27406984

  16. Bruton’s tyrosine kinase inhibitors and their clinical potential in the treatment of B-cell malignancies: focus on ibrutinib

    PubMed Central

    Aalipour, Amin

    2014-01-01

    Aberrant signaling of the B-cell receptor pathway has been linked to the development and maintenance of B-cell malignancies. Bruton’s tyrosine kinase (BTK), a protein early in this pathway, has emerged as a new therapeutic target in a variety of such malignancies. Ibrutinib, the most clinically advanced small molecule inhibitor of BTK, has demonstrated impressive tolerability and activity in a range of B-cell lymphomas which led to its recent approval for relapsed mantle cell lymphoma and chronic lymphocytic leukemia. This review focuses on the preclinical and clinical development of ibrutinib and discusses its therapeutic potential. PMID:25360238

  17. Evidence that the malignant lymphoma of Sjögren's syndrome is a monoclonal B-cell neoplasm.

    PubMed

    Zulman, J; Jaffe, R; Talal, N

    1978-11-30

    We studied the malignant lymphomas that developed in patients with Sjögren's syndrome and the antecedent benign salivary-gland lesions to determine their cellular characteristics. We used an immunoperoxidase technic that identified intracellular gamma, alpha and mu heavy chains and kappa and lambda light chains. In six of nine patients, the lymphomas were composed of cells containing intracytoplasmic immunoglobulin that was exclusively IgMK. The benign lymphoepithelial salivary-gland lesions preceding these malignant tumors consisted of approximately equal numbers of lymphoid cells containing either kappa or lambda light chains. Thus, in some patients with Sjögren's syndrome, there may be a progression in the lympho-proliferative lesions from a polyclonal infiltrate to a monoclonal neoplasm. Intracytoplasmic immunoglobulin identifies six of the nine cases as being B-cell in origin.

  18. Treatment of Relapsed and/or Chemotherapy Refractory B-cell Malignancy by CART19

    ClinicalTrials.gov

    2016-01-26

    Hematopoietic/Lymphoid Cancer; Adult Acute Lymphoblastic Leukemia in Remission; B-cell Adult Acute Lymphoblastic Leukemia; B-cell Chronic Lymphocytic Leukemia; Prolymphocytic Leukemia; 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; Refractory Chronic Lymphocytic Leukemia; Stage III Adult Diffuse Large Cell Lymphoma; Stage III Chronic Lymphocytic Leukemia; Stage III Grade 1 Follicular Lymphoma; Stage III Grade 2 Follicular Lymphoma; Stage III Grade 3 Follicular Lymphoma; Stage III Mantle Cell Lymphoma; Stage IV Adult Diffuse Large Cell Lymphoma; Stage IV Chronic Lymphocytic Leukemia; Stage IV Grade 1 Follicular Lymphoma; Stage IV Grade 2 Follicular Lymphoma; Stage IV Grade 3 Follicular Lymphoma; Stage IV Mantle Cell Lymphoma

  19. Role of Fractalkine/CX3CL1 and Its Receptor in the Pathogenesis of Inflammatory and Malignant Diseases with Emphasis on B Cell Malignancies

    PubMed Central

    Ferretti, Elisa; Pistoia, Vito; Corcione, Anna

    2014-01-01

    Fractalkine/CX3CL1, the only member of the CX3C chemokine family, exists as a membrane-anchored molecule as well as in soluble form, each mediating different biological activities. It is constitutively expressed in many hematopoietic and nonhematopoietic tissues such as endothelial and epithelial cells, lymphocytes, neurons, microglial osteoblasts. The biological activities of CX3CL1 are mediated by CX3CR1, that is expressed on different cell types such as NK cells, CD14+ monocytes, cytotoxic effector T cells, B cells, neurons, microglia, smooth muscle cells, and tumor cells. The CX3CL1/CX3CR1 axis is involved in the pathogenesis of several inflammatory cancer including various B cell malignancies. In tumors the interaction between cancer cells and cellular microenvironment creates a context that may promote tumor growth, increase tumor survival, and facilitate metastasis. Therefore the role of the CX3CL1/CX3CR1 has attracted interest as to the development of potential therapeutic approaches. Here we review the different effects of the CX3CL1/CX3CR1 axis in several inflammatory and neurodegenerative diseases and in cancer, with emphasis on human B cell lymphomas. PMID:24799766

  20. Malignant hematopoietic cell lines: in vitro models for the study of primary mediastinal B-cell lymphomas.

    PubMed

    Drexler, Hans G; Ehrentraut, Stefan; Nagel, Stefan; Eberth, Sonja; MacLeod, Roderick A F

    2015-01-01

    Primary mediastinal B-cell lymphoma (PMBL) is a highly aggressive disease with a unique set of biological, clinical, morphological, immunological and in particular genetic features that in the molecular era of defining lymphomas clearly distinguishes it as a separate entity from other diffuse large B-cell lymphomas (DLBCL). A precise molecular diagnosis of PMBL can be achieved by gene expression profiling. The signature gene expression profile of PMBL is more closely related to classic Hodgkin lymphoma (cHL) than to other DLBCL subgroups. A number of common genetic aberrations in PMBL and cHL further underscore their close relationship. To investigate the pathobiology of lymphomas in depth, many groups have turned to cell lines that are suitable models facilitating molecular studies and providing unique insights. For the purposes of the current perspective, we focus on four bona fide PMBL-derived cell lines (FARAGE, KARPAS-1106, MEDB-1, U-2940) that we identified and validated as such through hierarchical cluster analysis among a large collection of leukemia-lymphoma cell lines. These gene expression profiles showed that the four PMBL cell lines represent a distinct entity and are most similar to cHL cell lines, confirming derivation from a related cell type. A validated cell line resource for PMBL should assist those seeking druggable targets in this entity. This review aims to provide a comprehensive overview of the currently available cellular models for the study of PMBL. PMID:25480038

  1. CD5-positive B-cell malignancies frequently express cross-reactive idiotypes associated with IgM autoantibodies.

    PubMed Central

    Kipps, T. J.; Robbins, B. A.; Tefferi, A.; Meisenholder, G.; Banks, P. M.; Carson, D. A.

    1990-01-01

    Using monoclonal antibodies (MAb) specific for cross-reactive idiotypes (CRIs) associated with human monoclonal IgM autoantibodies, we examined 57 biopsy specimens that previously had been noted to have immunohistologic features of CD5-positive B-cell small lymphocytic (SL) non-Hodgkin's lymphoma (NHL). Twenty-five lymphoma specimens were noted to be from patients with chronic lymphocytic leukemia (CLL). Eight of thirty-four (24%) immunoglobulin (Ig) kappa light-chain expressing lymphomas reacted with 17.109, a MAb specific for a major CRI encoded by a conserved Ig kappa variable region gene (Vk gene) of the VkIIIb sub-subgroup. All 17.109-reactive tissues and two 17.109-negative specimens were recognized by another MAb specific for VkIIIb framework determinant(s). Seven of all fifty-six (13%) Ig-expressing tumors bound G6, a MAb specific for an autoantibody heavy-chain-associated CRI that is encoded by a conserved antibody heavy chain variable region gene(s) (VHgene) of the VH1 subgroup. All seven G6-positive lymphomas and two G6-negative tumors reacted with Cc1, another MAb specific for a rheumatoid factor heavy-chain-associated CRI. A third autoantibody-heavy-chain-associated CRI, termed Lc1, was expressed by seven (13%) other lymphomas. Finally, a fourth MAb specific for RF heavy-chain-associated CRI, named B6, detected two additional tumors. The expression frequencies of autoantibody-associated CRIs among SL NHL patients without peripheral lymphocytosis did not differ from those noted among patients with CLL but were significantly higher than those observed among patients with NHL of follicular center-cell origin. These data imply that the malignant B cells of patients with either CD5-positive B-cell SL NHL or CLL express a restricted set of Ig V genes that have not substantially diversified from the germline DNA. Images Figure 1 PMID:1691593

  2. Proliferation and apoptosis in malignant and normal cells in B-cell non-Hodgkin's lymphomas.

    PubMed Central

    Stokke, T.; Holte, H.; Smedshammer, L.; Smeland, E. B.; Kaalhus, O.; Steen, H. B.

    1998-01-01

    We have examined apoptosis and proliferation in lymph node cell suspensions from patients with B-cell non-Hodgkin's lymphoma using flow cytometry. A method was developed which allowed estimation of the fractions of apoptotic cells and cells in the S-phase of the cell cycle simultaneously with tumour-characteristic light chain expression. Analysis of the tumour S-phase fraction and the tumour apoptotic fraction in lymph node cell suspensions from 95 B-cell non-Hodgkin's lymphoma (NHL) patients revealed a non-normal distribution for both parameters. The median fraction of apoptotic tumour cells was 1.1% (25 percentiles 0.5%, 2.7%). In the same samples, the median fraction of apoptotic normal cells was higher than for the tumour cells (1.9%; 25 percentiles 0.7%, 4.0%; P = 0.03). The median fraction of tumour cells in S-phase was 1.4% (25 percentiles 0.8%, 4.8%), the median fraction of normal cells in S-phase was significantly lower than for the tumour cells (1.0%; 25 percentiles 0.6%, 1.9%; P = 0.004). When the number of cases was plotted against the logarithm of the S-phase fraction of the tumour cells, a distribution with two Gaussian peaks was needed to fit the data. One peak was centred around an S-phase fraction of 0.9%; the other was centred around 7%. These peaks were separated by a valley at approximately 3%, indicating that the S-phase fraction in NHL can be classified as 'low' (< 3%) or 'high' (> 3%), independent of the median S-phase fraction. The apoptotic fractions were log-normally distributed. The median apoptotic fraction was higher (1.5%) in the 'high' S-phase group than in the 'low' S-phase group (0.8%; P = 0.02). However, there was no significant correlation between the two parameters (P > 0.05). PMID:9667654

  3. Activation of the Endoplasmic Reticulum Stress-Associated Transcription Factor X Box-Binding Protein-1 Occurs in a Subset of Normal Germinal-Center B Cells and in Aggressive B-Cell Lymphomas with Prognostic Implications

    PubMed Central

    Balague, Olga; Mozos, Ana; Martinez, Daniel; Hernandez, Luis; Colomo, Lluis; Mate, Jose Luis; Teruya-Feldstein, Julie; Lin, Oscar; Campo, Elias; Lopez-Guillermo, Armando; Martinez, Antonio

    2009-01-01

    X box-binding protein 1 (Xbp-1) is a transcription factor that is required for the terminal differentiation of B lymphocytes into plasma cells. The Xbp-1 gene is activated in response to endoplasmic reticulum stress signals, which generate a 50-kDa nuclear protein that acts as a potent transactivator and regulates the expression of genes related to the unfolded protein response. Activated Xbp-1 is essential for cell survival in plasma-cell tumors but its role in B-cell lymphomas is unknown. We analyzed the expression of activated Xbp-1 in reactive lymphoid tissues, 411 lymphomas and plasma-cell neoplasms, and 24 B-cell lines. In reactive tissues, Xbp-1 was only found in nuclear extracts. Nuclear expression of Xbp-1 was observed in occasional reactive plasma cells and in a subpopulation of Irf-4+/Bcl-6−/Pax-5− B cells in the light zones of reactive germinal centers, probably representing cells committed to plasma-cell differentiation. None of the low-grade lymphomas showed evidence of Xbp-1 activation; however, Xbp-1 activation was found in 28% of diffuse large B-cell lymphomas, independent of germinal or postgerminal center phenotype, as well as in 48% of plasmablastic lymphomas and 69% of plasma-cell neoplasms. Diffuse large B-cell lymphomas with nuclear Xbp-1 expression had a significantly worse response to therapy and shorter overall survival compared with negative tumors. These findings suggest that Xbp-1 activation may play a role in the pathogenesis of aggressive B-cell lymphomas. PMID:19389935

  4. Lymphomagenic CARD11/BCL10/MALT1 signaling drives malignant B-cell proliferation via cooperative NF-κB and JNK activation

    PubMed Central

    Knies, Nathalie; Alankus, Begüm; Weilemann, Andre; Tzankov, Alexandar; Brunner, Kristina; Ruff, Tanja; Kremer, Marcus; Keller, Ulrich B.; Lenz, Georg; Ruland, Jürgen

    2015-01-01

    The aggressive activated B cell-like subtype of diffuse large B-cell lymphoma is characterized by aberrant B-cell receptor (BCR) signaling and constitutive nuclear factor kappa-B (NF-κB) activation, which is required for tumor cell survival. BCR-induced NF-κB activation requires caspase recruitment domain-containing protein 11 (CARD11), and CARD11 gain-of-function mutations are recurrently detected in human diffuse large B-cell lymphoma (DLBCL). To investigate the consequences of dysregulated CARD11 signaling in vivo, we generated mice that conditionally express the human DLBCL-derived CARD11(L225LI) mutant. Surprisingly, CARD11(L225LI) was sufficient to trigger aggressive B-cell lymphoproliferation, leading to early postnatal lethality. CARD11(L225LI) constitutively associated with B-cell CLL/lymphoma 10 (BCL10) and mucosa-associated lymphoid tissue lymphoma translocation gene 1 (MALT1) to simultaneously activate the NF-κB and c-Jun N-terminal kinase (JNK) signaling cascades. Genetic deficiencies of either BCL10 or MALT1 completely rescued the phenotype, and pharmacological inhibition of JNK was, similar to NF-κB blockage, toxic to autonomously proliferating CARD11(L225LI)-expressing B cells. Moreover, constitutive JNK activity was observed in primary human activated B cell-like (ABC)-DLBCL specimens, and human ABC-DLBCL cells were also sensitive to JNK inhibitors. Thus, our results demonstrate that enforced activation of CARD11/BCL10/MALT1 signaling is sufficient to drive transformed B-cell expansion in vivo and identify the JNK pathway as a therapeutic target for ABC-DLBCL. PMID:26668357

  5. CD19-CAR engineered NK-92 cells are sufficient to overcome NK cell resistance in B-cell malignancies.

    PubMed

    Romanski, Annette; Uherek, Christoph; Bug, Gesine; Seifried, Erhard; Klingemann, Hans; Wels, Winfried S; Ottmann, Oliver G; Tonn, Torsten

    2016-07-01

    Many B-cell acute and chronic leukaemias tend to be resistant to killing by natural killer (NK) cells. The introduction of chimeric antigen receptors (CAR) into T cells or NK cells could potentially overcome this resistance. Here, we extend our previous observations on the resistance of malignant lymphoblasts to NK-92 cells, a continuously growing NK cell line, showing that anti-CD19-CAR (αCD19-CAR) engineered NK-92 cells can regain significant cytotoxicity against CD19 positive leukaemic cell lines and primary leukaemia cells that are resistant to cytolytic activity of parental NK-92 cells. The 'first generation' CAR was generated from a scFv (CD19) antibody fragment, coupled to a flexible hinge region, the CD3ζ chain and a Myc-tag and cloned into a retrovirus backbone. No difference in cytotoxic activity of NK-92 and transduced αCD19-CAR NK-92 cells towards CD19 negative targets was found. However, αCD19-CAR NK-92 cells specifically and efficiently lysed CD19 expressing B-precursor leukaemia cell lines as well as lymphoblasts from leukaemia patients. Since NK-92 cells can be easily expanded to clinical grade numbers under current Good Manufactoring Practice (cGMP) conditions and its safety has been documented in several phase I clinical studies, treatment with CAR modified NK-92 should be considered a treatment option for patients with lymphoid malignancies.

  6. Clinical significance of co-expression of MYC and BCL2 protein in aggressive B-cell lymphomas treated with a second line immunochemotherapy.

    PubMed

    Miura, Katsuhiro; Takahashi, Hiromichi; Nakagawa, Masaru; Izu, Asami; Sugitani, Masahiko; Kurita, Daisuke; Sakagami, Masashi; Ohtake, Shimon; Uchino, Yoshihito; Hojo, Atsuko; Kodaira, Hitomi; Yagi, Mai; Kobayashi, Yujin; Iriyama, Noriyoshi; Kobayashi, Sumiko; Kiso, Satomi; Hirabayashi, Yukio; Hatta, Yoshihiro; Takei, Masami

    2016-01-01

    The clinical significance of concurrent expression of MYC and BCL2 protein, known as "double-expressor lymphoma" (DEL), among patients with relapsed or refractory aggressive B-cell lymphomas, remains unclear. A retrospective analysis was performed of 38 patients treated with a salvage treatment consisting of rituximab, ifosfamide, etoposide, cytarabine and dexamethasone followed by consolidative high-dose chemotherapies. A total of 17 cases (45%) were categorized as DEL using immunohistochemical assay with a cut-off value of positivity of 40% for MYC and 50% for BCL2, respectively. DEL was associated with a lower overall response rate (35% vs 71%, p = 0.0481), worse 2-year progression-free survival (9% vs 67%, p = 0.001) and overall survival (35% vs 71%, p = 0.037). This analysis suggests that DEL is common among patients with relapsed/refractory aggressive B-cell lymphomas and that such patients require novel treatment strategies.

  7. Chemotherapy-Refractory Diffuse Large B-Cell Lymphoma and Indolent B-Cell Malignancies Can Be Effectively Treated With Autologous T Cells Expressing an Anti-CD19 Chimeric Antigen Receptor

    PubMed Central

    Kochenderfer, James N.; Dudley, Mark E.; Kassim, Sadik H.; Somerville, Robert P.T.; Carpenter, Robert O.; Stetler-Stevenson, Maryalice; Yang, James C.; Phan, Giao Q.; Hughes, Marybeth S.; Sherry, Richard M.; Raffeld, Mark; Feldman, Steven; Lu, Lily; Li, Yong F.; Ngo, Lien T.; Goy, Andre; Feldman, Tatyana; Spaner, David E.; Wang, Michael L.; Chen, Clara C.; Kranick, Sarah M.; Nath, Avindra; Nathan, Debbie-Ann N.; Morton, Kathleen E.; Toomey, Mary Ann; Rosenberg, Steven A.

    2015-01-01

    Purpose T cells can be genetically modified to express an anti-CD19 chimeric antigen receptor (CAR). We assessed the safety and efficacy of administering autologous anti-CD19 CAR T cells to patients with advanced CD19+ B-cell malignancies. Patients and Methods We treated 15 patients with advanced B-cell malignancies. Nine patients had diffuse large B-cell lymphoma (DLBCL), two had indolent lymphomas, and four had chronic lymphocytic leukemia. Patients received a conditioning chemotherapy regimen of cyclophosphamide and fludarabine followed by a single infusion of anti-CD19 CAR T cells. Results Of 15 patients, eight achieved complete remissions (CRs), four achieved partial remissions, one had stable lymphoma, and two were not evaluable for response. CRs were obtained by four of seven evaluable patients with chemotherapy-refractory DLBCL; three of these four CRs are ongoing, with durations ranging from 9 to 22 months. Acute toxicities including fever, hypotension, delirium, and other neurologic toxicities occurred in some patients after infusion of anti-CD19 CAR T cells; these toxicities resolved within 3 weeks after cell infusion. One patient died suddenly as a result of an unknown cause 16 days after cell infusion. CAR T cells were detected in the blood of patients at peak levels, ranging from nine to 777 CAR-positive T cells/μL. Conclusion This is the first report to our knowledge of successful treatment of DLBCL with anti-CD19 CAR T cells. These results demonstrate the feasibility and effectiveness of treating chemotherapy-refractory B-cell malignancies with anti-CD19 CAR T cells. The numerous remissions obtained provide strong support for further development of this approach. PMID:25154820

  8. Global microRNA expression profiling uncovers molecular markers for classification and prognosis in aggressive B-cell lymphoma.

    PubMed

    Iqbal, Javeed; Shen, Yulei; Huang, Xin; Liu, Yanyan; Wake, Laura; Liu, Cuiling; Deffenbacher, Karen; Lachel, Cynthia M; Wang, Chao; Rohr, Joseph; Guo, Shuangping; Smith, Lynette M; Wright, George; Bhagavathi, Sharathkumar; Dybkaer, Karen; Fu, Kai; Greiner, Timothy C; Vose, Julie M; Jaffe, Elaine; Rimsza, Lisa; Rosenwald, Andreas; Ott, German; Delabie, Jan; Campo, Elias; Braziel, Rita M; Cook, James R; Tubbs, Raymond R; Armitage, James O; Weisenburger, Dennis D; Staudt, Louis M; Gascoyne, Randy D; McKeithan, Timothy W; Chan, Wing C

    2015-02-12

    We studied the global microRNA (miRNA) expression in diffuse large B-cell lymphoma (DLBCL; n = 79), Burkitt lymphoma (BL; n = 36), primary mediastinal B-cell lymphoma (PMBL; n = 12), B-cell lines (n = 11), and normal subsets of naïve B cells, centroblasts (CBs), and peripheral blood B cells along with their corresponding gene expression profiles (GEPs). The normal B-cell subsets have well-defined miRNA signatures. The CB miRNA signature was significantly associated with germinal center B-cell (GCB)-DLBCL compared with activated B-cell (ABC)-DLBCL (P = .002). We identified a 27-miRNA signature that included v-myc avian myelomatosis viral oncogene homolog (MYC) targets and enabled the differentiation of BL from DLBCL, a distinction comparable with the "gold standard" GEP-defined diagnosis. Distinct miRNA signatures were identified for DLBCL subgroups, including GCB-DLBCL, activated B-cell (ABC)-DLBCL, and PMBL. Interestingly, most of the unclassifiable-DLBCL by GEP showed a strong similarity to the ABC-DLBCL by miRNA expression profiling. Consistent results for BL and DLBCL subgroup classification were observed in formalin-fixed, paraffin-embedded tissue, making such tests practical for clinical use. We also identified predictive miRNA biomarker signatures in DLBCL, including high expression of miR-155, which is significantly associated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) treatment failure. This finding was further supported by the observation that high expression of miR-155 sensitizes cells to v-akt murine thymoma viral oncogene homolog-1 inhibitors in vitro, suggesting a novel treatment option for resistant DLBCL. PMID:25498913

  9. Global microRNA expression profiling uncovers molecular markers for classification and prognosis in aggressive B-cell lymphoma

    PubMed Central

    Shen, Yulei; Huang, Xin; Liu, Yanyan; Wake, Laura; Liu, Cuiling; Deffenbacher, Karen; Lachel, Cynthia M.; Wang, Chao; Rohr, Joseph; Guo, Shuangping; Smith, Lynette M.; Wright, George; Bhagavathi, Sharathkumar; Dybkaer, Karen; Fu, Kai; Greiner, Timothy C.; Vose, Julie M.; Jaffe, Elaine; Rimsza, Lisa; Rosenwald, Andreas; Ott, German; Delabie, Jan; Campo, Elias; Braziel, Rita M.; Cook, James R.; Tubbs, Raymond R.; Armitage, James O.; Weisenburger, Dennis D.; Staudt, Louis M.; Gascoyne, Randy D.; McKeithan, Timothy W.; Chan, Wing C.

    2015-01-01

    We studied the global microRNA (miRNA) expression in diffuse large B-cell lymphoma (DLBCL; n = 79), Burkitt lymphoma (BL; n = 36), primary mediastinal B-cell lymphoma (PMBL; n = 12), B-cell lines (n = 11), and normal subsets of naïve B cells, centroblasts (CBs), and peripheral blood B cells along with their corresponding gene expression profiles (GEPs). The normal B-cell subsets have well-defined miRNA signatures. The CB miRNA signature was significantly associated with germinal center B-cell (GCB)–DLBCL compared with activated B-cell (ABC)–DLBCL (P = .002). We identified a 27-miRNA signature that included v-myc avian myelomatosis viral oncogene homolog (MYC) targets and enabled the differentiation of BL from DLBCL, a distinction comparable with the “gold standard” GEP-defined diagnosis. Distinct miRNA signatures were identified for DLBCL subgroups, including GCB-DLBCL, activated B-cell (ABC)-DLBCL, and PMBL. Interestingly, most of the unclassifiable-DLBCL by GEP showed a strong similarity to the ABC-DLBCL by miRNA expression profiling. Consistent results for BL and DLBCL subgroup classification were observed in formalin-fixed, paraffin-embedded tissue, making such tests practical for clinical use. We also identified predictive miRNA biomarker signatures in DLBCL, including high expression of miR-155, which is significantly associated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) treatment failure. This finding was further supported by the observation that high expression of miR-155 sensitizes cells to v-akt murine thymoma viral oncogene homolog-1 inhibitors in vitro, suggesting a novel treatment option for resistant DLBCL. PMID:25498913

  10. Deregulation of miR-183 and KIAA0101 in Aggressive and Malignant Pituitary Tumors

    PubMed Central

    Roche, Magali; Wierinckx, Anne; Croze, Séverine; Rey, Catherine; Legras-Lachuer, Catherine; Morel, Anne-Pierre; Fusco, Alfredo; Raverot, Gérald; Trouillas, Jacqueline; Lachuer, Joel

    2015-01-01

    Changes in microRNAs (miRNAs) expression in many types of cancer suggest that they may be involved in crucial steps during tumor progression. Indeed, miRNAs deregulation has been described in pituitary tumorigenesis, but few studies have described their role in pituitary tumor progression toward aggressiveness and malignancy. To assess the role of miRNAs within the hierarchical cascade of events in prolactin (PRL) tumors during progression, we used an integrative genomic approach to associate clinical–pathological features, global miRNA expression, and transcriptomic profiles of the same human tumors. We describe the specific down-regulation of one principal miRNA, miR-183, in the 8 aggressive (A, grade 2b) compared to the 18 non-aggressive (NA, grades 1a, 2a) PRL tumors. We demonstrate that it acts as an anti-proliferative gene by directly targeting KIAA0101, which is involved in cell cycle activation and inhibition of p53–p21-mediated cell cycle arrest. Moreover, we show that miR-183 and KIAA0101 expression significantly correlate with the main markers of pituitary tumors aggressiveness, Ki-67 and p53. These results confirm the activation of proliferation in aggressive and malignant PRL tumors compared to non-aggressive ones. Importantly, these data also demonstrate the ability of such an integrative genomic strategy, applied in the same human tumors, to identify the molecular mechanisms responsible for tumoral progression even from a small cohort of patients. PMID:26322309

  11. Fixed nuclei as alternative template of BIOMED-2 multiplex polymerase chain reaction for immunoglobulin gene clonality testing in B-cell malignancies.

    PubMed

    Tang, Yuan; Chen, Jie; Wang, Jianchao; Zheng, Ke; Liao, Dianying; Liao, Xiaomei; Liu, Weiping; Wang, Lin

    2015-01-01

    Evaluation of immunoglobulin (Ig) gene rearrangements with BIOMED-2 multiplex PCR has become a standard detection of clonality in mature B cell malignancies. Conventionally, this method is relatively labor-intensive and time-consuming, as it requires DNA isolation from bone marrow aspirates (BM) or peripheral blood (PB) in patients with BM or PB involvement. On the other hand, fluorescence in situ hybridization (FISH) is routinely used as genetic screening in B cell malignancies, but the surplus fixed nuclei initially prepared for FISH usually turn useless afterwards. We sought to use these surplus nuclei after FISH as a template to perform PCR-based Ig gene clonality testing. Templates of 12 patients with mature B cell malignancies, which consisted of both DNA isolated with commercial DNA isolation kit from fresh BM or PB (DNA group) and the fixed nuclei initially prepared for FISH (nuclei group) from the same individuals, were subjected to PCR with BIOMED-2 primer sets for immunoglobulin heavy chain and kappa light chain under recommended conditions. Our result, for the first time, showed a high consistency between the two groups in detecting B cell clonality, which indicates that nuclei for FISH can function as a reliable template comparable to fresh tissue-isolated DNA in PCR based Ig clonality testing. This offers a simple, rapid and more economical alternative to standard Ig testing based on regular DNA.

  12. Retrospective analysis of protein kinase C-beta (PKC-β) expression in lymphoid malignancies and its association with survival in diffuse large B-cell lymphomas

    PubMed Central

    Li, Shuyu; Phong, Mark; Lahn, Michael; Brail, Leslie; Sutton, Susan; Lin, Boris K; Thornton, Donald; Liao, Birong

    2007-01-01

    Background Both mechanistic features and recent correlative findings suggest a potential role for protein kinase C-beta (PKC-β) in tumor pathogenesis, particularly in B-cell malignancies. To evaluate the role of this gene in lymphoid malignancies, we analyzed global gene expression data to quantify PKC-β expression across diagnostic groups and, when possible, determined correlations between PKC-β expression and survival. Results Our analysis showed that the level of PKC-β expression was highest in chronic lymphocytic leukemia and follicular lymphoma. Within diffuse large-B cell lymphoma (DLBCL), PKC-β expression was significantly higher in activated B-cell- like subtype than germinal center B-cell- like subtype (P < 0.0001). Elevated PKC-β appeared to be associated with worse survival in both of these subtypes. When analyzed within clinically defined risk groups established by the International Prognostic Index (IPI), PKC-β expression was lowest in patients with low IPI scores (0–1). Within intermediate- and high-risk IPI groups, elevated PKC-β expression was associated with worse survival, suggesting that PKC-β may expand the prognostic value of the IPI. Results of global gene expression analyses of DLBCL samples corroborate previous observations that anti-apoptosis, cell proliferation, and B-cell proliferation signaling pathways are functionally related to PKC-β. Conclusion We present a first detailed pharmacogenomics report comparing PKC-β mRNA expression across different lymphoid malignancies and evaluating it as an outcome predictor. Our findings suggest that DLBCL patients with elevated PKC-β have a worse prognosis, indicating that further evaluation of PKC-β as a chemotherapeutic target for lymphoid malignancies is warranted. Reviewers This article was reviewed by Dr. Pierre Pontarotti, Dr. Kateryna Makova, and Dr. Matthew Coleman (nominated by Dr. Sandrine Dudoit). PMID:17313671

  13. Delay in treatment of primary malignant and aggressive musculoskeletal tumours.

    PubMed

    Pan, K L; Zolqarnain, A; Chia, Y Y

    2006-02-01

    Patients with aggressive musculoskeletal tumours often arrive at specialised treatment centres late. Such a delay could mean disfavour for potentially curable or long-term disease-free outcome of limb preserving surgery. This study was undertaken to identify the underlying problem-related delay with a view to propose solution for solving it. We reviewed 30 patients to determine the periods of delay between onset of the first symptom and the definitive treatment. The delays were categorized as 'patient' delay, 'referral' delay and 'treatment' delay. There was 'patient' delay in 57% of patients (n=17), ranging from 1 to 18 months; 'referral' delay in 67% of patients (n=20) ranging from 1 to 19 months and 23% of patients (n=7) had treatment delay (average 23 days) at the treatment centre. The causes of late arrival are not solely patient-related but are multifactorial. Measures to minimize such delays include enhancing awareness only with high index of suspicion among primary care practitioners, creating a special lane specialized imaging studies and establishing a dedicated musculoskeletal tumour unit. PMID:17042231

  14. Role of B cells in Sjögren's syndrome--from benign lymphoproliferation to overt malignancy.

    PubMed

    Jonsson, Roland; Nginamau, Elisabeth; Szyszko, Ewa; Brokstad, Karl A

    2007-01-01

    The classical view of B cell biology is that these cells respond to foreign and self antigens and in this way promote protection, primarily by production of antibodies. However, recent studies suggest that B cells have diverse functions within the immune system other than antibody production, which could contribute to autoimmunity. This involves organization of lymphoid tissue, regulation of dendritic cells, antigen presentation, activation of T cells and production of cytokines. Both abnormalities in the distribution of B cell subsets, and recent discovery of clinical benefit after B cell depletion highlight the pivotal role of B cells in autoimmunity. This change in view of the role of B cells will be exemplified in one autoimmune disease namely Sjögren's syndrome.

  15. Germline antibody V regions as determinants of clonal persistence and malignant growth in the B cell compartment.

    PubMed Central

    Förster, I; Gu, H; Rajewsky, K

    1988-01-01

    Antibody V gene expression was studied in a subpopulation of murine B cells (Ly1 B) which was enriched by cell transfer and had earlier been shown to persist in the immune system over long periods of time. Among 17 hybridomas derived from Ly1 B cells of two different mice, eight were progeny of only three different B cell precursors which apparently had expanded to clones of large size, in the absence of detectable somatic mutation of their antibody V regions. Furthermore, several clonally independent cells expressed identical, unmutated V genes. These data define a novel pathway of B cell development in which cells expressing a selected set of germline antibodies are continuously propagated in the organism. A Ly1 B cell leukemia derived from a similar transfer experiment expressed a VH gene that had been isolated in three independent Ly1 B cell hybridomas, suggesting that the leukemic cells had been equally selected in this pathway. Images PMID:3264787

  16. Malignant thyroid teratoma: report of an aggressive tumor in a 64-year-old man.

    PubMed

    Vilallonga, R; Zafon, C; Ruiz-Marcellan, C; Obiols, G; Fort, J M; Baena, J A; Villanueva, B; Garcia, A; Sobrinho-Simões, M

    2013-09-01

    Malignant teratoma of the thyroid is a rare and aggressive tumor, frequent in children than in adults. Histologically, thyroid teratomas usually show a predominance of a neuroectodermal component. Mature cartilage and bone may be present. We present the case of primary malignant teratoma of the thyroid in a 64-year-old man. Histologically, the tumor displayed a predominant neuroectodermal component. The diagnosis was confirmed by immunohistochemistry. The patient underwent a radical thyroidectomy with central neck dissection as primary treatment and radioiodine treatment afterwards. The patient had local and distant recurrence. A second surgery was performed with poor results and the patient died 3 months afterwards.

  17. Protein kinase CK2 is widely expressed in follicular, Burkitt and diffuse large B-cell lymphomas and propels malignant B-cell growth.

    PubMed

    Pizzi, Marco; Piazza, Francesco; Agostinelli, Claudio; Fuligni, Fabio; Benvenuti, Pietro; Mandato, Elisa; Casellato, Alessandro; Rugge, Massimo; Semenzato, Gianpietro; Pileri, Stefano A

    2015-03-30

    Serine-threonine kinase CK2 is highly expressed and pivotal for survival and proliferation in multiple myeloma, chronic lymphocytic leukemia and mantle cell lymphoma. Here, we investigated the expression of α catalytic and β regulatory CK2 subunits by immunohistochemistry in 57 follicular (FL), 18 Burkitt (BL), 52 diffuse large B-cell (DLBCL) non-Hodgkin lymphomas (NHL) and in normal reactive follicles. In silico evaluation of available Gene Expression Profile (GEP) data sets from patients and Western blot (WB) analysis in NHL cell-lines were also performed. Moreover, the novel, clinical-grade, ATP-competitive CK2-inhibitor CX-4945 (Silmitasertib) was assayed on lymphoma cells. CK2 was detected in 98.4% of cases with a trend towards a stronger CK2α immunostain in BL compared to FL and DLBCL. No significant differences were observed between Germinal Center B (GCB) and non-GCB DLBCL types. GEP data and WB confirmed elevated CK2 mRNA and protein levels as well as active phosphorylation of specific targets in NHL cells. CX-4945 caused a dose-dependent growth-arresting effect on GCB, non-GCB DLBCL and BL cell-lines and it efficiently shut off phosphorylation of NF-κB RelA and CDC37 on CK2 target sites. Thus, CK2 is highly expressed and could represent a suitable therapeutic target in BL, FL and DLBCL NHL.

  18. Nature and nurture: a case of transcending haematological pre-malignancies in a pair of monozygotic twins adding possible clues on the pathogenesis of B-cell proliferations.

    PubMed

    Hansen, Marcus C; Nyvold, Charlotte G; Roug, Anne S; Kjeldsen, Eigil; Villesen, Palle; Nederby, Line; Hokland, Peter

    2015-05-01

    We describe a comprehensive molecular analysis of a pair of monozygotic twins, who came to our attention when one experienced amaurosis fugax and was diagnosed with JAK2+ polycythaemia vera. He (Twin A) was also found to have an asymptomatic B-cell chronic lymphocytic leukaemia (B-CLL). Although JAK2-, Twin B was subsequently shown to have a benign monoclonal B-cell lymphocytosis (MBL). Flow cytometric and molecular analyses of the B-cell compartments revealed different immunoglobulin light and heavy chain usage in each twin. We hypothesized that whole exome sequencing could help delineating the pattern of germline B-cell disorder susceptibility and reveal somatic mutations potentially contributing to the differential patterns of pre-malignancy. Comparing bone marrow cells and T cells and employing in-house engineered integrative analysis, we found aberrations in Twin A consistent with a myeloid neoplasm, i.e. in TET2, RUNX1, PLCB1 and ELF4. Employing the method for detecting high-ranking variants by extensive annotation and relevance scoring, we also identified shared germline variants in genes of proteins interacting with B-cell receptor signalling mediators and the WNT-pathway, including IRF8, PTPRO, BCL9L, SIT1 and SIRPB1, all with possible implications in B-cell proliferation. Similar patterns of IGHV-gene usage to those demonstrated here have been observed in inherited acute lymphoblastic leukaemia. Collectively, these findings may help in facilitating identification of putative master gene(s) involved in B-cell proliferations in general and MBL and B-CLL in particular. PMID:25752595

  19. Nature and nurture: a case of transcending haematological pre-malignancies in a pair of monozygotic twins adding possible clues on the pathogenesis of B-cell proliferations.

    PubMed

    Hansen, Marcus C; Nyvold, Charlotte G; Roug, Anne S; Kjeldsen, Eigil; Villesen, Palle; Nederby, Line; Hokland, Peter

    2015-05-01

    We describe a comprehensive molecular analysis of a pair of monozygotic twins, who came to our attention when one experienced amaurosis fugax and was diagnosed with JAK2+ polycythaemia vera. He (Twin A) was also found to have an asymptomatic B-cell chronic lymphocytic leukaemia (B-CLL). Although JAK2-, Twin B was subsequently shown to have a benign monoclonal B-cell lymphocytosis (MBL). Flow cytometric and molecular analyses of the B-cell compartments revealed different immunoglobulin light and heavy chain usage in each twin. We hypothesized that whole exome sequencing could help delineating the pattern of germline B-cell disorder susceptibility and reveal somatic mutations potentially contributing to the differential patterns of pre-malignancy. Comparing bone marrow cells and T cells and employing in-house engineered integrative analysis, we found aberrations in Twin A consistent with a myeloid neoplasm, i.e. in TET2, RUNX1, PLCB1 and ELF4. Employing the method for detecting high-ranking variants by extensive annotation and relevance scoring, we also identified shared germline variants in genes of proteins interacting with B-cell receptor signalling mediators and the WNT-pathway, including IRF8, PTPRO, BCL9L, SIT1 and SIRPB1, all with possible implications in B-cell proliferation. Similar patterns of IGHV-gene usage to those demonstrated here have been observed in inherited acute lymphoblastic leukaemia. Collectively, these findings may help in facilitating identification of putative master gene(s) involved in B-cell proliferations in general and MBL and B-CLL in particular.

  20. The Tol2 transposon system mediates the genetic engineering of T-cells with CD19-specific chimeric antigen receptors for B-cell malignancies.

    PubMed

    Tsukahara, T; Iwase, N; Kawakami, K; Iwasaki, M; Yamamoto, C; Ohmine, K; Uchibori, R; Teruya, T; Ido, H; Saga, Y; Urabe, M; Mizukami, H; Kume, A; Nakamura, M; Brentjens, R; Ozawa, K

    2015-02-01

    Engineered T-cell therapy using a CD19-specific chimeric antigen receptor (CD19-CAR) is a promising strategy for the treatment of advanced B-cell malignancies. Gene transfer of CARs to T-cells has widely relied on retroviral vectors, but transposon-based gene transfer has recently emerged as a suitable nonviral method to mediate stable transgene expression. The advantages of transposon vectors compared with viral vectors include their simplicity and cost-effectiveness. We used the Tol2 transposon system to stably transfer CD19-CAR into human T-cells. Normal human peripheral blood lymphocytes were co-nucleofected with the Tol2 transposon donor plasmid carrying CD19-CAR and the transposase expression plasmid and were selectively propagated on NIH3T3 cells expressing human CD19. Expanded CD3(+) T-cells with stable and high-level transgene expression (~95%) produced interferon-γ upon stimulation with CD19 and specifically lysed Raji cells, a CD19(+) human B-cell lymphoma cell line. Adoptive transfer of these T-cells suppressed tumor progression in Raji tumor-bearing Rag2(-/-)γc(-/-) immunodeficient mice compared with control mice. These results demonstrate that the Tol2 transposon system could be used to express CD19-CAR in genetically engineered T-cells for the treatment of refractory B-cell malignancies.

  1. Laser-based microdissection of single cells from tissue sections and PCR analysis of rearranged immunoglobulin genes from isolated normal and malignant human B cells.

    PubMed

    Küppers, Ralf; Schneider, Markus; Hansmann, Martin-Leo

    2013-01-01

    Normal and malignant B cells carry rearranged immunoglobulin (Ig) variable region genes, which due to their practically limitless diversity represent ideal clonal markers for these cells. We describe here an approach to isolate single cells from frozen tissue sections by microdissection using a laser-based method. From the isolated cells rearranged IgH and Igκ genes are amplified in a semi-nested PCR approach, using a collection of V gene family-specific primers recognizing nearly all V gene segments together with primers for the J gene segments. By sequence analysis of V genes from distinct cells, the clonal relationship of the B lineage cells can unequivocally be determined and related to the histological distribution of the cells. The approach is also useful to determine V, D, and J gene usage. Moreover, the presence and pattern of somatic Ig V gene mutations give valuable insight into the stage of differentiation of the B cells.

  2. Analysis of the miRNA-mRNA networks in malignant transformation BEAS-2B cells induced by alpha-particles.

    PubMed

    Nie, Ji-Hua; Chen, Zhi-Hai; Shao, Chun-Lin; Pei, Wei-Wei; Zhang, Jie; Zhang, Shu-Yu; Jiao, Yang; Tong, Jian

    2016-01-01

    The aim of this study was to determine the toxicity induced by irradiation with alpha-particles on malignant transformation of immortalized human bronchial epithelial cells (BEAS-2B) using miRNA-mRNA networks. The expression of BEAS-2B cells was determined by measuring colony formation, mtDNA, mitochondrial membrane potential (MMP), and ROS levels. Changes in BEAS-2B cell gene expression were observed and quantified using microarrays that included an increase in 157 mRNA and 20 miRNA expression and a decrease in 77 mRNA and 48 miRNA. Bioinformatic software was used to analyze these different mRNA and miRNA, which indicated that miR-107 and miR-494 play an important role in alpha-particles-mediated cellular malignant transformation processes. The pathways related to systemic lupus erythematosus, cytokine-cytokine receptor interaction, MAPK signaling pathway, regulation of actin cytoskeleton, and cell adhesion molecules (CAMs) were stimulated, while those of ribosome, transforming growth factor (TGF)-beta signaling pathway, and metabolic pathways were inhibited. Data suggest that miRNA and mRNA play a crucial role in alpha-particles-mediated malignant transformation processes. It is worth noting that three target genes associated with lung cancer were identified and upregulated PEG 10 (paternally expressed gene 10), ARHGAP26, and IRS1. PMID:27267825

  3. A phase 1 clinical trial of the selective BTK inhibitor ONO/GS-4059 in relapsed and refractory mature B-cell malignancies.

    PubMed

    Walter, Harriet S; Rule, Simon A; Dyer, Martin J S; Karlin, Lionel; Jones, Ceri; Cazin, Bruno; Quittet, Philippe; Shah, Nimish; Hutchinson, Claire V; Honda, Hideyuki; Duffy, Kevin; Birkett, Joseph; Jamieson, Virginia; Courtenay-Luck, Nigel; Yoshizawa, Toshio; Sharpe, John; Ohno, Tomoya; Abe, Shinichiro; Nishimura, Akihisa; Cartron, Guillaume; Morschhauser, Franck; Fegan, Christopher; Salles, Gilles

    2016-01-28

    We report the results of a multicenter phase 1 dose-escalation study of the selective Bruton tyrosine kinase (BTK) inhibitor ONO/GS-4059 in 90 patients with relapsed/refractory B-cell malignancies. There were 9 dose-escalation cohorts ranging from 20 mg to 600 mg once daily with twice-daily regimens of 240 mg and 300 mg. Twenty-four of 25 evaluable chronic lymphocytic leukemia (CLL) patients (96%) responded to ONO/GS-4059, with a median treatment duration of 80 weeks; 21 CLL patients remain on treatment. Lymph node responses were rapid and associated with a concurrent lymphocytosis. Eleven of 12 evaluable patients with mantle cell lymphoma (92%) responded (median treatment duration, 40 weeks). Eleven of 31 non-germinal center B-cell diffuse large B-cell lymphoma patients (35%) responded but median treatment duration was 12 weeks due to development of progressive disease. ONO/GS-4059 was very well tolerated with 75% of adverse events (AEs) being Common Toxicity Criteria for Adverse Events version 4.0 grade 1 or grade 2. Grade 3/4 AEs were mainly hematologic and recovered spontaneously during therapy. One CLL patient experienced a grade 3 treatment-related bleeding event (spontaneous muscle hematoma) but no clinically significant diarrhea, cardiac dysrhythmias, or arthralgia were observed. No maximal tolerated dose (MTD) was reached in the CLL cohort. In the non-Hodgkin lymphoma cohort, 4 patients developed a dose-limiting toxicity, yielding an MTD of 480 mg once daily. ONO/GS-4059 has significant activity in relapsed/refractory B-cell malignancies without major drug-related toxicity. The selectivity of ONO/GS-4059 should confer advantages in combination therapies. This trial was registered at www.clinicaltrials.gov as #NCT01659255. PMID:26542378

  4. Efficiency of CD19 chimeric antigen receptor-modified T cells for treatment of B cell malignancies in phase I clinical trials: a meta-analysis

    PubMed Central

    Shi, Ni; Zhang, Zhen; Luo, Zhenzhen; Yue, Dongli; Zhang, Zimeng; Wang, Liping; Han, Weidong; Xu, Zhongwei; Chen, Hu; Zhang, Yi

    2015-01-01

    Chimeric antigen receptor (CAR) modified T cells targeted CD19 showed promising clinical outcomes in treatment of B cell malignances such as chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL) and other indolent lymphomas. However, the clinical benefit varies tremendously among different trials. This meta-analysis investigated the efficacy (response rates and survival time) of CD19-CAR T cells in refractory B cell malignances in Phase I clinical trials. We searched publications between 1991 and 2014 from PubMed and Web of Science. Pooled response rates were calculated using random-effects models. Heterogeneity was investigated by subgroup analysis and meta-regression. Fourteen clinical trials including 119 patients were eligible for response rate evaluation, 62 patients in 12 clinical trials were eligible for progression-free survival analysis. The overall pooled response rate of CD19-CAR T cells was 73% (95% confidence interval [CI]: 46-94%). Significant heterogeneity across estimates of response rates was observed (p < 0.001, I2=88.3%). ALL patients have higher response rate (93%, 95% CI: 65-100%) than CLL (62%, 95% CI: 27-93%) and lymphoma patients (36%, 95% CI: 1-83%). Meta-regression analysis identified lymphodepletion and no IL-2 administrated T cells as two key factors associated with better clinical response. Lymphodepletion and higher infused CAR T cell number were associated with better prognosis. In conclusion, this meta-analysis showed a high clinical response rate of CD19-CAR T cell-based immunotherapy in treatment of refractory B cell malignancies. Lymphodepletion and increasing number of infused CD19-CAR T cells have positive correlations with the clinical efficiency, on the contrary, IL-2 administration to T cells is not recommended. PMID:26376680

  5. Reduced-Intensity Conditioning with Fludarabine, Cyclophosphamide, and Rituximab Is Associated with Improved Outcomes Compared with Fludarabine and Busulfan after Allogeneic Stem Cell Transplantation for B Cell Malignancies.

    PubMed

    Kennedy, Vanessa E; Savani, Bipin N; Greer, John P; Kassim, Adetola A; Engelhardt, Brian G; Goodman, Stacey A; Sengsayadeth, Salyka; Chinratanalab, Wichai; Jagasia, Madan

    2016-10-01

    Reduced-intensity conditioning (RIC) has been used increasingly for allogeneic hematopoietic cell transplantation to minimize transplant-related mortality while maintaining the graft-versus-tumor effect. In B cell lymphoid malignancies, reduced-intensity regimens containing rituximab, an antiCD20 antibody, have been associated with favorable survival; however, the long-term outcomes of rituximab-containing versus nonrituximab-containing regimens for allogeneic hematopoietic cell transplantation in B cell lymphoid malignancies remain to be determined. We retrospectively analyzed 94 patients who received an allogeneic transplant for a B cell lymphoid malignancy. Of these, 33 received RIC with fludarabine, cyclophosphamide, and rituximab (FCR) and graft-versus-host disease (GVHD) prophylaxis with a calcineurin inhibitor and mini-methotrexate, and 61 received RIC with fludarabine and busulfan (FluBu) and GVHD prophylaxis with a calcineurin inhibitor and mycophenolate mofetil. The 2-year overall survival was superior in patients who received FCR versus FluBu (72.7% versus 54.1%, P = .031), and in multivariable analysis adjusted for Disease Risk Index and donor type, only the conditioning regimen (FluBu versus FCR: HR, 2.06; 95% CI, 1.04 to 4.08; P = .037) and Disease Risk Index (low versus intermediate/high: HR, .38; 95% CI, .17 to .86; P = .02) were independent predictors of overall survival. The 2-year cumulative incidence of chronic GVHD was lower in patients who received FCR versus FluBu (24.2% versus 51.7%, P = .01). There was no difference in rate of relapse/progression or acute GVHD. Our results demonstrate that the use of RIC with FCR and GVHD prophylaxis with a calcineurin inhibitor and mini-methotrexate is associated with decreased chronic GVHD and improved overall survival.

  6. Monotherapy with pixantrone in histologically confirmed relapsed or refractory aggressive B-cell non-Hodgkin lymphoma: post-hoc analyses from a phase III trial.

    PubMed

    Pettengell, Ruth; Sebban, Catherine; Zinzani, Pier Luigi; Derigs, Hans Gunter; Kravchenko, Sergey; Singer, Jack W; Theocharous, Panteli; Wang, Lixia; Pavlyuk, Mariya; Makhloufi, Kahina M; Coiffier, Bertrand

    2016-09-01

    This post hoc analysis of a phase 3 trial explored the effect of pixantrone in patients (50 pixantrone, 47 comparator) with relapsed or refractory aggressive B-cell non-Hodgkin lymphoma (NHL) confirmed by centralized histological review. Patients received 28-d cycles of 85 mg/m(2) pixantrone dimaleate (equivalent to 50 mg/m(2) in the approved formulation) on days 1, 8 and 15, or comparator. The population was subdivided according to previous rituximab use and whether they received the study treatment as 3rd or 4th line. Median number of cycles was 4 (range, 2-6) with pixantrone and 3 (2-6) with comparator. In 3rd or 4th line, pixantrone was associated with higher complete response (CR) (23·1% vs. 5·1% comparator, P = 0·047) and overall response rate (ORR, 43·6% vs. 12·8%, P = 0·005). In 3rd or 4th line with previous rituximab (20 pixantrone, 18 comparator), pixantrone produced better ORR (45·0% vs. 11·1%, P = 0·033), CR (30·0% vs. 5·6%, P = 0·093) and progression-free survival (median 5·4 vs. 2·8 months, hazard ratio 0·52, 95% confidence interval 0·26-1·04) than the comparator. Similar results were found in patients without previous rituximab. There were no unexpected safety issues. Pixantrone monotherapy is more effective than comparator in relapsed or refractory aggressive B-cell NHL in the 3rd or 4th line setting, independently of previous rituximab.

  7. An aggressive solitary fibrous tumor with evidence of malignancy: a rare case report.

    PubMed

    Vimi, S; Punnya, V A; Kaveri, H; Rekha, K

    2008-09-01

    Solitary fibrous tumor (SFT) is rare mesenchymal neoplasm that has been originally and most often documented in the pleura. Recently, the ubiquitous nature of the SFT has been recognized with reports of involvement of numerous sites all over the body, i.e, upper respiratory tract, breast, somatic tissue, mediastinum, head, and neck, etc. The diagnosis of SFT still remains an enigma in our field. Furthermore, malignant SFT is extremely rare and only two cases have been reported in the oral cavity till date. Here, we present a rare case report of an aggressive solitary fibrous tumor which presented as a palatal mass and extended throughout the middle cranial fossa and exhibited features of malignancy.

  8. 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

    2016-07-08

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

  9. A phase II study of belinostat (PXD101) in relapsed and refractory aggressive B-cell lymphomas: SWOG S0520.

    PubMed

    Puvvada, Soham D; Li, Hongli; Rimsza, Lisa M; Bernstein, Steven H; Fisher, Richard I; LeBlanc, Michael; Schmelz, Monika; Glinsmann-Gibson, Betty; Miller, Thomas P; Maddox, Anne-Marie; Friedberg, Jonathan W; Smith, Sonali M; Persky, Daniel O

    2016-10-01

    Recent advances in diffuse large B-cell lymphomas (DLBCL) have underscored the importance of tumor microenvironment in escaping host anti-tumor responses. One mechanism is loss of major histocompatibility Class II antigens (MHCII) associated with decreased tumor infiltrating T lymphocytes (TIL) and poor survival. Transcription of MHCII is controlled by CIITA which in turn is regulated by histone acetylation. In this study, we hypothesized that HDAC inhibition with belinostat increases MHCII, CIITA expression, TIL and improves patient outcomes. Primary objective was evaluation of toxicity and response. Twenty-two patients were enrolled for the study. Belinostat was well tolerated with mild toxicity. Two partial responses were observed at 5, 13 months after registration for an overall response rate (ORR) (95% CI) of 10.5% (1.3-33.1%), and three patients had stable disease for 4.7, 42.3+, and 68.4 + months with minimum 3-year follow-up. Included correlative studies support the hypothesis and serve as the basis for SWOG S0806 combining vorinostat with R-CHOP.

  10. Oral malignant melanoma: An aggressive clinical entity - Report of a rare case with review of literature.

    PubMed

    Hasan, Shamimul; Jamdar, Sami Faisal; Jangra, Jogender; Al Beaiji, Sadun Mohammad Al Ageel

    2016-01-01

    Melanomais one of the most dreaded and aggressive neoplasms, being derived from epidermal melanocytes. The majority of melanomas are seen to involve the skin, and primary mucosal melanomas account for less than 1% of all melanomas. Oral malignant melanomas (OMM) are asymptomatic at the initial presentation, but later they become painful with growth and expansion. In the late stages, the patient may present with ulceration, bleeding, tooth mobility, paresthesia, ill-fitting prosthesis, and delayed healing of the extraction sockets. Diagnosis is often delayed due to asymptomatic clinical presentation, with silent progression of the lesion. OMM are associated with poor prognosis due to their invasive and metastasizing tendencies. The condition has poor survival rates, and metastatic melanomas show even worse prognosis. The 5-year survival rate for OMM ranges 4.5-29%, with 18.5 months being the mean survival rate. The tumor is best managed by wide surgical resection; however, consideration should also be made for adjunctive therapies such as chemotherapy, immunotherapy, and radiotherapy. Recurrences may be seen even 10-15 years after the primary therapy. This paper aims to present an interesting report of aggressive OMM in a 50-year-old male patient and emphasizes the role of dental professionals in maintaining a high degree of vigilance for the pigmented lesions of the oral cavity. Pigmented lesions of uncertain origin should be routinely biopsied to rule out malignancy. Early diagnosis of this dreadful entity entails thorough history taking, physical examination, and radiographic features coupled with histopathology. PMID:27114959

  11. Oral malignant melanoma: An aggressive clinical entity - Report of a rare case with review of literature

    PubMed Central

    Hasan, Shamimul; Jamdar, Sami Faisal; Jangra, Jogender; Al Beaiji, Sadun Mohammad Al Ageel

    2016-01-01

    Melanomais one of the most dreaded and aggressive neoplasms, being derived from epidermal melanocytes. The majority of melanomas are seen to involve the skin, and primary mucosal melanomas account for less than 1% of all melanomas. Oral malignant melanomas (OMM) are asymptomatic at the initial presentation, but later they become painful with growth and expansion. In the late stages, the patient may present with ulceration, bleeding, tooth mobility, paresthesia, ill-fitting prosthesis, and delayed healing of the extraction sockets. Diagnosis is often delayed due to asymptomatic clinical presentation, with silent progression of the lesion. OMM are associated with poor prognosis due to their invasive and metastasizing tendencies. The condition has poor survival rates, and metastatic melanomas show even worse prognosis. The 5-year survival rate for OMM ranges 4.5–29%, with 18.5 months being the mean survival rate. The tumor is best managed by wide surgical resection; however, consideration should also be made for adjunctive therapies such as chemotherapy, immunotherapy, and radiotherapy. Recurrences may be seen even 10–15 years after the primary therapy. This paper aims to present an interesting report of aggressive OMM in a 50-year-old male patient and emphasizes the role of dental professionals in maintaining a high degree of vigilance for the pigmented lesions of the oral cavity. Pigmented lesions of uncertain origin should be routinely biopsied to rule out malignancy. Early diagnosis of this dreadful entity entails thorough history taking, physical examination, and radiographic features coupled with histopathology. PMID:27114959

  12. B-cell gene rearrangement in benign and malignant lymphoid proliferations of mucosa-associated lymphoid tissue and lymph nodes.

    PubMed

    Torlakovic, E; Cherwitz, D L; Jessurun, J; Scholes, J; McGlennen, R

    1997-02-01

    The polymerase chain reaction (PCR) with polyacrylamide gel electrophoresis was used to study patterns of immunoglobulin heavy chain (IgH) gene rearrangement (GR) in formalin-fixed, paraffin-embedded specimens of lymphomas and reactive conditions of mucosa-associated lymphoid tissue (MALT) and lymph node. DNA amplification was performed directly on sections obtained from paraffin blocks. Five patterns of PCR products were observed: a single band, two or more discrete bands, smearing, a single band overlying a smear, and two or more bands over a smear. A pure polyclonal pattern (smear) was observed in all of the reactive lymph nodes but in only 15% of cases of Helicobacter pylori (HP) gastritis with lymphoid hyperplasia, 25% of cases of HP gastritis without lymphoid hyperplasia, and 37% of colonic specimens of various types. Patterns consisting of multiple bands with or without background smearing were common in gastritis, colitis, and gastric lymphomas. Single bands or dominant bands were present in all lymph node and salivary gland lymphomas, 12 of 14 cases of gastric lymphoma, and 17 of 20 cases of HP gastritis with lymphoid hyperplasia. These bands were reproducible in deeper sections from the same paraffin block or similar areas sampled in different blocks in all of the lymph node and salivary gland lymphomas, 11 of 12 gastric lymphomas, but only 1 of 17 cases of HP gastritis with lymphoid hyperplasia. Bands were also found in 3 of 20 cases of HP gastritis without lymphoid hyperplasia and 17 of 38 colonic specimens, but these were not reproducible. The complexity of patterns of IgH GR in acquired MALT compared with lymph nodes may be the result of a relative paucity of B-cell clones or preferential proliferation of B-cell clones with a limited area of distribution.

  13. EBV-negative aggressive B-cell lymphomas of donor origin after allogeneic hematopoietic stem cell transplantation: a report of three cases.

    PubMed

    Federmann, Birgit; Bonzheim, Irina; Schittenhelm, Jens; Quintanilla-Martínez, Leticia; Mankel, Barbara; Vogel, Wichard; Faul, Christoph; Bethge, Wolfgang; Fend, Falko

    2016-11-01

    Post-transplant lymphoproliferative disorders (PTLD) develop as a consequence of iatrogenic immunosuppression, and the majority is associated with EBV. PTLD after allogeneic hematopoietic stem cell transplantation (allo-HCT) are rare. Most cases are donor-derived, reflecting immune reconstitution by malignant transformed donor cells, and are EBV-positive. We report three unusual cases of aggressive EBV-negative PTLD of monomorphic type after allo-HCT. All cases were of donor origin and arose with long latency, 4-12 years after HCT. The patients had a history of severe graft-versus-host disease (GVHD) resulting in prolonged immunosuppression before the diagnosis of lymphoma. In one case, the temporal evolution of the malignant clone was analyzed by clone-specific PCR targeting the immunoglobulin heavy chain rearrangement. A tumor-specific product was already detected 3 years before lymphoma development. This indicates that chronic antigenic stimulation and reduced immune surveillance, may promote the outgrowth of premalignant donor-derived clones after acquisition of additional genetic alterations.

  14. Ibritumomab consolidation after 3 cycles of CHOP plus radiotherapy in high-risk limited-stage aggressive B-cell lymphoma: SWOG S0313

    PubMed Central

    Miller, Thomas P.; Unger, Joseph M.; Spier, Catherine M.; Puvvada, Soham; Stea, B. Dino; Press, Oliver W.; Constine, Louis S.; Barton, Kevin P.; Friedberg, Jonathan W.; LeBlanc, Michael; Fisher, Richard I.

    2015-01-01

    In the S0313 trial, we evaluated the impact of adding ibritumomab tiuxetan consolidation to 3 cycles of standard cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy plus involved field radiotherapy (IFRT) in patients with limited-stage aggressive B-cell non-Hodgkin lymphoma (LD-NHL). Patients with at least 1 stage-modified adverse risk factor (nonbulky stage II, age >60 years, elevated lactate dehydrogenase, or World Health Organization performance status of 2) were treated with CHOP on days 1, 22, and 43, followed 3 weeks later by 40 to 50 Gy of IFRT. An ibritumomab tiuxetan regimen was initiated 3 to 6 weeks following IFRT. Forty-six patients were registered and eligible, with median follow-up of 7.3 years. The progression-free survival estimate is 89% at 2 years, 82% at 5 years, and 75% at 7 years. The overall survival estimate is 91% at 2 years, 87% at 5 years, and 82% at 7 years. Grade 4 adverse events occurring more than once included neutropenia (8), leukopenia (5), and lymphopenia (2). Febrile neutropenia was observed in 4 patients. No cases of treatment-related myeloid neoplasms were noted. In conclusion, patients with high-risk LD-NHL treated with 3 cycles of CHOP plus IFRT followed by ibritumomab tiuxetan consolidation had outcomes that compare favorably to our historical experience. The clinical trial was registered at www.clinicaltrials.gov as #NCT00070018. PMID:25395425

  15. Multiple myeloma oncogene 1 (MUM1)/interferon regulatory factor 4 (IRF4) upregulates monokine induced by interferon-gamma (MIG) gene expression in B-cell malignancy.

    PubMed

    Uranishi, M; Iida, S; Sanda, T; Ishida, T; Tajima, E; Ito, M; Komatsu, H; Inagaki, H; Ueda, R

    2005-08-01

    MUM1 (multiple myeloma oncogene 1)/IRF4 (interferon regulatory factor 4) is a transcription factor that is activated as a result of t(6;14)(p25;q32) in multiple myeloma. MUM1 expression is seen in various B-cell lymphomas and predicts an unfavorable outcome in some lymphoma subtypes. To elucidate its role in B-cell malignancies, we prepared MUM1-expressing Ba/F3 cells, which proliferated until higher cellular density than the parental cells, and performed cDNA microarray analysis to identify genes whose expression is regulated by MUM1. We found that the expression of four genes including FK506-binding protein 3 (FKBP3), the monokine induced by interferon-gamma(MIG), Fas apoptotic inhibitory molecule (Faim) and Zinc-finger protein 94 was altered in the MUM1-expressing cells. We then focused on MIG since its expression was immediately upregulated by MUM1. In reporter assays, MUM1 activated the MIG promoter in cooperation with PU.1, and the interaction between MUM1 and the MIG promoter sequence was confirmed. The expression of MIG was correlated with that of MUM1 in B-CLL cell lines, and treatment with neutralizing antibodies against MIG and its receptor, CXCR3, slightly inhibited the proliferation of two MUM1-expressing lines. These results suggest that MUM1 plays roles in the progression of B-cell lymphoma/leukemia by regulating the expression of various genes including MIG. Leukemia (2005) 19, 1471-1478. doi:10.1038/sj.leu.2403833; published online 16 June 2005.

  16. Metastatic chondroblastoma. Report of a fatal case with a review of the literature on atypical, aggressive, and malignant chondroblastoma.

    PubMed

    Kyriakos, M; Land, V J; Penning, H L; Parker, S G

    1985-04-15

    A boy with metastatic and fatal chondroblastoma is presented. Unlike previously published examples of metastatic chondroblastoma, these metastases developed before any operative manipulation of the primary tumor. The histologic characteristics of the primary, metastatic, and locally recurrent tumors were those of a conventional chondroblastoma. A review of published cases of atypical, aggressive, and malignant chondroblastoma is presented with current follow-up information. Although some metastatic chondroblastomas may result from operative manipulation of the primary tumor and are clinically benign, other histologically benign chondroblastomas exist that are capable of pursuing a malignant course. The authors designate these as malignant chondroblastomas. No histologic criteria exist for the separation of these tumors.

  17. Metastatic chondroblastoma. Report of a fatal case with a review of the literature on atypical, aggressive, and malignant chondroblastoma.

    PubMed

    Kyriakos, M; Land, V J; Penning, H L; Parker, S G

    1985-04-15

    A boy with metastatic and fatal chondroblastoma is presented. Unlike previously published examples of metastatic chondroblastoma, these metastases developed before any operative manipulation of the primary tumor. The histologic characteristics of the primary, metastatic, and locally recurrent tumors were those of a conventional chondroblastoma. A review of published cases of atypical, aggressive, and malignant chondroblastoma is presented with current follow-up information. Although some metastatic chondroblastomas may result from operative manipulation of the primary tumor and are clinically benign, other histologically benign chondroblastomas exist that are capable of pursuing a malignant course. The authors designate these as malignant chondroblastomas. No histologic criteria exist for the separation of these tumors. PMID:3978565

  18. Systematic review of the recent evidence for the efficacy and safety of chlorambucil in the treatment of B-cell malignancies.

    PubMed

    Lepretre, Stéphane; Dartigeas, C; Feugier, P; Marty, M; Salles, G

    2016-01-01

    Emergence of new agents has deeply modified treatment options and the role of chlorambucil (CLB) in B-cell malignancies. We conducted a systematic review of prospective, randomized, controlled trials (RCTs) investigating the benefits and harms of CLB used alone or in combination with other treatment in patients suffering from chronic lymphocytic leukemia (CLL), low-grade non-Hodgkin lymphoma (NHL) or Waldenström macroglobulinemia (WM). For CLL, review of the nine RCTs showed that the main advantage of CLB is its low toxicity in comparison with purine nucleoside analogs like fludarabine in either CLL or NHL. In CLL, the major disadvantage is the very low rate of complete response, except when combining an anti-CD20 antibody. For B-cell lymphoma and WM, six RCTs were summarized. Results according to the usual criteria are presented and the role of CLB, used mostly in combination with an anti-CD20 antibody, is discussed for each indication, in particular for unfit patients. PMID:26308278

  19. Systematic review of the recent evidence for the efficacy and safety of chlorambucil in the treatment of B-cell malignancies.

    PubMed

    Lepretre, Stéphane; Dartigeas, C; Feugier, P; Marty, M; Salles, G

    2016-01-01

    Emergence of new agents has deeply modified treatment options and the role of chlorambucil (CLB) in B-cell malignancies. We conducted a systematic review of prospective, randomized, controlled trials (RCTs) investigating the benefits and harms of CLB used alone or in combination with other treatment in patients suffering from chronic lymphocytic leukemia (CLL), low-grade non-Hodgkin lymphoma (NHL) or Waldenström macroglobulinemia (WM). For CLL, review of the nine RCTs showed that the main advantage of CLB is its low toxicity in comparison with purine nucleoside analogs like fludarabine in either CLL or NHL. In CLL, the major disadvantage is the very low rate of complete response, except when combining an anti-CD20 antibody. For B-cell lymphoma and WM, six RCTs were summarized. Results according to the usual criteria are presented and the role of CLB, used mostly in combination with an anti-CD20 antibody, is discussed for each indication, in particular for unfit patients.

  20. Gall bladder carcinoma: Aggressive malignancy with protean loco-regional and distant spread

    PubMed Central

    Dwivedi, Amit Nandan Dhar; Jain, Shivi; Dixit, Ruhi

    2015-01-01

    The most common malignancy of biliary tract is gallbladder cancer (GBC) which is the third most common cancer in gastrointestinal tract. It is a lethal disease for most patients in spite of growing awareness and improved diagnostic techniques. GBC has a very poor prognosis and the 5 year survival rate is < 10%. Although etiology of the carcinoma of the gallbladder is still obscure, various factors have been implicated, cholelithiasis being the most frequent. The incidence of GBC worldwide is based on the gender, geography and ethnicity which suggest that both genetic and environmental factors can cause GBC. The major route of spread of gallbladder cancer (GC) is loco-regional rather than distant. It spreads by lymphatic, vascular, neural, intraperitoneal, and intraductal routes. Sonography is usually the most common imaging test to evaluate symptoms of biliary tract disease including suspected GC. With recent advances in imaging modalities like multi-detector computed tomography (CT) scanners, magnetic resonance imaging-positron emission tomography/CT diagnosis of gallbladder cancer has improved. Studies have also targeted molecular and genetic pathways. Treatment options have included extended and radical surgeries and adjuvant chemotherapy. This review article deals in detail with important aspects of carcinoma gallbladder and its manifestations and challenges. Role of various imaging modalities in characterization and accurate staging has been discussed. The loco-regional spread of this aggressive malignancy is dealt explicitly. PMID:25789296

  1. Feasibility of Telomerase-Specific Adoptive T-cell Therapy for B-cell Chronic Lymphocytic Leukemia and Solid Malignancies.

    PubMed

    Sandri, Sara; Bobisse, Sara; Moxley, Kelly; Lamolinara, Alessia; De Sanctis, Francesco; Boschi, Federico; Sbarbati, Andrea; Fracasso, Giulio; Ferrarini, Giovanna; Hendriks, Rudi W; Cavallini, Chiara; Scupoli, Maria Teresa; Sartoris, Silvia; Iezzi, Manuela; Nishimura, Michael I; Bronte, Vincenzo; Ugel, Stefano

    2016-05-01

    Telomerase (TERT) is overexpressed in 80% to 90% of primary tumors and contributes to sustaining the transformed phenotype. The identification of several TERT epitopes in tumor cells has elevated the status of TERT as a potential universal target for selective and broad adoptive immunotherapy. TERT-specific cytotoxic T lymphocytes (CTL) have been detected in the peripheral blood of B-cell chronic lymphocytic leukemia (B-CLL) patients, but display low functional avidity, which limits their clinical utility in adoptive cell transfer approaches. To overcome this key obstacle hindering effective immunotherapy, we isolated an HLA-A2-restricted T-cell receptor (TCR) with high avidity for human TERT from vaccinated HLA-A*0201 transgenic mice. Using several relevant humanized mouse models, we demonstrate that TCR-transduced T cells were able to control human B-CLL progression in vivo and limited tumor growth in several human, solid transplantable cancers. TERT-based adoptive immunotherapy selectively eliminated tumor cells, failed to trigger a self-MHC-restricted fratricide of T cells, and was associated with toxicity against mature granulocytes, but not toward human hematopoietic progenitors in humanized immune reconstituted mice. These data support the feasibility of TERT-based adoptive immunotherapy in clinical oncology, highlighting, for the first time, the possibility of utilizing a high-avidity TCR specific for human TERT. Cancer Res; 76(9); 2540-51. ©2016 AACR.

  2. Multi-Detector Computed Tomography in Evaluating Locally Aggressive and Malignant Bone Tumours

    PubMed Central

    Ramavathu, Kumar Venu Madhav; Garga, U.C.

    2015-01-01

    Objective: To evaluate the ability of Multi-Detector Computed Tomography in preoperative evaluation of locally aggressive and malignant bone tumours in correlation with histopathological findings. Materials and Methods: Twenty patients suspected of malignant bone tumours on the basis of their clinical profile were selected. Following a plain radiograph evaluation, all of them were subjected to CT scan examination. Multi Planar Reconstruction (MPR) was done in sagittal and coronal planes and also three-dimensional Volume Rendering (VR) and Maximum Intensity Projection (MIP) images were obtained. Results: Of the 20 patients, 18 underwent surgery, and their histopathological findings were compared and correlated with MDCT findings. MDCT was 92.8% sensitive and 100% specific in determining the vascularity of the tumour and also can detect displacement/ encasement/ involvement of adjacent vessels. It has a sensitivity and specificity of 100% in determining cortical break, calcification and periosteal reaction. However, it is less sensitive in detecting joint involvement. Post contrast enhancement gives details of the extent of the soft tissue component. Conclusion: Although MRI is a preferred modality in preoperative evaluation of bone tumours, CT may be used an alternative in case of non-availability of MRI, which has faster acquisition time and better resolution. Using three dimensional MPR imaging, the location and extent of the tumour can be studied. It is also useful in determining cortical discontinuity, periosteal reaction, and calcification. By virtue of MIP and VR imaging, vascularity of the tumour and its relationship with the adjacent vasculature can be established. However, it is inferior to MRI in soft tissue characterization and has poor sensitivity in detecting marrow and joint involvement. PMID:26023618

  3. Maintenance Therapy with Interferon Alfa 2b Improves Outcome in Aggressive Malignant Lymphoma.

    PubMed

    Avilés, A; Díaz-Maqueo, J C; Talavera, A; García, E L; Nambo, M J

    1998-01-01

    To assess the efficacy and toxicity of interferon alfa 2b (IFN) as maintenance therapy in patients with malignant lymphoma on complete response after conventional chemotherapy we start a randomized clinical trial. One hundred and seventy patients were randomized to received either IFN 5.0 MU three time at week by one year or no further treatment, as control group. At a median follow-up of 9.0 years (range 4.3 to 11 years) median freedom from relapse (FFR) has not been reached in patients who received IFN, it is statistically significant to patients in control group with a median FFR of 60 months (p <.001). Actuarial curves show that at 10-years, 58 patients (66%, 95% confidence interval (CI) 53% to 79%) remain in first remission, statistical different to control group 33 patients (40%, 95% Cl: 33% to 57%) (p <.001). Event free survival (EFS) shown that a 10-years 63 patients (71%, 95% CI: 59% to 81%) are alive free of disease in the IFN arm compared to only 38 patients (45%, 95% CI: 37% to 57%) in the control group (p <.001). Toxicity was mild, 81 patients received the planned doses of IFN on time and 6 patients had transitory delay secondary to hematological toxicity (grade 1 or 2) and completed the treatment on 13 months. No late side effects has been observed. After a long term follow-up we confirm that IFN used as maintenance therapy improves outcome in patients with aggressive malignant lymphoma who were in complete remission after conventional chemotherapy without excessive toxicity. We feld that IFN will be consider in controlled clinical trials to define the role of this therapeutic option. PMID:27414082

  4. Anti-CD20 Radioimmunotherapy Before Chemotherapy and Stem Cell Transplant in Treating Patients With High-Risk B-Cell Malignancies

    ClinicalTrials.gov

    2016-06-13

    Adult Burkitt Lymphoma; Adult Diffuse Large B-Cell Lymphoma; CD20-Positive Neoplastic Cells Present; Indolent Adult Non-Hodgkin Lymphoma; Mantle Cell Lymphoma; Recurrent B-Cell Non-Hodgkin Lymphoma; Refractory Mature B-Cell Non-Hodgkin Lymphoma

  5. Generation of clinical-grade CD19-specific CAR-modified CD8+ memory stem cells for the treatment of human B-cell malignancies.

    PubMed

    Sabatino, Marianna; Hu, Jinhui; Sommariva, Michele; Gautam, Sanjivan; Fellowes, Vicki; Hocker, James D; Dougherty, Sean; Qin, Haiying; Klebanoff, Christopher A; Fry, Terry J; Gress, Ronald E; Kochenderfer, James N; Stroncek, David F; Ji, Yun; Gattinoni, Luca

    2016-07-28

    Long-lived, self-renewing, multipotent T memory stem cells (TSCM) can trigger profound and sustained tumor regression but their rareness poses a major hurdle to their clinical application. Presently, clinically compliant procedures to generate relevant numbers of this T-cell population are undefined. Here, we provide a strategy for deriving large numbers of clinical-grade tumor-redirected TSCM starting from naive precursors. CD8(+)CD62L(+)CD45RA(+) naive T cells enriched by streptamer-based serial-positive selection were activated by CD3/CD28 engagement in the presence of interleukin-7 (IL-7), IL-21, and the glycogen synthase-3β inhibitor TWS119, and genetically engineered to express a CD19-specific chimeric antigen receptor (CD19-CAR). These conditions enabled the generation of CD19-CAR-modified CD8(+) TSCM that were phenotypically, functionally, and transcriptomically equivalent to their naturally occurring counterpart. Compared with CD8(+) T cells generated with clinical protocols currently under investigation, CD19-CAR-modified CD8(+) TSCM exhibited enhanced metabolic fitness and mediated robust, long-lasting antitumor responses against systemic acute lymphoblastic leukemia xenografts. This clinical-grade platform provides the basis for a phase 1 trial evaluating the activity of CD19-CAR-modified CD8(+) TSCM in patients with B-cell malignancies refractory to prior allogeneic hematopoietic stem cell transplantation. PMID:27226436

  6. Impact of age and socioeconomic status on treatment and survival from aggressive lymphoma: a UK population-based study of diffuse large B-cell lymphoma

    PubMed Central

    Smith, Alexandra; Crouch, Simon; Howell, Debra; Burton, Cathy; Patmore, Russell; Roman, Eve

    2015-01-01

    Aim To examine the influence of patient’s age and socio-economic status on treatment and outcome in diffuse large B-cell lymphoma (DLBCL); an aggressive curable cancer, with an incidence rate that increases markedly with age but varies little with socio-economic status. Methods Set within a representative UK population of around 4 million, data are from an established patient cohort. This report includes all patients (≥18years) newly diagnosed with DLBCL 2004–2012, with follow-up to February 2015. Results Of the 2137 patients (median age 70.2 years) diagnosed with denovo DLBCL, 1709 (80%) were treated curatively/intensively and 1161(54.3%) died during follow-up. Five-year overall and relative survival (RS) estimates were 46.2% (95% CI 44.0–48.4%) and 54.6% (52.1%-57.0%) respectively for all patients, and 58.5% (56.1–60.9%) and 67.0% (64.3–69.6%) for intensively treated patients. 96.3% of patients <55 years (366/380) and 96.4% of those with the best performance status (543/563) were treated curatively: 5-year RSs being 77.9% (73.1–82%) and 87.1% (82.5–90.6%) respectively. At the other end of the age/fitness spectrum, 33.3% of those ≥85 years (66/198) and 41.1% with the worst performance (94/225) were treated curatively: the corresponding 5-year RSs being 50.5% (27.1–69.0%) and 22.9% (14.0–33.2%). The proportion of patients whose cancer was fully staged fell with increasing age and worsening performance status. No socio-economic variations with treatment, stage at presentation or outcome were detected. Conclusions Performance status is more discriminatory of survival than chronological age, with fitter patients benefiting from treatment across all ages. Socio-economic factors are not predictive of outcome in patients with DLBCL in the UK. PMID:26341588

  7. PF-04691502, a dual PI3K/mTOR inhibitor has potent pre-clinical activity by inducing apoptosis and G1 cell cycle arrest in aggressive B-cell non-Hodgkin lymphomas.

    PubMed

    Chen, Deyu; Mao, Chaoming; Zhou, Yuepeng; Su, Yuting; Liu, Shenzha; Qi, Wen-Qing

    2016-01-01

    The PI3K/Akt/mTOR pathway is activated in a variety of human tumors including B-cell non-Hodgkin lymphoma (B-NHL). Targeting this pathway has been validated in solid and hematological tumors. In the present study, we demonstrated that PF-04691502, a novel PI3K/mTOR inhibitor has potent activity in a panel of aggressive B-NHL cell lines including diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphoma (MCL). MTS analysis showed that PF-04691502 effectively inhibited cell proliferation with IC50 values ranging from 0.12 to 0.55 µM. Cells treated with PF-04691502 exhibited decreased phosphorylation of Akt and S6 ribosomal protein confirming the mechanism of action of a PI3K/mTOR inhibitor. Also, treatment of B-NHL cell lines with PF-04691502 induced apoptosis in a dose- and time-dependent manner. Moreover, PF-04691502 significantly induced G1 cell cycle arrest associated with a decrease in cyclin D1 which contributed to suppression of cell proliferation. Finally, rituximab enhanced apoptosis induced by PF-04691502. Taken together, our findings provide for the first time that PF-04691502 inhibits the constitutively activated PI3K/mTOR pathway in aggressive B-cell NHL cell lines associated with inhibition of cell cycle progression, cell proliferation and promotion of apoptosis. These findings suggest that PF-04691502 is a novel therapeutic strategy in aggressive B-cell NHL and warrants early phase clinical trial evaluation with and without rituximab. PMID:26549638

  8. N-terminally truncated FOXP1 protein expression and alternate internal FOXP1 promoter usage in normal and malignant B cells

    PubMed Central

    Brown, Philip J.; Gascoyne, Duncan M.; Lyne, Linden; Spearman, Hayley; Felce, Suet Ling; McFadden, Nora; Chakravarty, Probir; Barrans, Sharon; Lynham, Steven; Calado, Dinis P.; Ward, Malcolm; Banham, Alison H.

    2016-01-01

    Strong FOXP1 protein expression is a poor risk factor in diffuse large B-cell lymphoma and has been linked to an activated B-cell-like subtype, which preferentially expresses short FOXP1 (FOXP1S) proteins. However, both short isoform generation and function are incompletely understood. Here we prove by mass spectrometry and N-terminal antibody staining that FOXP1S proteins in activated B-cell-like diffuse large B-cell lymphoma are N-terminally truncated. Furthermore, a rare strongly FOXP1-expressing population of normal germinal center B cells lacking the N-terminus of the regular long protein (FOXP1L) was identified. Exon-targeted silencing and transcript analyses identified three alternate 5′ non-coding exons [FOXP1-Ex6b(s), FOXP1-Ex7b and FOXP1-Ex7c], downstream of at least two predicted promoters, giving rise to FOXP1S proteins. These were differentially controlled by B-cell activation and methylation, conserved in murine lymphoma cells, and significantly correlated with FOXP1S protein expression in primary diffuse large B-cell lymphoma samples. Alternatively spliced isoforms lacking exon 9 (e.g. isoform 3) did not encode FOXP1S, and an alternate long human FOXP1 protein (FOXP1AL) likely generated from a FOXP1-Ex6b(L) transcript was detected. The ratio of FOXP1L:FOXP1S isoforms correlated with differential expression of plasmacytic differentiation markers in U-2932 subpopulations, and altering this ratio was sufficient to modulate CD19 expression in diffuse large B-cell lymphoma cell lines. Thus, the activity of multiple alternate FOXP1 promoters to produce multiple protein isoforms is likely to regulate B-cell maturation. PMID:27056922

  9. Treatment of high-risk aggressive B-cell non-Hodgkin lymphomas with rituximab, intensive induction and high-dose consolidation: long-term analysis of the R-MegaCHOP-ESHAP-BEAM Trial.

    PubMed

    Pytlík, Robert; Belada, David; Kubáčková, Kateřina; Vášová, Ingrid; Kozák, Tomáš; Pirnos, Jan; Bolomská, Ingrid; Matuška, Milan; Přibylová, Jana; Campr, Vít; Burešová, Lucie; Sýkorová, Alice; Berková, Adéla; Klener, Pavel; Trněný, Marek

    2015-01-01

    We have studied the feasibility and efficacy of intensified R-MegaCHOP-ESHAP-BEAM therapy in high-risk aggressive B-cell lymphomas. Altogether 105 patients (19-64 years) with diffuse large B-cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma (PMBL) or follicular lymphoma grade 3 (FL3) with an age-adjusted International Prognostic Index of 2-3 were recruited. Treatment consisted of three cycles of high-dose R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone), followed by three cycles of R-ESHAP (rituximab, etoposide, methylprednisolone, cytarabine, cisplatin) and high-dose consolidation with BEAM (BCNU, etoposide, cytarabine, melphalan) and autologous stem cell transplant. The 5-year progression-free survival (PFS) was 72% (DLBCL 60%, PMBL 89%) and overall survival (OS) was 74% (DLBCL 61%, PMBL 89%) after a median follow-up of 85 months. However, an independent prognostic factor was age only, with patients ≤ 45 years having 5-year PFS 90% and patients > 45 years having PFS 54%. PMBL had better prognosis than DLBCL/FL3 in patients > 45 years (PFS, 88% vs. 48%), but not in younger patients (PFS, 91% vs. 94%). PMID:24628294

  10. [Rare malignant tumors of the ovaries in adolescents--clinical aspects in deciding therapeutic aggressiveness].

    PubMed

    Schröder, W; Bau, O

    1990-01-01

    4 patients below the age of 20 years have been treated for a malignant tumor of the ovary during the period November 1, 1984 until April 30, 1988. Dysgerminoma was the diagnosis in two cases, as the third patient suffered from a bilateral malignant teratoma. Burkitt's Lymphoma involved both ovaries primarily in an 17-year-old girl. Retrospectively we analyzed diagnosis, therapy and clinical course of these young patients. Regarding the different histological types of the tumors that have been found we discuss critically current recommendations in therapeutic managements referring chemotherapy and/or radiotherapy. Defined conditions provided surgical treatment, that preserves fertility in early stages of malignant germ cell tumors of adolescent women, may be justified, especially for dysgerminomas. A real benefit relate to survival and quality of life by using chemotherapeutic agents can only be expected, if all prognostic factors are regarded.

  11. Clinical association of baseline levels of conjugated dienes in low-density lipoprotein and nitric oxide with aggressive B-cell non-Hodgkin lymphoma and their relationship with immunoglobulins and Th1-to-Th2 ratio

    PubMed Central

    Haddouche, Mustapha; Meziane, Warda; Hadjidj, Zeyneb; Mesli, Naima; Aribi, Mourad

    2016-01-01

    Objective The aim of this study was to highlight the clinical association of baseline levels of conjugated dienes in low-density lipoprotein (LDL-BCD) and nitric oxide (NO) with immunoglobulins (Igs) and T helper (Th)1/Th2 ratio in patients with newly diagnosed B-cell non-Hodgkin lymphoma (NHL). Patients and methods Thirty-two newly diagnosed patients with aggressive B-cell NHL and 25 age-, sex-, and body-mass-index-matched healthy controls were randomly selected for a cross-sectional case–control study conducted at the Hematology Department of Tlemcen Medical Centre University (northwest of Algeria). Results Circulating levels of LDL-BCD and NO and those of IgA and IgM were significantly higher in patients than in controls. The levels of Th1/Th2 ratio and plasma total antioxidant capacity were significantly lower in patients compared with controls, while malondialdehyde and protein carbonyl levels were significantly higher in patients. B-cell NHL was significantly associated with high levels of LDL-BCD from 25th to 75th percentile (25th percentile: relative risk [RR] =2.26, 95% confidence interval [CI] 1.42–3.59, P=0.014; 50th percentile: RR =2.84, 95% CI 1.72–4.68, P<0.001; 75th percentile: RR =5.43, 95% CI 2.58–11.42, P<0.001). Similarly, the disease was significantly associated with high levels of NO production from 25th to 75th percentile (25th percentile: RR =2.07, 95% CI 1.25–3.44, P=0.024; 50th percentile: RR =2.78, 95% CI 1.63–4.72, P<0.001; 75th percentile: RR =4.68, 95% CI 2.21–9.91, P<0.001). Moreover, LDL-BCD levels were positively and significantly correlated with interferon (IFN)-γ, whereas NO levels were inversely and significantly correlated with IFN-γ and Th1/Th2 ratio. Conclusion LDL-BCD and NO production seem to be associated with aggressive B-cell NHL and alteration of Th1/Th2 ratio. Our results have to be examined using ex vivo mechanistic studies leading to further investigations of these parameters, with an interest in the

  12. Central nervous system prophylaxis in patients with aggressive diffuse large B cell lymphoma: an analysis of 3,258 patients in a single center.

    PubMed

    Avilés, Agustin; Jesús Nambo, M; Neri, Natividad

    2013-06-01

    Central nervous system (CNS) relapse continues to be a frequent and usually fatal complication in patients with diffuse large B cell lymphoma (DLBCL). Multiple factors identify the possibility of relapse and justify neurological prophylaxis; however, most of these have not been confirmed. Thus, the use of prophylaxis has not been defined. From 1988 to 2008, 3,258 patients with DLBCL with higher clinical risks and multiple extranodal involvement that have been treated with standard anthracycline-based chemotherapy: CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) or CHOP-R (CHOP plus rituximab) and that achieve complete response were retrospectively analyzed to assess the efficacy of CNS prophylaxis. One thousand five patients received different schedules for CNS prophylaxis, and 2,253 patients did not receive CNS prophylaxis. CNS relapse was similar in patients who receive prophylaxis (6 %) compared to patients who did not receive prophylaxis (5.9 %). Overall survival of patients who either receive or did not receive prophylaxis was not statistically significant: 49 % versus 53 % (p = 0.802). Thus, it seems that CNS prophylaxis did not improve outcome in this special setting of patients, and no prognostic factors to predict the presence of CNS relapse were identified. It is evident that multicentric studies are necessary to define the role of prophylaxis in order to prevent CNS relapse and that the therapeutic procedure will be carefully revised. PMID:23456620

  13. Unusual involvement of scalp and bilateral kidneys in an aggressive mediastinal diffuse large B cell lymphoma: documentation by FDG-PET imaging.

    PubMed

    Basu, Sandip; Ramani, S K; Lad, S

    2009-09-01

    In the present communication, an unusual combination of scalp soft tissue and underlying brain involvement with intact skull bone coupled with bilateral renal involvement from a mediastinal diffuse large B cell lymphoma (DLBL) is presented. A 45-year-old man, a diagnosed case of mediastinal DLBL with bilateral lung involvement, was treated with conventional 6 cycles of chemotherapy and local external radiotherapy with initial good treatment response evidenced by considerable regression in mass size and regression in pulmonary lesions. Three months later, he returned with complaints of soft tissue swelling over the scalp; one of them in the high parietal bone and the other over the occipital region. A whole body FDG-PET at this time showed 2 moderate-sized foci in the scalp (with preservation of both tables of skull bone) and corresponding large foci in the brain parenchyma beneath, a superior mediastinal focus, a few foci in the apical and lower zone of left lung, extensive irregular uptake in the right pleura and the right lung parenchyma coupled with a loculated effusion in its lower zone and studded foci of hypermetabolism throughout the bilaterally enlarged kidneys. CT of the head confirmed the FDG-PET findings and histopathology of the biopsy from the scalp swelling was suggestive of DLBL. Ultrasound imaging of the abdomen showed lobulated bilaterally enlarged kidneys with multiple hypoechoic areas within them. The patient underwent palliative local external radiotherapy to the brain and systemic chemotherapy with poor clinical results with raised serum beta-2 microglobulin and serum LDH levels and deranged renal function. The patient died within a month after the FDG-PET study. The event of scalp and bilateral renal involvement from DLBL is rare in lymphoma literature and this report highlights that such unusual events can occur as part of widespread dissemination and underscores the importance of whole-body imaging with FDG-PET. PMID:19692836

  14. Clinical aggressiveness of malignant gliomas is linked to augmented metabolism of amino acids.

    PubMed

    Panosyan, Eduard H; Lasky, Joseph L; Lin, Henry J; Lai, Albert; Hai, Yang; Guo, Xiuqing; Quinn, Michael; Nelson, Stanley F; Cloughesy, Timothy F; Nghiemphu, P Leia

    2016-05-01

    Glutamine, glutamate, asparagine, and aspartate are involved in an enzyme-network that controls nitrogen metabolism. Branched-chain-amino-acid aminotransferase-1 (BCAT1) promotes proliferation of gliomas with wild-type IDH1 and is closely connected to the network. We hypothesized that metabolism of asparagine, glutamine, and branched-chain-amino-acids is associated with progression of malignant gliomas. Gene expression for asparagine synthetase (ASNS), glutaminase (GLS), and BCAT1 were analyzed in 164 gliomas from 156 patients [33-anaplastic gliomas (AG) and 131-glioblastomas (GBM), 64 of which were recurrent GBMs]. ASNS and GLS were twofold higher in GBMs versus AGs. BCAT1 was also higher in GBMs. ASNS expression was twofold higher in recurrent versus new GBMs. Five patients had serial samples: 4-showed higher ASNS and 3-higher GLS at recurrence. We analyzed grade and treatment in 4 groups: (1) low ASNS, GLS, and BCAT1 (n = 96); (2) low ASNS and GLS, but high BCAT1 (n = 26); (3) high ASNS or GLS, but low BCAT1 (n = 25); and (4) high ASNS or GLS and high BCAT1 (n = 17). Ninety-one  % of patients (29/32) with grade-III lesions were in group 1. In contrast, 95 % of patients (62/65) in groups 2-4 had GBMs. Treatment was similar in 4 groups (radiotherapy-80 %; temozolomide-30 %; other chemotherapy-50 %). High expression of ASNS, GLS, and BCAT1 were each associated with poor survival in the entire group. The combination of lower ASNS, GLS, and BCAT1 levels correlated with better survival for newly diagnosed GBMs (66 patients; P = 0.0039). Only tumors with lower enzymes showed improved outcome with temozolomide. IDH1(WT) gliomas had higher expression of these genes. Manipulation of amino acid metabolism in malignant gliomas may be further studied for therapeutics development. PMID:26922345

  15. Differential PAX5 levels promote malignant B cell infiltration, progression and drug resistance and predict a poor prognosis in MCL patients independent of CCND1

    PubMed Central

    Teo, Albert E.; Chen, Zheng; Miranda, Roberto N.; McDonnell, Timothy; Medeiros, L. Jeffrey; McCarty, Nami

    2015-01-01

    Reduced PAX5 levels play important roles in the pathogenesis of human B-cell acute lymphoblastic leukemia. However, the role of PAX5 in human lymphoma remains unclear. We generated PAX5-silenced cells using mantle cell lymphoma (MCL) as a model system. These PAX5− MCL cells exhibited unexpected phenotypes, including increased proliferation in vitro, enhanced tumor infiltration in vivo, robust adhesion to bone marrow stromal cells, and increased retention of quiescent stem-like cells. These phenotypes were attributed to alterations in the expression of genes including p53 and Rb and to PI3 kinase/mTOR and pSTAT3 pathway hyperactivation. Upon PAX5 silencing, the MCL cells displayed upregulated IL-6 expression and increased responses to paracrine IL-6. Moreover, decreased PAX5 levels in CD19+ MCL cells correlated with their increased infiltration and progression; thus, PAX5 levels can be used as a prognostic marker independent of cyclin D1 in advanced MCL patients. Importantly, high-throughput screening of 3800 chemical compounds revealed that PAX5−MCL cells are highly drug-resistant compared to PAX5 wild-type MCL cells. Collectively, the results of our study support a paradigm shift regarding the functions of PAX5 in human B cell cancer and encourage future efforts to design effective therapies against MCL. PMID:26073757

  16. Immunotherapy with the trifunctional anti-CD20 x anti-CD3 antibody FBTA05 (Lymphomun) in paediatric high-risk patients with recurrent CD20-positive B cell malignancies.

    PubMed

    Schuster, Friedhelm R; Stanglmaier, Michael; Woessmann, Wilhelm; Winkler, Beate; Siepermann, Meinolf; Meisel, Roland; Schlegel, Paul G; Hess, Jürgen; Lindhofer, Horst; Borkhardt, Arndt; Buhmann, Raymund

    2015-04-01

    Children with B cell malignancies refractory to standard therapy are known to have a poor prognosis and very limited treatment options. Here, we report on the treatment and follow-up of ten patients diagnosed with relapsed or refractory mature B-cell Non Hodgkin Lymphoma (B-NHL), Burkitt leukaemia (B-AL) or pre B-acute lymphoblastic leukaemia (pre B-ALL). All children were treated with FBTA05 (now designated Lymphomun), an anti-CD3 x anti-CD20 trifunctional bispecific antibody (trAb) in compassionate use. Within individual treatment schedules, Lymphomun was applied (a) after allogeneic stem cell transplantation (allo-SCT, n = 6) to induce sustained long-term remission, or (b) stand alone prior to subsequent chemotherapy to eradicate residual disease before allo-SCT (n = 4). Nine of ten children displayed a clinical response: three stable diseases (SD), one partial remission (PR) and five induced or sustained complete remissions (CR). Five of these nine responders died during follow-up. The other patients still maintain CR with a current overall survival of 874-1424 days (median: 1150 days). In conclusion, despite the dismal clinical prognosis of children refractory to standard therapy, immunotherapy with Lymphomun resulted in a favourable clinical outcome in this cohort of refractory paediatric patients. PMID:25495919

  17. The miR-17-92 MicroRNA Cluster Is Regulated by Multiple Mechanisms in B-Cell Malignancies

    PubMed Central

    Ji, Ming; Rao, Enyu; Ramachandrareddy, Himabindu; Shen, Yulei; Jiang, Chunsun; Chen, Jianxiu; Hu, Yiqiao; Rizzino, Angie; Chan, Wing C.; Fu, Kai; McKeithan, Timothy W.

    2011-01-01

    A cluster of six microRNAs (miRNAs), miR-17-92, is processed from the transcript of C13orf25, a gene amplified in some lymphomas and solid tumors. We find that levels of the miRNAs in the cluster do not vary entirely in parallel with each other or with the primary RNA in B-cell lines or normal cells, suggesting that processing or stability of the miRNAs is differentially regulated. Using luciferase reporter assays, we identified the region required for maximum promoter activity. Additional deletions and mutations indicated that the promoter is regulated by the collaborative activity of several transcription factors, most of which individually have only a moderate effect; mutation of a cluster of putative SP1-binding sites, however, reduces promoter activity by 70%. MYC is known to regulate C13orf25; surprisingly, mutation of a putative promoter MYC-binding site enhanced promoter activity. We found that the inhibitory MYC family member MXI1 bound to this region. The chromatin structure of a >22.5-kb region encompassing the gene contains peaks of activating histone marks, suggesting the presence of enhancers, and we confirmed that at least two regions have enhancer activity. Because the miR-17-92 cluster acts as an important oncogene in several cancers and targets genes important in regulating cell proliferation and survival, further studies of its transcriptional control are warranted. PMID:21806958

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

    PubMed Central

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

    2009-01-01

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

  19. G-rich proto-oncogenes are targeted for genomic instability in B-cell lymphomas.

    PubMed

    Duquette, Michelle L; Huber, Michael D; Maizels, Nancy

    2007-03-15

    Diffuse large B-cell lymphoma is the most common lymphoid malignancy in adults. It is a heterogeneous disease with variability in outcome. Genomic instability of a subset of proto-oncogenes, including c-MYC, BCL6, RhoH, PIM1, and PAX5, can contribute to initial tumor development and has been correlated with poor prognosis and aggressive tumor growth. Lymphomas in which these proto-oncogenes are unstable derive from germinal center B cells that express activation-induced deaminase (AID), the B-cell-specific factor that deaminates DNA to initiate immunoglobulin gene diversification. Proto-oncogene instability is evident as both aberrant hypermutation and translocation, paralleling programmed instability which diversifies the immunoglobulin loci. We have asked if genomic sequence correlates with instability in AID-positive B-cell lymphomas. We show that instability does not correlate with enrichment of the WRC sequence motif that is the consensus for deamination by AID. Instability does correlate with G-richness, evident as multiple runs of the base guanine on the nontemplate DNA strand. Extending previous analysis of c-MYC, we show experimentally that transcription of BCL6 and RhoH induces formation of structures, G-loops, which contain single-stranded regions targeted by AID. We further show that G-richness does not characterize translocation breakpoints in AID-negative B- and T-cell malignancies. These results identify G-richness as one feature of genomic structure that can contribute to genomic instability in AID-positive B-cell malignancies.

  20. Primary bilateral adrenal B-cell lymphoma associated with EBV and JCV infection

    PubMed Central

    Barzon, Luisa; Trevisan, Marta; Marino, Filippo; Guzzardo, Vincenza; Palù, Giorgio

    2009-01-01

    Primary lymphoma of the adrenal gland is a rare and highly aggressive disease, with only a few reports in the literature. The pathogenesis is unknown, but detection of Epstein Barr virus (EBV) genome sequences and gene expression in some cases of primary adrenal lymphomas suggested the virus might be a causative agent of the malignancy. While investigating the presence of genome sequences of oncogenic viruses in a large series of adrenal tumors, both EBV and JC polyomavirus (JCV) DNA sequences were detected in a diffuse large primary bilateral B-cell non-Hodgkin lymphoma of the adrenal gland, which was diagnosed only at postmortem examination in a 77 year-old woman with incidentally discovered adrenal masses and primary adrenal insufficiency. The presence of both EBV and JCV genome sequences suggests the relevance of EBV and JCV coinfection in the pathogenesis of this rare form of B-cell lymphoma. PMID:19146683

  1. Analysis of memory-like natural killer cells in human cytomegalovirus-infected children undergoing αβ+T and B cell-depleted hematopoietic stem cell transplantation for hematological malignancies.

    PubMed

    Muccio, Letizia; Bertaina, Alice; Falco, Michela; Pende, Daniela; Meazza, Raffaella; Lopez-Botet, Miguel; Moretta, Lorenzo; Locatelli, Franco; Moretta, Alessandro; Della Chiesa, Mariella

    2016-03-01

    We analyzed the impact of human cytomegalovirus infection on the development of natural killer cells in 27 pediatric patients affected by hematological malignancies, who had received a HLA-haploidentical hematopoietic stem cell transplantation, depleted of both α/β+ T cells and B cells. In line with previous studies in adult recipients of umbilical cord blood transplantation, we found that human cytomegalovirus reactivation accelerated the emergence of mature natural killer cells. Thus, most children displayed a progressive expansion of a memory-like natural killer cell subset expressing NKG2C, a putative receptor for human cytomegalovirus, and CD57, a marker of terminal natural killer cell differentiation. NKG2C(+)CD57(+) natural killer cells were detectable by month 3 following hematopoietic stem cell transplantation and expanded until at least month 12. These cells were characterized by high killer Ig-like receptors (KIRs) and leukocyte inhibitory receptor 1 (LIR-1) and low Siglec-7, NKG2A and Interleukin-18Rα expression, killed tumor targets and responded to cells expressing HLA-E (a NKG2C ligand). In addition, they were poor Interferon-γ producers in response to Interleukin-12 and Interleukin-18. The impaired response to these cytokines, together with their highly differentiated profile, may reflect their skewing toward an adaptive condition specialized in controlling human cytomegalovirus. In conclusion, in pediatric patients receiving a type of allograft different from umbilical cord blood transplantation, human cytomegalovirus also induced memory-like natural killer cells, possibly contributing to controlling infections and reinforcing anti-leukemia effects.

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

    PubMed

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

    2014-12-01

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

  3. The Genetic Basis of Diffuse Large B Cell Lymphoma

    PubMed Central

    Pasqualucci, Laura

    2014-01-01

    Purpose of review Diffuse large B cell lymphoma (DLBCL) is an aggressive disease featuring heterogeneous genetic, phenotypic and clinical characteristics. Understanding the basis for this heterogeneity represents a critical step toward further progress in the management of this disease, which remains a clinical challenge in approximately one third of patients. This review summarizes current knowledge about the molecular pathogenesis of DLBCL, and describes how recent advances in the genomic characterization of this cancer have provided new insights into its biology, revealing several potential targets for improved diagnosis and therapy. Recent findings In the past few years, the development of high-resolution technologies has provided significant help in identifying genetic lesions and/or disrupted signaling pathways that are required for DLBCL initiation and progression. These studies uncovered the involvement of cellular programs that had not been previously appreciated, including histone/chromatin remodeling and immune recognition. Alterations in these pathways could favor epigenetic reprogramming and escape from cellular immunity. Summary The identification of genetic alterations that contribute to the malignant transformation of a B cell into a DLBCL is helping to better understand the biology of this disease and to identify critical nodes driving tumor progression or resistance to therapy. The rapid pace at which these discoveries are taking place is poised to have significant impact for patients stratification based on molecular predictors and for the development of rational targeted therapies. PMID:23673341

  4. Dominant neurologic symptomatology in intravascular large B-cell lymphoma.

    PubMed

    Kubisova, K; Martanovic, P; Sisovsky, V; Tomleinova, Z; Steno, A; Janega, P; Rychly, B; Babal, P

    2016-01-01

    Intravascular large B-cell lymphoma (IVLBCL) is a rare variant of extranodal large B-cell lymphoma and it is characterized by selective intravascular proliferation of malignant cells. Typical features of the disease include aggressive behavior, rapid and frequently fatal course. Clinical picture is non-specific and heterogeneous, depending on the affected organ. It is not uncommon that this unique type of lymphoma is diagnosed post mortem. Herein, we report two cases of IVLBCL with neurologic symptomatology. In our clinical study patient 1 was an 80-year-old male with mixed paraparesis of lower extremities and difficulties with sphincter control. Patient 2 (56-year-old male) had vision malfunction, mental status changes and defect in phatic and motor functions. In both cases definite diagnosis was established by histological examination of necroptic material. We propose to include IVLBCL in differential diagnostic considerations in patients presenting with gradually impairing neurological status and spinal cord damage of unknown etiology (Fig. 2, Ref. 9). PMID:27546361

  5. B cells in transplantation

    PubMed Central

    Dijke, Esme I.; Platt, Jeffrey L.; Blair, Paul; Clatworthy, Menna R.; Patel, Jignesh K.; Kfoury, A.G.; Cascalho, Marilia

    2016-01-01

    B cell responses underlie the most vexing immunological barriers to organ transplantation. Much has been learned about the molecular mechanisms of B cell responses to antigen and new therapeutic agents that specifically target B cells or suppress their functions are available. Yet, despite recent advances, there remains an incomplete understanding about how B cell functions determine the fate of organ transplants and how, whether or when potent new therapeutics should optimally be used. This gap in understanding reflects in part the realization that besides producing antibodies, B cells can also regulate cellular immunity, contribute to the genesis of tolerance and induce accommodation. Whether non-specific depletion of B cells, their progeny or suppression of their functions would undermine these non-cognate functions and whether graft outcome would suffer as a result is unknown. These questions were discussed at a symposium on “B cells in transplantation” at the 2015 ISHLT annual meeting. Those discussions are summarized here and a new perspective is offered. PMID:26996930

  6. A comprehensive review of lenalidomide in B-cell non-Hodgkin lymphoma

    PubMed Central

    Arora, Mili; Gowda, Sonia; Tuscano, Joseph

    2016-01-01

    Lenalidomide, an immunomodulatory drug that the US Food and Drug Administration (FDA) approved for the treatment of multiple myeloma, 5q- myelodysplasia and mantle-cell lymphoma (MCL), has encouraging efficacy in other B-cell malignancies. Its unique mechanism of action is in part due to altering the tumor microenvironment and potentiating the activity of T and natural-killer (NK) cells. Impressive clinical activity and excellent tolerability allows broad applicability. Lenalidomide has been used in a wide range of B-cell malignancies for years, but in 2013, the FDA marked its approval as a single agent only in relapsed/refractory mantle-cell lymphoma. Perhaps most impressive is the efficacy of lenalidomide when combined with monoclonal antibodies. Impressive efficacy and toxicity profiles with the combination of lenalidomide and rituximab in B-cell lymphomas in both the upfront and relapsed/refractory setting may allow a shift in our current treatment paradigm in both indolent and aggressive non-Hodgkin lymphoma (NHL). This review will summarize the current data in the relapsed/refractory and front-line setting of NHL with single-agent lenalidomide as well as its use in combination with other agents. PMID:27493711

  7. A comprehensive review of lenalidomide in B-cell non-Hodgkin lymphoma.

    PubMed

    Arora, Mili; Gowda, Sonia; Tuscano, Joseph

    2016-08-01

    Lenalidomide, an immunomodulatory drug that the US Food and Drug Administration (FDA) approved for the treatment of multiple myeloma, 5q- myelodysplasia and mantle-cell lymphoma (MCL), has encouraging efficacy in other B-cell malignancies. Its unique mechanism of action is in part due to altering the tumor microenvironment and potentiating the activity of T and natural-killer (NK) cells. Impressive clinical activity and excellent tolerability allows broad applicability. Lenalidomide has been used in a wide range of B-cell malignancies for years, but in 2013, the FDA marked its approval as a single agent only in relapsed/refractory mantle-cell lymphoma. Perhaps most impressive is the efficacy of lenalidomide when combined with monoclonal antibodies. Impressive efficacy and toxicity profiles with the combination of lenalidomide and rituximab in B-cell lymphomas in both the upfront and relapsed/refractory setting may allow a shift in our current treatment paradigm in both indolent and aggressive non-Hodgkin lymphoma (NHL). This review will summarize the current data in the relapsed/refractory and front-line setting of NHL with single-agent lenalidomide as well as its use in combination with other agents. PMID:27493711

  8. Renal Medullary Carcinoma: Case Report of an Aggressive Malignancy with Near-Complete Response to Dose-Dense Methotrexate, Vinblastine, Doxorubicin, and Cisplatin Chemotherapy

    PubMed Central

    Amjad, Ali Imran; Ali, Hira; Appleman, Leonard J.; Parwani, Anil; Dhir, Rajiv; Roy, Somak; Parikh, Rahul A.

    2014-01-01

    Renal medullary carcinoma (RMC) is a rare but aggressive malignancy affecting young individuals with sickle cell trait. Renal medullary carcinoma commonly presents with advanced or metastatic disease and is associated with a rapidly progressive clinical course and an extremely short overall survival measured in weeks to few months. Due to the rarity of RMC, there is no proven effective therapy and patients are often treated with platinum-based chemotherapy. We report near-complete radiological and pathological response in a patient treated with dose-dense MVAC (methotrexate, vinblastine, doxorubicin, and cisplatin) chemotherapy. The patient underwent consolidation nephrectomy and retroperitoneal lymph node dissection and had a 16-month progression-free survival, one of the longest reported in patients with RMC. PMID:25215253

  9. [Aggressive fibromatoses].

    PubMed

    Döhler, J R; Hamelmann, H; Lasson, U

    1984-03-01

    Benign by nature, aggressive fibromatoses (desmoid fibromas) may represent as difficult therapeutic problems as malignant tumours. When subtotally resected they tend to recur. But spontaneous regression is possible. Expense and limits of their surgical treatment are discussed with reference to seven patients. In five cases primary affliction of bone was evident. There are three reports given in detail: In the first, malignant transformation may be due to radiation therapy and hemipelvectomy could not prevent recurrence. In the second, spontaneous regression of untreated pelvic affection may have occurred. In the third, several resections and amputation of the leg failed to cure congenital infantile fibromatosis.

  10. Aggressive Cunninghamella pneumonia in an adolescent.

    PubMed

    Malkan, Alpin D; Wahid, Fazal N; Rao, Bhaskar N; Sandoval, John A

    2014-10-01

    Children with hematologic malignancies may be challenged with life-threatening, invasive fungal infections by organisms that would otherwise have a low potential for virulence in healthy hosts. Presented is a case of a 15-year-old adolescent with B-cell acute lymphoblastic leukemia who was receiving steroids and chemotherapy. He developed cough associated with left chest pain with suspicion for fungal pneumonia. He began systemic antifungal therapy, underwent computed tomography of the chest demonstrating a large cavitary lesion (reversed halo sign) in the left lung. Over a 48-hour period the patient clinically deteriorated with worsening pneumonia and required left thoracotomy with nonanatomic pulmonary resection. This case illustrates the aggressive nature of Cunninghamella pneumonia in patients with hematologic malignancies, and the multidisciplinary approach required to have the greatest possible outcome. PMID:25089609

  11. The molecular biology of diffuse large B-cell lymphoma.

    PubMed

    Frick, Mareike; Dörken, Bernd; Lenz, Georg

    2011-12-01

    Diffuse large B-cell lymphoma (DLBCL) represents the most common type of malignant lymphoma. In the last few years, significant progress has been achieved in the understanding of the molecular pathogenesis of this entity. Gene expression profiling has identified three molecular DLBCL subtypes, termed germinal-center B-cell-like (GCB) DLBCL, activated B-cell-like (ABC) DLBCL, and primary mediastinal B-cell lymphoma (PMBL). In this review, we summarize our current understanding of the biology of these DLBCL subtypes with a special emphasis on novel diagnostic and therapeutic approaches. PMID:23556103

  12. β-alanine suppresses malignant breast epithelial cell aggressiveness through alterations in metabolism and cellular acidity in vitro

    PubMed Central

    2014-01-01

    Background Deregulated energetics is a property of most cancer cells. This phenomenon, known as the Warburg Effect or aerobic glycolysis, is characterized by increased glucose uptake, lactate export and extracellular acidification, even in the presence of oxygen. β-alanine is a non-essential amino acid that has previously been shown to be metabolized into carnosine, which functions as an intracellular buffer. Because of this buffering capacity, we investigated the effects of β-alanine on the metabolic cancerous phenotype. Methods Non-malignant MCF-10a and malignant MCF-7 breast epithelial cells were treated with β-alanine at 100 mM for 24 hours. Aerobic glycolysis was quantified by measuring extracellular acidification rate (ECAR) and oxidative metabolism was quantified by measuring oxygen consumption rate (OCR). mRNA of metabolism-related genes was quantified by qRT-PCR with corresponding protein expression quantified by immunoblotting, or by flow cytometry which was verified by confocal microscopy. Mitochondrial content was quantified using a mitochondria-specific dye and measured by flow cytometry. Results Cells treated with β-alanine displayed significantly suppressed basal and peak ECAR (aerobic glycolysis), with simultaneous increase in glucose transporter 1 (GLUT1). Additionally, cells treated with β-alanine exhibited significantly reduced basal and peak OCR (oxidative metabolism), which was accompanied by reduction in mitochondrial content with subsequent suppression of genes which promote mitochondrial biosynthesis. Suppression of glycolytic and oxidative metabolism by β-alanine resulted in the reduction of total metabolic rate, although cell viability was not affected. Because β-alanine treatment reduces extracellular acidity, a constituent of the invasive microenvironment that promotes progression, we investigated the effect of β-alanine on breast cell viability and migration. β-alanine was shown to reduce both cell migration and proliferation

  13. B Cell Lymphoma mimicking Rheumatoid Arthritis.

    PubMed

    Cosatti, M A; Pisoni, C N; Altuve, J L; Lorente, C

    2016-01-01

    Non Hodking´s lymphoma (NHL) may involve bones but synovial involvement is uncommon. We describe a patient who presented with polyarthritis, sicca symptoms and rash suggestive of rheumatoid arthritis. An atypical skin rash prompted skin and synovial biopsies. A diagnosis of synovial and skin malignant large B-cell lymphoma anaplastic subtype was performed. Chemotherapy with dexamethasone, vincristine and rituximab was started. Following treatment the patient had complete resolution of cutaneous and articular lymphoma manifestations. PMID:27419896

  14. Pathological features of lymphoid proliferations of the salivary glands: lymphoepithelial sialadenitis versus low-grade B-cell lymphoma of the malt type.

    PubMed

    Carbone, A; Gloghini, A; Ferlito, A

    2000-12-01

    Lymphoid proliferations of the salivary glands can be either reactive or neoplastic. Reactive lesions include the lymphoepithelial sialadenitis (LESA; also known as myoepithelial sialadenitis [MESA]) of Sjogren's syndrome. Lymphomas of the salivary glands are predominantly B-cell type and include extranodal marginal zone B-cell lymphoma of the mucosa-associated lymphoid tissue (MALT) type. The spectrum of histopathologic features of LESA/MESA includes 1) "fully benign lymphoid infiltrate," with or without an associated lymphoid follicular structure, without immunoglobulin (Ig) light chain restriction in B-cells, and without any features of aggressive behavior, and 2) "lymphoproliferative lesions," with or without areas of Ig light chain restriction in B-cells, with the usual presence of centrocyte-like cells. A more or less pronounced lymphoepithelial aggressiveness may be present without definite evidence of malignancy. B-cell clones are detected in over 50% of cases of LESA/MESA by molecular genetic methods, but this does not correlate with morphological or clinical evidence of overt lymphoma. On the other hand, "marginal zone B-cell lymphoma of the MALT type" of the salivary glands produces a dense lymphoid infiltrate diffusely involving the gland, with obliteration of acini. The centrocyte-like cells form broad "halos" around the epithelial cell nests and broad strands between lymphoepithelial lesions, often linking together several lymphoepithelial lesions. Further, lymphoma cells express monotypic surface Ig, and in the majority of the cases, the plasma cells are also monoclonal. In conclusion, the diagnosis of LESA/MESA versus marginal zone B-cell lymphoma of the MALT type still relies on the evaluation of morphological features. It seems that molecular genetic analysis has little or no practical role in the clinical diagnosis of salivary gland lymphoma in a setting of LESA/MESA and Sjögren's syndrome.

  15. The Genetic Landscape of Diffuse Large B Cell Lymphoma

    PubMed Central

    Pasqualucci, Laura; Dalla-Favera, Riccardo

    2015-01-01

    Diffuse large B cell lymphoma (DLBCL), the most common lymphoid malignancy in the western world, is an aggressive disease that remains incurable in approximately 30% of patients. Over the past decade, the rapid expansion of sequencing technologies allowing the genome-wide assessment of genomic and transcriptional changes has revolutionized our understanding of the genetic basis of DLBCL by providing a comprehensive and unbiased view of the genes/pathways that are disrupted by genetic alterations in this disease, and may contribute to tumor initiation and expansion. These studies uncovered the existence of several previously unappreciated alterations in key cellular pathways that may also influence treatment outcome. Indeed, a number of newly identified genetic lesions are currently being explored as markers for improved diagnosis and risk stratification, or are entering clinical trials as promising therapeutic targets. This review focuses on recent advances in the genomic characterization of DLBCL and discusses how information gained from these efforts has provided new insights into its biology, uncovering potential targets of prognostic and therapeutic relevance. PMID:25805586

  16. Intravascular large B-cell lymphoma with hemophagocytic syndrome (Asian variant) in a Caucasian patient.

    PubMed

    Fung, Kar-Ming; Chakrabarty, Jennifer H; Kern, William F; Magharyous, Hany; Gehrs, Bradley C; Li, Shibo

    2012-01-01

    Intravascular lymphoma is an aggressive and extremely rare extranodal lymphoma with neoplastic lymphoid cells confined exclusively within intravascular spaces. The histopathologic findings are subtle due to the rarity of the neoplastic cells in blood vessels. Clinical presentations are non-specific and focal space-occupying lesions or lymphoadenopathy are always lacking. It is a diagnostic challenge. Secondary hemophagocytic syndrome is uncommon and is typically associated with infection, malignancy, and suppressed immune states. Intravascular lymphoma has a strong association with hemophagocytic syndrome in Asian patients, the so-called "Asian variant", but not in Western patients. We report a case of intravascular B-cell lymphoma in a Caucasian patient associated with secondary hemophagocytic syndrome. The patient was diagnosed by core liver biopsy and successfully treated. This case demonstrates the importance of high index of suspicion and astute histopathologic examination in recognition of this unusual clinical and pathologic combination.

  17. NK cell depletion diminish tumour-specific B cell responses.

    PubMed

    Jensen, Markus; Tawadros, Samir; Sedlacek, Hans-Harald; Schultze, Joachim L; Berthold, Frank

    2004-05-15

    Natural killer (NK) cells can exercise immediate cytotoxicity against malignant cells and thus far modulate the development of tumour directed T cell immunity. To investigate the impact of NK cells on the development of tumour directed B cell immunity mice were immunised with IMR5-75 human neuroblastoma cells with or without prior in vivo NK cell depletion. Flow cytometry analyses gave evidence for an impaired IgG response against the cells immunised with. Dissection of Th1 (IgG2a) and Th2 (IgG1) oriented B cell responses revealed Th1 responses as primarily affected, while Th2 oriented B cell responses as measured by flow cytometry and GD2 ganglioside-specific ELISA were enforced. The data reveal an unexpected impact of NK cells on the development of tumour directed B cell responses. Consequently, NK cell function has also to be taken into account when developing B cell-based cancer immunotherapy.

  18. Protocol of the Australasian Malignant Pleural Effusion-2 (AMPLE-2) trial: a multicentre randomised study of aggressive versus symptom-guided drainage via indwelling pleural catheters

    PubMed Central

    Azzopardi, Maree; Thomas, Rajesh; Muruganandan, Sanjeevan; Lam, David C L; Garske, Luke A; Kwan, Benjamin C H; Rashid Ali, Muhammad Redzwan S; Nguyen, Phan T; Yap, Elaine; Horwood, Fiona C; Ritchie, Alexander J; Bint, Michael; Tobin, Claire L; Shrestha, Ranjan; Piccolo, Francesco; De Chaneet, Christian C; Creaney, Jenette; Newton, Robert U; Hendrie, Delia; Murray, Kevin; Read, Catherine A; Feller-Kopman, David; Maskell, Nick A; Lee, Y C Gary

    2016-01-01

    Introduction Malignant pleural effusions (MPEs) can complicate most cancers, causing dyspnoea and impairing quality of life (QoL). Indwelling pleural catheters (IPCs) are a novel management approach allowing ambulatory fluid drainage and are increasingly used as an alternative to pleurodesis. IPC drainage approaches vary greatly between centres. Some advocate aggressive (usually daily) removal of fluid to provide best symptom control and chance of spontaneous pleurodesis. Daily drainages however demand considerably more resources and may increase risks of complications. Others believe that MPE care is palliative and drainage should be performed only when patients become symptomatic (often weekly to monthly). Identifying the best drainage approach will optimise patient care and healthcare resource utilisation. Methods and analysis A multicentre, open-label randomised trial. Patients with MPE will be randomised 1:1 to daily or symptom-guided drainage regimes after IPC insertion. Patient allocation to groups will be stratified for the cancer type (mesothelioma vs others), performance status (Eastern Cooperative Oncology Group status 0–1 vs ≥2), presence of trapped lung (vs not) and prior pleurodesis (vs not). The primary outcome is the mean daily dyspnoea score, measured by a 100 mm visual analogue scale (VAS) over the first 60 days. Secondary outcomes include benefits on physical activity levels, rate of spontaneous pleurodesis, complications, hospital admission days, healthcare costs and QoL measures. Enrolment of 86 participants will detect a mean difference of VAS score of 14 mm between the treatment arms (5% significance, 90% power) assuming a common between-group SD of 18.9 mm and a 10% lost to follow-up rate. Ethics and dissemination The Sir Charles Gairdner Group Human Research Ethics Committee has approved the study (number 2015-043). Results will be published in peer-reviewed journals and presented at scientific meetings. Trial registration

  19. Rituximab Maintenance Therapy After Autologous Stem-Cell Transplantation in Patients With Relapsed CD20+ Diffuse Large B-Cell Lymphoma: Final Analysis of the Collaborative Trial in Relapsed Aggressive Lymphoma

    PubMed Central

    Gisselbrecht, Christian; Schmitz, Norbert; Mounier, Nicolas; Singh Gill, Devinder; Linch, David C.; Trneny, Marek; Bosly, Andre; Milpied, Noel J.; Radford, John; Ketterer, Nicolas; Shpilberg, Ofer; Dührsen, Ulrich; Hagberg, Hans; Ma, David D.; Viardot, Andreas; Lowenthal, Ray; Brière, Josette; Salles, Gilles; Moskowitz, Craig H.; Glass, Bertram

    2012-01-01

    Purpose The standard treatment for relapsed diffuse large B-cell lymphoma (DLBCL) is salvage chemotherapy followed by high-dose therapy and autologous stem-cell transplantation (ASCT). The impact of maintenance rituximab after ASCT is not known. Patients and Methods In total, 477 patients with CD20+ DLBCL who were in their first relapse or refractory to initial therapy were randomly assigned to one of two salvage regimens. After three cycles of salvage chemotherapy, the responding patients received high-dose chemotherapy followed by ASCT. Then, 242 patients were randomly assigned to either rituximab every 2 months for 1 year or observation. Results After ASCT, 122 patients received rituximab, and 120 patients were observed only. The median follow-up time was 44 months. The 4-year event-free survival (EFS) rates after ASCT were 52% and 53% for the rituximab and observation groups, respectively (P = .7). Treatment with rituximab was associated with a 15% attributable risk of serious adverse events after day 100, with more deaths (six deaths v three deaths in the observation arm). Several factors affected EFS after ASCT (P < .05), including relapsed disease within 12 months (EFS: 46% v 56% for relapsed disease after 12 months), secondary age-adjusted International Prognostic Index (saaIPI) more than 1 (EFS: 37% v 61% for saaIPI < 1), and prior treatment with rituximab (EFS: 47% v 59% for no prior rituximab). A significant difference in EFS between women (63%) and men (46%) was also observed in the rituximab group. In the Cox model for maintenance, the saaIPI was a significant prognostic factor (P < .001), as was male sex (P = .01). Conclusion In relapsed DLBCL, we observed no difference between the control group and the rituximab maintenance group and do not recommend rituximab after ASCT. PMID:23091101

  20. 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

  1. Addition of Rice Bran Arabinoxylan to Curcumin Therapy May Be of Benefit to Patients With Early-Stage B-Cell Lymphoid Malignancies (Monoclonal Gammopathy of Undetermined Significance, Smoldering Multiple Myeloma, or Stage 0/1 Chronic Lymphocytic Leukemia): A Preliminary Clinical Study.

    PubMed

    Golombick, Terry; Diamond, Terrence H; Manoharan, Arumugam; Ramakrishna, Rajeev

    2016-06-01

    Hypothesis Prior studies on patients with early B-cell lymphoid malignancies suggest that early intervention with curcumin may lead to delay in progressive disease and prolonged survival. These patients are characterized by increased susceptibility to infections. Rice bran arabinoxylan (Ribraxx) has been shown to have immunostimulatory, anti-inflammatory, and proapoptotic effects. We postulated that addition of Ribraxx to curcumin therapy may be of benefit. Study design Monoclonal gammopathy of undetermined significance (MGUS)/smoldering multiple myeloma (SMM) or stage 0/1 chronic lymphocytic leukemia (CLL) patients who had been on oral curcumin therapy for a period of 6 months or more were administered both curcumin (as Curcuforte) and Ribraxx. Methods Ten MGUS/SMM patients and 10 patients with stage 0/1 CLL were administered 6 g of curcumin and 2 g Ribraxx daily. Blood samples were collected at baseline and at 2-month intervals for a period of 6 months, and various markers were monitored. MGUS/SMM patients included full blood count (FBC); paraprotein; free light chains/ratio; C-reactive protein (CRP)and erythrocyte sedimentation rate (ESR); B2 microglobulin and immunological markers. Markers monitored for stage 0/1 CLL were FBC, CRP and ESR, and immunological markers. Results Of 10 MGUS/SMM patients,5 (50%) were neutropenic at baseline, and the Curcuforte/Ribraxx combination therapy showed an increased neutrophil count, varying between 10% and 90% among 8 of the 10 (80%) MGUS/SMM patients. An additional benefit of the combination therapy was the potent effect in reducing the raised ESR in 4 (44%) of the MGUS/SMM patients. Conclusion Addition of Ribraxx to curcumin therapy may be of benefit to patients with early-stage B-cell lymphoid malignancies. PMID:27154182

  2. Diffuse Large B Cell Lymphoma Mimicking Granulomatosis with Polyangiitis

    PubMed Central

    Horowitz, Netanel; Ben-Itzhak, Ofer; Braun-Moscovici, Yolanda

    2016-01-01

    In a patient with systemic multiorgan disease with overlapping features, the differential diagnosis included infectious diseases, malignancies, and systemic autoimmune or inflammatory diseases. We present an unusual case of a young male with B cell lymphoma who presented with symptoms mimicking systemic vasculitis and review the existing literature. PMID:27293945

  3. NEMO Binding Domain peptide inhibits constitutive NF-κB activity and reduces tumor burden in a canine model of relapsed, refractory Diffuse Large B-Cell Lymphoma

    PubMed Central

    Gaurnier-Hausser, Anita; Patel, Reema; Baldwin, Albert S.; May, Michael J.; Mason, Nicola J.

    2011-01-01

    Purpose Activated B-Cell Diffuse Large B-Cell Lymphoma (ABC-DLBCL) is an aggressive, poorly chemoresponsive lymphoid malignancy characterized by constitutive canonical NF-κB activity that promotes lymphomagenesis and chemotherapy resistance via over-expression of anti-apoptotic NF-κB target genes. Inhibition of the canonical NF-κB pathway may therefore have therapeutic relevance in ABC-DLBCL. Here we set out to determine whether dogs with spontaneous DLBCL have comparative aberrant constitutive NF-κB activity and to determine the therapeutic relevance of NF-κB inhibition in dogs with relapsed, resistant DLBCL. Experimental Design Canonical NF-κB activity was evaluated by electrophoretic mobility shift assays and immunoblot analyses, and NF-κB target gene expression was measured by qRT-PCR. Primary malignant canine B lymphocytes were treated with the selective IKK complex inhibitor Nemo Binding Domain (NBD) peptide, and evaluated for NF-κB activity and apoptosis. NBD peptide was administered intra-nodally to dogs with relapsed B-cell lymphoma and NF-κB target gene expression and tumor burden were evaluated pre and post treatment. Results Constitutive canonical NF-κB activity and increased NF-κB target gene expression was detected in primary DLBCL tissue. NBD peptide inhibited this activity and induced apoptosis of primary malignant B cells in vitro. Intra-tumoral injections of NBD peptide to dogs with relapsed DLBCL inhibited NF-κB target gene expression and reduced tumor burden. Conclusions This work shows that dogs with spontaneous DLBCL represent a clinically relevant, spontaneous, large animal model for human ABC-DLBCL and demonstrates the therapeutic relevance of NF-κB inhibition in the treatment of ABC-DLBCL. These results have important translational relevance for ABC-DLBCL treatment in human patients. PMID:21610150

  4. 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

  5. Primary Mediastinal B-Cell Lymphoma

    PubMed Central

    Pileri, Stefano A.; Gaidano, Gianluca; Zinzani, Pier Luigi; Falini, Brunangelo; Gaulard, Philippe; Zucca, Emanuele; Pieri, Federica; Berra, Eva; Sabattini, Elena; Ascani, Stefano; Piccioli, Milena; Johnson, Peter W. M.; Giardini, Roberto; Pescarmona, Edoardo; Novero, Domenico; Piccaluga, Pier Paolo; Marafioti, Teresa; Alonso, Miguel A.; Cavalli, Franco

    2003-01-01

    Although primary mediastinal (thymic) large B-cell lymphoma has been primarily studied, its precise phenotype, molecular characteristics, and histogenesis are still a matter of debate. The International Extranodal Lymphoma Study Group collected 137 such cases for extensive pathological review. Histologically, the lymphomatous growth was predominantly diffuse with fibrosis that induced compartmentalized cell aggregation. It consisted of large cells with varying degrees of nuclear polymorphism and clear to basophilic cytoplasm. On immunohistochemistry, the following phenotype was observed: CD45+, CD20+, CD79a+, PAX5/BSAP+, BOB.1+, Oct-2+, PU.1+, Bcl-2+, CD30+, HLA-DR+, MAL protein+/−, Bcl-6+/−, MUM1/IRF4+/−, CD10−/+, CD21−, CD15−, CD138−, CD68−, and CD3−. Immunoglobulins were negative both at immunohistochemistry and in situ hybridization. Molecular analysis, performed in 45 cases, showed novel findings. More than half of the cases displayed BCL-6 gene mutations, which usually occurred along with functioning somatic IgVH gene mutations and Bcl-6 and/or MUM1/IRF4 expression. The present study supports the concept that a sizable fraction of cases of this lymphoma are from activated germinal center or postgerminal center cells. However, it differs from other aggressive B-cell lymphomas in that it shows defective immunoglobulin production despite the expression of OCT-2, BOB.1, and PU.1 transcription factors and the lack of IgVH gene crippling mutations. PMID:12507907

  6. Significance of p27 Immunostaining in B-Cell Neoplasm.

    PubMed

    El-Kerdany, Tahany A; Shams Eldin El Telbany, Manal A; Esmaeel, Manal M; Mahmoud, Hanan M

    2016-08-01

    P27 is an important cell cycle regulatory protein. Many reports have validated the utility of p27 as a prognostic marker in different human cancers and to prove its prognostic role in B-cell neoplasm; 80 newly diagnosed B-cell neoplasm patients with mean age of 46.6 years recruited from Hematology/Oncology Unit of Ain Shams University Hospitals during the period from January 2008 till June 2010 were studied for their p27 immunostaining results which showed that all cases of chronic lymphocytic leukemia (CLL) were positive for p27, whereas all mantly cell lymphoma cases were negative for it. There was significantly higher p27 positivity in CLL cases compared with non-Hodgkin lymphoma and that indolent cases showed significantly higher rate of positivity when compared with aggressive and highly aggressive cases. So, we can use this marker to differentiate CLL and mantly cell lymphoma in cases of confusion.

  7. Transcriptional analysis of the B cell germinal center reaction

    PubMed Central

    Klein, Ulf; Tu, Yuhai; Stolovitzky, Gustavo A.; Keller, Jeffrey L.; Haddad, Joseph; Miljkovic, Vladan; Cattoretti, Giorgio; Califano, Andrea; Dalla-Favera, Riccardo

    2003-01-01

    The germinal center (GC) reaction is crucial for T cell-dependent immune responses and is targeted by B cell lymphomagenesis. Here we analyzed the transcriptional changes that occur in B cells during GC transit (naïve B cells → centroblasts → centrocytes → memory B cells) by gene expression profiling. Naïve B cells, characterized by the expression of cell cycle-inhibitory and antiapoptotic genes, become centroblasts by inducing an atypical proliferation program lacking c-Myc expression, switching to a proapoptotic program, and down-regulating cytokine, chemokine, and adhesion receptors. The transition from GC to memory cells is characterized by a return to a phenotype similar to that of naïve cells except for an apoptotic program primed for both death and survival and for changes in the expression of cell surface receptors including IL-2 receptor β. These results provide insights into the dynamics of the GC reaction and represent the basis for the analysis of B cell malignancies. PMID:12604779

  8. The Histological Classification of Diffuse Large B-cell Lymphomas

    PubMed Central

    Xie, Yi; Pittaluga, Stefania; Jaffe, Elaine S.

    2015-01-01

    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 WHO 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 (cHL) and DLBCL as well as between Burkitt Lymphoma (BL) 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

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

    PubMed

    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

  10. T-Cell/Histiocyte-Rich Large B-Cell Lymphoma Presenting as a Primary Central Nervous System Lymphoma.

    PubMed

    Advani, Pooja; Starr, Jason; Swaika, Abhisek; Jiang, Liuyan; Qiu, Yushi; Li, Zhimin; Tun, Han W

    2015-12-29

    Primary central nervous system (PCNSL) lymphoma is an aggressive extranodal non-Hodgkin lymphoma, and most cases are classified as diffuse large B-cell lymphoma (DLBCL) by histology. T-cell/histiocyte-rich large B-cell lymphoma (TCRLBCL) represents a distinct subtype of diffuse large B-cell lymphoma and is characterized by the presence of scattered large neoplastic B-cells in a background of abundant T-cells and histiocytes. This is in contrast to the dense perivascular cuffing of neoplastic B-cells in classic DLBCL. T-cell/histiocyte-rich large B-cell lymphoma should be considered in PCNSL cases in which neoplastic B-cells are sparse and scattered. Immunohistochemistry will help identify the B-cells and surrounding infiltrate rich in Tlymphocytes and histiocytes. Future studies exploring the biology of TCRLBCL and the crosstalk between the neoplastic cells and the surrounding inflammatory infiltrate may provide exciting prospects for future therapies for TCRLBCL. PMID:26788280

  11. The double-edge role of B cells in mediating antitumor T-cell immunity: Pharmacological strategies for cancer immunotherapy.

    PubMed

    Wang, Jing-Zhang; Zhang, Yu-Hua; Guo, Xin-Hua; Zhang, Hong-Yan; Zhang, Yuan

    2016-07-01

    Emerging evidence reveals the controversial role of B cells in antitumor immunity, but the underlying mechanisms have to be explored. Three latest articles published in the issue 521 of Nature in 2015 reconfirmed the puzzling topic and put forward some explanations of how B cells regulate antitumor T-cell responses both positively and negatively. This paper attempts to demonstrate that different B-cell subpopulations have distinct immunological properties and that they are involved in either antitumor responses or immunosuppression. Recent studies supporting the positive and negative roles of B cells in tumor development were summarized comprehensively. Several specific B-cell subpopulations, such as IgG(+), IgA(+), IL-10(+), and regulatory B cells, were described in detail. The mechanisms underlying the controversial B-cell effects were mainly attributed to different B-cell subpopulations, different B-cell-derived cytokines, direct B cell-T cell interaction, different cancer categories, and different malignant stages, and the immunological interaction between B cells and T cells is mediated by dendritic cells. Promising B-cell-based antitumor strategies were proposed and novel B-cell regulators were summarized to present interesting therapeutic targets. Future investigations are needed to make sure that B-cell-based pharmacological strategies benefit cancer immunotherapy substantially.

  12. Bryostatin and Vincristine in B-Cell Malignancies

    ClinicalTrials.gov

    2013-01-10

    Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Immunoblastic Large Cell Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Refractory Chronic Lymphocytic Leukemia; Refractory Multiple Myeloma; Stage III Multiple Myeloma

  13. Tetraspanin CD37 protects against the development of B cell lymphoma.

    PubMed

    de Winde, Charlotte M; Veenbergen, Sharon; Young, Ken H; Xu-Monette, Zijun Y; Wang, Xiao-Xiao; Xia, Yi; Jabbar, Kausar J; van den Brand, Michiel; van der Schaaf, Alie; Elfrink, Suraya; van Houdt, Inge S; Gijbels, Marion J; van de Loo, Fons A J; Bennink, Miranda B; Hebeda, Konnie M; Groenen, Patricia J T A; van Krieken, J Han; Figdor, Carl G; van Spriel, Annemiek B

    2016-02-01

    Worldwide, B cell non-Hodgkin lymphoma is the most common hematological malignancy and represents a substantial clinical problem. The molecular events that lead to B cell lymphoma are only partially defined. Here, we have provided evidence that deficiency of tetraspanin superfamily member CD37, which is important for B cell function, induces the development of B cell lymphoma. Mice lacking CD37 developed germinal center-derived B cell lymphoma in lymph nodes and spleens with a higher incidence than Bcl2 transgenic mice. We discovered that CD37 interacts with suppressor of cytokine signaling 3 (SOCS3); therefore, absence of CD37 drives tumor development through constitutive activation of the IL-6 signaling pathway. Moreover, animals deficient for both Cd37 and Il6 were fully protected against lymphoma development, confirming the involvement of the IL-6 pathway in driving tumorigenesis. Loss of CD37 on neoplastic cells in patients with diffuse large B cell lymphoma (DLBCL) directly correlated with activation of the IL-6 signaling pathway and with worse progression-free and overall survival. Together, this study identifies CD37 as a tumor suppressor that directly protects against B cell lymphomagenesis and provides a strong rationale for blocking the IL-6 pathway in patients with CD37- B cell malignancies as a possible therapeutic intervention. PMID:26784544

  14. Tetraspanin CD37 protects against the development of B cell lymphoma

    PubMed Central

    de Winde, Charlotte M.; Veenbergen, Sharon; Young, Ken H.; Xu-Monette, Zijun Y.; Wang, Xiao-xiao; Xia, Yi; Jabbar, Kausar J.; van den Brand, Michiel; van der Schaaf, Alie; Elfrink, Suraya; van Houdt, Inge S.; Gijbels, Marion J.; van de Loo, Fons A.J.; Bennink, Miranda B.; Hebeda, Konnie M.; Groenen, Patricia J.T.A.; van Krieken, J. Han; Figdor, Carl G.; van Spriel, Annemiek B.

    2016-01-01

    Worldwide, B cell non-Hodgkin lymphoma is the most common hematological malignancy and represents a substantial clinical problem. The molecular events that lead to B cell lymphoma are only partially defined. Here, we have provided evidence that deficiency of tetraspanin superfamily member CD37, which is important for B cell function, induces the development of B cell lymphoma. Mice lacking CD37 developed germinal center–derived B cell lymphoma in lymph nodes and spleens with a higher incidence than Bcl2 transgenic mice. We discovered that CD37 interacts with suppressor of cytokine signaling 3 (SOCS3); therefore, absence of CD37 drives tumor development through constitutive activation of the IL-6 signaling pathway. Moreover, animals deficient for both Cd37 and Il6 were fully protected against lymphoma development, confirming the involvement of the IL-6 pathway in driving tumorigenesis. Loss of CD37 on neoplastic cells in patients with diffuse large B cell lymphoma (DLBCL) directly correlated with activation of the IL-6 signaling pathway and with worse progression-free and overall survival. Together, this study identifies CD37 as a tumor suppressor that directly protects against B cell lymphomagenesis and provides a strong rationale for blocking the IL-6 pathway in patients with CD37– B cell malignancies as a possible therapeutic intervention. PMID:26784544

  15. [Regulatory B cells in human autoimmune diseases].

    PubMed

    Miyagaki, Tomomitsu

    2015-01-01

    B cells have been generally considered to be positive regulators of immune responses because of their ability to produce antigen-specific antibodies and to activate T cells through antigen presentation. Impairment of B cell development and function may cause autoimmune diseases. Recently, specific B cell subsets that can negatively regulate immune responses have been described in mouse models of a wide variety of autoimmune diseases. The concept of those B cells, termed regulatory B cells, is now recognized as important in the murine immune system. Among several regulatory B cell subsets, IL-10-producing regulatory B cells are the most widely investigated. On the basis of discoveries from studies of such mice, human regulatory B cells that produce IL-10 in most cases are becoming an active area of research. There have been emerging data suggesting the importance of human regulatory B cells in various diseases. Revealing the immune regulation mechanisms of human regulatory B cells in human autoimmune diseases could lead to the development of novel B cell targeted therapies. This review highlights the current knowledge on regulatory B cells, mainly IL-10-producing regulatory B cells, in clinical research using human samples. PMID:26725860

  16. Expression of sprouty2 inhibits B-cell proliferation and is epigenetically silenced in mouse and human B-cell lymphomas

    PubMed Central

    Frank, Matthew J.; Dawson, David W.; Bensinger, Steven J.; Hong, Jason S.; Knosp, Wendy M.; Xu, Lizhong; Balatoni, Cynthia E.; Allen, Eric L.; Shen, Rhine R.; Bar-Sagi, Dafna; Martin, Gail R.

    2009-01-01

    B-cell lymphoma is the most common immune system malignancy. TCL1 transgenic mice (TCL1-tg), in which TCL1 is ectopically expressed in mature lymphocytes, develop multiple B- and T-cell leukemia and lymphoma subtypes, supporting an oncogenic role for TCL1 that probably involves AKT and MAPK-ERK signaling pathway augmentation. Additional, largely unknown genetic and epigenetic alterations cooperate with TCL1 during lymphoma progression. We examined DNA methylation patterns in TCL1-tg B-cell tumors to discover tumor-associated epigenetic changes, and identified hypermethylation of sprouty2 (Spry2). Sprouty proteins are context-dependent negative or positive regulators of MAPK-ERK pathway signaling, but their role(s) in B-cell physiology or pathology are unknown. Here we show that repression of Spry2 expression in TCL1-tg mouse and human B-cell lymphomas and cell lines is associated with dense DNA hypermethylation and was reversed by inhibition of DNA methylation. Spry2 expression was induced in normal splenic B cells by CD40/B-cell receptor costimulation and regulated a negative feedback loop that repressed MAPK-ERK signaling and decreased B-cell viability. Conversely, loss of Spry2 function hyperactivated MAPK-ERK signaling and caused increased B-cell proliferation. Combined, these results implicate epigenetic silencing of Spry2 expression in B lymphoma progression and suggest it as a companion lesion to ectopic TCL1 expression in enhancing MAPK-ERK pathway signaling. PMID:19147787

  17. Role of Tyrosine Kinase Inhibitors in Indolent and Other Mature B-Cell Neoplasms

    PubMed Central

    Kutsch, Nadine; Marks, Reinhard; Ratei, Richard; Held, Thomas K; Schmidt-Hieber, Martin

    2015-01-01

    Targeting tyrosine kinases represents a highly specific treatment approach for different malignancies. This also includes non-Hodgkin lymphoma since it is well known that these enzymes are frequently involved in the lymphomagenesis. Hereby, tyrosine kinases might either be dysregulated intrinsically or be activated within signal transduction pathways leading to tumor survival and growth. Among others, Bruton’s tyrosine kinase (Btk) is of particular interest as a potential therapeutic target. Btk is stimulated by B-cell receptor signaling and activates different transcription factors such as nuclear factor κB. The Btk inhibitor ibrutinib has been approved for the treatment of chronic lymphocytic leukemia and mantle-cell lymphoma recently. Numerous clinical trials evaluating this agent in different combinations (eg, with rituximab or classical chemotherapeutic agents) as a treatment option for aggressive and indolent lymphoma are under way. Here, we summarize the role of tyrosine kinase inhibitors in the treatment of indolent and other non-Hodgkin lymphomas (eg, mantle-cell lymphoma). PMID:26327780

  18. Multiple Curricula for B Cell Developmental Programming.

    PubMed

    Rothenberg, Ellen V

    2016-09-20

    B-1 B cells differ from conventional B-2 B cells functionally, but how these differences relate to the ontogeny of these lineages has been unclear. Two recent Immunity articles, Kristiansen et al. (2016) and Montecino-Rodriguez et al. (2016), now provide insight into the origins of B-1 and B-2 B cells, revealing a multi-layered developmental program and successive waves of B cell precursors.

  19. Multiple Curricula for B Cell Developmental Programming.

    PubMed

    Rothenberg, Ellen V

    2016-09-20

    B-1 B cells differ from conventional B-2 B cells functionally, but how these differences relate to the ontogeny of these lineages has been unclear. Two recent Immunity articles, Kristiansen et al. (2016) and Montecino-Rodriguez et al. (2016), now provide insight into the origins of B-1 and B-2 B cells, revealing a multi-layered developmental program and successive waves of B cell precursors. PMID:27653594

  20. Large anaplastic spinal B-cell lymphoma in a cat.

    PubMed

    Flatland, Bente; Fry, Michael M; Newman, Shelley J; Moore, Peter F; Smith, Joanne R; Thomas, William B; Casimir, Roslyn H

    2008-12-01

    A 5-year-old female spayed domestic shorthair cat was presented for evaluation of tetraparesis. The neurologic lesion was localized to the cervical spinal segment (C1-C6). A left axillary mass was identified, and the results of fine needle aspiration cytology indicated malignant round cell neoplasia of possible histiocytic origin. The cells were large, had marked anisocytosis and anisokaryosis, occasional bi- and multinucleation, and cytoplasmic vacuolation. Euthanasia was performed due to the poor prognosis associated with severe, progressive neurologic signs and a malignant neoplasm. Postmortem examination revealed spinal cord compression and an extradural mass at the C1-C2 spinal segment, with neoplastic cells in the adjacent vertebral bodies, surrounding skeletal muscle, left axillary lymph node, and bone marrow from the right femur. The initial histologic diagnosis was anaplastic sarcoma, but immunohistochemical results indicated the cells were CD20+ and CD45R+ and CD3-, compatible with a diagnosis of B-cell lymphoma. CD79a staining was nonspecific and uninterpretable. Weak to moderate CD18 positivity and E-cadherin positivity were also observed. Clonality of the B-cell population could not be demonstrated using PCR testing for antigen receptor gene rearrangement. To the authors' knowledge, this is the first reported case of a feline spinal anaplastic B-cell lymphoma exhibiting bi- and multinucleated cells. The prognostic significance of this cell morphology and immunophenotype is unknown.

  1. Large anaplastic spinal B-cell lymphoma in a cat.

    PubMed

    Flatland, Bente; Fry, Michael M; Newman, Shelley J; Moore, Peter F; Smith, Joanne R; Thomas, William B; Casimir, Roslyn H

    2008-12-01

    A 5-year-old female spayed domestic shorthair cat was presented for evaluation of tetraparesis. The neurologic lesion was localized to the cervical spinal segment (C1-C6). A left axillary mass was identified, and the results of fine needle aspiration cytology indicated malignant round cell neoplasia of possible histiocytic origin. The cells were large, had marked anisocytosis and anisokaryosis, occasional bi- and multinucleation, and cytoplasmic vacuolation. Euthanasia was performed due to the poor prognosis associated with severe, progressive neurologic signs and a malignant neoplasm. Postmortem examination revealed spinal cord compression and an extradural mass at the C1-C2 spinal segment, with neoplastic cells in the adjacent vertebral bodies, surrounding skeletal muscle, left axillary lymph node, and bone marrow from the right femur. The initial histologic diagnosis was anaplastic sarcoma, but immunohistochemical results indicated the cells were CD20+ and CD45R+ and CD3-, compatible with a diagnosis of B-cell lymphoma. CD79a staining was nonspecific and uninterpretable. Weak to moderate CD18 positivity and E-cadherin positivity were also observed. Clonality of the B-cell population could not be demonstrated using PCR testing for antigen receptor gene rearrangement. To the authors' knowledge, this is the first reported case of a feline spinal anaplastic B-cell lymphoma exhibiting bi- and multinucleated cells. The prognostic significance of this cell morphology and immunophenotype is unknown. PMID:19055573

  2. Targeting B-cell receptor signaling kinases in chronic lymphocytic leukemia: the promise of entospletinib

    PubMed Central

    Sharman, Jeff; Di Paolo, Julie

    2016-01-01

    The B-cell receptor signaling pathway has emerged as an important therapeutic target in chronic lymphocytic leukemia and other B-cell malignancies. Novel agents have been developed targeting the signaling enzymes spleen tyrosine kinase (SYK), Bruton’s tyrosine kinase, and phosphoinositide 3-kinase delta. This review discusses the rationale for targeting these enzymes, as well as the preclinical and clinical evidence supporting their role as therapeutic targets, with a particular focus on SYK inhibition with entospletinib. PMID:27247756

  3. Malignant mesothelioma

    PubMed Central

    Ahmed, Ishtiaq; Ahmed Tipu, Salman; Ishtiaq, Sundas

    2013-01-01

    Malignant Mesothelioma (MM) is a rare but rapidly fatal and aggressive tumor of the pleura and peritoneum with limited knowledge of its natural history. The incidence has increased in the past two decades but still it is a rare tumor. Etiology of all forms of mesothelioma is strongly associated with industrial pollutants, of which asbestos is the principal carcinogen. Mesothelioma is an insidious neoplasm arising from mesothelial surfaces i.e., pleura (65%-70%), peritoneum (30%), tunica vaginalis testis, and pericardium (1%-2%). The diagnosis of peritoneal and Pleural mesothelioma is often delayed, due to a long latent period between onset and symptoms and the common and nonspecific clinical presentation. The definite diagnosis can only be established by diagnostic laparoscopy or open surgery along with biopsy to obtain histological examination and immunocytochemical analysis. Different treatment options are available but Surgery can achieve a complete or incomplete resection and Radical resection is the preferred treatment. Chemotherapy has an important role in palliative treatment. Photodynamic therapy is also an option under trial. Patients who successfully underwent surgical resection had a considerably longer median survival as well as a significantly higher 5-year survival. Source of Data/Study Selection: The data were collected from case reports, cross-sectional studies, Open-label studies and phase –II trials between 1973-2012. Data Extraction: Web sites and other online resources of American college of surgeons, Medline, NCBI and Medscape resource centers were used to extract data. Conclusion: Malignant Mesothelioma (MM) is a rare but rapidly fatal and aggressive tumor with limited knowledge of its natural history. The diagnosis of peritoneal and Pleural mesothelioma is often delayed, so level of index of suspicion must be kept high. PMID:24550969

  4. Early B-cell Factor 1 Regulates the Expansion of B-cell Progenitors in a Dose-dependent Manner*

    PubMed Central

    Åhsberg, Josefine; Ungerbäck, Jonas; Strid, Tobias; Welinder, Eva; Stjernberg, Jenny; Larsson, Malin; Qian, Hong; Sigvardsson, Mikael

    2013-01-01

    Transcription factor doses are of importance for normal and malignant B-lymphocyte development; however, the understanding of underlying mechanisms and functional consequences of reduced transcription factor levels is limited. We have analyzed progenitor and B-lineage compartments in mice carrying heterozygote mutations in the E2a, Ebf1, or Pax5 gene. Although lymphoid progenitors from Ebf1 or Pax5 heterozygote mice were specified and lineage-restricted in a manner comparable with Wt progenitors, this process was severely impaired in E2a heterozygote mutant mice. This defect was not significantly enhanced upon combined deletion of E2a with Ebf1 or Pax5. Analysis of the pre-B-cell compartment in Ebf1 heterozygote mice revealed a reduction in cell numbers. These cells expressed Pax5 and other B-lineage-associated genes, and global gene expression analysis suggested that the reduction of the pre-B-cell compartment was a result of impaired pre-B-cell expansion. This idea was supported by a reduction in IL2Rα-expressing late pre-B-cells as well as by cell cycle analysis and by the finding that the complexity of the VDJ rearrangement patterns was comparable in Wt and Ebf1+/− pre-B-cells, although the number of progenitors was reduced. Heterozygote deletion of Ebf1 resulted in impaired response to IL7 in vitro and reduced expression levels of pre-BCR on the cell surface, providing possible explanations for the observed stage-specific reduction in cellular expansion. Thus, transcription factor doses are critical for specification as well as expansion of B-lymphoid progenitors, providing increased insight into the molecular regulation of B-cell development. PMID:24078629

  5. Emerging immunotherapy and strategies directly targeting B cells for the treatment of diffuse large B-cell lymphoma.

    PubMed

    Witkowska, Magdalena; Smolewski, Piotr

    2015-01-01

    During the last decade, significant prolonged survival in diffusive large B-cell lymphoma (DLBCL) has been observed. The efficacy of initial treatment improved mostly due to addition of a chimeric anti-CD20 monoclonal antibody (rituximab) to standard chemotherapeutic regimens. Moreover, accurate understanding of DLBCL pathogenesis and remarkable progress in gene expression profiling have led to the development of a variety of tumor-specific regimens. Novel agents target directly the pathways involved in signal transduction, lead to apoptosis and cancer cells differentiation. In this article, we mainly focus on new treatment options, such as monoclonal antibodies, tyrosine kinase inhibitors and immunomodulatory drugs, currently investigated in aggressive B-cell lymphoma with particular attention to DLBCL type.

  6. "Malignant Cutaneous Ulcer".

    PubMed

    Sundriyal, Deepak; Kotwal, Sumedha

    2016-09-01

    Renal cell carcinoma (RCC) is an aggressive malignancy and the rich vascular supply enables it to metastasize early via haematogenous route. Skin lesions are a late manifestation of the disease. Clinicians should be aware of cutaneous presentation of RCC while evaluating a case of unknown primary with skin lesions. PMID:27651705

  7. Bilateral conjunctival extranodal marginal zone B-cell lymphoma.

    PubMed

    Kram, David E; Brathwaite, Carole D; Khatib, Ziad A

    2010-12-15

    Extranodal marginal zone B-cell lymphomas (EMZLs), while relatively common in adults, are rare entities in the pediatric population. A subclass of the typically aggressive non-Hodgkin lymphomas, the few reported pediatric cases indicate that, as in adults, these tumors tend to be indolent. We present a case of EMZL arising in the conjunctivae in a 9-year-old male with bilateral disease. The patient was treated with surgical excision alone and has remained disease-free 6 years after the operation. PMID:20981695

  8. Pediatric common variable immunodeficiency: immunologic and phenotypic associations with switched memory B cells.

    PubMed

    Yong, Pierre L; Orange, Jordan S; Sullivan, Kathleen E

    2010-08-01

    Recent studies suggest that patients with common variable immunodeficiency (CVID) and low numbers of switched memory B cells have lower IgG levels and higher rates of autoimmune disease, splenomegaly, and granulomatous disease; however, no prior literature has focused exclusively on pediatric cases. We examined the relationship between switched memory B cells and clinical and immunologic manifestations of CVID in a pediatric population. Forty-five patients were evaluated. Patients were categorized as Group I (<5 switched memory B cells/ml, n = 24) or Group II (> or =5 switched memory B cells/mL, n = 21). CD3(+) T-cell counts and CD19(+) B-cell levels were lower among Group I patients. Only those in Group I had meningitis, sepsis, bronchiectasis, granulomatous lung disease, autoimmune cytopenias, or hematologic malignancies. Segregation of pediatric patients into high risk (Group I) and average risk (Group II) may assist in targeting surveillance appropriately.

  9. 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

  10. B Cell Autonomous TLR Signaling and Autoimmunity

    PubMed Central

    Meyer-Bahlburg, Almut; Rawlings, David J

    2009-01-01

    B cells play a central role in the pathogenesis of multiple autoimmune diseases and the recognition of importance of B cells in these disorders has grown dramatically in association with the remarkable success of B-cell depletion as a treatment for autoimmunity. The precise mechanisms that promote alterations in B cell tolerance remain incompletely defined. There is increasing evidence, however, that TLRs play a major role in these events. Stimulation of B cells via the TLR pathway not only leads to an increase in antibody production but also promotes additional changes including cytokine production and upregulation of activation markers increasing the effectiveness of B cells as APCs. Understanding the role of TLRs in systemic autoimmunity will not only provide insight into the disease pathogenesis but may also lead to the development of novel therapies. This article gives an overview of TLR signaling in B cells and the possible involvement of such signals in autoimmune diseases. PMID:18295736

  11. Microbes and B cell development.

    PubMed

    Wesemann, Duane R

    2015-01-01

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

  12. The unexpected evolution of a case of diffuse large B-cell non-Hodgkin lymphoma.

    PubMed

    Găman, Amelia; Bold, Adriana; Găman, G

    2011-01-01

    The diffuse large B-cell lymphoma (DLBCL) represents the most common type of aggressive non-Hodgkin's lymphoma with a heterogeneous morphology, biology and clinical presentation. Gene expression profiling studies identified three distinct molecular subtypes of DLCBL arisen from B-cells at different stages of differentiation: germinal center B-cell-like (GCB) DLBCL, activated B-cell-like (ABC) DLBCL, primary mediastinal B-cell lymphoma (PMBL). The most relevant oncogenic pathways in diffuse large B-cell lymphoma are: deregulated B-cell receptor/proliferation signaling, BCL6 and NF-kB constitutive expression, defects in apoptosis and neoangiogenesis. The treatment of DLBCL has been completely modified in the last ten years by combination of anti-CD20 monoclonal antibody (rituximab) and CHOP chemotherapy, which is now the first line therapy. In the last years, there have been reported several cases of progressive multifocal leukoencephalopathy (PML) at patients with rheumatoid arthritis treated with rituximab. Progressive multifocal leukoencephalopathy is possible as an adverse reaction to rituximab at patients treated with R-CHOP for diffuse large B-cell lymphoma. PMID:21655667

  13. Inducible resistance to Fas-mediated apoptosis in B cells.

    PubMed

    Rothstein, T L

    2000-12-01

    Apoptosis produced in B cells through Fas (APO-1, CD95) triggering is regulated by signals derived from other surface receptors: CD40 engagement produces upregulation of Fas expression and marked susceptibility to Fas-induced cell death, whereas antigen receptor engagement, or IL-4R engagement, inhibits Fas killing and in so doing induces a state of Fas-resistance, even in otherwise sensitive, CD40-stimulated targets. Surface immunoglobulin and IL-4R utilize at least partially distinct pathways to produce Fas-resistance that differentially depend on PKC and STAT6, respectively. Further, surface immunoglobulin signaling for inducible Fas-resistance bypasses Btk, requires NF-kappaB, and entails new macromolecular synthesis. Terminal effectors of B cell Fas-resistance include the known anti-apoptotic gene products, Bcl-xL and FLIP, and a novel anti-apoptotic gene that encodes FAIM (Fas Apoptosis Inhibitory Molecule). faim was identified by differential display and exists in two alternatively spliced forms; faim-S is broadly expressed, but faim-L expression is tissue-specific. The FAIM sequence is highly evolu- tionarily conserved, suggesting an important role for this molecule throughout phylogeny. Inducible resistance to Fas killing is hypothesized to protect foreign antigen-specific B cells during potentially hazardous interactions with FasL-bearing T cells, whereas autoreactive B cells fail to become Fas-resistant and are deleted via Fas-dependent cytotoxicity. Inadvertent or aberrant acquisition of Fas-resistance may permit autoreactive B cells to escape Fas deletion, and malignant lymphocytes to impede anti-tumor immunity.

  14. [Aggressive fibromatoses in orthopedics].

    PubMed

    Adler, C P; Stock, D

    1986-01-01

    Aggressive fibromatoses which may develop either in soft tissue or in the bone present considerable problems for the pathologist trying to establish a diagnosis as well as for the radiologist and surgeon. In radiographs, a destruction of the soft and osseous tissue is seen which suggests a malignant tumor. Histologically a monomorphic connective tissue prevails in the biopsy showing no essential signs of malignancy. Under pathoanatomical aspects often a benign proliferation of the connective tissue is assumed. Surgically the tumor may either be removed in a too radical and mutilating way, or the excision may remain incomplete. Two cases of desmoplastic bone fibroma (aggressive fibromatosis in the ulna and in the sacrum) are described in which the complete tumor removal led to healing, whereas the incomplete excision of the tumor resulted in recurrences. Aggressive fibromatosis represents a semimalignant tumor which has a locally destructive and invasive growth tendency but does not metastasize. The various fibromatoses are defined with regard to their biological growth tendency and the therapeutic consequences are discussed.

  15. Signaling aggression.

    PubMed

    van Staaden, Moira J; Searcy, William A; Hanlon, Roger T

    2011-01-01

    From psychological and sociological standpoints, aggression is regarded as intentional behavior aimed at inflicting pain and manifested by hostility and attacking behaviors. In contrast, biologists define aggression as behavior associated with attack or escalation toward attack, omitting any stipulation about intentions and goals. Certain animal signals are strongly associated with escalation toward attack and have the same function as physical attack in intimidating opponents and winning contests, and ethologists therefore consider them an integral part of aggressive behavior. Aggressive signals have been molded by evolution to make them ever more effective in mediating interactions between the contestants. Early theoretical analyses of aggressive signaling suggested that signals could never be honest about fighting ability or aggressive intentions because weak individuals would exaggerate such signals whenever they were effective in influencing the behavior of opponents. More recent game theory models, however, demonstrate that given the right costs and constraints, aggressive signals are both reliable about strength and intentions and effective in influencing contest outcomes. Here, we review the role of signaling in lieu of physical violence, considering threat displays from an ethological perspective as an adaptive outcome of evolutionary selection pressures. Fighting prowess is conveyed by performance signals whose production is constrained by physical ability and thus limited to just some individuals, whereas aggressive intent is encoded in strategic signals that all signalers are able to produce. We illustrate recent advances in the study of aggressive signaling with case studies of charismatic taxa that employ a range of sensory modalities, viz. visual and chemical signaling in cephalopod behavior, and indicators of aggressive intent in the territorial calls of songbirds.

  16. Maintenance therapy with interferon-alpha 2b, cyclophosphamide, and prednisone in aggressive diffuse large cell lymphoma.

    PubMed

    Avilés, Agustin; Neri, Natividad; Nambo, M Jesús; Castañeda, Claudia; Talavera, Alejandra; Huerta-Guzmán, Judith; Murillo, Edgar

    2004-04-01

    Maintenance therapy in patients with aggressive malignant lymphoma using biological modifiers remains uncertain. We conducted a controlled clinical trial to evaluate the efficacy and toxicity of interferon-alpha 2b, cyclophosphamide, and prednisone as maintenance therapy in patients with aggressive diffuse large B cell lymphomas in complete remission after aggressive chemotherapy. In an intent-to-treat analysis, 169 patients were eligible for this study; the end points were event-free survival (EFS) and overall survival (OS). With a median follow-up of 49.3 months, no statistical differences were observed and actuarial curves at 5 years showed that EFS was 71% (95% confidence interval [CI], 63-79%) for patients who received maintenance compared to 63% (95% CI, 59-71%) for patients in control group (p = 0.05). No statistical differences were observed in OS between maintenance arm: 84% (95% CI, 78-89%) and control group 83% (95% CI, 77-88%) in control group (p = 0.2). All patients received the maintenance therapy as planned and in time, thus dose intensity was considered 1.0 in all cases. Acute toxicity was mild, and no delay or suspension of treatment was necessary. Late toxicity was not evident until now. We conclude that use of maintenance therapy combining interferon-alpha 2b, cyclophosphamide, and prednisone is not useful in patients with aggressive lymphoma if they had been treated with aggressive combined chemotherapy. PMID:15186737

  17. T-cell/histiocyte-rich large B-cell lymphoma of stomach.

    PubMed

    Barut, Figen; Kandemir, Nilufer Onak; Gun, Banu Dogan; Ozdamar, Sukru Oguz

    2016-07-01

    T-cell/histiocyte-rich large B-cell lymphoma is an unusually encountered lymphoid neoplasm of stomach with aggressive course, and is an uncommon morphologic variant of diffuse large B-cell lymphoma. An ulcerated mass, 7x5x1 cm in size was observed within the gastrectomy specimen of a 76-year-old female patient. In cross sections, besides mature lymphoid cells displaying T-cell phenotype, a neoplastic formation composed of large, pleomorphic atypical lymphoid cells with, prominent nucleoli, vesicular nuclei and abundant eosinophilic cytoplasm displaying B-cell phenotype were observed. Meanwhile, histiocyte-like mononuclear cells and Reed-Sternberg-like multinuclear cells expressing CD68 and Mac387 were also observed. The diagnosis of the case was T cell/histiocyte-rich large B-cell lymphoma. This rarely encountered neoplasm should be kept in mind in the differential diagnosis of primary gastric lymphomas. PMID:27427148

  18. Production of RANKL by Memory B Cells

    PubMed Central

    Meednu, Nida; Zhang, Hengwei; Owen, Teresa; Sun, Wen; Wang, Victor; Cistrone, Christopher; Rangel-Moreno, Javier; Xing, Lianping; Anolik, Jennifer H.

    2016-01-01

    Objective Rheumatoid arthritis (RA) is a systemic autoimmune disease that often leads to joint damage. The mechanisms of bone damage in RA are complex, involving activation of bone-resorbing osteoclasts (OCs) by synoviocytes and Th17 cells. This study was undertaken to investigate whether B cells play a direct role in osteoclastogenesis through the production of RANKL, the essential cytokine for OC development. Methods RANKL production by total B cells or sorted B cell subpopulations in the peripheral blood and synovial tissue from healthy donors or anti–cyclic citrullinated peptide–positive patients with RA was examined by flow cytometry, real-time polymerase chain reaction, enzyme-linked immunosorbent assay, and immunohistochemical analysis. To define direct effects on osteoclastogenesis, B cells were cocultured with CD14+ monocytes, and OCs were enumerated by tartrate-resistant acid phosphatase staining. Results Healthy donor peripheral blood B cells were capable of expressing RANKL upon stimulation, with switched memory B cells (CD27+IgD−) having the highest propensity for RANKL production. Notably, switched memory B cells in the peripheral blood from RA patients expressed significantly more RANKL compared to healthy controls. In RA synovial fluid and tissue, memory B cells were enriched and spontaneously expressed RANKL, with some of these cells visualized adjacent to RANK+ OC precursors. Critically, B cells supported OC differentiation in vitro in a RANKL-dependent manner, and the number of OCs was higher in cultures with RA B cells than in those derived from healthy controls. Conclusion These findings reveal the critical importance of B cells in bone homeostasis and their likely contribution to joint destruction in RA. PMID:26554541

  19. The CD40 ligand expressed by human B cells costimulates B cell responses.

    PubMed

    Grammer, A C; Bergman, M C; Miura, Y; Fujita, K; Davis, L S; Lipsky, P E

    1995-05-15

    The possibility that activated B cells might express a ligand for CD40 that was of functional importance for B cell responses was examined by using highly purified human peripheral blood B cells, as well as a variety of B lymphoblastoid cell lines and hybridomas. Following stimulation with the combination of a calcium ionophore and a phorbol ester, human B cells bound a soluble fusion protein containing the extracellular portion of CD40 and the Fc region of IgG1 (CD40.Ig). A variety of B cell lines and hybridomas also bound CD40.Ig, either constitutively or after activation. In addition, CD40.Ig specifically immunoprecipitated a 33-kDa glycoprotein from surface 125I-labeled activated B cells. The nucleotide sequence of the coding region of the CD40 ligand mRNA amplified by RT-PCR from activated T cells and B cell lines was identical. The CD40 ligand expressed on human B cells was important functionally because homotypic aggregation of CD40 ligand-expressing B cells was inhibited by the CD40.Ig construct. Additionally, RNA and DNA synthesis as well as Ig production by polyclonally activated, highly purified peripheral B cells and a variety of B cell lines were inhibited significantly by the CD40.Ig construct. Finally, B cell lines expressing the CD40 ligand induced Ig production from resting normal B cells in a CD40-dependent manner. These results indicate that human B cells express a ligand for CD40 that is identical with that expressed by activated T cells and that the B cell-expressed CD40 ligand plays an important role in facilitating responses of activated B cells.

  20. Molecular underpinning of B-cell anergy

    PubMed Central

    Yarkoni, Yuval; Getahun, Andrew; Cambier, John C.

    2010-01-01

    Summary A byproduct of the largely stochastic generation of a diverse B-cell specificity repertoire is production of cells that recognize autoantigens. Indeed, recent studies indicate that more than half of the primary repertoire consists of autoreactive B cells that must be silenced to prevent autoimmunity. While this silencing can occur by multiple mechanisms, it appears that most autoreactive B cells are silenced by anergy, wherein they populate peripheral lymphoid organs and continue to express unoccupied antigen receptors yet are unresponsive to antigen stimulation. Here we review molecular mechanisms that appear operative in maintaining the antigen unresponsiveness of anergic B cells. In addition, we present new data indicating that the failure of anergic B cells to mobilize calcium in response to antigen stimulation is not mediated by inactivation of stromal interacting molecule 1, a critical intermediary in intracellular store depletion-induced calcium influx. PMID:20727040

  1. Antigen selection in B-cell lymphomas--tracing the evidence.

    PubMed

    Sutton, Lesley-Ann; Agathangelidis, Andreas; Belessi, Chrysoula; Darzentas, Nikos; Davi, Frederic; Ghia, Paolo; Rosenquist, Richard; Stamatopoulos, Kostas

    2013-12-01

    While signaling through the B cell receptor (BcR) facilitates B cell development and maintenance, it also carries intertwined risks for the development of lymphomas since malignant B cells can exploit these pathways in order to trigger and fuel clonal expansion. This corruption of the normal B cell response to antigens, leading to sustained BcR signaling, has given great impulse to investigate in detail the role of antigen in lymphomas. Suffice it to conclude from such studies, largely immunogenetics based, that the evidence implicating antigens (exogenous or self) in lymphoma development is substantial and that lymphomagenesis is functionally driven and dynamic, rather than a simple stochastic process. As the paradigm of antigen-driven lymphoma evolves, further investigation will be paramount to the identification of the inciting agent(s) that may be responsible for immunoproliferative neoplasms and also for the development of therapeutic agents targeting effectors of the BcR signaling pathway.

  2. Molecular characterization of primary mediastinal B cell lymphoma.

    PubMed

    Tsang, P; Cesarman, E; Chadburn, A; Liu, Y F; Knowles, D M

    1996-06-01

    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. PMID:8669486

  3. 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

  4. Expression cloning of human B cell immunoglobulins.

    PubMed

    Wardemann, Hedda; Kofer, Juliane

    2013-01-01

    The majority of lymphomas originate from B cells at the germinal center stage or beyond. Preferential selection of B cell clones by a limited set of antigens has been suggested to drive lymphoma development. However, little is known about the specificity of the antibodies expressed by lymphoma cells, and the role of antibody-specificity in lymphomagenesis remains elusive. Here, we describe a strategy to characterize the antibody reactivity of human B cells. The approach allows the unbiased characterization of the human antibody repertoire on a single cell level through the generation of recombinant monoclonal antibodies from single primary human B cells of defined origin. This protocol offers a detailed description of the method starting from the flow cytometric isolation of single human B cells, to the RT-PCR-based amplification of the expressed Igh, Igκ, and Igλ chain genes, and Ig gene expression vector cloning for the in vitro production of monoclonal antibodies. The strategy may be used to obtain information on the clonal evolution of B cell lymphomas by single cell Ig gene sequencing and on the antibody reactivity of human lymphoma B cells.

  5. Primary cutaneous B-cell lymphoma.

    PubMed

    Bogle, Melissa A; Riddle, Christy C; Triana, Emily M; Jones, Dan; Duvic, Madeleine

    2005-09-01

    Primary cutaneous B-cell lymphomas include extranodal marginal zone B-cell lymphoma, follicular lymphoma, large B-cell lymphoma, and, rarely, mantle cell lymphoma. Our purpose in conducting this review was to determine the clinical and behavioral characteristics of primary cutaneous B-cell lymphomas, their relationship to infectious triggers, and therapeutic response. We conducted a retrospective chart review of 23 adult patients presenting to the dermatology clinic at M. D. Anderson Cancer Center with primary cutaneous B-cell lymphoma between January 1999 and May 2003. Primary cutaneous B-cell lymphomas generally present on the head and neck, with the trunk and extremities afflicted to a lesser extent. Patients were found to have serologic evidence of prior infection with Borrelia burgdorferi (n = 10), Helicobacter pylori (n = 5), and Epstein-Barr virus (n = 6). Overall, treatment of primary cutaneous B-cell lymphoma should involve multiple modalities; however, specific treatment aimed at concurrent or suspected infection, particularly B burgdorferi, is a helpful adjunct and may achieve complete remission in a small subset of patients.

  6. The B cell in systemic lupus erythaematosus: a rational target for more effective therapy.

    PubMed

    Driver, C B; Ishimori, M; Weisman, M H

    2008-10-01

    Current treatment options for systemic lupus erythaematosus (SLE) are diverse and poorly defined, and aggressive therapy can be associated with serious toxicity and tolerability issues. There is, therefore, a need for new and improved treatments to be studied thoroughly in well-designed controlled trials. B Cell dysfunction has emerged as a key pathophysiological component of SLE and is a prime target for the development of new agents for a wide range of lupus severity, including advanced disease. Although many current drugs appear to modify B cell function, the advent of new, targeted therapies offers the hope of improved efficacy and a better long-term tolerability profile.

  7. Malignant hemangiopericytoma of pituitary fossa.

    PubMed

    Das, Prasenjit; Haresh, Kunhi P; Suri, Vaishali; Sharma, Mehar Chand; Sharma, Bhawani Shankar; Sarkar, Chitra

    2010-01-01

    Intracranial hemangiopericytomas are rare tumors with aggressive behavior. Other than the meninges, this lesion has rarely been reported in periventricular and sellar region. We report a case of malignant hemangiopericytoma in sellar region in a 47-year-old male who presented with history of sudden onset of bilateral visual disturbances. To best of our knowledge, this is the second case report of malignant hemangiopericytoma in this location. As this intracranial lesion shows aggressive behavior, in the form of recurrence or extracranial metastasis in comparison to its extracranial counterparts, diagnosis should be made cautiously. PMID:20090235

  8. The Histological and Biological Spectrum of Diffuse Large B-cell Lymphoma in the WHO Classification

    PubMed Central

    Menon, Madhu P.; Pittaluga, Stefania; Jaffe, Elaine S.

    2012-01-01

    Diffuse large B cell lymphomas (DLBCL) are aggressive B-cell lymphomas that are clinically, pathologically and genetically diverse, in part reflecting the functional diversity of the B-cell system. The focus in recent years has been towards incorporation of clinical features, morphology, immunohistochemistry and ever evolving genetic data into the classification scheme. The 2008 WHO classification reflects this complexity with the addition of several new entities and variants. The discovery of distinct subtypes by gene expression profiling (GEP) heralded a new era with a focus on pathways of transformation as well as a promise of more targeted therapies, directed at specific pathways. Some DLBCLs exhibit unique clinical characteristics with a predilection for specific anatomic sites; the anatomic site often reflects underlying biological distinctions. Recently, the spectrum of EBV-driven B-cell proliferations in patients without iatrogenic or congenital immunosuppression has been better characterized; most of these occur in patients of advanced age, and include EBV-positive large B-cell lymphoma of the elderly. HHV-8 is involved in the pathogenesis of primary effusion lymphoma, which can present as a “solid variant.” Two borderline categories were created; one deals with tumors at the interface between classical Hodgkin lymphoma (cHL) and DLBCL. The second confronts the interface between Burkitt Lymphoma (BL) and DLBCL, so called “B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma (DLBCL) and Burkitt lymphoma” in the 2008 classification. Most cases harbor both MYC and BCL2 translocations, and are highly aggressive. Another interesting entity is ALK+ DLBCL, which renders itself potentially targetable by ALK inhibitors. Ongoing investigations at the genomic level, with both exome and whole genome sequencing, are sure to reveal new pathways of transformation in the future. PMID:23006945

  9. Cell-specific uptake of mantle cell lymphoma-derived exosomes by malignant and non-malignant B-lymphocytes.

    PubMed

    Hazan-Halevy, Inbal; Rosenblum, Daniel; Weinstein, Shiri; Bairey, Osnat; Raanani, Pia; Peer, Dan

    2015-08-01

    Mantle cell lymphoma (MCL) is an aggressive and incurable mature B cell neoplasm. The current treatments are based on chemotherapeutics and new class of drugs (e.g. Ibrutinib(®)), which in most cases ends with tumor resistance and relapse. Therefore, further development of novel therapeutic modalities is needed. Exosomes are natural extracellular vesicles, which play an important role in intercellular communication. The specificity of exosome uptake by different target cells remains unknown. In this study, we observed that MCL exosomes are taken up rapidly and preferentially by MCL cells. Only a minor fraction of exosomes was internalized into T-cell leukemia and bone marrow stroma cell lines, when these cells were co-cultured with MCL cells. Moreover, MCL patients' exosomes were taken up by both healthy and patients' B-lymphocytes with no apparent internalization to T lymphocytes and NK cells. Exosome internalization was not inhibited by specific siRNA against caveolin1 and clathrin but was found to be mediated by a cholesterol-dependent pathway. These findings demonstrate natural specificity of exosomes to B-lymphocytes and ultimately might be used for therapeutic intervention in B cells malignancies.

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

    PubMed Central

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

    2012-01-01

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

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

    PubMed

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

    2012-11-19

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

  12. Enhanced Cultivation Of Stimulated Murine B Cells

    NASA Technical Reports Server (NTRS)

    Sammons, David W.

    1994-01-01

    Method of in vitro cultivation of large numbers of stimulated murine B lymphocytes. Cells electrofused with other cells to produce hybridomas and monoclonal antibodies. Offers several advantages: polyclonally stimulated B-cell blasts cultivated for as long as 14 days, hybridomas created throughout culture period, yield of hybridomas increases during cultivation, and possible to expand polyclonally in vitro number of B cells specific for antigenic determinants first recognized in vivo.

  13. Intravascular Large B-Cell Lymphoma: A Difficult Diagnostic Challenge.

    PubMed

    Khan, Maria S; McCubbin, Mark; Nand, Sucha

    2014-01-01

    Case Presentation. A 69-year-old Hispanic male, with a past history of diabetes and coronary disease, was admitted for fever, diarrhea, and confusion of 4 weeks duration. Physical examination showed a disoriented patient with multiple ecchymoses, possible ascites, and bilateral scrotal swelling. Hemoglobin was 6.7, prothrombin time (PT) 21.4 seconds with international normalized ratio 2.1, partial thromboplastin time (PTT) 55.6 seconds, fibrin split 10 µg/L, and lactate dehydrogenase (LDH) 1231 IU/L. Except for a positive DNA test for Epstein-Barr virus (EBV) infection, extensive diagnostic workup for infections, malignancy, or a neurological cause was negative. Mixing studies revealed a nonspecific inhibitor of PT and PTT but Factor VIII levels were normal. The patient was empirically treated with antibiotics but developed hypotension and died on day 27 of admission. At autopsy, patient was found to have intravascular diffuse large B-cell lymphoma involving skin, testes, lung, and muscles. The malignant cells were positive for CD20, CD791, Mum-1, and Pax-5 and negative for CD3, CD5, CD10, CD30, and Bcl-6. The malignant cells were 100% positive for Ki-67. Discussion. Intravascular large cell B-cell lymphoma (IVLBCL) is rare form of diffuse large B-cell lymphoma and tends to proliferate within small blood vessels, particularly capillaries and postcapillary venules. The cause of its affinity for vascular bed remains unknown. In many reports, IVLBCL was associated with HIV, HHV8, and EBV infections. The fact that our case showed evidence of EBV infection lends support to the association of this diagnosis to viral illness. The available literature on this subject is scant, and in many cases, the diagnosis was made only at autopsy. The typical presentation of this disorder is with B symptoms, progressive neurologic deficits, and skin findings. Bone marrow, spleen, and liver are involved in a minority of patients. Nearly all patients have elevated LDH, and about 65% are

  14. Understanding Aggression.

    ERIC Educational Resources Information Center

    Scott, J. P.

    Research in many fields of the social and biological sciences indicates that there are ecological, cultural, social, psychological, physiological, and genetic causes of aggression. The agonistic behavior system, which adapts to situations of social conflict, includes several patterns of conduct ranging from overt fighting to complete passivity. In…

  15. Fc gamma receptor IIb on target B cells promotes rituximab internalization and reduces clinical efficacy.

    PubMed

    Lim, Sean H; Vaughan, Andrew T; Ashton-Key, Margaret; Williams, Emily L; Dixon, Sandra V; Chan, H T Claude; Beers, Stephen A; French, Ruth R; Cox, Kerry L; Davies, Andrew J; Potter, Kathleen N; Mockridge, C Ian; Oscier, David G; Johnson, Peter W M; Cragg, Mark S; Glennie, Martin J

    2011-09-01

    The anti-CD20 mAb rituximab is central to the treatment of B-cell malignancies, but resistance remains a significant problem. We recently reported that resistance could be explained, in part, by internalization of rituximab (type I anti-CD20) from the surface of certain B-cell malignancies, thus limiting engagement of natural effectors and increasing mAb consumption. Internalization of rituximab was most evident in chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL), but the extent of internalization was heterogeneous within each disease. Here, we show that the inhibitory FcγRIIb on target B cells promotes this process and is largely responsible for the observed heterogeneity across a range of B-cell malignancies. Internalization correlated strongly with FcγRIIb expression on normal and malignant B cells, and resulted in reduced macrophage phagocytosis of mAb-coated targets. Furthermore, transfection of FcγRIIb into FcγRIIb negative Ramos cells increased internalization of rituximab in a dose-dependent manner. Target-cell FcγRIIb promoted rituximab internalization in a cis fashion and was independent of FcγRIIb on neighboring cells. It became phosphorylated and internalized along with CD20:anti-CD20 complexes before lysosomal degradation. In MCL patients, high FcγRIIb expression predicted less durable responses after rituximab-containing regimens. Therefore, target-cell FcγRIIb provides a potential biomarker of response to type I anti-CD20 mAb.

  16. Deletion of Rb1 induces both hyperproliferation and cell death in murine germinal center B cells.

    PubMed

    He, Zhiwen; O'Neal, Julie; Wilson, William C; Mahajan, Nitin; Luo, Jun; Wang, Yinan; Su, Mack Y; Lu, Lan; Skeath, James B; Bhattacharya, Deepta; Tomasson, Michael H

    2016-03-01

    The retinoblastoma gene (RB1) has been implicated as a tumor suppressor in multiple myeloma (MM), yet its role remains unclear because in the majority of cases with 13q14 deletions, un-mutated RB1 remains expressed from the retained allele. To explore the role of Rb1 in MM, we examined the functional consequences of single- and double-copy Rb1 loss in germinal center B cells, the cells of origin of MM. We generated mice without Rb1 function in germinal center B cells by crossing Rb1(Flox/Flox) with C-γ-1-Cre (Cγ1) mice expressing the Cre recombinase in class-switched B cells in a p107(-/-) background to prevent p107 from compensating for Rb1 loss (Cγ1-Rb1(F/F)-p107(-/-)). All mice developed normally, but B cells with two copies of Rb1 deleted (Cγ1-Rb1(F/F)-p107(-/-)) exhibited increased proliferation and cell death compared with Cγ1-Rb1(+/+)-p107(-/-) controls ex vivo. In vivo, Cγ1-Rb1(F/F)-p107(-/-) mice had a lower percentage of splenic B220+ cells and reduced numbers of bone marrow antigen-specific secreting cells compared with control mice. Our data indicate that Rb1 loss induces both cell proliferation and death in germinal center B cells. Because no B-cell malignancies developed after 1 year of observation, our data also suggest that Rb1 loss is not sufficient to transform post-germinal center B cells and that additional, specific mutations are likely required to cooperate with Rb1 loss to induce malignant transformation.

  17. Primary bladder lymphoma, diffuse large B-cell type: Case report and literature review of 26 cases.

    PubMed

    Simpson, W Greg; Lopez, Armando; Babbar, Paurush; Payne, Lynnetta Faith

    2015-01-01

    Primary lymphoma of the urinary bladder is exceedingly rare, representing 0.2% of all extranodal non-Hodgkin's lymphoma. Although Matsuno et al. and others state the most common type is mucosa-associated lymphoid tissue (MALT) lymphoma, 20% of all the primary lymphomas of the urinary bladder are considered to be high grade neoplasms; the majority being diffuse large B-cell lymphoma (DLBCL). This is a case report of a 48-year-old man that presented with hematuria, frequency, nocturia, and flank pain that was found to have high grade DLBCL. Twenty-six other cases of both low and high grade primary bladder lymphomas were selected in order to provide a thorough comparison of different treatment modalities. Of the cases reviewed, bladder lymphoma was more common in females (2:1). The average age at diagnosis was 63.9 years old (low grade: 68.7 years old, high grade: 58.8 years old). The most common low-grade neoplasm was MALT lymphoma (85.7%). For the low-grade malignancies, the most successful treatments were simple therapies (2 transurethral resection of a bladder tumour [TURBT], 1 antibiotics), solitary chemotherapy, and combination TURBT/chemo; all 3 of which achieved 100% clinical remission (CR) in the cases reviewed. The most common high grade neoplasm was DLBCL (76.9%). The most successful therapies used to treat high grade lesions were solitary chemotherapy (cyclophosphamide, duanorubacin, vincristine, prednisolone [CHOP] or ritoximab, CHOP [R-CHOP]) and combination therapies (2 radiation/CHOP, 2 surgery/CHOP). In the agreement with the current literature, this review has shown that simple therapies (TURBT) are equally as effective as aggressive treatments (chemotherapy, radiation) and should therefore be used as first line treatment in low grade tumors. For high grade malignancies, chemotherapy (R-CHOP or CHOP) alone or combination therapy (CHOP/surgery or CHOP/radiation) is recommended. PMID:25837971

  18. 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

  19. CCI-779 in Treating Patients With Recurrent or Refractory B-Cell Non-Hodgkin's Lymphoma or Chronic Lymphocytic Leukemia

    ClinicalTrials.gov

    2014-05-07

    B-cell Chronic Lymphocytic Leukemia; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Malignant Neoplasm; Nodal Marginal Zone B-cell Lymphoma; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Immunoblastic Large Cell Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Small Lymphocytic Lymphoma; Refractory Chronic Lymphocytic Leukemia; Splenic Marginal Zone Lymphoma; Waldenström Macroglobulinemia

  20. The pre-B-cell receptor checkpoint in acute lymphoblastic leukaemia.

    PubMed

    Eswaran, J; Sinclair, P; Heidenreich, O; Irving, J; Russell, L J; Hall, A; Calado, D P; Harrison, C J; Vormoor, J

    2015-08-01

    The B-cell receptor (BCR) and its immature form, the precursor-BCR (pre-BCR), have a central role in the control of B-cell development, which is dependent on a sequence of cell-fate decisions at specific antigen-independent checkpoints. Pre-BCR expression provides the first checkpoint, which controls differentiation of pre-B to immature B-cells in normal haemopoiesis. Pre-BCR signalling regulates and co-ordinates diverse processes within the pre-B cell, including clonal selection, proliferation and subsequent maturation. In B-cell precursor acute lymphoblastic leukaemia (BCP-ALL), B-cell development is arrested at this checkpoint. Moreover, malignant blasts avoid clonal extinction by hijacking pre-BCR signalling in favour of the development of BCP-ALL. Here, we discuss three mechanisms that occur in different subtypes of BCP-ALL: (i) blocking pre-BCR expression; (ii) activating pre-BCR-mediated pro-survival and pro-proliferative signalling, while inhibiting cell cycle arrest and maturation; and (iii) bypassing the pre-BCR checkpoint and activating pro-survival signalling through pre-BCR independent alternative mechanisms. A complete understanding of the BCP-ALL-specific signalling networks will highlight their application in BCP-ALL therapy.

  1. B-Cell Lymphoma of the Mandible: A Case Report

    PubMed Central

    Adouani, Ali; Bouguila, Jed; Jeblaoui, Yassine; Ben Aicha, Mehdi; Abdelali, Mouhamed Ali; Hellali, Mouna; Zitouni, Karima; Amani, Landolsi; Issam, Zairi

    2008-01-01

    Summary Introduction The mandible is an infrequent localisation of primary osseous non-Hodgkin’s lymphomas. Few cases of mandibular non-Hodgkin’s lymphomas (NHL) have been reported. Case report A rare condition of primary malignant non-Hodgkin’s lymphoma of the mandible in 53-year-old man, was reported at the Department of Maxillofacial and Plastic Surgery in Charles Nicolle Hospital (Tunis, Tunisia). Histologic and Immunohistochemical (IHC) examination Confirmed a B-Cell lymphoma. Discussion The purpose of this report is to describe this rare case of NHL of the mandible, explore the diagnosis and workup, and discuss treatment strategies. In this localisation, neither the clinical features nor the radiologic appearances are often pathognomonic. Conclusion Particular care must be taken to consider lymphoma in the differential diagnosis because this uncommon lesion can pose significant diagnostic problems and is frequently misdiagnosed. PMID:21892315

  2. Cyclin Dl expression in B-cell non Hodgkin lymphoma.

    PubMed

    Aref, Salah; Mossad, Y; El-Khodary, T; Awad, M; El-Shahat, E

    2006-10-01

    Disorders of the cell cycle regulatory machinery play a key role in the pathogenesis of cancer. Over-expression of cyclin D1 protein has been reported in several solid tumors and certain lymphoid malignancies, but little is known about the effect of its expression on clinical behavior and outcome in B-cell Non-Hodgkin lymphoma (NHL). In this study, we investigated the expression of cyclin Dl in group of patients with NHL and correlated the results with the clinical and laboratory data. The degree of expression of cyclin Dl protein was evaluated by flow cytometry in a group of NHL patients (n = 46) and in normal control group (n = 10). Cyclin Dl over expression was detected in 10 out of 46 (21.7%) patients; they were 5/5-mantle cell lymphoma (MCL) (100%) and 5/28 large B-cell lymphoma (17.8%). All other NHL subtypes showed normal cyclin D1 expression. The clinical signs (hepatomegaly, splenomegaly and B-symptoms, clinical staging) and laboratory data (hemoglobin, white cell count (WBCs), platelet count, and bone marrow infiltration) were not significantly different between NHL subgroup with cyclin Dl over expression and that with normal cyclin Dl expression. Serum lactic dehydrogenase (LDH) levels and lymphadenopathy were significantly higher in NHL group with cyclin D1 over expression as compared to those without. Also, cyclin D1 over expression is associated with poor outcome of NHL patients. Cyclin Dl over expression was evident among all cases of MCL and few cases of large B-cell lymphoma. Cyclin Dl over expression might be used as adjuvant tool for diagnosis of MCL; has role in NHL biology and is bad prognostic index in NHL. PMID:17607588

  3. Cerebral toxoplasmosis in a diffuse large B cell lymphoma patient

    PubMed Central

    Savsek, Lina; Opaskar, Tanja Ros

    2016-01-01

    Background Toxoplasmosis is an opportunistic protozoal infection that has, until now, probably been an underestimated cause of encephalitis in patients with hematological malignancies, independent of stem cell or bone marrow transplant. T and B cell depleting regimens are probably an important risk factor for reactivation of a latent toxoplasma infection in these patients. Case report We describe a 62-year-old HIV-negative right-handed Caucasian female with systemic diffuse large B cell lymphoma who presented with sudden onset of high fever, headache, altered mental status, ataxia and findings of pancytopenia, a few days after receiving her final, 8th cycle of rituximab, cyclophosphamide, vincristine, doxorubicin, prednisolone (R-CHOP) chemotherapy regimen. A progression of lymphoma to the central nervous system was suspected. MRI of the head revealed multiple on T2 and fluid attenuated inversion recovery (FLAIR) hyperintense parenchymal lesions with mild surrounding edema, located in both cerebral and cerebellar hemispheres that demonstrated moderate gadolinium enhancement. The polymerase chain reaction on cerebrospinal fluid (CSF PCR) was positive for Toxoplasma gondii. The patient was diagnosed with toxoplasmic encephalitis and successfully treated with sulfadiazine, pyrimethamine and folic acid. Due to the need for maintenance therapy with rituximab for lymphoma remission, the patient now continues with secondary prophylaxis of toxoplasmosis. Conclusions With this case report, we wish to emphasize the need to consider cerebral toxoplasmosis in patients with hematological malignancies on immunosuppressive therapy when presenting with new neurologic deficits. In such patients, there are numerous differential diagnoses for cerebral toxoplasmosis, and the CNS lymphoma is the most difficult among all to distinguish it from. If left untreated, cerebral toxoplasmosis has a high mortality rate; therefore early recognition and treatment are of essential importance. PMID

  4. A Case of p63 Positive Diffuse Large B Cell Lymphoma of the Bladder

    PubMed Central

    Jones, Carol

    2016-01-01

    Diffuse large B cell lymphoma (DLBCL), currently the most common type of non-Hodgkin lymphoma (NHL), is an aggressive B cell neoplasm that typically presents in older adults as a rapidly enlarging mass. The enlarging mass typically represents a lymph node, although extranodal disease can occur in a significant percentage (40%) of cases. The most common extranodal sites of involvement include the gastrointestinal tract and skin; primary bladder lymphoma represents only 0.2% of extranodal non-Hodgkin lymphomas. We report a case of diffuse large B cell lymphoma occurring in the bladder of an 83-year-old gentleman with an initial presentation of hematuria. This neoplasm displayed large, atypical cells with vesicular chromatin and prominent nucleoli that involved the bladder mucosa with invasion into muscularis propria, prostate, and urethra. Positive staining for p63 initially raised suspicion for poorly differentiated urothelial carcinoma; however, lack of staining for pancytokeratin and positive staining for LCA, CD20, CD79a, and PAX-5 confirmed the diagnosis of diffuse large B cell lymphoma. Though it does not occur in all cases, p63 can be positive in a significant percentage of cases of DLBCL; therefore, a diagnosis of lymphoma remains an important entity on the differential diagnosis of aggressive and particularly poorly differentiated neoplasms. PMID:27648316

  5. A Case of p63 Positive Diffuse Large B Cell Lymphoma of the Bladder

    PubMed Central

    Jones, Carol

    2016-01-01

    Diffuse large B cell lymphoma (DLBCL), currently the most common type of non-Hodgkin lymphoma (NHL), is an aggressive B cell neoplasm that typically presents in older adults as a rapidly enlarging mass. The enlarging mass typically represents a lymph node, although extranodal disease can occur in a significant percentage (40%) of cases. The most common extranodal sites of involvement include the gastrointestinal tract and skin; primary bladder lymphoma represents only 0.2% of extranodal non-Hodgkin lymphomas. We report a case of diffuse large B cell lymphoma occurring in the bladder of an 83-year-old gentleman with an initial presentation of hematuria. This neoplasm displayed large, atypical cells with vesicular chromatin and prominent nucleoli that involved the bladder mucosa with invasion into muscularis propria, prostate, and urethra. Positive staining for p63 initially raised suspicion for poorly differentiated urothelial carcinoma; however, lack of staining for pancytokeratin and positive staining for LCA, CD20, CD79a, and PAX-5 confirmed the diagnosis of diffuse large B cell lymphoma. Though it does not occur in all cases, p63 can be positive in a significant percentage of cases of DLBCL; therefore, a diagnosis of lymphoma remains an important entity on the differential diagnosis of aggressive and particularly poorly differentiated neoplasms.

  6. Targeting Stereotyped B Cell Receptors from Chronic Lymphocytic Leukemia Patients with Synthetic Antigen Surrogates.

    PubMed

    Sarkar, Mohosin; Liu, Yun; Qi, Junpeng; Peng, Haiyong; Morimoto, Jumpei; Rader, Christoph; Chiorazzi, Nicholas; Kodadek, Thomas

    2016-04-01

    Chronic lymphocytic leukemia (CLL) is a disease in which a single B-cell clone proliferates relentlessly in peripheral lymphoid organs, bone marrow, and blood. DNA sequencing experiments have shown that about 30% of CLL patients have stereotyped antigen-specific B-cell receptors (BCRs) with a high level of sequence homology in the variable domains of the heavy and light chains. These include many of the most aggressive cases that haveIGHV-unmutated BCRs whose sequences have not diverged significantly from the germ line. This suggests a personalized therapy strategy in which a toxin or immune effector function is delivered selectively to the pathogenic B-cells but not to healthy B-cells. To execute this strategy, serum-stable, drug-like compounds able to target the antigen-binding sites of most or all patients in a stereotyped subset are required. We demonstrate here the feasibility of this approach with the discovery of selective, high affinity ligands for CLL BCRs of the aggressive, stereotyped subset 7P that cross-react with the BCRs of several CLL patients in subset 7p, but not with BCRs from patients outside this subset.

  7. Recurrent mutations of the STAT6 DNA binding domain in primary mediastinal B-cell lymphoma.

    PubMed

    Ritz, Olga; Guiter, Chrystelle; Castellano, Flavia; Dorsch, Karola; Melzner, Julia; Jais, Jean-Philippe; Dubois, Gwendoline; Gaulard, Philippe; Möller, Peter; Leroy, Karen

    2009-08-01

    Primary mediastinal B-cell lymphoma (PMBL) is a separate entity of aggressive B-cell lymphoma, characterized by a constitutive activation of janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling pathway, also observed in Hodgkin lymphoma. Although many cancers exhibit constitutive JAK-STAT pathway activation, mutations of STAT genes have not been reported in neoplasms. Here, we show that MedB-1 PMBL-derived and L1236 Hodgkin-derived cell lines and 20 of 55 (36%) PMBL cases harbor heterozygous missense mutations in STAT6 DNA binding domain, whereas no mutation was found in 25 diffuse large B-cell lymphoma samples. In 3 cases, somatic origin was indicated by the absence of the mutations in the nontumoral tissue. The pattern of STAT6 mutations was different from the classical features of somatic hypermutations. The mutant STAT6 proteins showed a decreased DNA binding ability in transfected HEK cells, but no decrease in expression of STAT6 canonical target genes was observed in PMBL cases with a mutated STAT6 gene. Although the oncogenic properties of STAT6 mutant proteins remain to be determined, their recurrent selection in PMBL strongly argues for their involvement in the pathogenesis of this aggressive B-cell lymphoma. PMID:19423726

  8. A Case of p63 Positive Diffuse Large B Cell Lymphoma of the Bladder.

    PubMed

    Deel, Chelsey D; Jones, Carol; Scordino, Teresa

    2016-01-01

    Diffuse large B cell lymphoma (DLBCL), currently the most common type of non-Hodgkin lymphoma (NHL), is an aggressive B cell neoplasm that typically presents in older adults as a rapidly enlarging mass. The enlarging mass typically represents a lymph node, although extranodal disease can occur in a significant percentage (40%) of cases. The most common extranodal sites of involvement include the gastrointestinal tract and skin; primary bladder lymphoma represents only 0.2% of extranodal non-Hodgkin lymphomas. We report a case of diffuse large B cell lymphoma occurring in the bladder of an 83-year-old gentleman with an initial presentation of hematuria. This neoplasm displayed large, atypical cells with vesicular chromatin and prominent nucleoli that involved the bladder mucosa with invasion into muscularis propria, prostate, and urethra. Positive staining for p63 initially raised suspicion for poorly differentiated urothelial carcinoma; however, lack of staining for pancytokeratin and positive staining for LCA, CD20, CD79a, and PAX-5 confirmed the diagnosis of diffuse large B cell lymphoma. Though it does not occur in all cases, p63 can be positive in a significant percentage of cases of DLBCL; therefore, a diagnosis of lymphoma remains an important entity on the differential diagnosis of aggressive and particularly poorly differentiated neoplasms. PMID:27648316

  9. Targeting Stereotyped B Cell Receptors from Chronic Lymphocytic Leukemia Patients with Synthetic Antigen Surrogates.

    PubMed

    Sarkar, Mohosin; Liu, Yun; Qi, Junpeng; Peng, Haiyong; Morimoto, Jumpei; Rader, Christoph; Chiorazzi, Nicholas; Kodadek, Thomas

    2016-04-01

    Chronic lymphocytic leukemia (CLL) is a disease in which a single B-cell clone proliferates relentlessly in peripheral lymphoid organs, bone marrow, and blood. DNA sequencing experiments have shown that about 30% of CLL patients have stereotyped antigen-specific B-cell receptors (BCRs) with a high level of sequence homology in the variable domains of the heavy and light chains. These include many of the most aggressive cases that haveIGHV-unmutated BCRs whose sequences have not diverged significantly from the germ line. This suggests a personalized therapy strategy in which a toxin or immune effector function is delivered selectively to the pathogenic B-cells but not to healthy B-cells. To execute this strategy, serum-stable, drug-like compounds able to target the antigen-binding sites of most or all patients in a stereotyped subset are required. We demonstrate here the feasibility of this approach with the discovery of selective, high affinity ligands for CLL BCRs of the aggressive, stereotyped subset 7P that cross-react with the BCRs of several CLL patients in subset 7p, but not with BCRs from patients outside this subset. PMID:26851280

  10. 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.

  11. Immunotherapy for malignant glioma.

    PubMed

    Suryadevara, Carter M; Verla, Terence; Sanchez-Perez, Luis; Reap, Elizabeth A; Choi, Bryan D; Fecci, Peter E; Sampson, John H

    2015-01-01

    Malignant gliomas (MG) are the most common type of primary malignant brain tumor. Most patients diagnosed with glioblastoma (GBM), the most common and malignant glial tumor, die within 12-15 months. Moreover, conventional treatment, which includes surgery followed by radiation and chemotherapy, can be highly toxic by causing nonspecific damage to healthy brain and other tissues. The shortcomings of standard-of-care have thus created a stimulus for the development of novel therapies that can target central nervous system (CNS)-based tumors specifically and efficiently, while minimizing off-target collateral damage to normal brain. Immunotherapy represents an investigational avenue with the promise of meeting this need, already having demonstrated its potential against B-cell malignancy and solid tumors in clinical trials. T-cell engineering with tumor-specific chimeric antigen receptors (CARs) is one proven approach that aims to redirect autologous patient T-cells to sites of tumor. This platform has evolved dramatically over the past two decades to include an improved construct design, and these modern CARs have only recently been translated into the clinic for brain tumors. We review here emerging immunotherapeutic platforms for the treatment of MG, focusing on the development and application of a CAR-based strategy against GBM.

  12. The B-cell tumor–associated antigen ROR1 can be targeted with T cells modified to express a ROR1-specific chimeric antigen receptor

    PubMed Central

    Schmitt, Thomas M.; Baskar, Sivasubramanian; Lupo-Stanghellini, Maria Teresa; Nishida, Tetsuya; Yamamoto, Tori N.; Bleakley, Marie; Turtle, Cameron J.; Chang, Wen-Chung; Greisman, Harvey A.; Wood, Brent; Maloney, David G.; Jensen, Michael C.; Rader, Christoph; Riddell, Stanley R.

    2010-01-01

    Monoclonal antibodies and T cells modified to express chimeric antigen receptors specific for B-cell lineage surface molecules such as CD20 exert antitumor activity in B-cell malignancies, but deplete normal B cells. The receptor tyrosine kinase-like orphan receptor 1 (ROR1) was identified as a highly expressed gene in B-cell chronic lymphocytic leukemia (B-CLL), but not normal B cells, suggesting it may serve as a tumor-specific target for therapy. We analyzed ROR1-expression in normal nonhematopoietic and hematopoietic cells including B-cell precursors, and in hematopoietic malignancies. ROR1 has characteristics of an oncofetal gene and is expressed in undifferentiated embryonic stem cells, B-CLL and mantle cell lymphoma, but not in major adult tissues apart from low levels in adipose tissue and at an early stage of B-cell development. We constructed a ROR1-specific chimeric antigen receptor that when expressed in T cells from healthy donors or CLL patients conferred specific recognition of primary B-CLL and mantle cell lymphoma, including rare drug effluxing chemotherapy resistant tumor cells that have been implicated in maintaining the malignancy, but not mature normal B cells. T-cell therapies targeting ROR1 may be effective in B-CLL and other ROR1-positive tumors. However, the expression of ROR1 on some normal tissues suggests the potential for toxi-city to subsets of normal cells. PMID:20702778

  13. Bruton tyrosine kinase inhibitors: a promising novel targeted treatment for B cell lymphomas

    PubMed Central

    Aalipour, Amin; Advani, Ranjana H.

    2015-01-01

    Summary Constitutive or aberrant signalling of the B cell receptor signalling cascade has been implicated in the propagation and maintenance of a variety of B cell malignancies. Small molecule inhibitors of Bruton tyrosine kinase (BTK), a protein early in this cascade and specifically expressed in B cells, have emerged as a new class of targeted agents. There are several BTK inhibitors, including ONO-WG-307, LFM-A13, dasatinib, CC-292, and PCI-32765 (ibrutinib), in preclinical and/or clinical development of which ibrutinib is currently in phase III trials. Recent clinical data suggest significant activity of ibrutinib as a first in class oral inhibitor of BTK. This review provides an overview of ongoing clinical studies of BTK inhibitors. PMID:24111579

  14. AID-induced remodeling of immunoglobulin genes and B cell fate.

    PubMed

    Laffleur, Brice; Denis-Lagache, Nicolas; Péron, Sophie; Sirac, Christophe; Moreau, Jeanne; Cogné, Michel

    2014-03-15

    Survival and phenotype of normal and malignant B lymphocytes are critically dependent on constitutive signals by the B cell receptor (BCR) for antigen. In addition, either antigen ligation of the BCR or various mitogenic stimuli result in B cell activation and induction of activation-induced deaminase (AID). AID activity can in turn mediate somatic hypermutation (SHM) of immunoglobulin (Ig) V regions and also deeply remodel the Ig heavy chain locus through class switch recombination (CSR) or locus suicide recombination (LSR). In addition to changes linked to affinity for antigen, modifying the class/isotype (i.e. the structure and function) of the BCR or suddenly deleting BCR expression also modulates the fate of antigen-experienced B cells.

  15. Genetic drivers of NF-κB deregulation in diffuse large B-cell lymphoma.

    PubMed

    Pasqualucci, Laura; Zhang, Baochun

    2016-08-01

    Diffuse large B cell lymphoma (DLBCL) is the most common form of B cell non-Hodgkin lymphoma worldwide and comprises a heterogeneous group of malignancies that originate from the malignant transformation of germinal center (GC) B cells. Over the past decade, significant improvement has been achieved in our understanding of the molecular pathogenesis underlying this disease, thanks in part to the implementation of powerful genomic technologies allowing genome-wide structural and functional analyses. These studies revealed the presence of multiple oncogenic alterations dysregulating signal transduction pathways that are normally required for the normal biology of the cells from which these tumors are derived. Among the pathways identified as recurrent targets of genetic lesions in DLBCL, NF-κB has emerged as a central player in the development and maintenance of this disease, particularly in the less curable, activated B cell (ABC)- like subtype. These lesions reveal vulnerabilities of the lymphoma cells that can be exploited for the design of more rationale therapeutic approaches. The purpose of this review is to summarize recent progresses in understanding the role of NF-κB deregulation in the pathogenesis of DLBCL, with emphasis on the genetic basis underlying its aberrant activation, in relationship to the normal biology of B lymphocytes, and the modelling of these lesions in the mouse. PMID:27546290

  16. Interaction of Staphylococci with Human B cells

    PubMed Central

    Nygaard, Tyler K.; Kobayashi, Scott D.; Freedman, Brett; Porter, Adeline R.; Voyich, Jovanka M.; Otto, Michael; Schneewind, Olaf; DeLeo, Frank R.

    2016-01-01

    Staphylococcus aureus is a leading cause of human infections worldwide. The pathogen produces numerous molecules that can interfere with recognition and binding by host innate immune cells, an initial step required for the ingestion and subsequent destruction of microbes by phagocytes. To better understand the interaction of this pathogen with human immune cells, we compared the association of S. aureus and S. epidermidis with leukocytes in human blood. We found that a significantly greater proportion of B cells associated with S. epidermidis relative to S. aureus. Complement components and complement receptors were important for the binding of B cells with S. epidermidis. Experiments using staphylococci inactivated by ultraviolet radiation and S. aureus isogenic deletion mutants indicated that S. aureus secretes molecules regulated by the SaeR/S two-component system that interfere with the ability of human B cells to bind this bacterium. We hypothesize that the relative inability of B cells to bind S. aureus contributes to the microbe’s success as a human pathogen. PMID:27711145

  17. B cell abnormalities in systemic lupus erythematosus

    PubMed Central

    2003-01-01

    Systemic lupus erythematosus (SLE) is a chronic, multisystem autoimmune disease characterized by the differentiation of short- and long-lived immunoglobulin secreting plasma cells that secrete pathogenic autoantibodies. Ectopic germinal centers and plasma cells secreting autoantibodies have been observed in lupus nephritis kidneys. Candidate genetic susceptibility loci for SLE include genes that affect differentiation and survival of plasma cells, such as those that influence activation, proliferation, cytokine and chemokine secretion/responsiveness, and apoptosis of the T and B cells that are involved in humoral immunity generated in germinal centers, as well as genes that are involved in presentation and clearance of apoptotic material and autoantigens by antigen presenting cells and other phagocytes. Emerging data have demonstrated that B lymphocytes are active participants in humoral immune responses that lead to T-dependent and T-independent differentiation of immunoglobulin-secreting plasma cells by homotypic CD154–CD40 interactions as well as continued stimulation by B cell activating factor through B cell maturation antigen, B cell activating factor receptor and transmembrane activater. PMID:15180894

  18. B cell abnormalities in systemic lupus erythematosus.

    PubMed

    Grammer, Amrie C; Lipsky, Peter E

    2003-01-01

    Systemic lupus erythematosus (SLE) is a chronic, multisystem autoimmune disease characterized by the differentiation of short- and long-lived immunoglobulin secreting plasma cells that secrete pathogenic autoantibodies. Ectopic germinal centers and plasma cells secreting autoantibodies have been observed in lupus nephritis kidneys. Candidate genetic susceptibility loci for SLE include genes that affect differentiation and survival of plasma cells, such as those that influence activation, proliferation, cytokine and chemokine secretion/responsiveness, and apoptosis of the T and B cells that are involved in humoral immunity generated in germinal centers, as well as genes that are involved in presentation and clearance of apoptotic material and autoantigens by antigen presenting cells and other phagocytes. Emerging data have demonstrated that B lymphocytes are active participants in humoral immune responses that lead to T-dependent and T-independent differentiation of immunoglobulin-secreting plasma cells by homotypic CD154-CD40 interactions as well as continued stimulation by B cell activating factor through B cell maturation antigen, B cell activating factor receptor and transmembrane activater.

  19. DNA methylation dynamics during B cell maturation underlie a continuum of disease phenotypes in chronic lymphocytic leukemia.

    PubMed

    Oakes, Christopher C; Seifert, Marc; Assenov, Yassen; Gu, Lei; Przekopowitz, Martina; Ruppert, Amy S; Wang, Qi; Imbusch, Charles D; Serva, Andrius; Koser, Sandra D; Brocks, David; Lipka, Daniel B; Bogatyrova, Olga; Weichenhan, Dieter; Brors, Benedikt; Rassenti, Laura; Kipps, Thomas J; Mertens, Daniel; Zapatka, Marc; Lichter, Peter; Döhner, Hartmut; Küppers, Ralf; Zenz, Thorsten; Stilgenbauer, Stephan; Byrd, John C; Plass, Christoph

    2016-03-01

    Charting differences between tumors and normal tissue is a mainstay of cancer research. However, clonal tumor expansion from complex normal tissue architectures potentially obscures cancer-specific events, including divergent epigenetic patterns. Using whole-genome bisulfite sequencing of normal B cell subsets, we observed broad epigenetic programming of selective transcription factor binding sites coincident with the degree of B cell maturation. By comparing normal B cells to malignant B cells from 268 patients with chronic lymphocytic leukemia (CLL), we showed that tumors derive largely from a continuum of maturation states reflected in normal developmental stages. Epigenetic maturation in CLL was associated with an indolent gene expression pattern and increasingly favorable clinical outcomes. We further uncovered that most previously reported tumor-specific methylation events are normally present in non-malignant B cells. Instead, we identified a potential pathogenic role for transcription factor dysregulation in CLL, where excess programming by EGR and NFAT with reduced EBF and AP-1 programming imbalances the normal B cell epigenetic program. PMID:26780610

  20. DNA methylation dynamics during B cell maturation underlie a continuum of disease phenotypes in chronic lymphocytic leukemia

    PubMed Central

    Oakes, Christopher C; Seifert, Marc; Assenov, Yassen; Gu, Lei; Przekopowitz, Martina; Ruppert, Amy S; Wang, Qi; Imbusch, Charles D; Serva, Andrius; Koser, Sandra D; Brocks, David; Lipka, Daniel B; Bogatyrova, Olga; Weichenhan, Dieter; Brors, Benedikt; Rassenti, Laura; Kipps, Thomas J; Mertens, Daniel; Zapatka, Marc; Lichter, Peter; Döhner, Hartmut; Küppers, Ralf; Zenz, Thorsten; Stilgenbauer, Stephan; Byrd, John C; Plass, Christoph

    2016-01-01

    Charting differences between tumors and normal tissue is a mainstay of cancer research. However, clonal tumor expansion from complex normal tissue architectures potentially obscures cancer-specific events, including divergent epigenetic patterns. Using whole-genome bisulfite sequencing of normal B cell subsets, we observed broad epigenetic programming of selective transcription factor binding sites coincident with the degree of B cell maturation. By comparing normal B cells to malignant B cells from 268 patients with chronic lymphocytic leukemia (CLL), we showed that tumors derive largely from a continuum of maturation states reflected in normal developmental stages. Epigenetic maturation in CLL was associated with an indolent gene expression pattern and increasingly favorable clinical outcomes. We further uncovered that most previously reported tumor-specific methylation events are normally present in non-malignant B cells. Instead, we identified a potential pathogenic role for transcription factor dysregulation in CLL, where excess programming by EGR and NFAT with reduced EBF and AP-1 programming imbalances the normal B cell epigenetic program. PMID:26780610

  1. Intraoral malignant melanoma

    PubMed Central

    Babburi, Suresh; Subramanyam, R. V.; Aparna, V.; Sowjanya, P.

    2013-01-01

    Primary oral mucosal melanoma is a rare aggressive neoplasm and accounts for only 0.2-8% of all reported melanomas. It is a malignant neoplasm of melanocytes that may arise from a benign melanocytic lesion or de novo from melanocytes within normal skin or mucosa. It is considered to be the most deadly and biologically unpredictable of all human neoplasms, having the worst prognosis. In this article, we report a case of oral melanoma in a 52-year-old female patient with a chief complaint of black discolouration of the maxillary gingiva and palate. PMID:24249959

  2. A human follicular lymphoma B cell line hypermutates its functional immunoglobulin genes in vitro.

    PubMed

    Wu, H; Pelkonen, E; Knuutila, S; Kaartinen, M

    1995-12-01

    The functional immunoglobulin (Ig) genes of B lymphocytes undergo somatic mutations during immune responses. These mutations modify the antigen binding site of the immunoglobulins, thereby enhancing the average affinity of the antibodies produced. The molecular mechanism underlying these B cell hypermutations remains unresolved, partly because it is difficult to grow normal B cells in long-term cell cultures and because there is no suitable transformed or malignant B cell line which generates mutations in its immunoglobulin genes in vitro. Here, we show that the recently established follicular lymphoma line HF-1.3.4 generates somatic hypermutations in vitro at a high frequency of 0.7 x 10(-6) mutations per base pair per generation in standard cell cultures (RPMI 1640 + 5% fetal calf serum). This shows for the first time that B cell hypermutation can occur without T cells or T cell factors. The mutation frequency increased approximately tenfold to 1 x 10(-5) mutations/base pair/generation with B cell-specific growth factors (interleukins-2 and -4 and three antibodies stimulatory to HF-1.3.4 cells). This HF-1.3.4 lymphoma line may help to elucidate the molecular mechanism of Ig gene hypermutation.

  3. Hyaluronan in human malignancies

    SciTech Connect

    Sironen, R.K.; Tammi, M.; Tammi, R.; Auvinen, P.K.; Anttila, M.; Kosma, V-M.

    2011-02-15

    Hyaluronan, a major macropolysaccharide in the extracellular matrix of connective tissues, is intimately involved in the biology of cancer. Hyaluronan accumulates into the stroma of various human tumors and modulates intracellular signaling pathways, cell proliferation, motility and invasive properties of malignant cells. Experimental and clinicopathological evidence highlights the importance of hyaluronan in tumor growth and metastasis. A high stromal hyaluronan content is associated with poorly differentiated tumors and aggressive clinical behavior in human adenocarcinomas. Instead, the squamous cell carcinomas and malignant melanomas tend to have a reduced hyaluronan content. In addition to the stroma-cancer cell interaction, hyaluronan can influence stromal cell recruitment, tumor angiogenesis and epithelial-mesenchymal transition. Hyaluronan receptors, hyaluronan synthases and hyaluronan degrading enzymes, hyaluronidases, are involved in the modulation of cancer progression, depending on the tumor type. Furthermore, intracellular signaling and angiogenesis are affected by the degradation products of hyaluronan. Hyaluronan has also therapeutic implications since it is involved in multidrug resistance.

  4. Nicotinamide Phosphoribosyltransferase in Malignancy

    PubMed Central

    Shackelford, Rodney E.; Mayhall, Kim; Maxwell, Nicole M.; Kandil, Emad

    2013-01-01

    Nicotinamide phosphoribosyltransferase (Nampt) catalyzes the rate-limiting step of nicotinamide adenine dinucleotide (NAD) synthesis. Both intracellular and extracellular Nampt (iNampt and eNampt) levels are increased in several human malignancies and some studies demonstrate increased iNampt in more aggressive/invasive tumors and in tumor metastases. Several different molecular targets have been identified that promote carcinogenesis following iNampt overexpression, including SirT1, CtBP, and PARP-1. Additionally, eNampt is elevated in several human cancers and is often associated with a higher tumor stage and worse prognoses. Here we review the roles of Nampt in malignancy, some of the known mechanisms by which it promotes carcinogenesis, and discuss the possibility of employing Nampt inhibitors in cancer treatment. PMID:24386506

  5. 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 β 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

  6. Multifunctional Role of Bcl-2 in Malignant Transformation and Tumorigenesis of Cr(VI)-Transformed Lung Cells

    PubMed Central

    Azad, Neelam; Wang, Liying; Jiang, Bing-Hua; Davis, Mary E.; Barnett, John B.; Guo, Lan; Rojanasakul, Yon

    2012-01-01

    B-cell lymphoma-2 (Bcl-2) is an antiapoptotic protein known to be important in the regulation of apoptosis in various cell types. However, its role in malignant transformation and tumorigenesis of human lung cells is not well understood. We previously reported that chronic exposure of human lung epithelial cells to the carcinogenic hexavalent chromium Cr(VI) caused malignant transformation and Bcl-2 upregulation; however, the role of Bcl-2 in the transformation is unclear. Using a gene silencing approach, we showed that Bcl-2 plays an important role in the malignant properties of Cr(VI)-transformed cells. Downregulation of Bcl-2 inhibited the invasive and proliferative properties of the cells as well as their colony forming and angiogenic activities, which are upregulated in the transformed cells as compared to control cells. Furthermore, animal studies showed the inhibitory effect of Bcl-2 knockdown on the tumorigenesis of Cr(VI)-transformed cells. The role of Bcl-2 in malignant transformation and tumorigenesis was confirmed by gene silencing experiments using human lung carcinoma NCI-H460 cells. These cells exhibited aggressive malignant phenotypes similar to those of Cr(VI)-transformed cells. Knockdown of Bcl-2 in the H460 cells inhibited malignant and tumorigenic properties of the cells, indicating the general role of Bcl-2 in human lung tumorigenesis. Ingenuity Pathways Analysis (IPA) revealed potential effectors of Bcl-2 in tumorigenesis regulation. Additionally, using IPA together with ectopic expression of p53, we show p53 as an upstream regulator of Bcl-2 in Cr(VI)-transformed cells. Together, our results indicate the novel and multifunctional role of Bcl-2 in malignant transformation and tumorigenesis of human lung epithelial cells chronically exposed to Cr(VI). PMID:22666341

  7. Pathobiology of primary mediastinal B-cell lymphoma.

    PubMed

    Pileri, Stefano A; Zinzani, Pier L; Gaidano, Gianluca; Falini, Brunangelo; Gaulard, Philippe; Zucca, Emanuele; Sabattini, Elena; Ascani, Stefano; Rossi, Maura; Cavalli, Franco

    2003-01-01

    consisted of large cells with varying degrees of nuclear polymorphism and clear to basophilic cytoplasm. Molecular analysis was performed on 40 cases and showed novel findings. More than half of the cases displayed bcl-6 gene mutations, which usually occurred together with functioning somatic IgV(H) gene mutations, and BCL-6 and/or MUM1/IRF4 expression. The present study supports the concept that PBML is derived from activated GC or post-germinal center cells. However, it differs from other aggressive B-cell lymphomas in that it shows defective Ig production despite the expression of Oct-2, BOB.1, and PU.1 transcription factors, and a lack of IgV(H) gene crippling mutations. PMID:15202521

  8. Advances in Human B Cell Phenotypic Profiling

    PubMed Central

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

    2012-01-01

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

  9. Malignant external otitis: CT evaluation

    SciTech Connect

    Curtin, H.D.; Wolfe, P.; May, M.

    1982-11-01

    Malignant external otitis is an aggressive infection caused by Pseudomonas aeruginosa that most often occurs in elderly diabetics. Malignant external otitis often spreads inferiorly from the external canal to involve the subtemporal area and progresses medially towards the petrous apex leading to multiple cranial nerve palsies. The computed tomographic (CT) findings in malignant external otitis include obliteration of the normal fat planes in the subtemporal area as well as patchy destruction of the bony cortex of the mastoid. The point of exit of the various cranial nerves can be identified on CT scans, and the extent of the inflammatory mass correlates well with the clinical findings. Four cases of malignant external otitis are presented. In each case CT provided a good demonstration of involvement of the soft tissues at the base of the skull.

  10. Detection of immunoglobulin IGH gene rearrangements on formalin-fixed, paraffin embedded tissue in lymphoid malignancies.

    PubMed

    Moharrami, G; Ghorbian, S; Seifi, M; Estiar, M A; Fakhrjoo, A; Sakhinia, M; Sakhinia, E

    2014-01-01

    Human lymphomas are aggressive malignant diseases, which can be categorized based on their B and T cell lineage. B-cell lymphomas form around 90% of the total lymphoma cases, the remnants of malignancies arise from the T cell branch. Lymphomas are mostly characterized as clonal proliferations of specific tumor cells. The detection of malignant lymphomas are extensively investigated by their morphological features, immunohistochemistry and flowcytometric immunophenotyping, but in some of cases remained unknown. The BIOMED-2 protocols were used to determine the clonality of IGH gene rearrangements in patients with lymphoma. PCR amplification was performed on FFPE of 50 patients with B-cell lymphoma, which consisted of 11 cases with HLs, 25 cases of B-NHLs and 14 cases of B-LPD (lymphoproliferative disorders) that diagnosed as unclassifiable lymphoma. The rate of positive clonality was detected in 96% (24/25) of B-NHLs, whereas in 4% (1/25) of cases clonality was showed in a polyclonal pattern. In B-HLs, 82% (9/11) of cases showed clonality and 18% (2/11) of the cases showed polyclonality. The rate of positive clonality observed in 64.3% (9/14) of cases with B-LPD and 35.7% (5/14) of cases clonality was not detected in any of immunoglobulin gene family (FR1, FR2, FR3). In groups with DLBCL, clonality was detected in 95% (19/20) of the cases. In patients diagnosed with FL and MALTs 100% cases showed clonality for complete IGH. Our study revealed that EuroClonality BIOMED-2 protocols could be considered as a valuable and reliable method for clonality detection, especially in IGH analysis.

  11. 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.

  12. Epigenetics and B-cell Lymphoma

    PubMed Central

    Shaknovich, Rita; Melnick, Ari

    2011-01-01

    STRUCTURED ABSTRACT Purpose of review It has only recently become apparent that mutations in epigenetic mechanisms and perturbation of epigenomic patterning are frequent events in B-cell lymphomas. The purpose of this review is to highlight these new findings and provide a conceptual framework for understanding how epigenetic modifications might contribute to lymphomagenesis. Recent findings Somatic mutations affecting histone methyltransferases such as EZH2 and MLL2, histone demethylases including UTX and JMJD2C and histone acetyltransferases including CBP and p300 are recurrent and common in lymphomas. These mutations result in disruption of chromatin structure and functions of other proteins, ultimately causing aberrant transcriptional programming affecting multiple gene networks. Widespread perturbation of cytosine methylation patterning now appears to be a hallmark of B-cell lymphomas and occurs in specific patterns that can distinguish disease subtypes. Therapeutic targeting strategies can overcome abnormal epigenetic mechanisms and potently kill lymphoma cells. Summary Newly discovered epigenetic lesions may provide critical insights into the genesis of B-cell lymphomas but further studies are required to understand how they affect biological mechanism. Epigenetic lesions offer tremendous opportunities for the development of improved biomarkers and treatments. PMID:21577103

  13. Metachronous/concomitant B-cell neoplasms with discordant light-chain or heavy-chain isotype restrictions: evidence of distinct B-cell neoplasms rather than clonal evolutions.

    PubMed

    Wei, Qiang; Sebastian, Siby; Papavassiliou, Paulie; Rehder, Catherine; Wang, Endi

    2014-10-01

    Metachronous/concomitant B-cell neoplasms with distinct morphology are usually considered clonally related. We retrospectively analyzed 4 cases of metachronous/concomitant B-cell neoplasms with discordant light-chain/heavy-chain restrictions. The primary diagnoses included chronic lymphocytic leukemia (CLL; n = 2), lymphoplasmacytic lymphoma (n = 1), and pediatric follicular lymphoma (FL; n = 1). The respective secondary diagnoses included diffuse large B-cell lymphoma (DLBCL; n = 2), plasmablastic myeloma, and pediatric FL. The secondary B-cell neoplasm occurred after the primary diagnosis in 3 cases, with the median interval of 120 months (range, 21-216), whereas the remaining 1 case had the 2 neoplasms (CLL/DLBCL) diagnosed concurrently. Histology suggested aggressive transformation in 3 cases and recurrence in 1 case (FL). Nonetheless, 3 cases showed discordant light-chain restrictions between the 2 B-cell neoplasms, whereas in the remaining case (lymphoplasmacytic lymphoma/plasmablastic myeloma), the 2 neoplasms shared κ light-chain restriction but expressed different heavy-chain isotypes (IgM versus IgA). The 2 CLL/DLBCL cases had polymerase chain reaction-based IGH/K gene rearrangement study and amplicon sequence analysis performed, which demonstrated distinct clonal amplicons between the 2 B-cell neoplasms in each case. Concomitant/metachronous B-cell neoplasms may be clonally unrelated, which can be confirmed by immunoglobulin isotype analysis and/or genotypic studies. We advocate analysis of clonal identities in large cell transformation or recurrent disease compared with primary indolent B-cell neoplasm because of a potential difference in prognosis between clonally related and unrelated secondary B-cell neoplasms.

  14. Class-switched B cells display response to therapeutic B-cell depletion in rheumatoid arthritis

    PubMed Central

    Möller, Burkhard; Aeberli, Daniel; Eggli, Stefan; Fuhrer, Martin; Vajtai, Istvan; Vögelin, Esther; Ziswiler, Hans-Rudolf; Dahinden, Clemens A; Villiger, Peter M

    2009-01-01

    Introduction Reconstitution of peripheral blood (PB) B cells after therapeutic depletion with the chimeric anti-CD20 antibody rituximab (RTX) mimics lymphatic ontogeny. In this situation, the repletion kinetics and migratory properties of distinct developmental B-cell stages and their correlation to disease activity might facilitate our understanding of innate and adaptive B-cell functions in rheumatoid arthritis (RA). Methods Thirty-five 'RTX-naïve' RA patients with active arthritis were treated after failure of tumour necrosis factor blockade in an open-label study with two infusions of 1,000 mg RTX. Prednisone dose was tapered according to clinical improvement from a median of 10 mg at baseline to 5 mg at 9 and 12 months. Conventional disease-modifying antirheumatic drugs were kept stable. Subsets of CD19+ B cells were assessed by flow cytometry according to their IgD and CD27 surface expression. Their absolute number and relative frequency in PB were followed every 3 months and were determined in parallel in synovial tissue (n = 3) or synovial fluid (n = 3) in the case of florid arthritis. Results Six of 35 patients fulfilled the European League Against Rheumatism criteria for moderate clinical response, and 19 others for good clinical response. All PB B-cell fractions decreased significantly in number (P < 0.001) after the first infusion. Disease activity developed independently of the total B-cell number. B-cell repopulation was dominated in quantity by CD27-IgD+ 'naïve' B cells. The low number of CD27+IgD- class-switched memory B cells (MemB) in the blood, together with sustained reduction of rheumatoid factor serum concentrations, correlated with good clinical response. Class-switched MemB were found accumulated in flaring joints. Conclusions The present data support the hypothesis that control of adaptive immune processes involving germinal centre-derived, antigen, and T-cell-dependently matured B cells is essential for successful RTX treatment. PMID

  15. Ongoing in vivo immunoglobulin class switch DNA recombination in chronic lymphocytic leukemia B cells.

    PubMed

    Cerutti, Andrea; Zan, Hong; Kim, Edmund C; Shah, Shefali; Schattner, Elaine J; Schaffer, András; Casali, Paolo

    2002-12-01

    Chronic lymphocytic leukemia (CLL) results from the expansion of malignant CD5(+) B cells that usually express IgD and IgM. These leukemic cells can give rise in vivo to clonally related IgG(+) or IgA(+) elements. The requirements and modalities of this process remain elusive. Here we show that leukemic B cells from 14 of 20 CLLs contain the hallmarks of ongoing Ig class switch DNA recombination (CSR), including extrachromosomal switch circular DNAs and circle transcripts generated by direct S micro -->Sgamma, S micro -->Salpha, and S micro -->Sepsilon as well as sequential Sgamma-->Salpha and Sgamma-->Sepsilon CSR. Similar CLL B cells express transcripts for activation-induced cytidine deaminase, a critical component of the CSR machinery, and contain germline I(H)-C(H) and mature V(H)DJ(H)-C(H) transcripts encoded by multiple Cgamma, Calpha, and Cepsilon genes. Ongoing CSR occurs in only a fraction of the CLL clone, as only small proportions of CD5(+)CD19(+) cells express surface IgG or IgA and lack IgM and IgD. In vivo class-switching CLL B cells down-regulate switch circles and circle transcripts in vitro unless exposed to exogenous CD40 ligand and IL-4. In addition, CLL B cells that do not class switch in vivo activate the CSR machinery and secrete IgG, IgA, or IgE upon in vitro exposure to CD40 ligand and IL-4. These findings indicate that in CLL at least some members of the malignant clone actively differentiate in vivo along a pathway that induces CSR. They also suggest that this process is elicited by external stimuli, including CD40 ligand and IL-4, provided by bystander immune cells.

  16. Diffuse large B-cell lymphoma in patient after treatment of angioimmunoblastic T-cell lymphoma.

    PubMed

    Skugor, Nives Dzeko; Perić, Zinaida; Vrhovac, Radovan; Radić-Kristo, Delfa; Kardum-Skelin, Ika; Jaksić, Branimir

    2010-03-01

    -induced proliferation of latently or newly EBV-infected B-cells with eventual clonal selection and progression to aggressive B-cell lymphoma. PMID:20432757

  17. CONCEPT ANALYSIS: AGGRESSION

    PubMed Central

    Liu, Jianghong

    2006-01-01

    The concept of aggression is important to nursing because further knowledge of aggression can help generate a better theoretical model to drive more effective intervention and prevention approaches. This paper outlines a conceptual analysis of aggression. First, the different forms of aggression are reviewed, including the clinical classification and the stimulus-based classification. Then the manifestations and measurement of aggression are described. Finally, the causes and consequences of aggression are outlined. It is argued that a better understanding of aggression and the causal factors underlying it are essential for learning how to prevent negative aggression in the future. PMID:15371137

  18. B-cell-specific conditional expression of Myd88p.L252P leads to the development of diffuse large B-cell lymphoma in mice.

    PubMed

    Knittel, Gero; Liedgens, Paul; Korovkina, Darya; Seeger, Jens M; Al-Baldawi, Yussor; Al-Maarri, Mona; Fritz, Christian; Vlantis, Katerina; Bezhanova, Svetlana; Scheel, Andreas H; Wolz, Olaf-Oliver; Reimann, Maurice; Möller, Peter; López, Cristina; Schlesner, Matthias; Lohneis, Philipp; Weber, Alexander N R; Trümper, Lorenz; Staudt, Louis M; Ortmann, Monika; Pasparakis, Manolis; Siebert, Reiner; Schmitt, Clemens A; Klatt, Andreas R; Wunderlich, F Thomas; Schäfer, Stephan C; Persigehl, Thorsten; Montesinos-Rongen, Manuel; Odenthal, Margarete; Büttner, Reinhard; Frenzel, Lukas P; Kashkar, Hamid; Reinhardt, H Christian

    2016-06-01

    The adaptor protein MYD88 is critical for relaying activation of Toll-like receptor signaling to NF-κB activation. MYD88 mutations, particularly the p.L265P mutation, have been described in numerous distinct B-cell malignancies, including diffuse large B-cell lymphoma (DLBCL). Twenty-nine percent of activated B-cell-type DLBCL (ABC-DLBCL), which is characterized by constitutive activation of the NF-κB pathway, carry the p.L265P mutation. In addition, ABC-DLBCL frequently displays focal copy number gains affecting BCL2 Here, we generated a novel mouse model in which Cre-mediated recombination, specifically in B cells, leads to the conditional expression of Myd88(p.L252P) (the orthologous position of the human MYD88(p.L265P) mutation) from the endogenous locus. These mice develop a lymphoproliferative disease and occasional transformation into clonal lymphomas. The clonal disease displays the morphologic and immunophenotypical characteristics of ABC-DLBCL. Lymphomagenesis can be accelerated by crossing in a further novel allele, which mediates conditional overexpression of BCL2 Cross-validation experiments in human DLBCL samples revealed that both MYD88 and CD79B mutations are substantially enriched in ABC-DLBCL compared with germinal center B-cell DLBCL. Furthermore, analyses of human DLBCL genome sequencing data confirmed that BCL2 amplifications frequently co-occurred with MYD88 mutations, further validating our approach. Finally, in silico experiments revealed that MYD88-mutant ABC-DLBCL cells in particular display an actionable addiction to BCL2. Altogether, we generated a novel autochthonous mouse model of ABC-DLBCL that could be used as a preclinical platform for the development and validation of novel therapeutic approaches for the treatment of ABC-DLBCL. PMID:27048211

  19. FDG-PET imaging in hematological malignancies.

    PubMed

    Valls, L; Badve, C; Avril, S; Herrmann, K; Faulhaber, P; O'Donnell, J; Avril, N

    2016-07-01

    The majority of aggressive lymphomas is characterized by an up regulated glycolytic activity, which enables the visualization by F-18 FDG-PET/CT. One-stop hybrid FDG-PET/CT combines the functional and morphologic information, outperforming both, CT and FDG-PET as separate imaging modalities. This has resulted in several recommendations using FDG-PET/CT for staging, restaging, monitoring during therapy, and assessment of treatment response as well as identification of malignant transformation. FDG-PET/CT may obviate the need for a bone marrow biopsy in patients with Hodgkin's lymphoma and diffuse large B cell lymphoma. FDG-PET/CT response assessment is recommended for FDG-avid lymphomas, whereas CT-based response evaluation remains important in lymphomas with low or variable FDG avidity. The treatment induced change in metabolic activity allows for assessment of response after completion of therapy as well as prediction of outcome early during therapy. The five-point scale Deauville Criteria allows the assessment of treatment response based on visual FDG-PET analysis. Although the use of FDG-PET/CT for prediction of therapeutic response is promising it should only be conducted in the context of clinical trials. Surveillance FDG-PET/CT after complete remission is discouraged due to the relative high number of false-positive findings, which in turn may result in further unnecessary investigations. Future directions include the use of new PET tracers such as F-18 fluorothymidine (FLT), a surrogate biomarker of cellular proliferation and Ga-68 CXCR4, a chemokine receptor imaging biomarker as well as innovative digital PET/CT and PET/MRI techniques. PMID:27090170

  20. High-level DNA amplifications are common genetic aberrations in B-cell neoplasms.

    PubMed Central

    Werner, C. A.; Döhner, H.; Joos, S.; Trümper, L. H.; Baudis, M.; Barth, T. F.; Ott, G.; Möller, P.; Lichter, P.; Bentz, M.

    1997-01-01

    Gene amplification is one of the molecular mechanisms resulting in the up-regulation of gene expression. In non-Hodgkin's lymphomas, such gene amplifications have been identified rarely. Using comparative genomic hybridization, a technique that has proven to be very sensitive for the detection of high-level DNA amplifications, we analyzed 108 cases of B-cell neoplasms (42 chronic B-cell leukemias, 5 mantle cell lymphomas, and 61 aggressive B-cell lymphomas). Twenty-four high-level amplifications were identified in 13% of the patients and mapped to 15 different genomic regions. Regions most frequently amplified were bands Xq26-28, 2p23-24, and 2p14-16 as well as 18q21 (three times each). Amplification of several proto-oncogenes and a cell cycle control gene (N-MYC (two cases), BCL2, CCND2, and GLI) located within the amplified regions was demonstrated by Southern blot analysis or fluorescence in situ hybridization to interphase nuclei of tumor cells. These data demonstrate that gene amplifications in B-cell neoplasms are much more frequent than previously assumed. The identification of highly amplified DNA regions and genes included in the amplicons provides important information for further analyses of genetic events involved in lymphomagenesis. Images Figure 2 Figure 3 PMID:9250147

  1. Malignant adenolymphoma.

    PubMed

    Moosavi, H; Ryan, C; Schwartz, S; Donnelly, J A

    1980-01-01

    Adenolymphoma (Warthin's tumor) is a well studied benign tumor of the salivary gland. Malignant transformation of such a tumor is rare and not well documented in the literature. The light microscopic and ultrastructural features of an undifferentiated carcinoma arising in an adenolymphoma in the parotid gland of a middle aged male are described, and the relevant literature is reviewed. Similarities between the benign adenolymphoma and the undifferentiated malignant tumor, such as the presence of interstitial lymphoplasmacytic cell infiltrates, dark and light epithelial cells, similar cytoplasmic organelles, and nuclear morphology, suggest a malignant transformation of a previously existing benign adenolymphoma.

  2. Treatment of ongoing autoimmune encephalomyelitis with activated B-cell progenitors maturing into regulatory B cells

    PubMed Central

    Korniotis, Sarantis; Gras, Christophe; Letscher, Hélène; Montandon, Ruddy; Mégret, Jérôme; Siegert, Stefanie; Ezine, Sophie; Fallon, Padraic G.; Luther, Sanjiv A.; Fillatreau, Simon; Zavala, Flora

    2016-01-01

    The influence of signals perceived by immature B cells during their development in bone marrow on their subsequent functions as mature cells are poorly defined. Here, we show that bone marrow cells transiently stimulated in vivo or in vitro through the Toll-like receptor 9 generate proB cells (CpG-proBs) that interrupt experimental autoimmune encephalomyelitis (EAE) when transferred at the onset of clinical symptoms. Protection requires differentiation of CpG-proBs into mature B cells that home to reactive lymph nodes, where they trap T cells by releasing the CCR7 ligand, CCL19, and to inflamed central nervous system, where they locally limit immunopathogenesis through interleukin-10 production, thereby cooperatively inhibiting ongoing EAE. These data demonstrate that a transient inflammation at the environment, where proB cells develop, is sufficient to confer regulatory functions onto their mature B-cell progeny. In addition, these properties of CpG-proBs open interesting perspectives for cell therapy of autoimmune diseases. PMID:27396388

  3. Inhibition of the PI3K/Akt/mTOR signaling pathway in diffuse large B-cell lymphoma: current knowledge and clinical significance.

    PubMed

    Majchrzak, Agata; Witkowska, Magdalena; Smolewski, Piotr

    2014-09-11

    Diffuse large B-cell lymphoma (DLBCL) is one of the most common non-Hodgkin lymphomas in adults. The disease is very heterogeneous in its presentation, that is DLBCL patients may differ from each other not only in regard to histology of tissue infiltration, clinical course or response to treatment, but also in respect to diversity in gene expression profiling. A growing body of knowledge on the biology of DLBCL, including abnormalities in intracellular signaling, has allowed the development of new treatment strategies, specifically directed against lymphoma cells. The phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling pathway plays an important role in controlling proliferation and survival of tumor cells in various types of malignancies, including DLBCL, and therefore it may be a promising target for therapeutic intervention. Currently, novel anticancer drugs are undergoing assessment in different phases of clinical trials in aggressive lymphomas, with promising outcomes. In this review we present a state of art review on various classes of small molecule inhibitors selectively involving PI3K/Akt/mTOR pathway and their clinical potential in this disease.

  4. Chemically linked phage idiotype vaccination in the murine B cell lymphoma 1 model

    PubMed Central

    2013-01-01

    Background B cell malignancies are characterized by clonal expansion of B cells expressing tumor-specific idiotypes on their surface. These idiotypes are ideal target antigens for an individualized immunotherapy. However, previous idiotype vaccines mostly lacked efficiency due to a low immunogenicity of the idiotype. The objective of the present study was the determination of the feasibility, safety and immunogenicity of a novel chemically linked phage idiotype vaccine. Methods In the murine B cell lymphoma 1 model, tumor idiotypes were chemically linked to phage particles used as immunological carriers. For comparison, the idiotype was genetically expressed on the major phage coat protein g8 or linked to keyhole limpet hemocynanin. After intradermal immunizations with idiotype vaccines, tolerability and humoral immune responses were assessed. Results Feasibility and tolerability of the chemically linked phage idiotype vaccine was demonstrated. Vaccination with B cell lymphoma 1 idiotype expressing phage resulted in a significant survival benefit in the murine B cell lymphoma 1 protection model (60.2 ± 23.8 days vs. 41.8 ± 1.6 days and 39.8 ± 3.8 days after vaccination with wild type phage or phosphate buffered saline, respectively). Superior immunogenicity of the chemically linked phage idiotype vaccine compared to the genetically engineered phage idiotype and keyhole limpet hemocynanin-coupled idiotype vaccine was demonstrated by significantly higher B cell lymphoma 1 idiotype-specific IgG levels after vaccination with chemically linked phage idiotype. Conclusion We present a novel, simple, time- and cost-efficient phage idiotype vaccination strategy, which represents a safe and feasible therapy and may produce a superior immune response compared to previously employed idiotype vaccination strategies. PMID:24152874

  5. Hepatitis C and double-hit B cell lymphoma successfully treated by antiviral therapy

    PubMed Central

    Galati, Giovanni; Rampa, Lorenzo; Vespasiani-Gentilucci, Umberto; Marino, Mirella; Pisani, Francesco; Cota, Carlo; Guidi, Alessandro; Picardi, Antonio

    2016-01-01

    B cells lymphoma is one of the most challenging extra-hepatic manifestations of hepatitis C virus (HCV). Recently, a new kind of B-cell lymphoma, named double-hit B (DHL), was characterized with an aggressive clinical course whereas a potential association with HCV was not investigated. The new antiviral direct agents (DAAs) against HCV are effective and curative in the majority of HCV infections. We report the first case, to our knowledge, of DHL and HCV-infection successfully treated by new DAAs. According to our experience, a DHL must be suspected in case of HCV-related lymphoma, and an early diagnosis could direct towards a different hematological management because a worse prognosis might be expected. A possible effect of DAAs on DHL regression should be investigated, but eradicating HCV would avoid life-threatening reactivation of viral hepatitis during pharmacological immunosuppression in onco-haematological diseases. PMID:27803769

  6. Preclinical targeting of human T-cell malignancies using CD4-specific chimeric antigen receptor (CAR)-engineered T cells.

    PubMed

    Pinz, K; Liu, H; Golightly, M; Jares, A; Lan, F; Zieve, G W; Hagag, N; Schuster, M; Firor, A E; Jiang, X; Ma, Y

    2016-03-01

    Peripheral T-cell lymphomas (PTCLs) are aggressive lymphomas with no effective upfront standard treatment and ineffective options in relapsed disease, resulting in poorer clinical outcomes as compared with B-cell lymphomas. The adoptive transfer of T cells engineered to express chimeric antigen receptors (CARs) is a promising new approach for treatment of hematological malignancies. However, preclinical reports of targeting T-cell lymphoma with CARs are almost non-existent. Here we have designed a CAR, CD4CAR, which redirects the antigen specificity of CD8+ cytotoxic T cells to CD4-expressing cells. CD4CAR T cells derived from human peripheral blood mononuclear cells and cord blood effectively redirected T-cell specificity against CD4+ cells in vitro. CD4CAR T cells efficiently eliminated a CD4+ leukemic cell line and primary CD4+ PTCL patient samples in co-culture assays. Notably, CD4CAR T cells maintained a central memory stem cell-like phenotype (CD8+CD45RO+CD62L+) under standard culture conditions. Furthermore, in aggressive orthotropic T-cell lymphoma models, CD4CAR T cells efficiently suppressed the growth of lymphoma cells while also significantly prolonging mouse survival. Combined, these studies demonstrate that CD4CAR-expressing CD8+ T cells are efficacious in ablating malignant CD4+ populations, with potential use as a bridge to transplant or stand-alone therapy for the treatment of PTCLs.

  7. Preclinical targeting of human T-cell malignancies using CD4-specific chimeric antigen receptor (CAR)-engineered T cells.

    PubMed

    Pinz, K; Liu, H; Golightly, M; Jares, A; Lan, F; Zieve, G W; Hagag, N; Schuster, M; Firor, A E; Jiang, X; Ma, Y

    2016-03-01

    Peripheral T-cell lymphomas (PTCLs) are aggressive lymphomas with no effective upfront standard treatment and ineffective options in relapsed disease, resulting in poorer clinical outcomes as compared with B-cell lymphomas. The adoptive transfer of T cells engineered to express chimeric antigen receptors (CARs) is a promising new approach for treatment of hematological malignancies. However, preclinical reports of targeting T-cell lymphoma with CARs are almost non-existent. Here we have designed a CAR, CD4CAR, which redirects the antigen specificity of CD8+ cytotoxic T cells to CD4-expressing cells. CD4CAR T cells derived from human peripheral blood mononuclear cells and cord blood effectively redirected T-cell specificity against CD4+ cells in vitro. CD4CAR T cells efficiently eliminated a CD4+ leukemic cell line and primary CD4+ PTCL patient samples in co-culture assays. Notably, CD4CAR T cells maintained a central memory stem cell-like phenotype (CD8+CD45RO+CD62L+) under standard culture conditions. Furthermore, in aggressive orthotropic T-cell lymphoma models, CD4CAR T cells efficiently suppressed the growth of lymphoma cells while also significantly prolonging mouse survival. Combined, these studies demonstrate that CD4CAR-expressing CD8+ T cells are efficacious in ablating malignant CD4+ populations, with potential use as a bridge to transplant or stand-alone therapy for the treatment of PTCLs. PMID:26526988

  8. Disseminated toxoplasmosis in non-allografted patients with hematologic malignancies: report of two cases and literature review.

    PubMed

    Scerra, S; Coignard-Biehler, H; Lanternier, F; Suarez, F; Charlier-Woerther, C; Bougnoux, M-E; Gilquin, J; Lecuit, M; Hermine, O; Lortholary, O

    2013-10-01

    Toxoplasmosis can be a severe opportunistic infection in patients with acquired immunodeficiency syndrome (AIDS), and also among solid organ transplant and allogeneic hematopoietic stem cell transplant (HSCT) patients. Patients with low-grade or chronic hematologic malignancies are treated with increasing immunosuppressive regimens and, therefore, represent an emerging population at risk for opportunistic diseases. We report here two cases of disseminated toxoplasmosis occurring in non-allografted hematologic patients with chronic lymphoproliferations. A review of 44 cases from the literature reveals that toxoplasmosis occurs increasingly in indolent B cell lymphoproliferative disorders. Aggressive lymphoproliferations, adenosine analogs, autologous HSCT, and the absence of chemoprophylaxis are the main risk factors for opportunistic toxoplasmosis. The central nervous system is the main organ involved. Fever is only present in half of all cases. Latent Toxoplasma cysts reactivation (LTCR) is the most common, but primary infection occurs in about 20% of cases. Global mortality is over 50%.

  9. Microsatellite instability in patients with chronic B-cell lymphocytic leukaemia

    PubMed Central

    Niv, E; Bomstein, Y; Yuklea, M; Lishner, M

    2005-01-01

    The purpose of our study was to evaluate the microsatellite instability (MSI) at selected loci with known involvement in the oncogenesis of chronic B-cell lymphocytic leukaemia (B-CLL). DNA from B cells (tumour cells) and from T cells (normal controls) of 27 samples of 26 patients with previously untreated B-CLL was extracted. Microsatellite instability in six microsatellite markers was tested using GeneScan Analysis Software. The rate of replication errors positive phenotype (RER+) was determined (MSI in more than 30% of examined loci). RER+ was found in four out of 27 paients (14.8%). A larger proportion of patients with stage C B-CLL exhibited RER+ than those with stage A or B (P<0.05). A higher prevalence of RER+ was demonstrated in a subgroup of patients with additional malignancies (three out of eight patients) in comparison with patients with B-CLL alone (1/19) (P=0.031). In conclusion, our study demonstrated that MSI might have a more prominent role in pathogenesis of B-CLL than reported todate. This may result from a selection of microsatellite markers adjacent to chromosomal loci, which are involved in B-cell malignancies, and using GeneScan Analysis Software, which is most modern and precise method of microsatellite analysis. PMID:15812543

  10. Therapy of advanced-stage mature B-cell lymphoma and leukemia in children and adolescents with rituximab and reduced intensity induction chemotherapy (B-NHL 2004M protocol): the results of a multicenter study.

    PubMed

    Samochatova, Elena V; Maschan, Alexey A; Shelikhova, Larisa N; Myakova, Natalia V; Belogurova, Margarita B; Khlebnikova, Olga P; Shamardina, Anastasia V; Ryskal, Olga V; Roumiantseva, Julia V; Konovalov, Dmitriy M; Dubrovina, Maria E; Rumyantsev, Alexander G

    2014-07-01

    Pediatric mature B-cell non-Hodgkin lymphomas (B-NHLs) are highly aggressive malignant tumors that are curable with chemotherapy (ChT). High-dose methotrexate (MTX) is considered indispensable for successful treatment, but this therapy frequently induces severe mucositis and infectious complications, especially in induction, which can cause treatment failure. A prospective multicenter trial of combined immunochemotherapy for advanced-stage B-NHL with rituximab and the modified NHL-BFM-90 protocol was conducted. The major differences from the original protocol were a decrease in the dose of MTX from 5000 to 1000 mg/m/24 h in the first 2 ChT blocks and the addition of rituximab at 375 mg/m to each of the first 4 blocks of ChT. Eighty-three newly diagnosed patients with a median age of 8.84 years with Burkitt lymphoma/leukemia and diffuse large B-cell lymphomas stage III to IV were included. Four patients died during induction ChT due to tumor lysis syndrome and infection. Two additional patients died subsequently due to tumor resistance. Complete remission was achieved in 77 (92.8%) patients; 2 patients relapsed at 1 and 3 months, and 2 developed secondary malignancies at 1 and 6.5 years, respectively, after the completion of therapy. The overall survival probability was 82%±8% with a median follow-up of 65.2 months. Combined therapy with rituximab and intensive ChT with a reduced MTX dose of 1 g/m in the 2 induction courses was feasible and produced high cure rates in patients with pediatric advanced-stage mature B-NHL. PMID:23823112

  11. Malignant hyperthermia.

    PubMed

    Brockhouse, R T

    1979-04-01

    A case has been presented that illustrates successful managment of a patient with suspected malignant hyperthermia. The causes of this disorder are uncertain. If screening procedures identify a patient as susceptible to this disorder, careful planning in the preoperative stage is indicated. Preparedness during the operative procedure for any emergency is mandatory. Early and effective treatment seems to be the only method of preventing mortality with patients experiencing malignant hyperthermia. PMID:285135

  12. Malignant oncocytoma.

    PubMed

    Laurian, N; Zohar, Y; Kende, L

    1977-09-01

    A case of malignant oncocytoma of the parotid gland in a 32-year-old male is presented. Ten months after parotidectomy an undifferentiated carcinoma, in which oncocytes still could be recognized, developed in the operated area. According to the literature available to us, this is the second reported case in which malignant transformation in a benign oncocytoma of the salivary gland has been observed.

  13. Mycosis Fungoides Associated with Kaposi's Sarcoma, T-cell Rich B-cell Lymphoma, and T-cell Lymphoma with Angioimmunoblastic Features.

    PubMed

    Samuelov, Liat; Gat, Andrea; Bergman, Reuven; Sprecher, Eli; Goldberg, Ilan

    2016-08-01

    A patient with mycosis fungoides (MF), Kaposi's sarcoma, T-cell rich B-cell lymphoma, and T-cell lymphoma with angioimmunoblastic features is described. The appearance of multiple malignancies in this patient may have been caused by previous exposure to radiation in the Chernobyl accident and/or systemic chemotherapy for the initial T-cell rich B-cell lymphoma which he underwent. PMID:27663924

  14. 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.

  15. Small Molecule Growth Inhibitors of Human Oncogenic Gammaherpesvirus Infected B-Cells

    PubMed Central

    Dzeng, Richard K.; Jha, Hem Chandra; Lu, Jie; Saha, Abhik; Banerjee, Sagarika; Robertson, Erle S.

    2014-01-01

    Epstein-Barr virus (EBV) and Kaposi’s sarcoma associated herpesvirus (KSHV) are two human gammaherpesviruses associated with a broad spectrum of B-cell lymphomas, most acutely in immuno-compromised populations. However, there are no drugs which specifically target KSHV or EBV-associated lymphomas. To identify small molecules which selectively inhibit the growth of EBV or KSHV-associated B-cell lines, we performed a fluorescence based high-throughput screen on multiple stable GFP expressing virus-infected or uninfected B-cell lines. We identified 40 initial compounds with selective growth inhibition and subsequently determined the 50% growth inhibitory concentrations (GI50) for each drug. We further examined compounds with higher specificity to explore the underlying molecular mechanisms using transcription factor analysis, as well as a sh-RNA based knockdown strategy. Our data identified ten compounds with relatively high efficacy for growth inhibition. Two novel small molecules, NSC#10010 and NSC#65381 were potent growth inhibitors for gammaherpesvirus-associated B-lymphomas through activation of both the NF-κB and c-Myc- mediated signaling pathways. These drugs can serve as potential lead compounds to expand the current therapeutic window against EBV or KSHV associated human B-cell malignancies. PMID:25306391

  16. EBV+ diffuse large B-cell lymphoma arising within atrial myxoma in Chinese immunocompetent patient

    PubMed Central

    Liu, Xiaoyan; Liu, Pu; Li, Jun

    2015-01-01

    The incidence rate of Primary cardiac lymphoma is very low. Primary cardiac lymphoma within myxoma is extremely rare disease. So far, these cases have been reported only eight in the world, which has not reported in Chinese so far. Hence, we reported the unique Chinese case of 52-year-old immunocompetent male with primary Epstein-Barr virus positive diffuse large B-cell lymphoma arising within atrial myxoma, and had no evidence of systemic lymphoma. The patient presented right sided body numbness, arm weakness no incentive and mouth twitch. A transthoracic echocardiogram revealed a large intraatrial mass, attached to the left atrial wall. The mass was removed by open thoracic surgery and subsequently diagnosed as malignant diffuse large B-cell lymphoma with myxoma by histopathology. This was the fourth case of discovered Epstein-Barr virus positive diffuse large B-cell lymphoma in a cardiac myxoma reported so far. The patient has been well by followed up for 5 months without chemotherapy. Now we discuss the importance of histodiagnosis and the proper treatment. Epstein-Barr virus positive diffuse large B-cell lymphoma arising within atrial myxoma is an extraordinary lymphoma for better prognosis, avoiding excessive treatment. PMID:25973119

  17. Malignant chondroid syringoma of the pinna.

    PubMed

    Krishnamurthy, Arvind; Aggarwal, Niharika; Deen, Suhail; Majhi, Urmila; Ramshankar, Vijayalakshmi

    2015-01-01

    Chondroid syringoma (CS) represents the cutaneous counterpart of mixed tumor (pleomorphic adenoma) of salivary glands. The malignant counterpart of CS, termed as "malignant CS" is a malignant eccrine neoplasm which lacks distinctive clinical features, often delaying initial diagnosis. Unlike its benign counterpart which often localizes in the head and neck region, malignant CS most often encountered in the trunk and the extremities. We report a rare case of an aggressive malignant CS of the left pinna with cervical lymph node metastasis. Our patient, to the best of our knowledge, possibly is the first case of malignant CS of the pinna and the fourth to arise in the head and neck region. The diagnostic challenges with an added emphasis on the role of positron emission tomography-computed tomography in aiding the management of this rare tumor are discussed.

  18. Malignant pleural mesothelioma.

    PubMed

    Ho, L; Sugarbaker, D J; Skarin, A T

    2001-01-01

    Malignant pleural mesothelioma remains a difficult tumor to treat, much less cure. Currently, the best chance for long-term survival lies with early diagnosis and aggressive surgical extirpation, but given the typically long delay between the onset of symptoms and diagnosis, this is only possible with a high index of suspicion and an aggressive diagnosis workup. Early referral to a tertiary center experienced in the treatment of MPM may be important for several reasons: (1) decreased risk of tumor spread along multiple thoracenesis/biopsy tracts, (2) the availability of specialized pathologic assays for definitive diagnosis, (3) the availability of critical staging modalities (aggressive mediastinoscopy +/- thoracoscopy, MRI scans performed according to specific mesothelioma protocols, and perhaps PET scans), (4) surgical experience with pleurectomy/decortication and/or extrapleural pneumonectomy, that may decrease morbidity and mortality, and (5) the availability of novel adjuvant protocols. Single-modality therapy is unlikely to result in long-term survival. Aggressive surgery is required for optimal debulking, and extrapleural pneumonectomy may offer better local control compared with pleurectomy/ecortication. Delivery of optimal radiation schedules, which may involve large fractions as well as large total doses, is limited by the presence of nearby dose-limiting structures. Current chemotherapy is severely lacking in producing objective responses and improved survival although gemcitabine and IL-2 may be active agents to be combined with radiation and/or other agents. Hyperthermia, photodynamic therapy, intracavitary therapy, and gene therapy are all relatively new techniques under active investigation that should be supported by enrollment in on-going protocols. Predictably, many of these techniques provide greater benefit when used in the setting of adjuvant protocols or minimal residual disease, emphasizing the importance of multimodality therapy.

  19. Aggressive behavior problems.

    PubMed

    Beaver, B V

    1986-12-01

    Accurate diagnosis of the cause of aggression in horses is essential to determining the appropriate course of action. The affective forms of aggression include fear-induced, pain-induced, intermale, dominance, protective, maternal, learned, and redirected aggressions. Non-affective aggression includes play and sex-related forms. Irritable aggression and hypertestosteronism in mares are medical problems, whereas genetic factors, brain dysfunction, and self-mutilation are also concerns. PMID:3492250

  20. Tracheal ulcer due to Epstein-Barr virus-positive diffuse large B-cell lymphoma of the elderly.

    PubMed

    Ito, Takeo; Fujisaki, Hideaki; Nishio, Suehiro; Hiroshige, Shigeo; Miyazaki, Eishi; Kadota, Jun-ichi

    2014-03-01

    A 74-year-old man was referred to our hospital because of a tracheal stenosis circumscribed with soft tissue density and a left pulmonary nodule. Open biopsy of a right submandibular lymph node revealed diffuse large B-cell lymphoma, and the malignant cells were positive for Epstein-Barr virus gene products. Bronchofiberscopy revealed a tracheal necrotizing ulcer. After chemotherapy, the tracheal ulcer resolved. To our knowledge, this is the first report of a case of Epstein-Barr virus-positive diffuse large B-cell lymphoma of the elderly with a tracheal ulcer.

  1. B cell biology: implications for treatment of systemic lupus erythematosus.

    PubMed

    Anolik, J H

    2013-04-01

    B cells are critical players in the orchestration of properly regulated immune responses, normally providing protective immunity without autoimmunity. Balance in the B cell compartment is achieved through the finely regulated participation of multiple B cell populations with different antibody-dependent and independent functions. Both types of functions allow B cells to modulate other components of the innate and adaptive immune system. Autoantibody-independent B cell functions include antigen presentation, T cell activation and polarization, and dendritic cell modulation. Several of these functions are mediated by the ability of B cells to produce immunoregulatory cytokines and chemokines and by their critical contribution to lymphoid tissue development and organization including the development of ectopic tertiary lymphoid tissue. Additionally, the functional versatility of B cells enables them to play either protective or pathogenic roles in autoimmunity. In turn, B cell dysfunction has been critically implicated in the pathophysiology of systemic lupus erythematosus (SLE), a complex disease characterized by the production of autoantibodies and heterogeneous clinical involvement. Thus, the breakdown of B cell tolerance is a defining and early event in the disease process and may occur by multiple pathways, including alterations in factors that affect B cell activation thresholds, B cell longevity, and apoptotic cell processing. Once tolerance is broken, autoantibodies contribute to autoimmunity by multiple mechanisms including immune-complex mediated Type III hypersensitivity reactions, type II antibody-dependent cytotoxicity, and by instructing innate immune cells to produce pathogenic cytokines including IFNα, TNF and IL-1. The complexity of B cell functions has been highlighted by the variable success of B cell-targeted therapies in multiple autoimmune diseases, including those conventionally viewed as T cell-mediated conditions. Given the widespread

  2. Cavitary pulmonary involvement of diffuse large B-cell lymphoma transformed from extra nodal marginal zone B-cell lymphoma MALT type.

    PubMed

    Yamane, Hiromichi; Ohsawa, Masahiro; Shiote, Yasuhiro; Umemura, Shigeki; Suwaki, Toshimitsu; Shirakawa, Atsuko; Kamei, Haruhito; Takigawa, Nagio; Kiura, Katsuyuki

    2011-12-01

    We describe a case of pulmonary diffuse large B-cell lymphoma (DLBCL), which was thought to arise from extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma). A 68-year-old woman presented with a 2-month history of cough and bloody sputum. The chest X-ray and computed tomography revealed a mass with cavitation in the right lower lobe. Transbronchial biopsy specimens revealed a granulomatous infiltration without malignant cells. However, diagnosis of MALT lymphoma was established from gastric biopsy specimen. Subsequently, a right lower lobectomy was performed because of hemoptysis. Examination of the resected specimen revealed a diffuse large B-cell lymphoma, which was considered to have transformed from MALT lymphoma, because both lung and stomach lesions had the chromosomal translocation t(11;18)(q21;q21) in common. In addition, there were no nodules, masses, alveolar or interstitial infiltrates in the lung fields, which are usually observed in the case of marginal zone B-cell lymphoma of bronchial mucosa-associated lymphoid tissue. These findings indicate that involvement of DLBCL have to be considered in patients with MALT lymphoma and cavitary lesion of the lung. PMID:26189744

  3. Circulating CD21low B cells in common variable immunodeficiency resemble tissue homing, innate-like B cells

    PubMed Central

    Rakhmanov, Mirzokhid; Keller, Baerbel; Gutenberger, Sylvia; Foerster, Christian; Hoenig, Manfred; Driessen, Gertjan; van der Burg, Mirjam; van Dongen, Jacques J.; Wiech, Elisabeth; Visentini, Marcella; Quinti, Isabella; Prasse, Antje; Voelxen, Nadine; Salzer, Ulrich; Goldacker, Sigune; Fisch, Paul; Eibel, Hermann; Schwarz, Klaus; Peter, Hans-Hartmut; Warnatz, Klaus

    2009-01-01

    The homeostasis of circulating B cell subsets in the peripheral blood of healthy adults is well regulated, but in disease it can be severely disturbed. Thus, a subgroup of patients with common variable immunodeficiency (CVID) presents with an extraordinary expansion of an unusual B cell population characterized by the low expression of CD21. CD21low B cells are polyclonal, unmutated IgM+IgD+ B cells but carry a highly distinct gene expression profile which differs from conventional naïve B cells. Interestingly, while clearly not representing a memory population, they do share several features with the recently defined memory-like tissue, Fc receptor-like 4 positive B cell population in the tonsils of healthy donors. CD21low B cells show signs of previous activation and proliferation in vivo, while exhibiting defective calcium signaling and poor proliferation in response to B cell receptor stimulation. CD21low B cells express decreased amounts of homeostatic but increased levels of inflammatory chemokine receptors. This might explain their preferential homing to peripheral tissues like the bronchoalveolar space of CVID or the synovium of rheumatoid arthritis patients. Therefore, as a result of the close resemblance to the gene expression profile, phenotype, function and preferential tissue homing of murine B1 B cells, we suggest that CD21low B cells represent a human innate-like B cell population. PMID:19666505

  4. 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

  5. Myeloid cell leukaemia 1 has a vital role in retinoic acid-mediated protection of Toll-like receptor 9-stimulated B cells from spontaneous and DNA damage-induced apoptosis.

    PubMed

    Holm, Kristine L; Indrevaer, Randi L; Myklebust, June Helen; Kolstad, Arne; Moskaug, Jan Øivind; Naderi, Elin H; Blomhoff, Heidi K

    2016-09-01

    Vitamin A is an essential anti-infective agent with pleiotropic effects on cells of the immune system. The goal of the present study was to unravel the impact of the vitamin A metabolite retinoic acid (RA) on B-cell survival related both to normal B-cell homeostasis and to the detrimental effects imposed by DNA-damaging agents. By combining RA with Toll-like receptor 9 (TLR9) ligands, we show that RA prevents spontaneous, irradiation- and doxorubicin-induced apoptosis of human B cells in an RA receptor-dependent manner. RA-mediated survival involved up-regulation of the anti-apoptotic protein myeloid cell leukemia 1 (MCL1) at the transcriptional level, and knock down of MCL1 by small interfering RNA partially reversed the effects of RA. To ensure that the combination of TLR9-ligands and RA would not promote the survival of malignant B cells, the combined effects of stimulation with RA and TLR9 ligands was assessed on cells from patients with B-cell malignancies. In contrast to the effects on normal B cells, the combination of TLR9 stimulation and RA neither enhanced the MCL1 levels nor inhibited the death of malignant B cells challenged by DNA-damaging agents. Taken together, the present results reveal a vital role of MCL1 in RA-mediated survival of normal B cells. Moreover, the findings suggest that RA in combination with TLR9 ligands might be useful adjuvants in the treatment of B-cell malignancies by selectively protecting normal and not malignant B cells from DNA-damage-induced cell death.

  6. T cell binding to B lymphoid cell lines in humans: a marker for T-B cell interaction?

    PubMed

    Goust, J M; Fudenberg, H H

    1983-04-15

    Binding of human circulating T cells to established normal and malignant B cell lines results in rosette formation. The percentage of B cells, circulating T cells, and thymocytes able to bind to the B-LCL Raji were 0%, 59 +/- 4% and 61 +/- 6%, respectively. The percentage of rosettes formed between Raji cells and circulating mononuclear cells from 92 normal individuals was 27.8 +/- 5.3%, and remained stable over several months. This phenomenon seems to involve relatively mature B cells, and a T cell marker which appears early in T cell ontogeny. In the peripheral blood, most of the B-LCL binding T cells exhibit a 'helper-inducer' phenotype, as determined with the monoclonal antibodies Leu 3a and OKT4. However, a significant percentage of T cells with so-called 'cytotoxic-suppressor' markers (Leu 2a and OKT8) also bind to B-LCL. The T cells involved in this morphological interactive reaction with B cells might conceivably be specifically involved in regulating B cell functions. Enumeration of this particular subset may be useful in conditions where abnormal T-B cell interactions are suspected. PMID:6601166

  7. A Gene Panel, Including LRP12, Is Frequently Hypermethylated in Major Types of B-Cell Lymphoma

    PubMed Central

    Bethge, Nicole; Honne, Hilde; Andresen, Kim; Hilden, Vera; Trøen, Gunhild; Liestøl, Knut; Holte, Harald; Delabie, Jan; Lind, Guro E.; Smeland, Erlend B.

    2014-01-01

    Epigenetic modifications and DNA methylation in particular, have been recognized as important mechanisms to alter gene expression in malignant cells. Here, we identified candidate genes which were upregulated after an epigenetic treatment of B-cell lymphoma cell lines (Burkitt's lymphoma, BL; Follicular lymphoma, FL; Diffuse large B-cell lymphoma, DLBCL activated B-cell like, ABC; and germinal center like, GCB) and simultaneously expressed at low levels in samples from lymphoma patients. Qualitative methylation analysis of 24 candidate genes in cell lines revealed five methylated genes (BMP7, BMPER, CDH1, DUSP4 and LRP12), which were further subjected to quantitative methylation analysis in clinical samples from 59 lymphoma patients (BL, FL, DLBCL ABC and GCB; and primary mediastinal B-cell lymphoma, PMBL). The genes LRP12 and CDH1 showed the highest methylation frequencies (94% and 92%, respectively). BMPER (58%), DUSP4 (32%) and BMP7 (22%), were also frequently methylated in patient samples. Importantly, all gene promoters were unmethylated in various control samples (CD19+ peripheral blood B cells, peripheral blood mononuclear cells and tonsils) as well as in follicular hyperplasia samples, underscoring a high specificity. The combination of LRP12 and CDH1 methylation could successfully discriminate between the vast majority of the lymphoma and control samples, emphasized by receiver operating characteristic analysis with a c-statistic of 0.999. These two genes represent promising epigenetic markers which may be suitable for monitoring of B-cell lymphoma. PMID:25226156

  8. A gene panel, including LRP12, is frequently hypermethylated in major types of B-cell lymphoma.

    PubMed

    Bethge, Nicole; Honne, Hilde; Andresen, Kim; Hilden, Vera; Trøen, Gunhild; Liestøl, Knut; Holte, Harald; Delabie, Jan; Lind, Guro E; Smeland, Erlend B

    2014-01-01

    Epigenetic modifications and DNA methylation in particular, have been recognized as important mechanisms to alter gene expression in malignant cells. Here, we identified candidate genes which were upregulated after an epigenetic treatment of B-cell lymphoma cell lines (Burkitt's lymphoma, BL; Follicular lymphoma, FL; Diffuse large B-cell lymphoma, DLBCL activated B-cell like, ABC; and germinal center like, GCB) and simultaneously expressed at low levels in samples from lymphoma patients. Qualitative methylation analysis of 24 candidate genes in cell lines revealed five methylated genes (BMP7, BMPER, CDH1, DUSP4 and LRP12), which were further subjected to quantitative methylation analysis in clinical samples from 59 lymphoma patients (BL, FL, DLBCL ABC and GCB; and primary mediastinal B-cell lymphoma, PMBL). The genes LRP12 and CDH1 showed the highest methylation frequencies (94% and 92%, respectively). BMPER (58%), DUSP4 (32%) and BMP7 (22%), were also frequently methylated in patient samples. Importantly, all gene promoters were unmethylated in various control samples (CD19+ peripheral blood B cells, peripheral blood mononuclear cells and tonsils) as well as in follicular hyperplasia samples, underscoring a high specificity. The combination of LRP12 and CDH1 methylation could successfully discriminate between the vast majority of the lymphoma and control samples, emphasized by receiver operating characteristic analysis with a c-statistic of 0.999. These two genes represent promising epigenetic markers which may be suitable for monitoring of B-cell lymphoma. PMID:25226156

  9. 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

  10. The Contribution of B Cells to Renal Interstitial Inflammation

    PubMed Central

    Heller, Florian; Lindenmeyer, Maja T.; Cohen, Clemens D.; Brandt, Ulrike; Draganovici, Dan; Fischereder, Michael; Kretzler, Matthias; Anders, Hans-Joachim; Sitter, Thomas; Mosberger, Isabella; Kerjaschki, Dontscho; Regele, Heinz; Schlöndorff, Detlef; Segerer, Stephan

    2007-01-01

    Local B-cell infiltrates play a role in tissue fibrosis, neolymphangiogenesis, and renal allograft survival. We sought to characterize the B-cell infiltrates, factors involved in B-cell recruitment, and lymphangiogenesis in renal interstitial injury (ie, acute and chronic interstitial nephritis and chronic IgA nephropathy). CD20-positive B cells formed a prominent part of the interstitial infiltrating cells. Together with CD3-positive T cells, the CD20-positive B cells formed larger nodular structures. CD10-positive pre-B cells were rare, and the majority were mature CD27-positive B cells. Proliferating B cells were detected within nodular infiltrates. The level of mRNA expression of the chemokine CXCL13 was increased and correlated with CD20 mRNA in the tubulointerstitial space. CXCL13 protein was predominantly found at sites of nodular infiltrates, in association with CXCR5-positive B cells. Furthermore, sites of chronic interstitial inflammation were associated with a high number of lymphatic vessels. B-cell infiltrates form a prominent part of the interstitial infiltrates both in primary interstitial lesions and in IgA nephropathy. CXCR5-positive B cells might be recruited via the chemokine CXCL13 and seem to contribute to the formation of intrarenal lymphoid follicle-like structures. These might represent an intrarenal immune system. PMID:17255314

  11. Epigenetics of Peripheral B-Cell Differentiation and the Antibody Response

    PubMed Central

    Zan, Hong; Casali, Paolo

    2015-01-01

    pathogens, and generation of pathogenic autoantibodies, IgE in allergic reactions, as well as B cell neoplasia. Epigenetic marks would be attractive targets for new therapeutics for autoimmune and allergic diseases, and B cell malignancies. PMID:26697022

  12. 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. PMID:27027096

  13. [Primary mediastinal B-cell lymphoma].

    PubMed

    Coso, D; Rey, J; Bouabdallah, R

    2010-02-01

    Primary mediastinal B-cell lymphoma (PMBL) is a clinicopathological entity among the world health organization classification of lymphoid neoplasms. PMBL often concerns young adults, and the disease remains a localized disease in the majority of cases. The outcome of patients with PMBL is variable and unlike diffuse large cell lymphomas, the international prognostic index seems to be less applicable to such disease. The combination of rituximab and chemotherapy is the gold standard treatment of patients with good prognosis features and allows high cure rates. However, high-dose chemotherapy supported by peripheral blood stem cell support is often warranted in poor-prognosis patients. The use of positrons emission tomography examination is more and more used in such situations to select the best therapeutic strategy. PMID:20207294

  14. The human intestinal B-cell response.

    PubMed

    Spencer, J; Sollid, L M

    2016-09-01

    The intestinal immune system is chronically challenged by a huge plethora of antigens derived from the lumen. B-cell responses in organized gut-associated lymphoid tissues and regional lymph nodes that are driven chronically by gut antigens generate the largest population of antibody-producing cells in the body: the gut lamina propria plasma cells. Although animal studies have provided insights into mechanisms that underpin this dynamic process, some very fundamental differences in this system appear to exist between species. Importantly, this prevents extrapolation from mice to humans to inform translational research questions. Therefore, in this review we will describe the structures and mechanisms involved in the propagation, dissemination, and regulation of this immense plasma cell population in man. Uniquely, we will seek our evidence exclusively from studies of human cells and tissues. PMID:27461177

  15. Rheumatoid factors, B cells and immunoglobulin genes.

    PubMed

    Jefferis, R

    1995-04-01

    The paradigm of self, non-self discrimination in the immune system is under review as autoreactive B or T cells are increasingly delineated within normal individuals. The products of autoreactive B cells are, mostly, polyspecific IgM antibodies of low affinity. These 'natural' antibodies include rheumatoid factors (RF) encoded by unmutated germline immunoglobulin genes. In rheumatoid arthritis (RA) the RF may be of the IgM, IgG or IgA isotype, show evidence of somatic mutation and have increased affinity; consistent with maturation of an antigen driven immune response. This response could be initiated or driven by an auto-immunogenic form of IgG or an exogenous cross-reactive antigen. Changes in galactosylation of IgG have been reported to be a valuable diagnostic and prognostic indicator in RA. Speculation that these changes may precipitate some of the disease processes is critically reviewed.

  16. Pleural malignancies.

    PubMed

    Vargas, F S; Teixeira, L R

    1996-07-01

    Carcinoma of the lung, metastatic breast carcinoma, and lymphoma are responsible for approximately 75% of all malignant pleural effusions. The presence of malignant cells in the pleural fluid or in the parietal pleura confirms the diagnosis. Recently, several authors have proposed the combination of morphometric procedures and quantitative analysis of nucleolar organizer regions stained by silver nitrate. Videothoracoscopy is recommended for patients suspected of having a malignant pleural effusion in whom the diagnosis is not established after two cytologic studies of the fluid and one needle biopsy. The standard treatment is the intrapleural instillation of a chemical agent to produce a pleurodesis. The recommended sclerosant is talc, a tetracycline derivative, or Corynebacterium parvum where it is available. When a patient is not an ideal candidate for chemical pleurodesis, the options include symptomatic treatment, serial thoracentesis, implantation of a pleuroperitoneal shunt, and pleurectomy. PMID:9363162

  17. Syk Tyrosine Kinase Is Required for the Positive Selection of Immature B Cells into the Recirculating B Cell Pool

    PubMed Central

    Turner, Martin; Gulbranson-Judge, Adam; Quinn, Marian E.; Walters, Alice E.; MacLennan, Ian C.M.; Tybulewicz, Victor L.J.

    1997-01-01

    The tyrosine kinase Syk has been implicated as a key signal transducer from the B cell antigen receptor (BCR). We show here that mutation of the Syk gene completely blocks the maturation of immature B cells into recirculating cells and stops their entry into B cell follicles. Furthermore, using radiation chimeras we demonstrate that this developmental block is due to the absence of Syk in the B cells themselves. Syk-deficient B cells are shown to have the life span of normal immature B cells. If this is extended by over-expression of Bcl-2, they accumulate in the T zone and red pulp of the spleen in increased numbers, but still fail to mature to become recirculating follicular B cells. Despite this defect in maturation, Syk-deficient B cells were seen to give rise to switched as well as nonswitched splenic plasma cells. Normally only a proportion of immature B cells is recruited into the recirculating pool. Our results suggest that Syk transduces a BCR signal that is absolutely required for the positive selection of immature B cells into the recirculating B cell pool. PMID:9396770

  18. Protein Ubiquitination in Lymphoid Malignancies

    PubMed Central

    Yang, Yibin; Staudt, Louis M.

    2014-01-01

    Summary Human lymphoid malignancies inherit gene expression networks from their normal B-cell counterpart and co-opt them for their own oncogenic purpose, which is usually governed by transcriptional factors and signaling pathways. These transcriptional factors and signaling pathways are precisely regulated at multiple steps, including ubiquitin modification. With a function involved in almost all cellular events, protein ubiquitination plays a role in many human diseases. In the past few years, multiple studies have expanded the role of ubiquitination in the genesis of diverse lymphoid malignancies. Here we discuss our current understanding of both proteolytic and nonproteolytic functions of the protein ubiquitination system and describe how it is involved in the pathogenesis of human lymphoid cancers. Lymphoid-restricted ubiquitination mechanisms, including ubiquitin E3 ligases and deubiquitinating enzymes, provide great opportunities for the development of targeted therapies for lymphoid cancers. PMID:25510281

  19. KSHV-Mediated Regulation of Par3 and SNAIL Contributes to B-Cell Proliferation

    PubMed Central

    Jha, Hem C.; Sun, Zhiguo; Upadhyay, Santosh K.; El-Naccache, Darine W.; Singh, Rajnish K.; Sahu, Sushil K.; Robertson, Erle S.

    2016-01-01

    Studies have suggested that Epithelial–Mesenchymal Transition (EMT) and transformation is an important step in progression to cancer. Par3 (partitioning-defective protein) is a crucial factor in regulating epithelial cell polarity. However, the mechanism by which the latency associated nuclear antigen (LANA) encoded by Kaposi's Sarcoma associated herpesvirus (KSHV) regulates Par3 and EMTs markers (Epithelial-Mesenchymal Transition) during viral-mediated B-cell oncogenesis has not been fully explored. Moreover, several studies have demonstrated a crucial role for EMT markers during B-cell malignancies. In this study, we demonstrate that Par3 is significantly up-regulated in KSHV-infected primary B-cells. Further, Par3 interacted with LANA in KSHV positive and LANA expressing cells which led to translocation of Par3 from the cell periphery to a predominantly nuclear signal. Par3 knockdown led to reduced cell proliferation and increased apoptotic induction. Levels of SNAIL was elevated, and E-cadherin was reduced in the presence of LANA or Par3. Interestingly, KSHV infection in primary B-cells led to enhancement of SNAIL and down-regulation of E-cadherin in a temporal manner. Importantly, knockdown of SNAIL, a major EMT regulator, in KSHV cells resulted in reduced expression of LANA, Par3, and enhanced E-cadherin. Also, SNAIL bound to the promoter region of p21 and can regulate its activity. Further a SNAIL inhibitor diminished NF-kB signaling through upregulation of Caspase3 in KSHV positive cells in vitro. This was also supported by upregulation of SNAIL and Par3 in BC-3 transplanted NOD-SCID mice which has potential as a therapeutic target for KSHV-associated B-cell lymphomas. PMID:27463802

  20. Reduced Levels of Hspa9 Attenuates Stat5 Activation in Mouse B-cells

    PubMed Central

    Krysiak, Kilannin; Tibbitts, Justin F.; Shao, Jin; Liu, Tuoen; Ndonwi, Matthew; Walter, Matthew J.

    2014-01-01

    HSPA9 is located on chromosome 5q31.2 in humans, a region that is commonly deleted in patients with myeloid malignancies [del(5q)], including myelodysplastic syndromes (MDS). HSPA9 expression is reduced by 50% in patients with del(5q)-associated MDS, consistent with haploinsufficient levels. Zebrafish mutants and knockdown studies in human and mouse cells have implicated a role for HSPA9 in hematopoiesis. To comprehensively evaluate the effects of Hspa9 haploinsufficiency on hematopoiesis, we generated an Hspa9 knockout mouse model. While homozygous knockout of Hspa9 is embryonic lethal, mice with heterozygous deletion of Hspa9 (Hspa9+/−) are viable and have a 50% reduction in Hspa9 expression. Hspa9+/− mice have normal basal hematopoiesis and do not develop MDS. However, Hspa9+/− mice have a cell- intrinsic reduction in bone marrow CFU-PreB colony formation without alterations in the number of B-cell progenitors in vivo, consistent with a functional defect in Hspa9+/− B-cell progenitors. We further reduced Hspa9 expression (<50%) using RNAi and observe reduced B-cell progenitors in vivo, indicating that appropriate levels (≥50%) of Hspa9 are required for normal B- lymphopoiesis in vivo. Knockdown of Hspa9 in an IL-7 dependent mouse B-cell line reduced Stat5 phosphorylation following IL-7 receptor stimulation, supporting a role for Hspa9 in Stat5 signaling in B-cells. Collectively, these data implicate a role for Hspa9 in B-lymphopoiesis and Stat5 activation downstream of IL-7 signaling. PMID:25550197

  1. Corruption of human follicular B-lymphocyte trafficking by a B-cell superantigen.

    PubMed

    Borhis, Gwenoline; Viau, Muriel; Badr, Gamal; Richard, Yolande; Zouali, Moncef

    2012-01-01

    Protein A (SpA) of Staphylococcus aureus is known to target the paratope of immunoglobulins expressing V(H)3 genes, and to delete marginal zone B cells and B-1a in vivo. We have discovered that SpA endows S. aureus with the potential to subvert B-cell trafficking in the host. We found that SpA, whose Fc-binding site has been inactivated, binds essentially to naïve B cells and induces a long-lasting decrease in CXCR4 expression and in B-cell chemotaxis to CXCL12. Competition experiments indicated that SpA does not interfere with binding of CXCR4 ligands and does not directly bind to CXCR4. This conclusion is strongly supported by the inability of SpA to modulate clathrin-mediated CXCR4 internalization, which contrasts with the potent effect of anti-immunoglobin M (IgM) antibodies. Microscopy and biochemical experiments confirmed that SpA binds to the surface IgM/IgD complex and induces its clathrin-dependent internalization. Concomitantly, the SpA-induced signaling leads to protein kinase C-dependent CXCR4 downmodulation, suggesting that SpA impairs the recycling of CXCR4, a postclathrin process that leads to either degradation into lysozomes or de novo expression at the cell surface. In addition to providing novel insight into disruption of B-cell trafficking by an infectious agent, our findings may have therapeutic implications. Because CXCR4 has been associated with cancer metastasis and with certain autoimmune diseases, SpA behaves as an evolutionary tailored highly specific, chemokine receptor inhibitor that may have value in addition to conventional cytotoxic therapy in patients with various malignancies and immune-mediated diseases.

  2. Primary bilateral adrenal intravascular large B-cell lymphoma associated with adrenal failure.

    PubMed

    Fukushima, Ayumi; Okada, Yosuke; Tanikawa, Takahisa; Onaka, Takashi; Tanaka, Aya; Higashi, Takehiro; Tsukada, Junichi; Tanaka, Yoshiya

    2003-07-01

    We report a rare case of bilateral primary adrenal non-Hodgkin's lymphoma with adrenal failure. A 66-year-old woman developed symptoms of adrenal failure. The cause of adrenal failure was suspected to be malignant lymphoma based on the high levels of serum soluble interleukin-2 receptor and LDH. Bilateral adrenalectomy was performed and pathological examination showed intravascular large B-cell lymphoma (IVL). Although complete remission was achieved, recurrence occurred three months later with brain metastases. IVL should be suspected in patients with bilateral adrenal tumors who present with rapidly progressive adrenal failure.

  3. Rare clinical presentation of diffuse large B-cell lymphoma as otitis media and facial palsy.

    PubMed

    Siddiahgari, Sirisha Rani; Yerukula, Pallavi; Lingappa, Lokesh; Moodahadu, Latha S

    2016-01-01

    Extra nodal presentation of Non Hodgkins Lymphoma (NHL) is a rare entity, and data available about the NHL that primarily involves of middle ear and mastoid is limited. We report a case of diffuse large B cell lymphoma (DLBCL), in a 2 year 8 month old boy, who developed otalgia and facial palsy. Computed tomography revealed a mass in the left mastoid. Mastoid exploration and histopathological examination revealed DLBCL. This case highlights the importance of considering malignant lymphoma as one of the differential diagnosis in persistent otitis media and/facial palsy.

  4. Hematologic malignancies

    SciTech Connect

    Hoogstraten, B.

    1986-01-01

    The principle aim of this book is to give practical guidelines to the modern treatment of the six important hematologic malignancies. Topics considered include the treatment of the chronic leukemias; acute leukemia in adults; the myeloproliferative disorders: polycythemia vera, essential thrombocythemia, and idiopathic myelofibrosis/agnogenic myeloid metaplasia; Hodgkin's Disease; non-Hodgkin's lymphoma; and Multiple Myeloma.

  5. Malignant hyperthermia.

    PubMed

    Taiclet, L

    1985-01-01

    Despite numerous reviews and clinical reports, much remains to be learned about the cause, treatment, and prevention of malignant hyperthermia.Among the most worrisome concerns of the clinician administering anesthesia is the malignant hyperthermia crisis. When it arises, it is always frightening-and sometimes fatal. Usually occurring very suddenly and without warning, malignant hyperthermia is considered to be a hypercatabolic crisis; the condition is known to affect humans and certain breeds of pigs. The exact triggering mechanisms of malignant hyperthermia (MH) in humans are not known, but a crisis can be initiated by volatile general anesthetics, neuromuscular blocking agents, and amide local anesthetics. Although a history of an MH crisis is a diagnostic aid, previous uneventful exposure to anesthesia does not guarantee the safety of the patient in subsequent anesthetic procedures.(1) For these reasons, it is important for the anesthesiologist to be aware of the initial signs of MH and to be prepared to provide immediate treatment to reverse such a crisis. PMID:3865561

  6. Malignant hyperthermia.

    PubMed Central

    Ben Abraham, R.; Adnet, P.; Glauber, V.; Perel, A.

    1998-01-01

    Malignant hyperthermia is a rare autosomal dominant trait that predisposes affected individuals to great danger when exposed to certain anaesthetic triggering agents (such as potent volatile anaesthetics and succinylcholine). A sudden hypermetabolic reaction in skeletal muscle leading to hyperthermia and massive rhabdomyolysis can occur. The ultimate treatment is dantrolene sodium a nonspecific muscle relaxant. Certain precautions should be taken before anaesthesia of patients known to be susceptible to malignant hyperthermia. These include the prohibition of the use of triggering agents, monitoring of central body temperature and expired CO2, and immediate availability of dantrolene. In addition, careful cleansing of the anaesthesia machine of vapours of halogenated agents is recommended. If these measures are taken, the chances of an MH episode are greatly reduced. When malignant hyperthermia-does occur in the operating room, prompt recognition and treatment usually prevent a potentially fatal outcome. The most reliable test to establish susceptibility to malignant hyperthermia is currently the in vitro caffeine-halothane contracture test. It is hoped that in the future a genetic test will be available. PMID:9538480

  7. An unusual and malignant intussusception in a child.

    PubMed

    D'Angelo, Gabriella; Marseglia, Lucia; Manti, Marta; Stroscio, Giovanni; Impollonia, Daniela; Arena, Salvatore; Impellizzeri, Pietro; Salpietro, Carmelo; Romeo, Carmelo; Gitto, Eloisa

    2016-08-01

    Intussusception is a common cause of bowel obstruction in the pediatric population. Malignant lesions account for up to 30 % of all cases of intussusception in the small intestine. We herein report an interesting case of ileo-colic intussusception caused by diffuse large B-cell lymphoma, in a child. The patient underwent laparoscopic right hemicolectomy. Pathologic evaluation revealed a diffuse large B-cell lymphoma.In cases of intussusception, especially in the older age group of children, a high index of suspicion for malignant lymphoma of the bowel should be observed.

  8. Sternal Resection and Reconstruction for Malignant Phylloides Tumor.

    PubMed

    Selvakumar, Veda Padma Priya; Poonia, Dharmaram; Agrawal, Juhi; Goel, Ashish; Mehta, Sandeep; Kumar, Kapil

    2015-08-01

    Malignant phylloides tumor is a locally aggressive breast neoplasm constituting less than 1 % of all breast cancers. It has a tendency for local recurrence and management is multidisciplinary. We hereby report a case of total sternal resection and reconstruction using Biopore HDPE prosthesis for Malignant Phylloides tumor. PMID:26702245

  9. Regulation of VH replacement by B cell receptor-mediated signaling in human immature B cells.

    PubMed

    Liu, Jing; Lange, Miles D; Hong, Sang Yong; Xie, Wanqin; Xu, Kerui; Huang, Lin; Yu, Yangsheng; Ehrhardt, Götz R A; Zemlin, Michael; Burrows, Peter D; Su, Kaihong; Carter, Robert H; Zhang, Zhixin

    2013-06-01

    VH replacement provides a unique RAG-mediated recombination mechanism to edit nonfunctional IgH genes or IgH genes encoding self-reactive BCRs and contributes to the diversification of Ab repertoire in the mouse and human. Currently, it is not clear how VH replacement is regulated during early B lineage cell development. In this article, we show that cross-linking BCRs induces VH replacement in human EU12 μHC(+) cells and in the newly emigrated immature B cells purified from peripheral blood of healthy donors or tonsillar samples. BCR signaling-induced VH replacement is dependent on the activation of Syk and Src kinases but is inhibited by CD19 costimulation, presumably through activation of the PI3K pathway. These results show that VH replacement is regulated by BCR-mediated signaling in human immature B cells, which can be modulated by physiological and pharmacological treatments.

  10. Brucella abortus-infected B cells induce osteoclastogenesis.

    PubMed

    Pesce Viglietti, Ayelén Ivana; Arriola Benitez, Paula Constanza; Giambartolomei, Guillermo Hernán; Delpino, María Victoria

    2016-09-01

    Brucella abortus is an intracellular bacterium that establishes lifelong infections in livestock and humans although the mechanisms of its chronicity are poorly understood. Activated B cells have long lifespan and B. abortus infection activates B cells. Our results indicate that the direct infection of B cells with B. abortus induced matrix metalloproteinase-9 (MMP-9), receptor activator for NF κB ligand (RANKL), tumor necrosis factor (TNF)-α and interleukin (IL)-6 secretion. In addition, supernatants from B. abortus-infected B cells induced bone marrow-derived monocytes to undergo osteoclastogenesis. Using osteoprotegerin, RANKL's decoy receptor, we determined that RANKL is involved in osteoclastogenesis induced by supernatants from B. abortus-infected B cells. The results presented here shed light on how the interactions of B. abortus with B cells may have a role in the pathogenesis of brucellar osteoarticular disease.

  11. Dual immunoglobulin light chain B cells: Trojan horses of autoimmunity?

    PubMed

    Pelanda, Roberta

    2014-04-01

    Receptor editing, a major mechanism of B cell tolerance, can also lead to allelic inclusion at the immunoglobulin light chain loci and the development of B cells that coexpress two different immunoglobulin light chains and, therefore, two antibody specificities. Most allelically included B cells express two κ chains, although rare dual-λ cells are also observed. Moreover, these cells typically coexpress an autoreactive and a nonautoreactive antibody. Thus, allelically included B cells could operate like 'Trojan horses': expression and function of the nonautoreactive antigen receptors might promote their maturation, activation, and terminal differentiation into effector cells that also express and secrete autoantibodies. Indeed, dual-κ B cells are greatly expanded into effector B cell subsets in some autoimmune mice, thus indicating they might play an important role in disease.

  12. A Case of De Novo CD5+ Disseminated Intravascular Large B-Cell Lymphoma Presenting as Multiorgan Failure

    PubMed Central

    Kapuria, Devika; Nanua, Suparna; Gaur, Rakesh

    2016-01-01

    Intravascular large B-cell lymphoma is an extremely rare extranodal lymphoma that proliferates in the lumen of the blood vessels while sparing the organ parenchyma. It usually presents with CNS and skin involvement. A 65-year-old Caucasian female presented with fevers and chills of 3-4 months' duration. Bone marrow biopsy done 3 months prior showed no significant myelodysplasia or lymphoid aggregates. The patient later died due to multiorgan failure. A bone marrow biopsy showed 20–30% CD5+ B cells consistent with infiltrative large B-cell lymphoma. An autopsy performed revealed diffuse intravascular invasion by lymphoma cells. Multiorgan involvement by intravascular B-cell lymphoma is very rare. Based on our literature review and to the best of our knowledge, there are only 5 case reports describing the presentation of this lymphoma with multiorgan failure. The immunophenotypic studies performed revealed that our patient had de novo CD5+ intravascular large B-cell lymphoma which is known to be aggressive with very poor prognosis. Although it is an extremely rare lymphoma, it should be considered as a potential cause of multiorgan failure when no other cause has been identified. A prompt tissue diagnosis and high-dose chemotherapy followed by ASCT can sometimes achieve remission. PMID:27777803

  13. Current trends in the treatment of primary mediastinal large B-cell lymphoma – an overview

    PubMed Central

    2015-01-01

    Primary mediastinal large B-cell lymphoma has been recognised as a distinct entity with unique clinical, pathologic, and genetic features. According to WHO 2008 classification it is marked as a variant of diffuse large B-cell lymphoma but shares characteristics with classic Hodgkin lymphoma. Genetic analysis has shown that amplification of the 9p24.1 region is the disease's specific structural alteration. Aggressive behaviour and a tendency to invade surrounding tissues of the thoracic cavity, often causing superior vena cava syndrome, or pleural or pericardial effusions, are the clinical hallmarks of this disease. For a long period of time it has been considered as a disease with poor prognosis, which responds poorly to the conventional treatment created for diffuse large B-cell lymphoma. An elective treatment has not yet been established, but recently the situation has became much more favourable. After the introduction of rituximab the cure rates have risen to over 80%, and the most recent results have demonstrated a new insight with dose-adjusted intensified continuous treatments, in which the cure rates have exceeded 90%. Current trends have led to the introduction of dose-adjusted intensified protocols becoming a standard of care, whereas the use of radiotherapy remains controversial because of the questionable predictive value of post-treatment PET/CT validity. The relapse rate is very low after two years of sustained complete remission. If the disease relapses or is resistant the outcome is very poor regardless of the applied treatment modality. PMID:26843837

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

    PubMed

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

    1993-11-01

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

  15. Calcitriol-mediated hypercalcemia in a patient with bilateral adrenal non-Hodgkin's B-cell lymphoma case report

    PubMed Central

    Abaroa-Salvatierra, Ana; Shaikh, Bilal; Deshmukh, Mrunalini; Alweis, Richard; Patel, Arti

    2016-01-01

    Calcitriol-mediated hypercalcemia is a frequent manifestation of hematological malignancies. However, there are a few reports of cases presenting with increased angiotensin-converting enzyme (ACE) level, which suggests a possible mechanism similar to that of granulomatous diseases. We present a patient with hypercalcemia, normal parathyroid hormone, and parathyroid hormone-related protein levels but high calcitriol and ACE levels that, after further investigation, was diagnosed with bilateral adrenal non-Hodgkin's B-cell lymphoma. Primary adrenal lymphoma represents only 1% of all non-Hodgkin's lymphomas and is usually asymptomatic but should be considered by clinicians among the malignancies that cause calcitriol-mediated hypercalcemia. PMID:27124160

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

    PubMed Central

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

    2016-01-01

    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

  17. Depletion of B cells in murine lupus: efficacy and resistance.

    PubMed

    Ahuja, Anupama; Shupe, Jonathan; Dunn, Robert; Kashgarian, Michael; Kehry, Marilyn R; Shlomchik, Mark J

    2007-09-01

    In mice, genetic deletion of B cells strongly suppresses systemic autoimmunity, providing a rationale for depleting B cells to treat autoimmunity. In fact, B cell depletion with rituximab is approved for rheumatoid arthritis patients, and clinical trials are underway for systemic lupus erythematosus. Yet, basic questions concerning mechanism, pathologic effect, and extent of B cell depletion cannot be easily studied in humans. To better understand how B cell depletion affects autoimmunity, we have generated a transgenic mouse expressing human CD20 on B cells in an autoimmune-prone MRL/MpJ-Fas(lpr) (MRL/lpr) background. Using high doses of a murine anti-human CD20 mAb, we were able to achieve significant depletion of B cells, which in turn markedly ameliorated clinical and histologic disease as well as antinuclear Ab and serum autoantibody levels. However, we also found that B cells were quite refractory to depletion in autoimmune-prone strains compared with non-autoimmune-prone strains. This was true with multiple anti-CD20 Abs, including a new anti-mouse CD20 Ab, and in several different autoimmune-prone strains. Thus, whereas successful B cell depletion is a promising therapy for lupus, at least some patients might be resistant to the therapy as a byproduct of the autoimmune condition itself.

  18. B-cell targeted therapeutics in clinical development

    PubMed Central

    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

  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. Invited article: inhibition of B cell functions: implications for neurology.

    PubMed

    Dalakas, Marinos C

    2008-06-01

    B cells are involved in the pathophysiology of many neurologic diseases, either in a causative or contributory role, via production of autoantibodies, cytokine secretion, or by acting as antigen-presenting cells leading to T cell activation. B cells are clonally expanded in various CNS disorders, such as multiple sclerosis (MS), paraneoplastic CNS disorders, or stiff-person syndrome, and are activated to produce pathogenic autoantibodies in demyelinating neuropathies and myasthenia. B cell activating factor (BAFF) and a proliferating inducing ligand (APRIL), key cytokines for B cell survival, are strongly unregulated in MS brain and in muscles of inflammatory myopathies. Modulation of B cell functions using a series of monoclonal antibodies against CD20+ B cells or the molecules that increase B cell survival, such as BAFF/APRIL and their receptors BAFF-R, TACI, and BCMA, provide a rational approach to the treatment of the aforementioned neurologic disorders. In controlled studies, rituximab, a B cell-depleting monoclonal antibody, has been encouraging in MS and paraproteinemic anti-MAG demyelinating neuropathy, exerting long-lasting remissions. In uncontrolled series, benefit has been reported in several disorders. B cell depletion is a well-tolerated therapeutic option currently explored in the treatment of several autoimmune neurologic disorders.

  1. True malignant mixed tumors (carcinosarcoma) of salivary glands.

    PubMed

    Stephen, J; Batsakis, J G; Luna, M A; von der Heyden, U; Byers, R M

    1986-06-01

    True malignant mixed tumors (carcinosarcomas) of salivary glands are of a high grade of malignancy and are distinguishable from the more frequently occurring carcinomas ex pleomorphic adenoma. Having a putative origin from a benign pleomorphic adenoma, the true malignant mixed tumor is an aggressive, often rapidly lethal neoplasm in which the sarcomatous element is most often a chondrosarcoma and the epithelial element is most often a ductal carcinoma. The twelve cases in this report represent the largest recorded series to date.

  2. Primary splenic B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and classical Hodgkin lymphoma: A case report

    PubMed Central

    Shi, Feng; Zhou, Quan; Gao, Ying; Cui, Xiang-Qing; Chang, Hong

    2016-01-01

    B-cell lymphoma (BCL), unclassifiable, with features intermediate between diffuse large BCL (DLBCL) and classical Hodgkin's lymphoma (CHL), is a novel entity to the World Health Organization classification system. These tumors are rare aggressive lymphomas that have a poor prognosis. The present study reports the case of a patient with one such lymphoma that occurred in the spleen, which expressed cluster of differentiation (CD)20, CD79α, melanoma associated antigen (mutated) 1, BCL6, CD15 and CD30. Polymerase chain reaction analysis demonstrated a clonal rearrangement of the genes coding for immunoglobulin heavy chains. The tumor cells demonstrated a negative reaction in the Epstein-Barr virus-encoded small RNA assay. Following the diagnosis of unclassifiable BCL, with intermediate features between DLBCL and CHL, the patient received 7 cycles of the CHOP regimen, and so far, has been in good general condition and tumor-free for 17 months. PMID:27602118

  3. The B-Cell-Specific src-Family Kinase Blk Is Dispensable for B-Cell Development and Activation

    PubMed Central

    Texido, Gemma; Su, I-hsin; Mecklenbräuker, Ingrid; Saijo, Kaoru; Malek, Sami N.; Desiderio, Stephen; Rajewsky, Klaus; Tarakhovsky, Alexander

    2000-01-01

    The B-cell lymphocyte kinase (Blk) is a src-family protein tyrosine kinase specifically expressed in B-lineage cells of mice. The early onset of Blk expression during B-cell development in the bone marrow and the high expression levels of Blk in mature B cells suggest a possible important role of Blk in B-cell physiology. To study the in vivo function of Blk, mice homozygous for the targeted disruption of the blk gene were generated. In homozygous mutant mice, neither blk mRNA nor Blk protein is expressed. Despite the absence of Blk, the development, in vitro activation, and humoral immune responses of B cells to T-cell-dependent and -independent antigens are unaltered. These data are consistent with functional redundancy of Blk in B-cell development and immune responses. PMID:10648608

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

    PubMed Central

    Henriques, Ana; Rodríguez-Caballero, Arancha; Criado, Ignacio; Langerak, Anton W.; Nieto, Wendy G.; Lécrevisse, Quentin; González, Marcos; Cortesão, Emília; 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

  5. Homeobox NKX2-3 promotes marginal-zone lymphomagenesis by activating B-cell receptor signalling and shaping lymphocyte dynamics

    PubMed Central

    Robles, Eloy F.; Mena-Varas, Maria; Barrio, Laura; Merino-Cortes, Sara V.; Balogh, Péter; Du, Ming-Qing; Akasaka, Takashi; Parker, Anton; Roa, Sergio; Panizo, Carlos; Martin-Guerrero, Idoia; Siebert, Reiner; Segura, Victor; Agirre, Xabier; Macri-Pellizeri, Laura; Aldaz, Beatriz; Vilas-Zornoza, Amaia; Zhang, Shaowei; Moody, Sarah; Calasanz, Maria Jose; Tousseyn, Thomas; Broccardo, Cyril; Brousset, Pierre; Campos-Sanchez, Elena; Cobaleda, Cesar; Sanchez-Garcia, Isidro; Fernandez-Luna, Jose Luis; Garcia-Muñoz, Ricardo; Pena, Esther; Bellosillo, Beatriz; Salar, Antonio; Baptista, Maria Joao; Hernandez-Rivas, Jesús Maria; Gonzalez, Marcos; Terol, Maria Jose; Climent, Joan; Ferrandez, Antonio; Sagaert, Xavier; Melnick, Ari M.; Prosper, Felipe; Oscier, David G.; Carrasco, Yolanda R.; Dyer, Martin J. S.; Martinez-Climent, Jose A.

    2016-01-01

    NKX2 homeobox family proteins have a role in cancer development. Here we show that NKX2-3 is overexpressed in tumour cells from a subset of patients with marginal-zone lymphomas, but not with other B-cell malignancies. While Nkx2-3-deficient mice exhibit the absence of marginal-zone B cells, transgenic mice with expression of NKX2-3 in B cells show marginal-zone expansion that leads to the development of tumours, faithfully recapitulating the principal clinical and biological features of human marginal-zone lymphomas. NKX2-3 induces B-cell receptor signalling by phosphorylating Lyn/Syk kinases, which in turn activate multiple integrins (LFA-1, VLA-4), adhesion molecules (ICAM-1, MadCAM-1) and the chemokine receptor CXCR4. These molecules enhance migration, polarization and homing of B cells to splenic and extranodal tissues, eventually driving malignant transformation through triggering NF-κB and PI3K-AKT pathways. This study implicates oncogenic NKX2-3 in lymphomagenesis, and provides a valid experimental mouse model for studying the biology and therapy of human marginal-zone B-cell lymphomas. PMID:27297662

  6. Homeobox NKX2-3 promotes marginal-zone lymphomagenesis by activating B-cell receptor signalling and shaping lymphocyte dynamics.

    PubMed

    Robles, Eloy F; Mena-Varas, Maria; Barrio, Laura; Merino-Cortes, Sara V; Balogh, Péter; Du, Ming-Qing; Akasaka, Takashi; Parker, Anton; Roa, Sergio; Panizo, Carlos; Martin-Guerrero, Idoia; Siebert, Reiner; Segura, Victor; Agirre, Xabier; Macri-Pellizeri, Laura; Aldaz, Beatriz; Vilas-Zornoza, Amaia; Zhang, Shaowei; Moody, Sarah; Calasanz, Maria Jose; Tousseyn, Thomas; Broccardo, Cyril; Brousset, Pierre; Campos-Sanchez, Elena; Cobaleda, Cesar; Sanchez-Garcia, Isidro; Fernandez-Luna, Jose Luis; Garcia-Muñoz, Ricardo; Pena, Esther; Bellosillo, Beatriz; Salar, Antonio; Baptista, Maria Joao; Hernandez-Rivas, Jesús Maria; Gonzalez, Marcos; Terol, Maria Jose; Climent, Joan; Ferrandez, Antonio; Sagaert, Xavier; Melnick, Ari M; Prosper, Felipe; Oscier, David G; Carrasco, Yolanda R; Dyer, Martin J S; Martinez-Climent, Jose A

    2016-06-14

    NKX2 homeobox family proteins have a role in cancer development. Here we show that NKX2-3 is overexpressed in tumour cells from a subset of patients with marginal-zone lymphomas, but not with other B-cell malignancies. While Nkx2-3-deficient mice exhibit the absence of marginal-zone B cells, transgenic mice with expression of NKX2-3 in B cells show marginal-zone expansion that leads to the development of tumours, faithfully recapitulating the principal clinical and biological features of human marginal-zone lymphomas. NKX2-3 induces B-cell receptor signalling by phosphorylating Lyn/Syk kinases, which in turn activate multiple integrins (LFA-1, VLA-4), adhesion molecules (ICAM-1, MadCAM-1) and the chemokine receptor CXCR4. These molecules enhance migration, polarization and homing of B cells to splenic and extranodal tissues, eventually driving malignant transformation through triggering NF-κB and PI3K-AKT pathways. This study implicates oncogenic NKX2-3 in lymphomagenesis, and provides a valid experimental mouse model for studying the biology and therapy of human marginal-zone B-cell lymphomas.

  7. Axl Inhibition Primes Chronic Lymphocytic Leukemia B-Cells to Apoptosis and Show Synergistic/Additive Effects in Combination with BTK inhibitors

    PubMed Central

    Sinha, Sutapa; Boysen, Justin; Nelson, Michael; Secreto, Charla; Warner, Steven L.; Bearss, David J.; Lesnick, Connie; Shanafelt, Tait D.; Kay, Neil E.; Ghosh, Asish K.

    2015-01-01

    Purpose B-cell chronic lymphocytic leukemia (CLL) is an incurable disease despite aggressive therapeutic approaches. We previously found that Axl receptor tyrosine kinase (RTK) plays a critical role in CLL B-cell survival. Here, we explored the possibility of using a high-affinity Axl inhibitor as a single agent or in combination with Bruton’s tyrosine kinase (BTK) inhibitors for future clinical trial to treat CLL patients. Experimental Design Expression/activation status of other members of the TAM (Tyro3, Axl, MER) family of RTKs in CLL B-cells was evaluated. Cells were treated with a high-affinity orally bioavailable Axl inhibitor TP-0903 with or without presence of CLL bone marrow stromal cells (BMSCs). Inhibitory effects of TP-0903 on Axl signaling pathway was also evaluated in CLL B-cells. Finally, cells were exposed to TP-0903 in combination with BTK inhibitors to determine any synergistic/additive effects of the combination. Results CLL B-cells overexpress Tyro3, but not MER. Of interest, Tyro3 remains as constitutively phosphorylated and form a complex with Axl in CLL B-cells. TP-0903 induces massive apoptosis in CLL B-cells with LD50 values of nanomolar ranges. Importantly, CLL BMSCs could not protect the leukemic B-cells from TP-0903 induced apoptosis. A marked reduction of the anti-apoptotic proteins Mcl-1, Bcl-2, XIAP and upregulation of the pro-apoptotic protein BIM in CLL B-cells were detected as a result of Axl inhibition. Finally, combination of TP-0903 with BTK inhibitors augments CLL B-cell apoptosis. Conclusion Administration of TP-0903 either as a single agent or in combination with BTK inhibitors may be effective in treating CLL patients. PMID:25673699

  8. Constitutively activated STAT3 promotes cell proliferation and survival in the activated B-cell subtype of diffuse large B-cell lymphomas

    PubMed Central

    Ding, B. Belinda; Yu, J. Jessica; Yu, Raymond Y.-L.; Mendez, Lourdes M.; Shaknovich, Rita; Zhang, Yonghui; Cattoretti, Giorgio

    2008-01-01

    Diffuse large B-cell lymphoma (DLBCL) consists of at least 2 phenotypic subtypes; that is, the germinal center B-cell–like (GCB-DLBCL) and the activated B-cell–like (ABC-DLBCL) groups. It has been shown that GCB-DLBCL responds favorably to chemotherapy and expresses high levels of BCL6, a transcription repressor known to play a causative role in lymphomagenesis. In comparison, ABC-DLBCL has lower levels of BCL6, constitutively activated nuclear factor-κB, and tends to be refractory to chemotherapy. Here, we report that the STAT3 gene is a transcriptional target of BCL6. As a result, high-level STAT3 expression and activation are preferentially detected in ABC-DLBCL and BCL6-negative normal germinal center B cells. Most importantly, inactivating STAT3 by either AG490 or small interference RNA in ABC-DLBCL cells inhibits cell proliferation and triggers apoptosis. These phenotypes are accompanied by decreased expression of several known STAT3 target genes, including c-Myc, JunB, and Mcl-1, and increased expression of the cell- cycle inhibitor p27. In addition to identifying STAT3 as a novel BCL6 target gene, our results define a second oncogenic pathway, STAT3 activation, which operates in ABC-DLBCL, suggesting that STAT3 may be a new therapeutic target in these aggressive lymphomas. PMID:17951530

  9. Relational aggression in marriage.

    PubMed

    Carroll, Jason S; Nelson, David A; Yorgason, Jeremy B; Harper, James M; Ashton, Ruth Hagmann; Jensen, Alexander C

    2010-01-01

    Drawing from developmental theories of relational aggression, this article reports on a study designed to identify if spouses use relationally aggressive tactics when dealing with conflict in their marriage and the association of these behaviors with marital outcomes. Using a sample of 336 married couples (672 spouses), results revealed that the majority of couples reported that relationally aggressive behaviors, such as social sabotage and love withdrawal, were a part of their marital dynamics, at least to some degree. Gender comparisons of partner reports of their spouse's behavior revealed that wives were significantly more likely to be relationally aggressive than husbands. Structural equation modeling demonstrated that relational aggression is associated with lower levels of marital quality and greater marital instability for both husbands and wives. Implications are drawn for the use of relational aggression theory in the future study of couple conflict and marital aggression.

  10. ABSENCE OF SCLEROSTIN ADVERSELY AFFECTS B CELL SURVIVAL

    PubMed Central

    Cain, Corey J.; Rueda, Randell; McLelland, Bryce; Collette, Nicole M.; Loots, Gabriela G.; Manilay, Jennifer O.

    2012-01-01

    Increased osteoblast activity in sclerostin-knockout (Sost−/−) mice results in generalized hyperostosis and bones with small bone marrow cavities due to hyperactive mineralizing osteoblast populations. Hematopoietic cell fate decisions are dependent on their local microenvironment, which contains osteoblast and stromal cell populations that support both hematopoietic stem cell quiescence and facilitate B cell development. In this study, we investigated whether high bone mass environments affect B cell development via the utilization of Sost−/− mice, a model of sclerosteosis. We found the bone marrow of Sost−/− mice to be specifically depleted of B cells, due to elevated apoptosis at all B cell developmental stages. In contrast, B cell function in the spleen was normal. Sost expression analysis confirmed that Sost is primarily expressed in osteocytes and is not expressed in any hematopoietic lineage, which indicated that the B cell defects in Sost−/− mice are non-cell autonomous and this was confirmed by transplantation of wildtype (WT) bone marrow into lethally irradiated Sost−/− recipients. WT→Sost−/− chimeras displayed a reduction in B cells, whereas reciprocal Sost−/−→WT chimeras did not, supporting the idea that the Sost−/− bone environment cannot fully support normal B cell development. Expression of the pre-B cell growth stimulating factor, Cxcl12, was significantly lower in bone marrow stromal cells of Sost−/− mice while the Wnt target genes Lef-1 and Ccnd1 remained unchanged in B cells. Taken together, these results demonstrate a novel role for Sost in the regulation of bone marrow environments that support B cells. PMID:22434688

  11. Tumor antigen ROR1 targeted drug delivery mediated selective leukemic but not normal B cell cytotoxicity in chronic lymphocytic leukemia

    PubMed Central

    Mani, Rajeswaran; Mao, Yicheng; Frissora, Frank W.; Chiang, Chi-Ling; Wang, Jiang; Zhao, Yuan; Wu, Yun; Yu, Bo; Yan, Ribai; Mo, Xiaokui; Yu, Lianbo; Flynn, Joseph; Jones, Jeffrey; Andritsos, Leslie; Baskar, Sivasubramanian; Rader, Christoph; Phelps, Mitch A; Chen, Ching-Shih; Lee, Robert J.; Byrd, John C.; Lee, L. James; Muthusamy, Natarajan

    2014-01-01

    Selective cytotoxicity to cancer cells without compromising their normal counterparts pose a huge challenge for traditional drug design. Here we developed a tumor antigen targeted delivery of immunonanoparticle carrying a novel non-immunosuppressive FTY720 derivative OSU-2S with potent cytotoxicity against leukemic B cells. OSU-2S induces activation of protein phosphatase 2A, phosphorylation and nuclear translocation of SHP1S591 and deregulation of multiple cellular processes in chronic lymphocytic leukemia (CLL) resulting in potent cytotoxicity. To preclude OSU-2S mediated effects on these ubiquitous phosphatases in unintended cells and avoid potential adverse effects we developed a OSU-2S targeted delivery immunonanoparticles (2A2-OSU-2S-ILP), that mediated selective cytotoxicity of CLL but not normal B cells through targeting receptor tyrosine kinase ROR1 expressed in leukemic but not normal B cells. Developing a novel spontaneous CLL mouse model expressing human ROR1 (hROR1) in all leukemic B cells, we demonstrate the therapeutic benefit of enhanced survival with 2A2-OSU-2S-ILP in-vivo. The newly developed non-immunosuppressive OSU-2S, its delivery using human CLL directed immunonanoparticles and the novel transgenic mouse model of CLL that expresses hROR1 exclusively in leukemic B cell surface are highly innovative and can be applied to CLL and other ROR1+ malignancies including mantle cell lymphoma and acute lymphoblastic leukemia. PMID:24947019

  12. The histone lysine methyltransferase KMT2D sustains a gene expression program that represses B cell lymphoma development.

    PubMed

    Ortega-Molina, Ana; Boss, Isaac W; Canela, Andres; Pan, Heng; Jiang, Yanwen; Zhao, Chunying; Jiang, Man; Hu, Deqing; Agirre, Xabier; Niesvizky, Itamar; Lee, Ji-Eun; Chen, Hua-Tang; Ennishi, Daisuke; Scott, David W; Mottok, Anja; Hother, Christoffer; Liu, Shichong; Cao, Xing-Jun; Tam, Wayne; Shaknovich, Rita; Garcia, Benjamin A; Gascoyne, Randy D; Ge, Kai; Shilatifard, Ali; Elemento, Olivier; Nussenzweig, Andre; Melnick, Ari M; Wendel, Hans-Guido

    2015-10-01

    The gene encoding the lysine-specific histone methyltransferase KMT2D has emerged as one of the most frequently mutated genes in follicular lymphoma and diffuse large B cell lymphoma; however, the biological consequences of KMT2D mutations on lymphoma development are not known. Here we show that KMT2D functions as a bona fide tumor suppressor and that its genetic ablation in B cells promotes lymphoma development in mice. KMT2D deficiency also delays germinal center involution and impedes B cell differentiation and class switch recombination. Integrative genomic analyses indicate that KMT2D affects methylation of lysine 4 on histone H3 (H3K4) and expression of a set of genes, including those in the CD40, JAK-STAT, Toll-like receptor and B cell receptor signaling pathways. Notably, other KMT2D target genes include frequently mutated tumor suppressor genes such as TNFAIP3, SOCS3 and TNFRSF14. Therefore, KMT2D mutations may promote malignant outgrowth by perturbing the expression of tumor suppressor genes that control B cell-activating pathways. PMID:26366710

  13. The histone lysine methyltransferase KMT2D sustains a gene expression program that represses B cell lymphoma development

    PubMed Central

    Ortega-Molina, Ana; Boss, Isaac W.; Canela, Andres; Pan, Heng; Jiang, Yanwen; Zhao, Chunying; Jiang, Man; Hu, Deqing; Agirre, Xabier; Niesvizky, Itamar; Lee, Ji-Eun; Chen, Hua-Tang; Ennishi, Daisuke; Scott, David W.; Mottok, Anja; Hother, Christoffer; Liu, Shichong; Cao, Xing-Jun; Tam, Wayne; Shaknovich, Rita; Garcia, Benjamin A.; Gascoyne, Randy D.; Ge, Kai; Shilatifard, Ali; Elemento, Olivier; Nussenzweig, Andre; Melnick, Ari M.; Wendel, Hans-Guido

    2015-01-01

    The lysine-specific histone methyltransferase KMT2D has emerged as one of the most frequently mutated genes in follicular lymphoma (FL) and diffuse large B cell lymphoma (DLBCL). However, the biological consequences of KMT2D mutations on lymphoma development are not known. Here we show that KMT2D functions as a bona fide tumor suppressor and that its genetic ablation in B cells promotes lymphoma development in mice. KMT2D deficiency also delays germinal center (GC) involution, impedes B cell differentiation and class switch recombination (CSR). Integrative genomic analyses indicate that KMT2D affects H3K4 methylation and expression of a specific set of genes including those in the CD40, JAK-STAT, Toll-like receptor, and B cell receptor pathways. Notably, other KMT2D target genes include frequently mutated tumor suppressor genes such as TNFAIP3, SOCS3, and TNFRSF14. Therefore, KMT2D mutations may promote malignant outgrowth by perturbing the expression of tumor suppressor genes that control B cell activating pathways. PMID:26366710

  14. Tissue-Specific B-Cell Dysfunction and Generalized Memory B-Cell Loss during Acute SIV Infection

    PubMed Central

    Peruchon, Sandrine; Chaoul, Nada; Burelout, Chantal; Delache, Benoit; Brochard, Patricia; Laurent, Pascale; Cognasse, Fabrice; Prévot, Sophie; Garraud, Olivier; Le Grand, Roger; Richard, Yolande

    2009-01-01

    Background Primary HIV-infected patients display severe and irreversible damage to different blood B-cell subsets which is not restored by highly efficient anti-retroviral therapy (HAART). Because longitudinal investigations of primary HIV-infection is limited by the availability of lymphoid organs, we studied the tissue-specific B-cell dysfunctions in acutely simian immunodeficiency virus (SIV) mac251-infected Cynomolgus macaques. Methods and Findings Experiments were performed on three groups of macaques infected for 14, 21 or 28 days and on three groups of animals treated with HAART for two-weeks either initiated at 4 h, 7 or 14 days post-infection (p.i.). We have simultaneously compared changes in B-cell phenotypes and functions and tissue organization of B-cell areas in various lymphoid organs. We showed that SIV induced a steady decline in SIgG-expressing memory (SIgD−CD27+) B-cells in spleen and lymph nodes during the first 4 weeks of infection, concomitant to selective homing/sequestration of B-cells to the small intestine and spleen. SIV non-specific Ig production was transiently increased before D14p.i., whereas SIV-specific Ig production was only detectable after D14p.i., coinciding with the presence of CD8+ T-cells and IgG-expressing plasma cells within germinal centres. Transient B-cell apoptosis on D14p.i. and commitment to terminal differentiation contributed to memory B-cell loss. HAART abrogated B-cell apoptosis, homing to the small intestine and SIV-specific Ig production but had minimal effect on early Ig production, increased B-cell proportions in spleen and loss of memory B-cells. Therefore, virus–B-cell interactions and SIV-induced inflammatory cytokines may differently contribute to early B-cell dysfunction and impaired SIV/HIV-specific antibody response. Conclusions These data establish tissue-specific impairments in B-cell trafficking and functions and a generalized and steady memory B-cell loss in secondary lymphoid organs

  15. BAFF enhances chemotaxis of primary human B cells: a particular synergy between BAFF and CXCL13 on memory B cells.

    PubMed

    Badr, Gamal; Borhis, Gwenoline; Lefevre, Eric A; Chaoul, Nada; Deshayes, Frederique; Dessirier, Valérie; Lapree, Genevieve; Tsapis, Andreas; Richard, Yolande

    2008-03-01

    B-cell-activating factor of the TNF family, (BAFF), and a proliferation-inducing ligand (APRIL) regulate B-lymphocyte survival and activation. We report that BAFF, but not APRIL, increased the chemotactic response of primary human B cells to CCL21, CXCL12, and CXCL13. The BAFF-induced increase in B-cell chemotaxis was totally abolished by blockade of BAFF-R and was strongly dependent on the activation of PI3K/AKT, NF-kappaB, and p38MAPK pathways. BAFF had similar effects on the chemotaxis of naive and memory B cells in response to CCL21 but increased more strongly that of memory B cells to CXCL13 than that of naive B cells. Our findings indicate a previously unreported role for the BAFF/BAFF-R pair in mature B-cell chemotaxis. The synergy between CXCL13 and BAFF produced by stromal cells and follicular dendritic cells may have important implications for B-cell homeostasis, the development of normal B-cell areas, and for the formation of germinal center-like follicles that may be observed in various autoimmune diseases.

  16. DOCK2 regulates cell proliferation through Rac and ERK activation in B cell lymphoma

    SciTech Connect

    Wang, Lei; Nishihara, Hiroshi; Kimura, Taichi; Kato, Yasutaka; Tanino, Mishie; Nishio, Mitsufumi; Obara, Masato; Endo, Tomoyuki; Koike, Takao; Tanaka, Shinya

    2010-04-23

    DOCK2; a member of the CDM protein family, regulates cell motility and cytokine production through the activation of Rac in mammalian hematopoietic cells and plays a pivotal role in the modulation of the immune system. Here we demonstrated the alternative function of DOCK2 in hematopoietic tumor cells, especially in terms of its association with the tumor progression. Immunostaining for DOCK2 in 20 cases of human B cell lymphoma tissue specimens including diffuse large B cell lymphoma and follicular lymphoma revealed the prominent expression of DOCK2 in all of the lymphoma cells. DOCK2-knockdown (KD) of the B cell lymphoma cell lines, Ramos and Raji, using the lentiviral shRNA system presented decreased cell proliferation compared to the control cells. Furthermore, the tumor formation of DOCK2-KD Ramos cell in nude mice was significantly abrogated. Western blotting analysis and pull-down assay using GST-PAK-RBD kimeric protein suggested the presence of DOCK2-Rac-ERK pathway regulating the cell proliferation of these lymphoma cells. This is the first report to clarify the prominent role of DOCK2 in hematopoietic malignancy.

  17. Role of EBNA-3 Family Proteins in EBV Associated B-cell Lymphomagenesis

    PubMed Central

    Bhattacharjee, Shaoni; Ghosh Roy, Shatadru; Bose, Priyanka; Saha, Abhik

    2016-01-01

    Epstein-Barr virus (EBV) is highly ubiquitous in human population and establishes a lifelong asymptomatic infection within the infected host unless the immune system is compromised. Following initial infection in the oropharyngeal epithelial cells, EBV primarily infects naive B-lymphocytes and develops a number of B-cell lymphomas particularly in immune-deficient individuals. In vitro, EBV can also infect and subsequently transform quiescent B-lymphocytes into continuously proliferating lymphoblastoid cell lines (LCLs) resembling EBV-induced lymphoproliferative disorders in which a subset of latent transcripts are detected. Genetic studies revealed that EBNA-3 family comprising of three adjacent genes in the viral genome—EBNA-3A and -3C, but not -3B, are critical for B-cell transformation. Nevertheless, all three proteins appear to significantly contribute to maintain the overall proliferation and viability of transformed cells, suggesting a critical role in lymphoma development. Apart from functioning as important viral transcriptional regulators, EBNA-3 proteins associate with many cellular proteins in different signaling networks, providing a suitable platform for lifelong survival of the virus and concurrent lymphoma development in the infected host. The chapter describes the function of each these EBV nuclear antigen 3 proteins employed by the virus as a means to understand viral pathogenesis of several EBV-associated B-cell malignancies. PMID:27092119

  18. Anti-cancer activity of withaferin A in B-cell lymphoma.

    PubMed

    McKenna, M K; Gachuki, B W; Alhakeem, S S; Oben, K N; Rangnekar, V M; Gupta, R C; Bondada, S

    2015-01-01

    Withaferin A (WA), a withanolide from the plant, Ashwagandha (Withania somnifera) used in Ayurvedic medicine, has been found to be valuable in the treatment of several medical ailments. WA has been found to have anticancer activity against various solid tumors, but its effects on hematological malignancies have not been studied in detail. WA strongly inhibited the survival of several human and murine B cell lymphoma cell lines. Additionally, in vivo studies with syngeneic-graft lymphoma cells suggest that WA inhibits the growth of tumor but does not affect other proliferative tissues. We demonstrate that WA inhibits the efficiency of NF-κB nuclear translocation in diffuse large B cell lymphomas and found that WA treatment resulted in a significant decrease in protein levels involved in B cell receptor signaling and cell cycle regulation. WA inhibited the activity of heat shock protein (Hsp) 90 as reflected by a sharp increase in Hsp70 expression levels. Hence, we propose that the anti-cancer effects of WA in lymphomas are likely due to its ability to inhibit Hsp90 function and subsequent reduction of critical kinases and cell cycle regulators that are clients of Hsp90. PMID:26020511

  19. Proteomics Based Identification of Proteins with Deregulated Expression in B Cell Lymphomas.

    PubMed

    Wu, Rui; Nijland, Marcel; Rutgers, Bea; Veenstra, Rianne; Langendonk, Myra; van der Meeren, Lotte E; Kluin, Philip M; Li, Guanwu; Diepstra, Arjan; Chiu, Jen-Fu; van den Berg, Anke; Visser, Lydia

    2016-01-01

    Follicular lymphoma and diffuse large B cell lymphomas comprise the main entities of adult B cell malignancies. Although multiple disease driving gene aberrations have been identified by gene expression and genomic studies, only a few studies focused at the protein level. We applied 2 dimensional gel electrophoresis to compare seven GC B cell non Hodgkin lymphoma (NHL) cell lines with a lymphoblastoid cell line (LCL). An average of 130 spots were at least two folds different in intensity between NHL cell lines and the LCL. We selected approximately 38 protein spots per NHL cell line and linked them to 145 unique spots based on the location in the gel. 34 spots that were found altered in at least three NHL cell lines when compared to LCL, were submitted for LC-MS/MS. This resulted in 28 unique proteins, a substantial proportion of these proteins were involved in cell motility and cell metabolism. Loss of expression of B2M, and gain of expression of PRDX1 and PPIA was confirmed in the cell lines and primary lymphoma tissue. Moreover, inhibition of PPIA with cyclosporine A blocked cell growth of the cell lines, the effect size was associated with the PPIA expression levels. In conclusion, we identified multiple differentially expressed proteins by 2-D proteomics, and showed that some of these proteins might play a role in the pathogenesis of NHL. PMID:26752561

  20. Blinatumomab for the Treatment of Philadelphia Chromosome-Negative, Precursor B-cell Acute Lymphoblastic Leukemia.

    PubMed

    Wolach, Ofir; Stone, Richard M

    2015-10-01

    Blinatumomab is a CD19/CD3 bispescific antibody designed to redirect T cells toward malignant B cells and induce their lysis. It recently gained accelerated approval by the FDA for the treatment of relapsed or refractory Philadelphia chromosome-negative B-cell acute lymphoblastic leukemia (RR-ALL). In the phase II trial that served as the basis for approval, blinatumomab demonstrated significant single-agent activity and induced remission [complete remission (CR) and CR with incomplete recovery of peripheral blood counts (CRh)] in 43% of 189 adult patients with RR-ALL; the majority of responders (82%) also attained negative minimal residual disease (MRD(-)) status that did not generally translate into long-term remissions in most cases. Additional studies show that blinatumomab can induce high response rates associated with lasting remissions in patients in first remission treated for MRD positivity, suggesting a role for blinatumomab in the upfront, MRD-positive setting. Blinatumomab infusion follows a predictable immunopharmacologic profile, including early cytokine release that can be associated with a clinical syndrome, T-cell expansion, and B-cell depletion. Neurologic toxicities represent a unique toxicity that shares similarities with adverse effects of other T-cell engaging therapies. Further studies are needed to clarify the optimal disease setting and timing for blinatumomab therapy. Additional insights into the pathogenesis, risk factors, and prevention of neurologic toxicities as well as a better understanding of the clinical consequences and biologic pathways that are associated with drug resistance are needed. PMID:26283683

  1. Dermatan Sulfate Interacts with Dead Cells and Regulates CD5+ B-Cell Fate

    PubMed Central

    Wang, Julia Y.; Lee, Jongmin; Yan, Ming; Rho, Jung-hyun; Roehrl, Michael H.A.

    2011-01-01

    CD5+ (B-1a) B cells play pivotal roles in autoimmunity through expression of autoreactive B-cell receptors and production of autoantibodies. The mechanism underlying their positive selection and expansion is currently unknown. This study demonstrates that dermatan sulfate (DS) expands the B-1a cell population and augments the specific antibody response to an antigen when it is in complex with DS. DS displays preferential affinity for apoptotic and dead cells, and DS-stimulated cell cultures produce antibodies to various known autoantigens. The companion article further illustrates that autoantigens can be identified by affinity to DS, suggesting that molecules with affinity to DS have a high propensity to become autoantigens. We thus propose that the association of antigens from dead cells with DS is a possible origin of autoantigens and that autoreactive B-1a cells are positively selected and expanded by DS∙autoantigen complexes. This mechanism may also explain the clonal expansion of B-1a cells in certain B-cell malignancies. PMID:21514431

  2. B Cell Lymphoma, Unclassifiable, Transformed from Follicular Lymphoma: A Rare Presentation with Review of the Literature

    PubMed Central

    Kanna, Anila; Agrawal, Swati; Jayant, Kumar; Kumar Pala, Varun; Altujjar, Mohammad; Hadid, Tarik; Khurram, Muhammad

    2015-01-01

    B cell lymphoma, unclassifiable, with features of diffuse large B cell lymphoma and classical Hodgkin's lymphoma (BCLu-DLBCL/CHL) is more commonly known as gray zone lymphoma. These cases more often present with mediastinal disease. In this report, we present a very rare case of BCLu-DLBCL/CHL without mediastinal involvement, transformed from follicular lymphoma (FL) to BCLu-DLBCL/CHL. This patient initially presented with a mass in the right neck; biopsy of the lymph node showed predominantly nodular, follicular pattern. Immunohistochemical (IHC) staining of tumor cells expressed positivity for mature B cell markers CD20, CD19, CD10, CD23, CD45, and CD38 but negative for CD5,11c. Hence, diagnosed with FL, he was given rituximab, cyclophosphamide, vincristine, and prednisone (RCVP) regimen, followed by maintenance rituximab. He showed good response. After 2 years, he presented again with a mass in the right side of the neck. Although the needle core biopsy of this mass was suggestive of B cell lymphoma, excisional biopsy showed morphological features of DLBCL as well as foci of histological pattern of CHL. IHC staining expressed positivity for CD20, CD79a, PAX5, and CD15 and CD30 consistent with DLBCL and CHL. He was diagnosed with BCLu-DLBCL/CHL. The patient received “ACVBP” (doxorubicin, cyclophosphamide, vindesine, bleomycin, and prednisone) followed by radiation. BCLu-DLBCL/CHL is clinically an aggressive tumor with poorer outcomes, but our case showed complete response to ACVBP regimen with tumor regression. PMID:26380128

  3. The role of B-cell receptor inhibitors in the treatment of patients with chronic lymphocytic leukemia

    PubMed Central

    Wiestner, Adrian

    2015-01-01

    Chronic lymphocytic leukemia is a malignancy of mature auto-reactive B cells. Genetic and functional studies implicate B-cell receptor signaling as a pivotal pathway in its pathogenesis. Full B-cell receptor activation requires tumor-microenvironment interactions in lymphoid tissues. Spleen tyrosine kinase, Bruton’s tyrosine kinase, and the phosphatidylinositol 3-kinase (PI3K) δ isoform are essential for B-cell receptor signal transduction but also mediate the effect of other pathways engaged in chronic lymphocytic leukemia cells in the tissue-microenvironment. Orally bioavailable inhibitors of spleen tyrosine kinase, Bruton’s tyrosine kinase, or PI3Kδ, induce high rates of durable responses. Ibrutinib, a covalent inhibitor of Bruton’s tyrosine kinase, and idelalisib, a selective inhibitor of PI3Kδ, have obtained regulatory approval in chronic lymphocytic leukemia. Ibrutinib and idelalisib are active in patients with high-risk features, achieving superior disease control in difficult-to-treat patients than prior best therapy, making them the preferred agents for chronic lymphocytic leukemia with TP53 aberrations and for patients resistant to chemoimmunotherapy. In randomized trials, both ibrutinib, versus ofatumumab, and idelalisib in combination with rituximab, versus placebo with rituximab improved survival in relapsed/refractory chronic lymphocytic leukemia. Responses to B-cell receptor inhibitors are mostly partial, and within clinical trials treatment is continued until progression or occurrence of intolerable side effects. Ibrutinib and idelalisib are, overall, well tolerated; notable adverse events include increased bruising and incidence of atrial fibrillation on ibrutinib and colitis, pneumonitis and transaminase elevations on idelalisib. Randomized trials investigate the role of B-cell receptor inhibitors in first-line therapy and the benefit of combinations. This review discusses the biological basis for targeted therapy of chronic lymphocytic

  4. Human bronchial epithelial BEAS-2B cells, an appropriate in vitro model to study heavy metals induced carcinogenesis.

    PubMed

    Park, Youn-Hee; Kim, Donghern; Dai, Jin; Zhang, Zhuo

    2015-09-15

    Occupational and environmental exposure to arsenic (III) and chromium VI (Cr(VI)) have been confirmed to cause lung cancer. Mechanisms of these metals carcinogenesis are still under investigation. Selection of cell lines to be used is essential for the studies. Human bronchial epithelial BEAS-2B cells are the cells to be utilized by most of scientists. However, due to p53 missense mutation (CCG→TCG) at codon 47 and the codon 72 polymorphism (CGC→CCC) in BEAS-2B cells, its usage has frequently been questioned. The present study has examined activity and expression of 53 and its downstream target protein p21 upon acute or chronic exposure of BEAS-2B cells to arsenic and Cr(VI). The results show that short-term exposure of BEAS-2B cells to arsenic or Cr(VI) was able to activate both p53 and p21. Chronic exposure of BEAS-2B cells to these two metals caused malignant cell transformation and tumorigenesis. In arsenic-transformed BEAS-2B cells reductions in p53 promoter activity, mRNA expression, and phosphorylation of p53 at Ser392 were observed, while the total p53 protein level remained the same compared to those in passage-matched parent ones. p21 promoter activity and expression were decreased in arsenic-transformed cells. Cr(VI)-transformed cells exhibit elevated p53 promoter activity, mRNA expression, and phosphorylation at Ser15, but reduced phosphorylation at Ser392 and total p53 protein level compared to passage-matched parent ones. p21 promoter activity and expression were elevated in Cr(VI)-transformed cells. These results demonstrate that p53 is able to respond to exposure of arsenic or Cr(VI), suggesting that BEAS-2B cells are an appropriate in vitro model to investigate arsenic or Cr(VI) induced lung cancer.

  5. Human bronchial epithelial BEAS-2B cells, an appropriate in vitro model to study heavy metals induced carcinogenesis

    PubMed Central

    Park, Youn-hee; Kim, Donghern; Dai, Jin; Zhang, Zhuo

    2015-01-01

    Occupational and environmental exposure to arsenic (III) and chromium VI (Cr(VI)) have been confirmed to cause lung cancer. Mechanisms of these metals-induced carcinogenesis are still under investigation. Selection of cell lines to be used is essential for the mechanistic studies. Human bronchial epithelial BEAS-2B cells are the cells to be utilized by most of scientists. However, due to p53 missense mutation (CCG → TCG) at codon 47 and the codon 72 polymorphism (CGC → CCC) in BEAS-2B cells, its usage has frequently been questioned. The present study has examined activity and expression of 53 and its downstream target protein p21 upon acute or chronic exposure of BEAS-2B cells to arsenic and Cr(VI). The results show that short-term exposure of BEAS-2B cells to arsenic or Cr(VI) was able to activate both p53 and p21. Chronic exposure of BEAS-2B cells to these two metals caused malignant cell transformation and tumorigenesis. In arsenic-transformed BEAS-2B cells reductions in p53 promoter activity, mRNA expression, and phosphorylation of p53 at Ser392 were observed, while the total p53 protein level remained the same compared to those in passage-matched parent ones. p21 promoter activity and expression were decreased in arsenic-transformed cells. Cr(VI)-transformed cells exhibit elevated p53 promoter activity, mRNA expression, and phosphorylation at Ser15, but reduced phosphorylation at Ser392 and total p53 protein level compared to passage-matched parent ones. p21 promoter activity and expression were elevated in Cr(VI)-transformed cells. These results demonstrate that p53 is able to respond to exposure of arsenic or Cr(VI), suggesting that BEAS-2B cells are an appropriate in vitro model to investigate arsenic or Cr(VI) induced lung cancer. PMID:26091798

  6. DC-SIGN–expressing macrophages trigger activation of mannosylated IgM B-cell receptor in follicular lymphoma

    PubMed Central

    Amin, Rada; Mourcin, Frédéric; Uhel, Fabrice; Pangault, Céline; Ruminy, Philippe; Dupré, Loic; Guirriec, Marion; Marchand, Tony; Fest, Thierry; Lamy, Thierry

    2015-01-01

    Follicular lymphoma (FL) results from the accumulation of malignant germinal center (GC) B cells leading to the development of an indolent and largely incurable disease. FL cells remain highly dependent on B-cell receptor (BCR) signaling and on a specific cell microenvironment, including T cells, macrophages, and stromal cells. Importantly, FL BCR is characterized by a selective pressure to retain surface immunoglobulin M (IgM) BCR despite an active class-switch recombination process, and by the introduction, in BCR variable regions, of N-glycosylation acceptor sites harboring unusual high-mannose oligosaccharides. However, the relevance of these 2 FL BCR features for lymphomagenesis remains unclear. In this study, we demonstrated that IgM+ FL B cells activated a stronger BCR signaling network than IgG+ FL B cells and normal GC B cells. BCR expression level and phosphatase activity could both contribute to such heterogeneity. Moreover, we underlined that a subset of IgM+ FL samples, displaying highly mannosylated BCR, efficiently bound dendritic cell–specific intercellular adhesion molecule-3–grabbing nonintegrin (DC-SIGN), which could in turn trigger delayed but long-lasting BCR aggregation and activation. Interestingly, DC-SIGN was found within the FL cell niche in situ. Finally, M2 macrophages induced a DC-SIGN–dependent adhesion of highly mannosylated IgM+ FL B cells and triggered BCR-associated kinase activation. Interestingly, pharmacologic BCR inhibitors abolished such crosstalk between macrophages and FL B cells. Altogether, our data support an important role for DC-SIGN–expressing infiltrating cells in the biology of FL and suggest that they could represent interesting therapeutic targets. PMID:26272216

  7. Human bronchial epithelial BEAS-2B cells, an appropriate in vitro model to study heavy metals induced carcinogenesis.

    PubMed

    Park, Youn-Hee; Kim, Donghern; Dai, Jin; Zhang, Zhuo

    2015-09-15

    Occupational and environmental exposure to arsenic (III) and chromium VI (Cr(VI)) have been confirmed to cause lung cancer. Mechanisms of these metals carcinogenesis are still under investigation. Selection of cell lines to be used is essential for the studies. Human bronchial epithelial BEAS-2B cells are the cells to be utilized by most of scientists. However, due to p53 missense mutation (CCG→TCG) at codon 47 and the codon 72 polymorphism (CGC→CCC) in BEAS-2B cells, its usage has frequently been questioned. The present study has examined activity and expression of 53 and its downstream target protein p21 upon acute or chronic exposure of BEAS-2B cells to arsenic and Cr(VI). The results show that short-term exposure of BEAS-2B cells to arsenic or Cr(VI) was able to activate both p53 and p21. Chronic exposure of BEAS-2B cells to these two metals caused malignant cell transformation and tumorigenesis. In arsenic-transformed BEAS-2B cells reductions in p53 promoter activity, mRNA expression, and phosphorylation of p53 at Ser392 were observed, while the total p53 protein level remained the same compared to those in passage-matched parent ones. p21 promoter activity and expression were decreased in arsenic-transformed cells. Cr(VI)-transformed cells exhibit elevated p53 promoter activity, mRNA expression, and phosphorylation at Ser15, but reduced phosphorylation at Ser392 and total p53 protein level compared to passage-matched parent ones. p21 promoter activity and expression were elevated in Cr(VI)-transformed cells. These results demonstrate that p53 is able to respond to exposure of arsenic or Cr(VI), suggesting that BEAS-2B cells are an appropriate in vitro model to investigate arsenic or Cr(VI) induced lung cancer. PMID:26091798

  8. Blinatumomab: Bridging the Gap in Adult Relapsed/Refractory B-Cell Acute Lymphoblastic Leukemia.

    PubMed

    Folan, Stephanie A; Rexwinkle, Amber; Autry, Jane; Bryan, Jeffrey C

    2016-08-01

    Adult patients with acute lymphoblastic leukemia who relapse after frontline therapy have extremely poor outcomes despite advances in chemotherapy and hematopoietic stem cell transplantation. Blinatumomab is a first-in-class bispecific T-cell engager that links T cells to tumor cells leading to T-cell activation and tumor cell lysis. In December 2014, the Food and Drug Administration approved blinatumomab for treatment of relapsed or refractory Philadelphia chromosome-negative precursor B-cell acute lymphoblastic leukemia. In a phase II trial, blinatumomab produced response rates of 43%, and 40% of patients achieving a complete remission proceeded to hematopoietic stem cell transplantation. Early use of blinatumomab was complicated with adverse effects, including cytokine release syndrome and neurotoxicity. Management strategies, including dexamethasone premedication and 2-step dose escalation during the first cycle of blinatumomab, have decreased the incidence and severity of these adverse effects. Blinatumomab currently is being studied for other B-cell malignancies and has the potential to benefit many patients with CD19+ malignancies in the future. PMID:27521320

  9. 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-α 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

  10. Are autoantibodies the targets of B-cell-directed therapy?

    PubMed

    Pisetsky, David S; Grammer, Amrie C; Ning, Tony C; Lipsky, Peter E

    2011-09-01

    B-cell-directed therapy-the use of agents that eliminate B cells or block cytokines important for B-cell function-is emerging as a promising approach to the treatment of rheumatic disease. Target diseases, including systemic lupus erythematosus (SLE), display diverse patterns of autoantibody production and aberrant activation of B cells. Despite the success of this general approach, the mechanisms by which B-cell-directed therapy ameliorates disease, and the role of autoantibodies as biomarkers of clinical response remain unclear. Importantly, although B-cell-directed therapy can reduce the production of some autoantibodies, the effects can be variable and heterogeneous, probably reflecting the critical (but ill-defined) roles of different B-cell and plasma cell populations in autoantibody production. Future studies during clinical trials of these agents are needed to define which B-cell and autoantibody populations are affected (or ought to be), and to discover informative biomarkers of clinical response that can be used to advance this therapeutic approach.

  11. A fine romance: T follicular helper cells and B cells.

    PubMed

    King, Cecile

    2011-06-24

    T follicular helper (Tfh) cells help B cells to generate affinity-matured antibodies. Three papers in this issue of Immunity (Choi et al., 2011; Kerfoot et al., 2011; Kitano et al., 2011) provide information about the reciprocal relationship between B cells and Tfh cells.

  12. 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.

  13. A fine romance: T follicular helper cells and B cells.

    PubMed

    King, Cecile

    2011-06-24

    T follicular helper (Tfh) cells help B cells to generate affinity-matured antibodies. Three papers in this issue of Immunity (Choi et al., 2011; Kerfoot et al., 2011; Kitano et al., 2011) provide information about the reciprocal relationship between B cells and Tfh cells. PMID:21703537

  14. B cells as therapeutic targets in autoimmune neurological disorders.

    PubMed

    Dalakas, Marinos C

    2008-10-01

    B cells have a fundamental role in the pathogenesis of various autoimmune neurological disorders, not only as precursors of antibody-producing cells, but also as important regulators of the T-cell activation process through their participation in antigen presentation, cytokine production, and formation of ectopic germinal centers in the intermeningeal spaces. Two B-cell trophic factors-BAFF (B-cell-activating factor) and APRIL (a proliferation-inducing ligand)-and their receptors are strongly upregulated in many immunological disorders of the CNS and PNS, and these molecules contribute to clonal expansion of B cells in situ. The availability of monoclonal antibodies or fusion proteins against B-cell surface molecules and trophic factors provides a rational approach to the treatment of autoimmune neurological diseases. This article reviews the role of B cells in autoimmune neurological disorders and summarizes the experience to date with rituximab, a B-cell-depleting monoclonal antibody against CD20, for the treatment of relapsing-remitting multiple sclerosis, autoimmune neuropathies, neuromyelitis optica, paraneoplastic neurological disorders, myasthenia gravis, and inflammatory myopathies. It is expected that ongoing controlled trials will establish the efficacy and long-term safety profile of anti-B-cell agents in several autoimmune neurological disorders, as well as exploring the possibility of a safe and synergistic effect with other immunosuppressants or immunomodulators.

  15. Therapeutic strategies targeting B-cells in multiple sclerosis.

    PubMed

    Milo, Ron

    2016-07-01

    Multiple sclerosis (MS) is a chronic inflammatory and demyelinating disease of the central nervous system (CNS) that traditionally has been considered to be mediated primarily by T-cells. Increasing evidence, however, suggests the fundamental role of B-cells in the pathogenesis of the disease. Recent strategies targeting B-cells in MS have demonstrated impressive and sometimes surprising results: B-cell depletion by monoclonal antibodies targeting the B-cell surface antigen CD20 (e.g. rituximab, ocrelizumab, ofatumumab) was shown to exert profound anti-inflammatory effect in MS with favorable risk-benefit ratio, with ocrelizumab demonstrating efficacy in both relapsing-remitting (RR) and primary-progressive (PP) MS in phase III clinical trials. Depletion of CD52 expressing T- and B-cells and monocytes by alemtuzumab resulted in impressive and durable suppression of disease activity in RRMS patients. On the other hand, strategies targeting B-cell cytokines such as atacicept resulted in increased disease activity. As our understanding of the biology of B-cells in MS is increasing, new compounds that target B-cells continue to be developed which promise to further expand the armamentarium of MS therapies and allow for more individualized therapy for patients with this complex disease.

  16. B cells do not present antigen covalently linked to microspheres.

    PubMed Central

    Galelli, A; Charlot, B; Dériaud, E; Leclerc, C

    1993-01-01

    B cells have been shown to present antigen to T cells very efficiently through their capacity to capture antigens by their membrane immunoglobulin. This direct cognate interaction of T and B cells results in the proliferation and differentiation of B cells. This concept has been established using soluble proteins. However, most of the antigens to which the immune system is exposed are included in complex particulate structures such as bacteria or parasites. The capacity of B cells to present these large and complex antigens is still unclear. To address this question we have studied the presentation by trinitrophenyl (TNP)-specific B cells of the same antigen TNP-KLH (keyhole limpet haemocyanin), either in a soluble form or covalently linked to poly(acrolein) microspheres, from 0.25 to 1.5 microns in diameter. In the presence of irradiated splenocytes or purified macrophages as a source of antigen-presenting cells (APC), KLH-specific T cells proliferated in response to soluble TNP-KLH or to TNP-KLH coupled to beads. In contrast, TNP-specific memory B cells were totally ineffective in presenting the TNP-KLH beads to KLH-specific T cells whereas they presented very efficiently soluble TNP-KLH. Similar results were obtained with the A20 B lymphoma or with lipopolysaccharide (LPS)-activated TNP-specific B cells. These results therefore indicate that B cells are unable to present large size particulate antigens such as bacteria or parasites. PMID:8509143

  17. Malignant Peripheral Nerve Sheath Tumor -A Rare Malignancy in Mandible.

    PubMed

    Majumdar, Sumit; Kotina, Sreekanth; Mahesh, Nirujogi; Uppala, Divya; Kumar, Singam Praveen

    2016-06-01

    Malignant Peripheral Nerve Sheath Tumor (MPNST) is biologically an aggressive tumor that is usually found in the extremities, trunk and infrequently found in the head and neck area particularly in the jaws, arising from the cells allied with nerve sheath. Mandibular MPNST may either arise from a preexisting neurofibroma or develop de novo. Because of the greater variability from case to case in overall appearance both clinically and histologically, a case of MPNST of the mandible in a 25-year-old female patient is reported. The lesion was excised and immunohistological studies (S-100 & Neuron specific enolase) were conducted to confirm the neural origin.

  18. Malignant Peripheral Nerve Sheath Tumor -A Rare Malignancy in Mandible

    PubMed Central

    Majumdar, Sumit; Kotina, Sreekanth; Uppala, Divya; Kumar, Singam Praveen

    2016-01-01

    Malignant Peripheral Nerve Sheath Tumor (MPNST) is biologically an aggressive tumor that is usually found in the extremities, trunk and infrequently found in the head and neck area particularly in the jaws, arising from the cells allied with nerve sheath. Mandibular MPNST may either arise from a preexisting neurofibroma or develop de novo. Because of the greater variability from case to case in overall appearance both clinically and histologically, a case of MPNST of the mandible in a 25-year-old female patient is reported. The lesion was excised and immunohistological studies (S-100 & Neuron specific enolase) were conducted to confirm the neural origin. PMID:27504425

  19. DHA-enriched fish oil targets B cell lipid microdomains and enhances ex vivo and in vivo B cell function

    PubMed Central

    Gurzell, Eric A.; Teague, Heather; Harris, Mitchel; Clinthorne, Jonathan; Shaikh, Saame Raza; Fenton, Jenifer I.

    2013-01-01

    DHA is a n-3 LCPUFA in fish oil that generally suppresses T lymphocyte function. However, the effect of fish oil on B cell function remains relatively understudied. Given the important role of B cells in gut immunity and increasing human fish oil supplementation, we sought to determine whether DFO leads to enhanced B cell activation in the SMAD−/− colitis-prone mouse model, similar to that observed with C57BL/6 mice. This study tested the hypothesis that DHA from fish oil is incorporated into the B cell membrane to alter lipid microdomain clustering and enhance B cell function. Purified, splenic B cells from DFO-fed mice displayed increased DHA levels and diminished GM1 microdomain clustering. DFO enhanced LPS-induced B cell secretion of IL-6 and TNF-α and increased CD40 expression ex vivo compared with CON. Despite increased MHCII expression in the unstimulated ex vivo B cells from DFO-fed mice, we observed no difference in ex vivo OVA-FITC uptake in B cells from DFO or CON mice. In vivo, DFO increased lymphoid tissue B cell populations and surface markers of activation compared with CON. Finally, we investigated whether these ex vivo and in vivo observations were consistent with systemic changes. Indeed, DFO-fed mice had significantly higher plasma IL-5, IL-13, and IL-9 (Th2-biasing cytokines) and cecal IgA compared with CON. These results support the hypothesis and an emerging concept that fish oil enhances B cell function in vivo. PMID:23180828

  20. Precursor B Cells Increase in the Lung during Airway Allergic Inflammation: A Role for B Cell-Activating Factor

    PubMed Central

    Malmhäll, Carina; Rådinger, Madeleine; Ramos-Ramirez, Patricia; Lu, You; Deák, Tünde; Semitekolou, Maria; Gaga, Mina; Sjöstrand, Margareta; Lötvall, Jan; Bossios, Apostolos

    2016-01-01

    Background B cells, key cells in allergic inflammation, differentiate in the bone marrow and their precursors include pro-B, pre-B and immature B cells. Eosinophil progenitor cells increase in the lung after allergen exposure. However, the existence and possible role of B cell precursors in the lung during allergic inflammation remains elusive. Methods A BALB/c mouse model of allergic airway inflammation was utilized to perform phenotypic and quantification analyses of pro-B and pre-B cells in the lung by flow cytometry. B cell maturation factors IL-7 and B cell-activating factor (BAFF) and their receptors (CD127 and BAFFR, BCMA, TACI, respectively) were also evaluated in the lung and serum. The effect of anti-BAFF treatment was investigated both in vivo (i.p. administration of BAFF-R-Ig fusion protein) and in vitro (colony forming cell assay). Finally, BAFF levels were examined in the bronchoalveolar lavage (BAL) of asthmatic patients and healthy controls. Results Precursor pro and pre-B cells increase in the lung after allergen exposure, proliferate in the lung tissue in vivo, express markers of chemotaxis (CCR10 and CXCR4) and co-stimulation (CD40, CD86) and are resistant to apoptosis (Bax). Precursor B cells express receptors for BAFF at baseline, while after allergen challenge both their ligand BAFF and the BCMA receptor expression increases in B cell precursors. Blocking BAFFR in the lung in vivo decreases eosinophils and proliferating precursor B cells. Blocking BAFFR in bone marrow cultures in vitro reduces pre-B colony formation units. BAFF is increased in the BAL of severe asthmatics. Conclusion Our data support the concept of a BAFF-mediated role for B cell precursors in allergic airway inflammation. PMID:27513955

  1. The regulation and activation of lupus-associated B cells.

    PubMed

    Fields, Michele L; Hondowicz, Brian D; Wharton, Gina N; Adair, Brigette S; Metzgar, Michele H; Alexander, Shawn T; Caton, Andrew J; Erikson, Jan

    2005-04-01

    Anti-double-stranded DNA (anti-dsDNA) B cells are regulated in non-autoimmune mice. While some are deleted or undergo receptor editing, a population of anti-dsDNA (VH3H9/V lambda 1) B cells that emigrate into the periphery has also been identified. These cells have an altered phenotype relative to normal B cells in that they have a reduced lifespan, appear developmentally arrested, and localize primarily to the T/B-cell interface in the spleen. This phenotype may be the consequence of immature B cells encountering antigen in the absence of T-cell help. When provided with T-cell help, the anti-dsDNA B cells differentiate into antibody-forming cells. In the context of the autoimmune-prone lpr/lpr or gld/gld mutations, the VH3H9/V lambda 1 anti-dsDNA B cells populate the B-cell follicle and by 12 weeks of age produce serum autoantibodies. The early event of anti-dsDNA B-cell follicular entry, in the absence of autoantibody production, is dependent upon CD4(+) T cells. We hypothesize that control of autoantibody production in young autoimmune-prone mice may be regulated by the counterbalancing effect of T-regulatory (T(reg)) cells. Consistent with this model, we have demonstrated that T(reg) cells are able to prevent autoantibody production induced by T-cell help. Additional studies are aimed at investigating the mechanisms of this suppression as well as probing the impact of distinct forms of T-cell-dependent and -independent activation on anti-dsDNA B cells.

  2. Malignant hyperthermia.

    PubMed

    Cantin, R Y; Poole, A; Ryan, J F

    1986-10-01

    The increasing use of intravenous and inhalation sedation in the dental office has the potential of increasing the incidence of malignant hyperthermia (MH) in susceptible subjects. The object of this article is to present two cases of MH and to discuss its pathophysiology, its clinical picture, and its management in the light of the current literature. Stringent screening procedures should be adopted and maintained in order to channel suspected cases to appropriate centers for expert consultation and management. It is further advocated that a program of education for patients and their families be instituted, as it is an essential prerequisite of effective prophylaxis. PMID:2946013

  3. Prolactin Rescues Immature B-Cells from Apoptosis Induced by B-Cell Receptor Cross-Linking

    PubMed Central

    Flores-Fernández, Rocio; Blanco-Favela, Francisco; Fuentes-Pananá, Ezequiel M.; Chávez-Sánchez, Luis; Gorocica-Rosete, Patricia; Pizaña-Venegas, Alberto; Chávez-Rueda, Adriana Karina

    2016-01-01

    Prolactin has an immunomodulatory effect and has been associated with B-cell-triggered autoimmune diseases, such as systemic lupus erythematosus (SLE). In mice that develop SLE, the PRL receptor is expressed in early bone marrow B-cells, and increased levels of PRL hasten disease manifestations, which are correlated with a reduction in the absolute number of immature B-cells. The aim of this work was to determine the effect of PRL in an in vitro system of B-cell tolerance using WEHI-231 cells and immature B-cells from lupus prone MRL/lpr mice. WEHI-231 cells express the long isoform of the PRL receptor, and PRL rescued the cells from cell death by decreasing the apoptosis induced by the cross-linking of the B-cell antigen receptor (BCR) as measured by Annexin V and active caspase-3. This decrease in apoptosis may have been due to the PRL and receptor interaction, which increased the relative expression of antiapoptotic Bcl-xL and decreased the relative expression of proapoptotic Bad. In immature B-cells from MRL/lpr mice, PRL increased the viability and decreased the apoptosis induced by the cross-linking of BCR, which may favor the maturation of self-reactive B-cells and contribute to the onset of disease. PMID:27314053

  4. Monocytes and T cells cooperate to favor normal and follicular lymphoma B-cell growth: role of IL-15 and CD40L signaling.

    PubMed

    Epron, G; Ame-Thomas, P; Le Priol, J; Pangault, C; Dulong, J; Lamy, T; Fest, T; Tarte, K

    2012-01-01

    Interleukin-15 (IL-15) has been extensively studied for its role in the survival and proliferation of NK and T cells through a unique mechanism of trans-presentation by producer cells. Conversely, whereas activated B cells have been described as IL-15-responding cells, the cellular and molecular context sustaining this effect remains unexplored. In this study, we found that, whereas human B cells could not respond to soluble IL-15, monocytes and lymphoid tissue-derived macrophages but not stromal cells efficiently trans-present IL-15 to normal B cells and cooperate with T-cell-derived CD40L to promote IL-15-dependent B-cell proliferation. Furthermore, CD40L signaling triggers a Src-independent upregulation of STAT5 expression and favors a Src-dependent phosphorylation of STAT5 in response to IL-15. In follicular lymphoma (FL), immunohistochemical studies reported a strong relationship between malignant B cells, infiltrating macrophages and T cells. We show here an overexpression of IL-15 in purified tumor-associated macrophages, and STAT5A in purified tumor B cells. Moreover, FL B cells respond to IL-15 trans-presented by monocytes/macrophages, in particular, in the presence of CD40L-mediated signaling. This cooperation between IL-15 and CD40L reinforces the importance of tumor microenvironment and unravels a mechanism of FL growth that should be considered if using IL-15 as a drug in this disease.

  5. Malignant hyperthermia

    PubMed Central

    2012-01-01

    Malignant hyperthermia (MH) is an uncommon, life-threatening pharmacogenetic disorder of the skeletal muscle. It presents as a hypermetabolic response in susceptible individuals to potent volatile anesthetics with/without depolarizing muscle relaxants; in rare cases, to stress from exertion or heat stress. Susceptibility to malignant hyperthermia (MHS) is inherited as an autosomally dominant trait with variable expression and incomplete penetrance. It is known that the pathophysiology of MH is related to an uncontrolled rise of myoplasmic calcium, which activates biochemical processes resulting in hypermetabolism of the skeletal muscle. In most cases, defects in the ryanodine receptor are responsible for the functional changes of calcium regulation in MH, and more than 300 mutations have been identified in the RYR1 gene, located on chromosome 19q13.1. The classic signs of MH include increase of end-tidal carbon dioxide, tachycardia, skeletal muscle rigidity, tachycardia, hyperthermia and acidosis. Up to now, muscle contracture test is regarded as the gold standard for the diagnosis of MHS though molecular genetic test is used, on a limited basis so far to diagnose MHS. The mortality of MH is dramatically decreased from 70-80% to less than 5%, due to an introduction of dantrolene sodium for treatment of MH, early detection of MH episode using capnography, and the introduction of diagnostic testing for MHS. This review summarizes the clinically essential and important knowledge of MH, and presents new developments in the field. PMID:23198031

  6. OX40 and 4-1BB downregulate Kaposi’s sarcoma-associated herpesvirus replication in lymphatic endothelial cells, but 4-1BB and not OX40 inhibits viral replication in B-cells.

    PubMed

    Cho, Min; Myoung, Jinjong

    2015-12-01

    Kaposi’s sarcoma-associated herpesvirus (KSHV) belongs to the human gammaherpesvirus subfamily and is associated with malignancies of endothelial origin (Kaposi’s sarcoma, KS) and B-cell origin [primary effusion lymphoma (PEL) and multicentric Castleman’s disease (MCD)]. Viral lytic replication is known to be required for KS and MCD. As KSHV-related tumours mostly develop in human subjects when the immune system is compromised by immunosuppressive regimen, human immunodeficiency virus infection or some genetic deficiencies, KSHV-specific immune responses are believed to be important in the control of KSHV replication. However, analysis of the roles of immune cells in viral pathogenesis has been difficult due to the lack of an adequate animal model. Recently, congenital OX40 deficiency, as determined by genome-wide exome sequencing, was shown to be associated with aggressive childhood KS in a patient, suggesting that disrupted OX40–OX40L interactions might be implicated in disease development. Here, we report that interaction of recombinant OX40 protein with OX40L expressed on endothelial cells severely impaired KSHV lytic replication. Furthermore, 4-1BB–4-1BBL interactions were also capable of efficiently inhibiting viral replication in B-cells and endothelial cells. To the best of our knowledge, this is the first direct evidence that ligation of tumour necrosis factor superfamily members and their cognate receptors is important for the control of viral lytic replication. These data are likely to pave the way for the development of KSHV-specific therapies for KS and MCD, in which viral lytic replication is a disease-determining factor. PMID:26467721

  7. CD19 CAR T Cells for B Cell Malignancies After Allogeneic Transplant

    ClinicalTrials.gov

    2015-08-04

    Philadelphia Chromosome Negative Adult Precursor Acute Lymphoblastic Leukemia; Philadelphia Chromosome Positive Adult Precursor Acute Lymphoblastic Leukemia; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Immunoblastic Large Cell Lymphoma; Recurrent Mantle Cell Lymphoma; Refractory Chronic Lymphocytic Leukemia

  8. Differential expression of Toll-like receptor (TLR) and B cell receptor (BCR) signaling molecules in primary diffuse large B-cell lymphoma of the central nervous system.

    PubMed

    Akhter, Ariz; Masir, Noraidah; Elyamany, Ghaleb; Phang, Kean-Chang; Mahe, Etienne; Al-Zahrani, Ali Matar; Shabani-Rad, Meer-Taher; Stewart, Douglas Allan; Mansoor, Adnan

    2015-01-01

    Primary diffuse large B-cell lymphoma of the central nervous system (CNS DLBCL) is a distinct and aggressive lymphoma that is confined to CNS. Since, central nervous system is barrier-protected and immunologically silent; role of TLR/BCR signaling in pathogenesis and biology of CNS DLBCL is intriguing. Genomic mutations in key regulators of TLR/BCR signaling pathway (MYD88/CD79B/CARD11) have recently been reported in this disease. These observations raised possible implications in novel targeted therapies; however, expression pattern of molecules related to TLR/BCR pathways in this lymphoma remains unknown. We have analyzed the expression of 19 genes encoding TLR/BCR pathways and targets in CNS DLBCLs (n = 20) by Nanostring nCounter™ analysis and compared it with expression patterns in purified reactive B-lymphocytes and systemic diffuse large B cell lymphoma (DLBCL) (n = 20). Relative expression of TLR4, TLR5, TLR9, CD79B and BLNK was higher in CNS DLBCLs than in control B-lymphocytes; where as TLR7, MALT1, BCL10, CD79A and LYN was lower in CNS DLBCLs (P < 0.0001). When compared with systemic DLBCL samples, higher expression of TLR9, CD79B, CARD11, LYN and BLNK was noted in CNS DLBCL (>1.5 fold change; P < 0.01). The B cell receptor molecules like BLNK and CD79B were also associated with higher expression of MYD88 dependent TLRs (TLR4/5/9). In conclusion, we have shown over expression of TLR/BCR related genes or their targets, where genomic mutations have commonly been identified in CNS DLBCL. We have also demonstrated that TLR over expression closely relate with up regulation of genes associated with BCR pathway like CD79B/BLNK and CARD11, which play an important role in NF-kB pathway activation. Our results provide an important insight into the possibility of TLR and/or B-cell receptor signaling molecules as possible therapeutic targets in CNS DLBCL. PMID:25391967

  9. Punishment of elicited aggression.

    PubMed

    Azrin, N H

    1970-07-01

    Aversive shocks are known to produce aggression when the shocks are not dependent on behavior and to suppress behavior when the shocks are arranged as a dependent punisher. These two processes were studied by presenting non-dependent shock to monkeys at regular intervals, thereby producing biting attacks on a pneumatic tube. Immediate shock punishment was stimultaneously delivered for each biting attack. The attacks were found to decrease as a function of increasing punishment intensity. These results show that aggression is eliminated by direct punishment of the aggression even when the stimulus that is used as a punisher otherwise causes the aggression. PMID:4988590

  10. 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

  11. Gallium arsenide exposure impairs splenic B cell accessory function.

    PubMed

    Gondre-Lewis, Timothy A; Hartmann, Constance B; Caffrey, Rebecca E; McCoy, Kathleen L

    2003-03-01

    Gallium arsenide (GaAs) is utilized in industries for its semiconductor and optical properties. Chemical exposure of animals systemically suppresses several immune functions. The ability of splenic B cells to activate antigen-specific helper CD4(+) T cell hybridomas was assessed, and various aspects of antigen-presenting cell function were examined. GaAs-exposed murine B cells were impaired in processing intact soluble protein antigens, and the defect was antigen dependent. In contrast, B cells after exposure competently presented peptides to the T cells, which do not require processing. Cell surface expression of major histocompatibility complex (MHC) class II molecules and several costimulatory molecules on splenic B cells, which are critical for helper T cell activation, was not affected by chemical exposure. GaAs exposure also did not influence the stability of MHC class II heterodimers, suggesting that the defect may precede peptide exchange. GaAs-exposed B cells contained a normal level of aspartyl cathepsin activity; however, proteolytic activities of thiol cathepsins B and L were approximately half the control levels. Furthermore, two cleavage fragments of invariant chain, a molecular chaperone of MHC class II molecules, were increased in GaAs-exposed B cells, indicative of defective degradation. Thus, diminished thiol proteolytic activity in B cells may be responsible for their impaired antigen processing and invariant chain degradation, which may contribute to systemic immunosuppression caused by GaAs exposure.

  12. YY1 Is Required for Germinal Center B Cell Development

    PubMed Central

    Vuyyuru, Raja; Jha, Vibha; Hodewadekar, Suchita; Manser, Tim; Atchison, Michael L.

    2016-01-01

    YY1 has been implicated as a master regulator of germinal center B cell development as YY1 binding sites are frequently present in promoters of germinal center-expressed genes. YY1 is known to be important for other stages of B cell development including the pro-B and pre-B cells stages. To determine if YY1 plays a critical role in germinal center development, we evaluated YY1 expression during B cell development, and used a YY1 conditional knock-out approach for deletion of YY1 in germinal center B cells (CRE driven by the immunoglobulin heavy chain γ1 switch region promoter; γ1-CRE). We found that YY1 is most highly expressed in germinal center B cells and is increased 3 fold in splenic B cells activated by treatment with anti-IgM and anti-CD40. In addition, deletion of the yy1 gene by action of γ1-CRE recombinase resulted in significant loss of GC cells in both un-immunized and immunized contexts with corresponding loss of serum IgG1. Our results show a crucial role for YY1 in the germinal center reaction. PMID:27167731

  13. 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.

  14. 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.

  15. 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

  16. Human Memory B Cells in Healthy Gingiva, Gingivitis, and Periodontitis.

    PubMed

    Mahanonda, Rangsini; Champaiboon, Chantrakorn; Subbalekha, Keskanya; Sa-Ard-Iam, Noppadol; Rattanathammatada, Warattaya; Thawanaphong, Saranya; Rerkyen, Pimprapa; Yoshimura, Fuminobu; Nagano, Keiji; Lang, Niklaus P; Pichyangkul, Sathit

    2016-08-01

    The presence of inflammatory infiltrates with B cells, specifically plasma cells, is the hallmark of periodontitis lesions. The composition of these infiltrates in various stages of homeostasis and disease development is not well documented. Human tissue biopsies from sites with gingival health (n = 29), gingivitis (n = 8), and periodontitis (n = 21) as well as gingival tissue after treated periodontitis (n = 6) were obtained and analyzed for their composition of B cell subsets. Ag specificity, Ig secretion, and expression of receptor activator of NF-κB ligand and granzyme B were performed. Although most of the B cell subsets in healthy gingiva and gingivitis tissues were CD19(+)CD27(+)CD38(-) memory B cells, the major B cell component in periodontitis was CD19(+)CD27(+)CD38(+)CD138(+)HLA-DR(low) plasma cells, not plasmablasts. Plasma cell aggregates were observed at the base of the periodontal pocket and scattered throughout the gingiva, especially apically toward the advancing front of the lesion. High expression of CXCL12, a proliferation-inducing ligand, B cell-activating factor, IL-10, IL-6, and IL-21 molecules involved in local B cell responses was detected in both gingivitis and periodontitis tissues. Periodontitis tissue plasma cells mainly secreted IgG specific to periodontal pathogens and also expressed receptor activator of NF-κB ligand, a bone resorption cytokine. Memory B cells resided in the connective tissue subjacent to the junctional epithelium in healthy gingiva. This suggested a role of memory B cells in maintaining periodontal homeostasis. PMID:27335500

  17. B-cell memory and the persistence of antibody responses.

    PubMed Central

    MacLennan, I C; García de Vinuesa, C; Casamayor-Palleja, M

    2000-01-01

    Antigens such as viral envelope proteins and bacterial exotoxins induce responses which result in the production of neutralizing antibody. These responses persist for years and provide highly efficient defence against reinfection. During these antibody responses a proportion of participating B cells mutate the genes that encode their immunoglobulin variable regions. This can increase the affinity of the antibody, but can also induce autoreactive B cells. Selection mechanisms operate which allow the cells with high affinity for the provoking antigen to persist, while other B cells recruited into the response die. PMID:10794052

  18. BAFF: a fundamental survival factor for B cells.

    PubMed

    Mackay, Fabienne; Browning, Jeffrey L

    2002-07-01

    B-cell-activating factor of the tumour-necrosis-factor family (BAFF) enhances B-cell survival--a function that is indispensable for B-cell maturation--and has a role in enhancing immune responses. Moreover, the overexpression of BAFF results in severe autoimmune disorders in mice, and elevated serum levels of BAFF occur in some patients who have autoimmune diseases. The elucidation of the role of BAFF has set the stage for a new approach to the treatment of autoimmune disease.

  19. PI3 Kinase signals BCR dependent mature B cell survival

    PubMed Central

    Srinivasan, Lakshmi; Sasaki, Yoshiteru; Calado, Dinis Pedro; Zhang, Baochun; Paik, Ji Hye; DePinho, Ronald A.; Kutok, Jeffrey L.; Kearney, John F.; Otipoby, Kevin L.; Rajewsky, Klaus

    2009-01-01

    Summary Previous work has shown that mature B cells depend upon survival signals delivered to the cells by their antigen receptor (BCR). To identify the molecular nature of this survival signal, we have developed a genetic approach in which ablation of the BCR is combined with the activation of specific, BCR dependent signaling cascades in mature B cells in vivo. Using this system, we provide evidence that the survival of BCR deficient mature B cells can be rescued by a single signaling pathway downstream of the BCR, namely PI3K signaling, with the FOXO1 transcription factor playing a central role. PMID:19879843

  20. Donor Atorvastatin Treatment in Preventing Severe Acute GVHD After Nonmyeloablative Peripheral Blood Stem Cell Transplant in Patients With Hematological Malignancies

    ClinicalTrials.gov

    2016-04-28

    Aggressive Non-Hodgkin Lymphoma; Myelodysplastic/Myeloproliferative Neoplasm; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Recurrent Aggressive Adult Non-Hodgkin Lymphoma; Recurrent Childhood Acute Lymphoblastic Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Recurrent Chronic Lymphocytic Leukemia; Recurrent Diffuse Large B-Cell Lymphoma; Recurrent Hodgkin Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Plasma Cell Myeloma; Waldenstrom Macroglobulinemia

  1. CD3+/CD16+CD56+ cell numbers in peripheral blood are correlated with higher tumor burden in patients with diffuse large B-cell lymphoma.

    PubMed

    Hus, Iwona; Starosławska, Elżbieta; Bojarska-Junak, Agnieszka; Dobrzyńska-Rutkowska, Aneta; Surdacka, Agata; Wdowiak, Paulina; Wasiak, Magdalena; Kusz, Maria; Twardosz, Anna; Dmoszyńska, Anna; Roliński, Jacek

    2011-01-01

    Diffuse large B-cell lymphoma is the commonest histological type of malignant lymphoma, and remains incurable in many cases. Developing more efficient immunotherapy strategies will require better understanding of the disorders of immune responses in cancer patients. NKT (natural killer-like T) cells were originally described as a unique population of T cells with the co-expression of NK cell markers. Apart from their role in protecting against microbial pathogens and controlling autoimmune diseases, NKT cells have been recently revealed as one of the key players in the immune responses against tumors. The objective of this study was to evaluate the frequency of CD3(+)/CD16(+)CD56(+) cells in the peripheral blood of 28 diffuse large B-cell lymphoma (DLBCL) patients in correlation with clinical and laboratory parameters. Median percentages of CD3(+)/CD16(+)CD56(+) were significantly lower in patients with DLBCL compared to healthy donors (7.37% vs. 9.01%, p = 0.01; 4.60% vs. 5.81%, p = 0.03), although there were no differences in absolute counts. The frequency and the absolute numbers of CD3(+)/CD16(+)CD56(+) cells were lower in advanced clinical stages than in earlier ones. The median percentage of CD3(+)/CD16(+)CD56(+) cells in patients in Ann Arbor stages 1-2 was 5.55% vs. 3.15% in stages 3-4 (p = 0.02), with median absolute counts respectively 0.26 G/L vs. 0.41 G/L (p = = 0.02). The percentage and absolute numbers of CD3(+)/CD16(+)CD56(+) cells were significantly higher in DL -BCL patients without B-symptoms compared to the patients with B-symptoms, (5.51% vs. 2.46%, p = 0.04; 0.21 G/L vs. 0.44 G/L, p = 0.04). The percentage of CD3(+)/CD16(+)CD56(+) cells correlated adversely with serum lactate dehydrogenase (R= -445; p 〈 0.05) which might influence NKT count. These figures suggest a relationship between higher tumor burden and more aggressive disease and decreased NKT numbers. But it remains to be explained whether low NKT cell counts in the peripheral blood

  2. Human bronchial epithelial BEAS-2B cells, an appropriate in vitro model to study heavy metals induced carcinogenesis

    SciTech Connect

    Park, Youn-hee; Kim, Donghern; Dai, Jin; Zhang, Zhuo

    2015-09-15

    Occupational and environmental exposure to arsenic (III) and chromium VI (Cr(VI)) have been confirmed to cause lung cancer. Mechanisms of these metals carcinogenesis are still under investigation. Selection of cell lines to be used is essential for the studies. Human bronchial epithelial BEAS-2B cells are the cells to be utilized by most of scientists. However, due to p53 missense mutation (CCG → TCG) at codon 47 and the codon 72 polymorphism (CGC → CCC) in BEAS-2B cells, its usage has frequently been questioned. The present study has examined activity and expression of 53 and its downstream target protein p21 upon acute or chronic exposure of BEAS-2B cells to arsenic and Cr(VI). The results show that short-term exposure of BEAS-2B cells to arsenic or Cr(VI) was able to activate both p53 and p21. Chronic exposure of BEAS-2B cells to these two metals caused malignant cell transformation and tumorigenesis. In arsenic-transformed BEAS-2B cells reductions in p53 promoter activity, mRNA expression, and phosphorylation of p53 at Ser392 were observed, while the total p53 protein level remained the same compared to those in passage-matched parent ones. p21 promoter activity and expression were decreased in arsenic-transformed cells. Cr(VI)-transformed cells exhibit elevated p53 promoter activity, mRNA expression, and phosphorylation at Ser15, but reduced phosphorylation at Ser392 and total p53 protein level compared to passage-matched parent ones. p21 promoter activity and expression were elevated in Cr(VI)-transformed cells. These results demonstrate that p53 is able to respond to exposure of arsenic or Cr(VI), suggesting that BEAS-2B cells are an appropriate in vitro model to investigate arsenic or Cr(VI) induced lung cancer. - Highlights: • Short-term exposure of BEAS-2B cells to arsenic or Cr(VI) activates p53 and p21. • Chronic exposure of BEAS-2B cells to arsenic or Cr(VI) causes cell transformation and tumorigenesis. • Arsenic-transformed cells exhibit

  3. A Strategic Approach to Aggression.

    ERIC Educational Resources Information Center

    Archer, John

    2001-01-01

    Discusses two issues raised by Underwood et al.: the distinction between indirect and relational forms of aggression, and implications of indirect aggression for definitions of aggression; and the normative view of aggression that indicates that aggressive individuals may be socially skilled. Suggests that both issues lead to the conclusion that…

  4. HIV-dependent depletion of influenza-specific memory B cells impacts B cell responsiveness to seasonal influenza immunisation

    PubMed Central

    Wheatley, Adam K.; Kristensen, Anne B.; Lay, William N.; Kent, Stephen J.

    2016-01-01

    Infection with HIV drives significant alterations in B cell phenotype and function that can markedly influence antibody responses to immunisation. Anti-retroviral therapy (ART) can partially reverse many aspects of B cell dysregulation, however complete normalisation of vaccine responsiveness is not always observed. Here we examine the effects of underlying HIV infection upon humoral immunity to seasonal influenza vaccines. Serological and memory B cell responses were assessed in 26 HIV+ subjects receiving ART and 30 healthy controls immunised with the 2015 Southern Hemisphere trivalent inactivated influenza vaccine (IIV3). Frequencies and phenotypes of influenza hemagglutinin (HA)-specific B cells were assessed by flow cytometry using recombinant HA probes. Serum antibody was measured using hemagglutination inhibition assays. Serological responses to IIV3 were comparable between HIV+ and HIV− subjects. Likewise, the activation and expansion of memory B cell populations specific for vaccine-component influenza strains was observed in both cohorts, however peak frequencies were diminished in HIV+ subjects compared to uninfected controls. Lower circulating frequencies of memory B cells recognising vaccine-component and historical influenza strains were observed in HIV+ subjects at baseline, that were generally restored to levels comparable with HIV− controls post-vaccination. HIV infection is therefore associated with depletion of selected HA-specific memory B cell pools. PMID:27220898

  5. 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

  6. B Cell Development in the Bone Marrow Is Regulated by Homeostatic Feedback Exerted by Mature B Cells

    PubMed Central

    Shahaf, Gitit; Zisman-Rozen, Simona; Benhamou, David; Melamed, Doron; Mehr, Ramit

    2016-01-01

    Cellular homeostasis in the B cell compartment is strictly imposed to balance cell production and cell loss. However, it is not clear whether B cell development in the bone marrow is an autonomous process or subjected to regulation by the peripheral B cell compartment. To specifically address this question, we used mice transgenic for human CD20, where effective depletion of B lineage cells is obtained upon administration of mouse anti-human CD20 antibodies, in the absence of any effect on other cell lineages and/or tissues. We followed the kinetics of B cell return to equilibrium by BrdU labeling and flow cytometry and analyzed the resulting data by mathematical modeling. Labeling was much faster in depleted mice. Compared to control mice, B cell-depleted mice exhibited a higher proliferation rate in the pro-/pre-B compartment, and higher cell death and lower differentiation in the immature B cell compartment. We validated the first result by analysis of the expression of Ki67, the nuclear protein expressed in proliferating cells, and the second using Annexin V staining. Collectively, our results suggest that B lymphopoiesis is subjected to homeostatic feedback mechanisms imposed by mature B cells in the peripheral compartment. PMID:27047488

  7. Transgelin-2 in B-Cells Controls T-Cell Activation by Stabilizing T Cell - B Cell Conjugates

    PubMed Central

    Chae, Myoung-Won; Kim, Hye-Ran; Kim, Chang-Hyun; Jun, Chang-Duk; Park, Zee-Yong

    2016-01-01

    The immunological synapse (IS), a dynamic and organized junction between T-cells and antigen presenting cells (APCs), is critical for initiating adaptive immunity. The actin cytoskeleton plays a major role in T-cell reorganization during IS formation, and we previously reported that transgelin-2, an actin-binding protein expressed in T-cells, stabilizes cortical F-actin, promoting T-cell activation in response to antigen stimulation. Transgelin-2 is also highly expressed in B-cells, although no specific function has been reported. In this study, we found that deficiency in transgelin-2 (TAGLN2-/-) in B-cells had little effect on B-cell development and activation, as measured by the expression of CD69, MHC class II molecules, and CD80/86. Nevertheless, in B-cells, transgelin-2 accumulated in the IS during the interaction with T-cells. These results led us to hypothesize that transgelin-2 may also be involved in IS stability in B-cells, thereby influencing T-cell function. Notably, we found that transgelin-2 deficiency in B-cells reduced T-cell activation, as determined by the release of IL-2 and interferon-γ and the expression of CD69. Furthermore, the reduced T-cell activation was correlated with reduced B-cell–T-cell conjugate formation. Collectively, these results suggest that actin stability in B-cells during IS formation is critical for the initiation of adaptive T-cell immunity. PMID:27232882

  8. Primary Cutaneous Diffuse Large B-Cell Lymphoma With a MYC-IGH Rearrangement and Gain of BCL2: Expanding the Spectrum of MYC/BCL2 Double-Hit Lymphomas.

    PubMed

    Testo, Natalia; Olson, Luke C; Subramaniyam, Shivakumar; Hanson, Ty; Magro, Cynthia M

    2016-10-01

    Aggressive extracutaneous B-cell lymphomas span the various stages of B-cell ontogeny and include B-cell lymphoblastic lymphoma, Burkitt lymphoma, mantle cell lymphoma, and diffuse large B-cell lymphoma. Diffuse large B-cell lymphomas represent the most common histologic subtype of non-Hodgkin lymphomas, comprising 30% of adult non-Hodgkin lymphomas in the United States. A distinctive form of diffuse large B-cell lymphoma is the double-hit lymphoma, with most cases exhibiting a combined MYC and BCL2 rearrangement, leading some hematopathologists to propose the term MYC/BCL2 lymphoma. More recently, MYC rearrangement with multiple copies/gain of BCL2 or multiple copies/gain of MYC with a BCL2 rearrangement have been described and exhibit a very similar clinical course to conventional double-hit lymphomas. We report the seventh case of diffuse large B-cell lymphoma exhibiting this distinct cytogenetic abnormality and the first reported case in the skin. The patient's clinical course was aggressive, succumbing to disease 18 months after his initial presentation. PMID:27391453

  9. Portraying the Expression Landscapes of B-Cell Lymphoma-Intuitive Detection of Outlier Samples and of Molecular Subtypes

    PubMed Central

    Hopp, Lydia; Lembcke, Kathrin; Binder, Hans; Wirth, Henry

    2013-01-01

    We present an analytic framework based on Self-Organizing Map (SOM) machine learning to study large scale patient data sets. The potency of the approach is demonstrated in a case study using gene expression data of more than 200 mature aggressive B-cell lymphoma patients. The method portrays each sample with individual resolution, characterizes the subtypes, disentangles the expression patterns into distinct modules, extracts their functional context using enrichment techniques and enables investigation of the similarity relations between the samples. The method also allows to detect and to correct outliers caused by contaminations. Based on our analysis, we propose a refined classification of B-cell Lymphoma into four molecular subtypes which are characterized by differential functional and clinical characteristics. PMID:24833231

  10. Girls' Aggressive Behavior

    ERIC Educational Resources Information Center

    Owens, Larry; Shute, Rosalyn; Slee, Phillip

    2004-01-01

    In contrast to boys' bullying behavior which is often overt and easily visible, girls' aggression is usually indirect and covert. Less research has been conducted on the types of bullying that girls usually engage in. Using focus groups composed of teenaged girls, Dr. Owens and colleagues examine the nature of teenage girls' indirect aggression.

  11. Third Person Instigated Aggression.

    ERIC Educational Resources Information Center

    Gaebelein, Jacquelyn

    Since many acts of aggression in society are more than simply an aggressor-victim encounter, the role played by third person instigated aggression also needs examination. The purpose of this study was to develop a laboratory procedure to systematically investigate instigation. In a competitive reaction time task, high and low Machiavellian Males…

  12. Social Aggression among Girls.

    ERIC Educational Resources Information Center

    Underwood, Marion K.

    Noting recent interest in girls' social or "relational" aggression, this volume offers a balanced, scholarly analysis of scientific knowledge in this area. The book integrates current research on emotion regulation, gender, and peer relations, to examine how girls are socialized to experience and express anger and aggression from infancy through…

  13. B-cell survival factors in autoimmune rheumatic disorders.

    PubMed

    Morais, Sandra A; Vilas-Boas, Andreia; Isenberg, David A

    2015-08-01

    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

  14. An eruption of European B-cell biology.

    PubMed

    Cancro, Michael P

    2010-09-01

    Volcanic ash clouds disrupted the 2010 ESF/EMBO meeting on B cells and protection. Nevertheless, the delegates who did make it to Catalonia put together their own programme of talks covering a range of themes from mutualism to epigenetics.

  15. 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.

  16. How Follicular Dendritic Cells Shape the B-Cell Antigenome

    PubMed Central

    Kranich, Jan; Krautler, Nike Julia

    2016-01-01

    Follicular dendritic cells (FDCs) are stromal cells residing in primary follicles and in germinal centers of secondary and tertiary lymphoid organs (SLOs and TLOs). There, they play a crucial role in B-cell activation and affinity maturation of antibodies. FDCs have the unique capacity to bind and retain native antigen in B-cell follicles for long periods of time. Therefore, FDCs shape the B-cell antigenome (the sum of all B-cell antigens) in SLOs and TLOs. In this review, we discuss recent findings that explain how this stromal cell type can arise in almost any tissue during TLO formation and, furthermore, focus on the mechanisms of antigen capture and retention involved in the generation of long-lasting antigen depots displayed on FDCs. PMID:27446069

  17. 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

  18. Chronic B-Cell Leukemias and Agent Orange

    MedlinePlus

    ... survivors' benefits . Research on B-cell leukemias and herbicides The Health and Medicine Division (HMD) (formally known ... sufficient evidence of an association between exposure to herbicides and chronic lymphocytic leukemia. In 2003, VA recognized ...

  19. 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.

  20. 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

  1. Protein kinase inhibitors against malignant lymphoma

    PubMed Central

    D’Cruz, Osmond J; Uckun, Fatih M

    2013-01-01

    Introduction Tyrosine kinases (TKs) are intimately involved in multiple signal transduction pathways regulating survival, activation, proliferation and differentiation of lymphoid cells. Deregulation or overexpression of specific oncogenic TKs is implicated in maintaining the malignant phenotype in B-lineage lymphoid malignancies. Several novel targeted TK inhibitors (TKIs) have recently emerged as active in the treatment of relapsed or refractory B-cell lymphomas that inhibit critical signaling pathways, promote apoptotic mechanisms or modulate the tumor microenvironment. Areas covered In this review, the authors summarize the clinical outcomes of newer TKIs in various B-cell lymphomas from published and ongoing clinical studies and abstracts from major cancer and hematology conferences. Expert opinion Multiple clinical trials have demonstrated that robust antitumor activity can be obtained with TKIs directed toward specific oncogenic TKs that are genetically deregulated in various subtypes of B-cell lymphomas. Clinical success of targeting TKIs is dependent upon on identifying reliable molecular and clinical markers associated with select cohorts of patients. Further understanding of the signaling pathways should stimulate the identification of novel molecular targets and expand the development of new therapeutic options and individualized therapies. PMID:23496343

  2. A Rapid Embryonic Stem Cell-Based Mouse Model for B-cell Lymphomas Driven by Epstein-Barr Virus Protein LMP1

    PubMed Central

    Ba, Zhaoqing; Meng, Fei-Long; Gostissa, Monica; Huang, Pei-Yi; Ke, Qiang; Wang, Zhe; Dao, Mai N.; Fujiwara, Yuko; Rajewsky, Klaus; Baochun, Zhang; Alt, Frederick W.

    2015-01-01

    The Epstein-Barr virus (EBV) latent membrane protein 1 (LMP1) contributes to oncogenic human B-cell transformation. Mouse B cells conditionally expressing LMP1 are not predisposed to B-cell malignancies, as LMP1-expressing B cells are eliminated by T cells. However, mice with conditional B-cell LMP1 expression and genetic elimination of α/β and γ/δ T cells (“CLT” mice) die early in association with B-cell lymphoproliferation and lymphomagenesis. Generation of CLT mice involves in-breeding multiple independently segregating alleles. Thus, while introduction of additional activating or knock-out mutations into the CLT model is desirable for further B-cell expansion and immunosurveillance studies, doing such experiments by germline breeding is time-consuming, expensive and sometimes unfeasible. To generate a more tractable model, we generated clonal CLT ES cells from CLT embryos and injected them into RAG2-deficient blastocysts to generate chimeric mice, which like germline CLT mice harbor splenic CLT B cells and lack T cells. CLT chimeric mice generated by this RAG2-deficient blastocyst complementation (“RDBC”) approach die rapidly in association with B-cell lymphoproliferation and lymphoma. As CLT lymphomas routinely express the Activation-Induced Cytidine Deaminase (AID) antibody diversifier, we tested potential AID roles by eliminating the AID gene in CLT ES cells and testing them via RDBC. We found that CLT and AID-deficient CLT ES chimeras had indistinguishable phenotypes, showing that AID is not essential for LMP1-induced lymphomagenesis. Beyond expanding accessibility and utility of CLT mice as a cancer immunotherapy model, our studies provide a new approach for facilitating generation of genetically complex mouse cancer models. PMID:25934172

  3. VISA is required for B cell expression of TLR7.

    PubMed

    Xu, Liang-Guo; Jin, Lei; Zhang, Bi-Cheng; Akerlund, Linda J; Shu, Hong-Bing; Cambier, John C

    2012-01-01

    B cells play a critical role in the initialization and development of the systemic lupus erythematosus that is dependent on the expression of the endosomal ssRNA receptor TLR7. Previous studies have established that B cell expression of TLR7 is controlled by the type I IFN secreted by plasmacytoid dendritic cells. In this article, we report that VISA, also known as MAVS, IPS-1, and CardIf, essential for RIG-I/MDA5-mediated signaling following sensing of cytosolic RNA, regulate B cell expression of TLR7 and CD23. We found that B cells from a VISA(-/-) mouse express reduced TLR7 but normal basal levels of type I IFN. We also show that although IFN-β and TLR7 agonists synergize to promote TLR7 expression in VISA(-/-) B cells, they do not fully complement the defect seen in VISA(-/-) cells. Cell transfer experiments revealed that the observed effects of VISA(-/-) are B cell intrinsic. The reduced TLR7 expression in B cells is correlated with impaired TLR7 agonist-induced upregulation of activation markers CD69 and CD86, cell proliferation, production of IFN-α, TNF, and IL-12, and NF-κB activation. Finally, studies indicate that genetic background may influence the observed phenotype of our VISA(-/-) mice, because VISA(-/-) B cells differ in CD23 and TLR7 expression when on C57BL/6 versus 129Sv-C57BL/6 background. Thus, our findings suggest an unexpected link between VISA-mediated cytosolic RLR signaling and autoimmunity.

  4. B CELL DEPLETION THERAPY EXACERBATES MURINE PRIMARY BILIARY CIRRHOSIS

    PubMed Central

    Dhirapong, Amy; Lleo, Ana; Yang, Guo-Xiang; Tsuneyama, Koichi; Dunn, Robert; Kehry, Marilyn; Packard, Thomas A.; Cambier, John C.; Liu, Fu-Tong; Lindor, Keith; Coppel, Ross L.; Ansari, Aftab A.; Gershwin, M. Eric

    2010-01-01

    Primary biliary cirrhosis (PBC) is considered a model autoimmune disease due to the clinical homogeneity of patients and the classic hallmark of anti-mitochondrial antibodies (AMAS). Indeed, the presence of AMAS is the most highly directed and specific autoantibody in autoimmune diseases. However, the contribution of B cells to the pathogenesis of PBC is unclear. Thus, although AMAs appear to interact with the biliary cell apotope and contribute to biliary pathology, there is no correlation of disease severity and titer of AMA. The recent development of well characterized mAbs specific for the B cell populations, anti-CD20 and anti-CD79, and the development of a well defined xenobiotic induced model of autoimmune cholangitis, prompted us to utilize these reagents and the model to address the contribution of B cells in the pathogenesis of murine PBC. Prior to the induction of autoimmune cholangitis, mice were treated with either anti-CD20, anti-CD79, or isotype matched control mAb and followed for B cell development, the appearance of AMAs, liver pathology and cytokine production. Results of the studies reported herein show that the in vivo depletion of B cells using either anti-CD20 or anti-CD79 led to the development of a more severe form of cholangitis than control mice which is in contrast with results from a number of other autoimmune models which have documented an important therapeutic role of B cell specific depletion. The anti-CD20/CD79 treated mice have increased liver T cell infiltrates and higher levels of pro-inflammatory cytokines. In conclusion, our results reflect a novel disease protective role of B cells in PBC and suggest that B cell depletion therapy in humans with PBC should be approached with caution. PMID:21274873

  5. Rituximab induces Interleukin-6 production by human B cells

    PubMed Central

    Jones, Jonathan D.; Hamilton, B. JoNell; Skopelja, Sladjana; Rigby, William F. C.

    2014-01-01

    Objective Rituximab (RTX), an anti-CD20 monoclonal antibody, is highly effective in the treatment of several autoimmune diseases. The mechanism by which RTX treatment improves Rheumatoid Arthritis and ANCA-Associated Vasculitis is not easily related to B cell depletion. We have shown that RTX mediates a rapid stripping of CD20 and CD19 from the human B cell through a process known as trogocytosis. We hypothesized that changes in B cell phenotype resulting from trogocytosis would diminish the ability of B cells to promote autoimmune disease. Methods Human PBMC were cultured with RTX under conditions that permitted trogocytosis. Changes in B cell phenotype and cytokine production were measured under basal and activated (IL-4/anti-CD40) conditions. The effects of RTX were characterized for their requirements for FcγR and Fc-dependent interactions. Results Trogocytosis induced a marked loss of surface CD19, IgD, CD40 and BR3, but did not alter induction of CD86 expression on purified B cells by IL-4/anti-CD40 treatment. Unexpectedly, RTX-dependent trogocytosis of normal human B cells in vitro led to a rapid upregulation of IL-6 production, with no effect on TNFα, IL-1β, INFγ, or IL-10 production. This effect was Fc-dependent and required the presence of an FcγR bearing cell. This effect involved the release of pre-formed intracellular IL-6 protein as well as marked increases in IL-6 mRNA levels. Conclusion RTX mediated trogocytosis of B cells in vitro results in acute production and release of IL-6. The nature of this effect and its relationship to acute infusion reactions seen with RTX administration remain to be determined. PMID:25080282

  6. Autoimmunity, polyclonal B-cell activation and infection.

    PubMed

    Granholm, N A; Cavallo, T

    1992-02-01

    It is widely believed that autoimmunity is an integral part of the immune system, and that genetic, immunologic, hormonal, environmental and other factors contribute to the pathogenesis of autoimmune disease. Thus, autoimmune disease may represent an abnormal expression of immune functions instead of loss of tolerance to self, and it can be organ specific or systemic in its manifestations. We review the various factors that contribute to the development of autoimmune disease; we also review the mechanisms of polyclonal B-cell activation, with emphasis on the role of infectious agents. We consider systemic lupus erythematosus in humans and in experimental animals as prototypic autoimmune disease, and we summarize data to indicate that polyclonal B-cell activation is central to the pathogenesis of systemic autoimmune disease. The effect of polyclonal B-cell activation, brought about by injections of a B-cell activator-lipopolysaccharide from Gram-negative bacteria-is sufficient to cause autoimmune disease in an immunologically normal host. In fact, autoimmune disease can be arrested if excessive polyclonal B-cell activation is suppressed; alternatively, autoimmune disease can be exacerbated if polyclonal B-cell activation is enhanced. We explore the mechanism of tissue injury when autoimmune disease is induced or exacerbated, and we consider the pathogenic roles of autoantibodies, immune complexes, complement, the blood cell carrier system, and the mononuclear phagocyte system. Although polyclonal B-cell activation may be the mechanism whereby various factors can cause or exacerbate systemic autoimmune disease, polyclonal B-cell activation may cause autoimmune disease on its own.

  7. Malignant triton tumor (MTT) of the neck.

    PubMed

    Sørensen, Kristine Bjørndal; Godballe, Christian; Krogdahl, Annelise

    2006-03-01

    Malignant Triton Tumor (MTT) is a rare, malignant periphere nerve sheath tumor with rhabdomyoblastic differentiation. One third of described MTT's were located at the head and neck region. One third of these are associated with neurofibromatosis type 1. MTT most often appears in the third decade. MTT's are very aggressive tumors with early metastases and the overall survival is poor (26%). Therefore, early diagnosis and correct treatment is of utmost importance. We report a case of MTT of the left supraclavicular region in a 41-year-old man. We present the pathological findings, both light and immunohistochemically. PMID:16185834

  8. Giant metastasizing malignant hidradenoma in a child

    PubMed Central

    Bajaj, Sunil K; Misra, Ritu; Gupta, Rohini; Bansal, Anju

    2016-01-01

    An 8-year-old girl presented with a scalp swelling. The swelling was recurrent, reappearing everytime after local excision. She underwent surgery and the histopathologic diagnosis was malignant hidradenoma. This very rare and aggressive tumor is known to occur in elderly population and is histopathologically distinct from its commonly occuring benign counterpart. Malignant hidradenoma is resistant to chemotherapy and radiotherapy. We empahsize that being cognizant of the possibility of this rare tumor would assist in timely action in the form of wide resection, with possible reduction in morbidity and mortality. PMID:27730041

  9. Is metastatic pancreatic cancer an untargetable malignancy?

    PubMed Central

    Kourie, Hampig Raphael; Gharios, Joseph; Elkarak, Fadi; Antoun, Joelle; Ghosn, Marwan

    2016-01-01

    Metastatic pancreatic cancer (MPC) is one of the most aggressive malignancies, known to be chemo-resistant and have been recently considered resistant to some targeted therapies (TT). Erlotinib combined to gemcitabine is the only targeted therapy that showed an overall survival benefit in MPC. New targets and therapeutic approaches, based on new-TT, are actually being evaluated in MPC going from immunotherapy, epigenetics, tumor suppressor gene and oncogenes to stromal matrix regulators. We aim in this paper to present the major causes rendering MPC an untargetable malignancy and to focus on the new therapeutic modalities based on TT in MPC. PMID:26989465

  10. B cells mediate chronic allograft rejection independently of antibody production.

    PubMed

    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

    2014-03-01

    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.

  11. Origin of B-Cell Neoplasms in Autoimmune Disease

    PubMed Central

    Hemminki, Kari; Liu, Xiangdong; Ji, Jianguang; Försti, Asta

    2016-01-01

    Autoimmune diseases (ADs) are associated with a number of B-cell neoplasms but the associations are selective in regard to the type of neoplasm and the conferred risks are variable. So far no mechanistic bases for these differential associations have been demonstrated. We speculate that developmental origin of B-cells might propose a mechanistic rationale for their carcinogenic response to autoimmune stimuli and tested the hypothesis on our previous studies on the risks of B-cell neoplasms after any of 33 ADs. We found that predominantly germinal center (GC)-derived B-cells showed multiple associations with ADs: diffuse large B cell lymphoma associated with 15 ADs, follicular lymphoma with 7 ADs and Hodgkin lymphoma with 11 ADs. Notably, these neoplasms shared significant associations with 5 ADs (immune thrombocytopenic purpura, polymyositis/dermatomyositis, rheumatoid arthritis, Sjogren syndrome and systemic lupus erythematosis). By contrast, primarily non-GC neoplasms, acute lymphocytic leukemia, chronic lymphocytic leukemia and myeloma associated with 2 ADs only and mantle cell lymphoma with 1 AD. None of the neoplasms shared associated ADs. These data may suggest that autoimmune stimulation critically interferes with the rapid cell division, somatic hypermutation, class switch recombination and immunological selection of maturing B-cell in the GC and delivers damage contributing to transformation. PMID:27355450

  12. 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

  13. Identification of the human mature B cell miRNome

    PubMed Central

    Basso, Katia; Sumazin, Pavel; Morozov, Pavel; Schneider, Christof; Maute, Roy L.; Kitagawa, Yukiko; Mandelbaum, Jonathan; Haddad, Joseph; Chen, Chang-Zheng; Califano, Andrea; Dalla-Favera, Riccardo

    2009-01-01

    The full set of microRNAs (miRNAs) in the human genome is not known. Because presently known miRNAs have been identified by virtue of their abundant expression in a few cell types, many tissue-specific miRNAs remain unrevealed. To understand the role of miRNAs in B-cell function and lymphomagenesis, we generated short-RNA libraries from normal human B cells at different stages of development (naïve, germinal-center, memory) and from a Burkitt lymphoma cell-line. A combination of cloning and computational analysis identified 178 miRNAs (miRNome) expressed in normal and/or transformed B-cell libraries. Most notably, the B-cell miRNome included 75 miRNAs which to our knowledge have not been previously reported and of which 66 have been validated by RNA blot and/or RT-PCR analyses. Numerous miRNAs were expressed in a stage- or transformation-specific fashion in B cells, suggesting specific functional or pathologic roles. These results provide a resource for studying the role of miRNAs in B-cell development, immune function, and lymphomagenesis. PMID:19446474

  14. Origin of B-Cell Neoplasms in Autoimmune Disease.

    PubMed

    Hemminki, Kari; Liu, Xiangdong; Ji, Jianguang; Försti, Asta

    2016-01-01

    Autoimmune diseases (ADs) are associated with a number of B-cell neoplasms but the associations are selective in regard to the type of neoplasm and the conferred risks are variable. So far no mechanistic bases for these differential associations have been demonstrated. We speculate that developmental origin of B-cells might propose a mechanistic rationale for their carcinogenic response to autoimmune stimuli and tested the hypothesis on our previous studies on the risks of B-cell neoplasms after any of 33 ADs. We found that predominantly germinal center (GC)-derived B-cells showed multiple associations with ADs: diffuse large B cell lymphoma associated with 15 ADs, follicular lymphoma with 7 ADs and Hodgkin lymphoma with 11 ADs. Notably, these neoplasms shared significant associations with 5 ADs (immune thrombocytopenic purpura, polymyositis/dermatomyositis, rheumatoid arthritis, Sjogren syndrome and systemic lupus erythematosis). By contrast, primarily non-GC neoplasms, acute lymphocytic leukemia, chronic lymphocytic leukemia and myeloma associated with 2 ADs only and mantle cell lymphoma with 1 AD. None of the neoplasms shared associated ADs. These data may suggest that autoimmune stimulation critically interferes with the rapid cell division, somatic hypermutation, class switch recombination and immunological selection of maturing B-cell in the GC and delivers damage contributing to transformation. PMID:27355450

  15. Altered B cell receptor signaling in human systemic lupus erythematosus

    PubMed Central

    Jenks, Scott A.; Sanz, Iñaki

    2009-01-01

    Regulation of B cell receptor signaling is essential for the development of specific immunity while retaining tolerance to self. Systemic lupus erythematosus (SLE) is characterized by a loss of B cell tolerance and the production of anti-self antibodies. Accompanying this break down in tolerance are alterations in B cell receptor signal transduction including elevated induced calcium responses and increased protein phosphorylation. Specific pathways that negatively regulate B cell signaling have been shown to be impaired in some SLE patients. These patients have reduced levels of the kinase Lyn in lipid raft microdomains and this reduction is inversely correlated with increased CD45 in lipid rafts. Function and expression of the inhibitory immunoglobulin receptor FcγRIIB is also reduced in Lupus IgM- CD27+ memory cells. Because the relative contribution of different memory and transitional B cell subsets can be abnormal in SLE patients, we believe studies targeted to well defined B cell subsets will be necessary to further our understanding of signaling abnormalities in SLE. Intracellular flow cytometric analysis of signaling is a useful approach to accomplish this goal. PMID:18723129

  16. Receptor editing and genetic variability in human autoreactive B cells.

    PubMed

    Lang, Julie; Ota, Takayuki; Kelly, Margot; Strauch, Pamela; Freed, Brian M; Torres, Raul M; Nemazee, David; Pelanda, Roberta

    2016-01-11

    The mechanisms by which B cells undergo tolerance, such as receptor editing, clonal deletion, and anergy, have been established in mice. However, corroborating these mechanisms in humans remains challenging. To study how autoreactive human B cells undergo tolerance, we developed a novel humanized mouse model. Mice expressing an anti-human Igκ membrane protein to serve as a ubiquitous neo self-antigen (Ag) were transplanted with a human immune system. By following the fate of self-reactive human κ(+) B cells relative to nonautoreactive λ(+) cells, we show that tolerance of human B cells occurs at the first site of self-Ag encounter, the bone marrow, via a combination of receptor editing and clonal deletion. Moreover, the amount of available self-Ag and the genetics of the cord blood donor dictate the levels of central tolerance and autoreactive B cells in the periphery. Thus, this model can be useful for studying specific mechanisms of human B cell tolerance and to reveal differences in the extent of this process among human populations.

  17. CD19xCD3 DART protein mediates human B-cell depletion in vivo in humanized BLT mice

    PubMed Central

    Tsai, Perry; Thayer, William O; Liu, Liqin; Silvestri, Guido; Nordstrom, Jeffrey L; Garcia, J Victor

    2016-01-01

    Novel therapeutic strategies are needed for the treatment of hematologic malignancies; and bispecific antibody-derived molecules, such as dual-affinity re-targeting (DART) proteins, are being developed to redirect T cells to kill target cells expressing tumor or viral antigens. Here we present our findings of specific and systemic human B-cell depletion by a CD19xCD3 DART protein in humanized BLT mice. Administration of the CD19xCD3 DART protein resulted in a dramatic sustained depletion of human CD19+ B cells from the peripheral blood, as well as a dramatic systemic reduction of human CD19+ B-cell levels in all tissues (bone marrow, spleen, liver, lung) analyzed. When human CD8+ T cells were depleted from the mice, no significant B-cell depletion was observed in response to CD19xCD3 DART protein treatment, confirming that human CD8+ T cells are the primary effector cells in this in vivo model. These studies validate the use of BLT humanized mice for the in vivo evaluation and preclinical development of bispecific molecules that redirect human T cells to selectively deplete target cells. PMID:27119115

  18. Identification of Stage-Specific Surface Markers in Early B Cell Development Provides Novel Tools for Identification of Progenitor Populations.

    PubMed

    Jensen, Christina T; Lang, Stefan; Somasundaram, Rajesh; Soneji, Shamit; Sigvardsson, Mikael

    2016-09-01

    Whereas the characterization of B lymphoid progenitors has been facilitated by the identification of lineage- and stage-specific surface markers, the continued identification of differentially expressed proteins increases our capacity to explore normal and malignant B cell development. To identify novel surface markers with stage-specific expression patterns, we explored the reactivity of CD19(+) B cell progenitor cells to Abs targeted to 176 surface proteins. Markers with stage-specific expression were identified using a transgenic reporter gene system subdividing the B cell progenitors into four surface IgM(-) stages. This approach affirmed the utility of known stage-specific markers, as well as identifying additional proteins that selectively marked defined stages of B cell development. Among the stage-specific markers were the cell adhesion proteins CD49E, CD11A, and CD54 that are highly expressed selectively on the most immature progenitors. This work identifies a set of novel stage-specific surface markers that can be used as a complement to the classical staining protocols to explore B lymphocyte development. PMID:27456481

  19. Preclinical Evaluation of the Novel BTK Inhibitor Acalabrutinib in Canine Models of B-Cell Non-Hodgkin Lymphoma.

    PubMed

    Harrington, Bonnie K; Gardner, Heather L; Izumi, Raquel; Hamdy, Ahmed; Rothbaum, Wayne; Coombes, Kevin R; Covey, Todd; Kaptein, Allard; Gulrajani, Michael; Van Lith, Bart; Krejsa, Cecile; Coss, Christopher C; Russell, Duncan S; Zhang, Xiaoli; Urie, Bridget K; London, Cheryl A; Byrd, John C; Johnson, Amy J; Kisseberth, William C

    2016-01-01

    Acalabrutinib (ACP-196) is a second-generation inhibitor of Bruton agammaglobulinemia tyrosine kinase (BTK) with increased target selectivity and potency compared to ibrutinib. In this study, we evaluated acalabrutinib in spontaneously occurring canine lymphoma, a model of B-cell malignancy similar to human diffuse large B-cell lymphoma (DLBCL). First, we demonstrated that acalabrutinib potently inhibited BTK activity and downstream effectors in CLBL1, a canine B-cell lymphoma cell line, and primary canine lymphoma cells. Acalabrutinib also inhibited proliferation in CLBL1 cells. Twenty dogs were enrolled in the clinical trial and treated with acalabrutinib at dosages of 2.5 to 20mg/kg every 12 or 24 hours. Acalabrutinib was generally well tolerated, with adverse events consisting primarily of grade 1 or 2 anorexia, weight loss, vomiting, diarrhea and lethargy. Overall response rate (ORR) was 25% (5/20) with a median progression free survival (PFS) of 22.5 days. Clinical benefit was observed in 30% (6/20) of dogs. These findings suggest that acalabrutinib is safe and exhibits activity in canine B-cell lymphoma patients and support the use of canine lymphoma as a relevant model for human non-Hodgkin lymphoma (NHL). PMID:27434128

  20. Preclinical Evaluation of the Novel BTK Inhibitor Acalabrutinib in Canine Models of B-Cell Non-Hodgkin Lymphoma

    PubMed Central

    Gardner, Heather L.; Izumi, Raquel; Hamdy, Ahmed; Rothbaum, Wayne; Coombes, Kevin R.; Covey, Todd; Kaptein, Allard; Gulrajani, Michael; Van Lith, Bart; Krejsa, Cecile; Coss, Christopher C.; Russell, Duncan S.; Zhang, Xiaoli; Urie, Bridget K.; London, Cheryl A.; Byrd, John C.; Johnson, Amy J.; Kisseberth, William C.

    2016-01-01

    Acalabrutinib (ACP-196) is a second-generation inhibitor of Bruton agammaglobulinemia tyrosine kinase (BTK) with increased target selectivity and potency compared to ibrutinib. In this study, we evaluated acalabrutinib in spontaneously occurring canine lymphoma, a model of B-cell malignancy similar to human diffuse large B-cell lymphoma (DLBCL). First, we demonstrated that acalabrutinib potently inhibited BTK activity and downstream effectors in CLBL1, a canine B-cell lymphoma cell line, and primary canine lymphoma cells. Acalabrutinib also inhibited proliferation in CLBL1 cells. Twenty dogs were enrolled in the clinical trial and treated with acalabrutinib at dosages of 2.5 to 20mg/kg every 12 or 24 hours. Acalabrutinib was generally well tolerated, with adverse events consisting primarily of grade 1 or 2 anorexia, weight loss, vomiting, diarrhea and lethargy. Overall response rate (ORR) was 25% (5/20) with a median progression free survival (PFS) of 22.5 days. Clinical benefit was observed in 30% (6/20) of dogs. These findings suggest that acalabrutinib is safe and exhibits activity in canine B-cell lymphoma patients and support the use of canine lymphoma as a relevant model for human non-Hodgkin lymphoma (NHL). PMID:27434128

  1. Hepatitis C virus and diffuse large B-cell lymphoma: Pathogenesis, behavior and treatment

    PubMed Central

    Visco, Carlo; Finotto, Silvia

    2014-01-01

    A significant association between hepatitis C virus (HCV) infection and B-cell lymphoma has been reported by epidemiological studies, most of them describing a strong relationship between indolent lymphomas and HCV. Furthermore, the curative potential of antiviral therapy on HCV related indolent lymphomas supports a specific role for the virus in lymphomagenesis. These observations are reinforced by numerous laboratory experiments that led to several hypothetical models of B-cell transformation by HCV. Diffuse large B-cell lymphoma (DLBCL), the most common lymphoma subtype in the western countries, has been associated to HCV infection despite its aggressive nature. This association seems particularly prominent in some geographical areas. Clinical presentation of HCV-associated DLBCL has consistently been reported to differ from the HCV-negative counterpart. Nevertheless, histopathology, tolerance to standard-of-care chemo-immunotherapy (R-CHOP or CHOP-like regimens) and final outcome of HCV-positive DLBCL patients is still matter of debate. Addition of rituximab has been described to enhance viral replication but the probability of severe hepatic complications remains low, with some exceptions (i.e., hepatitis B virus or immune immunodeficiency virus co-infected patients, presence of grade > 2 transaminases elevation, cirrhosis or hepatocarcinoma). HCV viral load in this setting is not necessarily directly associated with liver damage. Overall, treatment of HCV associated DLBCL should be performed in an interdisciplinary approach with hepatologists and hematologists with close monitoring of liver function. Available reports reveal that the final outcome of HCV-positive DLBCL that receive standard immunochemotherapy is not inferior to their HCV-negative counterpart. This review summarizes data on epidemiology, pathogenesis and therapeutic approach on HCV-associated DLBCL. Several issues that are matter of debate like clinical management of patients with transaminase

  2. [Malignant hyperthermia].

    PubMed

    Metterlein, T; Schuster, F; Graf, B M; Anetseder, M

    2014-12-01

    Malignant hyperthermia (MH) is a rare hereditary, mostly subclinical myopathy. Trigger substances, such as volatile anesthetic agents and the depolarizing muscle relaxant succinylcholine can induce a potentially fatal metabolic increase in predisposed patients caused by a dysregulation of the myoplasmic calcium (Ca) concentration. Mutations in the dihydropyridine ryanodine receptor complex in combination with the trigger substances are responsible for an uncontrolled release of Ca from the sarcoplasmic reticulum. This leads to activation of the contractile apparatus and a massive increase in cellular energy production. Exhaustion of the cellular energy reserves ultimately results in local muscle cell destruction and subsequent cardiovascular failure. The clinical picture of MH episodes is very variable. Early symptoms are hypoxia, hypercapnia and cardiac arrhythmia whereas the body temperature rise, after which MH is named, often occurs later. Decisive for the course of MH episodes is a timely targeted therapy. Following introduction of the hydantoin derivative dantrolene, the previously high mortality of fulminant MH episodes could be reduced to well under 10 %. An MH predisposition can be detected using the invasive in vitro contracture test (IVCT) or mutation analysis. Few elaborate diagnostic procedures are in the developmental stage. PMID:25384957

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

    PubMed

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

    2015-05-08

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

  4. Antibodies That Block or Activate Mouse B Cell Activating Factor of the Tumor Necrosis Factor (TNF) Family (BAFF), Respectively, Induce B Cell Depletion or B Cell Hyperplasia.

    PubMed

    Kowalczyk-Quintas, Christine; Schuepbach-Mallepell, Sonia; Vigolo, Michele; Willen, Laure; Tardivel, Aubry; Smulski, Cristian R; Zheng, Timothy S; Gommerman, Jennifer; Hess, Henry; Gottenberg, Jacques-Eric; Mackay, Fabienne; Donzé, Olivier; Schneider, Pascal

    2016-09-16

    B cell activating factor of the TNF family (BAFF), also known as B lymphocyte stimulator, is a ligand required for the generation and maintenance of B lymphocytes. In this study, the ability of different monoclonal antibodies to recognize, inhibit, or activate mouse BAFF was investigated. One of them, a mouse IgG1 named Sandy-2, prevented the binding of BAFF to all of its receptors, BAFF receptor, transmembrane activator and calcium modulating ligand interactor, and B cell maturation antigen, at a stoichiometric ratio; blocked the activity of mouse BAFF on a variety of cell-based reporter assays; and antagonized the prosurvival action of BAFF on primary mouse B cells in vitro A single administration of Sandy-2 in mice induced B cell depletion within 2 weeks, down to levels close to those observed in BAFF-deficient mice. This depletion could then be maintained with a chronic treatment. Sandy-2 and a previously described rat IgG1 antibody, 5A8, also formed a pair suitable for the sensitive detection of endogenous circulating BAFF by ELISA or using a homogenous assay. Interestingly, 5A8 and Sandy-5 displayed activities opposite to that of Sandy-2 by stimulating recombinant BAFF in vitro and endogenous BAFF in vivo These tools will prove useful for the detection and functional manipulation of endogenous mouse BAFF and provide an alternative to the widely used BAFF receptor-Fc decoy receptor for the specific depletion of BAFF in mice. PMID:27451394

  5. Intrinsic differences in the initiation of B cell receptor signaling favor responses of human IgG(+) memory B cells over IgM(+) naive B cells.

    PubMed

    Davey, Angel M; Pierce, Susan K

    2012-04-01

    The acquisition of long-lived memory B cells (MBCs) is critical for the defense against many infectious diseases. Despite their importance, little is known about how Ags trigger human MBCs, even though our understanding of the molecular basis of Ag activation of B cells in model systems has advanced considerably. In this study, we use quantitative, high-resolution, live-cell imaging at the single-cell and single-molecule levels to describe the earliest Ag-driven events in human isotype-switched, IgG-expressing MBCs and compare them with those in IgM-expressing naive B cells. We show that human MBCs are more robust than naive B cells at each step in the initiation of BCR signaling, including interrogation of Ag-containing membranes, formation of submicroscopic BCR oligomers, and recruitment and activation of signaling-associated kinases. Despite their robust response to Ag, MBCs remain highly sensitive to FcγRIIB-mediated inhibition. We also demonstrate that in the absence of Ag, a portion of MBC receptors spontaneously oligomerized, and phosphorylated kinases accumulated at the membrane and speculate that heightened constitutive signaling may play a role in maintaining MBC longevity. Using high-resolution imaging, we have provided a description of the earliest events in the Ag activation of MBCs and evidence for acquired cell-intrinsic differences in the initiation of BCR signaling in human naive and MBCs.

  6. [Malignant Pleural Mesotheliomas].

    PubMed

    Biancosino, C; Redwan, B; Krüger, M; Eberlein, M; Bölükbas, S

    2016-09-01

    Malignant pleural mesotheliomas (MPM) are very aggressive tumors, which originate from the mesothelial cells of the pleural surface. The main risk factor associated with MPM is exposure to asbestos. The latency period between asbestos exposure and MPM can be 30-60 years. Clinical symptoms and signs are often nonspecifc. The diagnosis of MPM requires an adequate tissue specimen for pathological examination, and video assisted thoracoscopic surgey (VATS) is associated with the highest diagnostic yield. MPM are histologically classified into epitheloid, sacromatoid and biphasic (mixed) sub-types. Accurate staging with invasive tests, if needed, is an important step before an interdisciplinary team can decide on an optimal (multi-modal) treatment approach. A multi-modal treatment approach (surgery, radiation oncology and chemotherapy) is superior to all approaches relying only on a single modality, if the patient qualifies for it from an oncological and functional standpoint. The goal of the surgical therapy is to achieve macroscopic complete resection. There are two competing surgical approaches and philosophies: extrapleural pneumonectomy (EPP) and radical pleurectomy (RP). Over the last years a paradigm shift from EPP to RP occurred and RP is now often the preferred surgical option. PMID:27612329

  7. Erk negative feedback control enables pre-B cell transformation and represents a therapeutic target in acute lymphoblastic leukemia

    PubMed Central

    Shojaee, Seyedmehdi; Caeser, Rebecca; Buchner, Maike; Park, Eugen; Swaminathan, Srividya; Hurtz, Christian; Geng, Huimin; Chan, Lai N; Klemm, Lars; Hofmann, Wolf-Karsten; Qiu, Yi Hua; Zhang, Nianxiang; Coombes, Kevin R.; Paietta, Elisabeth; Molkentin, Jeffery; Koeffler, H Phillip; Willman, Cheryl L; Hunger, Stephen P.; Melnick, Ari; Kornblau, Steven M.; Müschen, Markus

    2015-01-01

    Summary Studying mechanisms of malignant transformation of human pre-B cells, we found that acute activation of oncogenes induced immediate cell death in the vast majority of cells. Few surviving pre-B cell clones had acquired permissiveness to oncogenic signaling by strong activation of negative feedback regulation of Erk signaling. Studying negative feedback regulation of Erk in genetic experiments at three different levels, we found that Spry2, Dusp6 and Etv5 were essential for oncogenic transformation in mouse models for pre-B acute lymphoblastic leukemia (ALL). Interestingly, a small molecule inhibitor of DUSP6 selectively induced cell death in patient-derived pre-B ALL cells and overcame conventional mechanisms of drug-resistance. PMID:26073130

  8. STAT3 inhibition is a therapeutic strategy for ABC-like diffuse large B-cell lymphoma.

    PubMed

    Scuto, Anna; Kujawski, Maciej; Kowolik, Claudia; Krymskaya, Ludmila; Wang, Lin; Weiss, Lawrence M; Digiusto, David; Yu, Hua; Forman, Stephen; Jove, Richard

    2011-05-01

    Persistent STAT3 signaling contributes to malignant progression in many diverse types of human cancer. STAT3 is constitutively active in activated B-cell (ABC)-like diffuse large B-cell lymphomas (DLBCL), a class of nongerminal center derived DLBCL cells for which existing therapy is weakly effective. In this report, we provide a preclinical proof of concept that STAT3 is an effective molecular target for ABC-like DLBCL therapy. Direct inhibition of STAT3 with short hairpin RNA suppressed the growth of human ABC-like DLBCL in mouse models in a manner associated with apoptosis, repression of STAT3 target genes, and inhibition of a tumor-promoting microenvironment. Together, these results suggest that STAT3 is essential to maintain the pathophysiology of ABC-like DLBCL and therefore that STAT3 inhibition may offer a promising approach in its therapy.

  9. STK38 is a Critical Upstream Regulator of MYC’s Oncogenic Activity in Human B-cell lymphoma

    PubMed Central

    Bisikirska, Brygida C.; Adam, Stacey J.; Alvarez, Mariano J.; Rajbhandari, Presha; Cox, Rachel; Lefebvre, Celine; Wang, Kai; Rieckhof, Gabrielle E.; Felsher, Dean W.; Califano, Andrea

    2013-01-01

    The MYC proto-oncogene is associated with the pathogenesis of most human neoplasia. Conversely, its experimental inactivation elicits oncogene addiction. While MYC constitutes a formidable therapeutic target, it also plays an essential role in normal physiology, thus creating the need for context--specific targeting strategies. The analysis of post-translational MYC activity modulation yields novel targets for MYC inactivation. Specifically, following regulatory network analysis in human B cells, we identify a novel role of the STK38 kinase as a regulator of MYC activity and a candidate target for abrogating tumorigenesis in MYC addicted lymphoma. We found that STK38 regulates MYC protein stability and turnover in a kinase-activity-dependent manner. STK38 kinase inactivation abrogates apoptosis following B-cell receptor (BCR) activation, while its silencing significantly decreases MYC levels and increases apoptosis. Moreover, STK38 knockdown suppresses growth of MYC addicted tumors in vivo thus providing a novel viable target for treating these malignancies. PMID:23178486

  10. A benign maxillary tumour with malignant features.

    PubMed

    Ricalde, Rosario R; Lim, Aimee Caroline E; Lopa, Ramon Antonio B; Carnate, Jose M

    2010-06-01

    Non-specific biopsy results such as chronic inflammation, hemorrhage, necrosis can be frustrating to the clinician. This is especially true if the patient presents with clinical features suggestive of an aggressive tumour. This is a review of the clinical features, diagnostic dilemmas and surgical management of a benign maxillary mass with malignant features - a disease called hematoma-like mass of the maxillary sinus (HLMMS). Our experience with five cases will also be cited. PMID:20502750

  11. Safety and Tolerability Study of PCI-32765 in B Cell Lymphoma and Chronic Lymphocytic Leukemia

    ClinicalTrials.gov

    2016-04-26

    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

  12. Selective Immunophenotyping for Diagnosis of B-cell Neoplasms: Immunohistochemistry and Flow Cytometry Strategies and Results

    PubMed Central

    Boyd, Scott D.; Natkunam, Yasodha; Allen, John R.; Warnke, Roger A.

    2012-01-01

    Determining the immunophenotype of hematologic malignancies is now an indispensible part of diagnostic classification, and can help to guide therapy, or to predict clinical outcome. Diagnostic workup should be guided by morphologic findings and evaluate clinically important markers, but ideally should avoid the use of overly-broad panels of immunostains that can reveal incidental findings of uncertain significance and give rise to increased costs. Here, we outline our approach to diagnosis of B cell neoplasms, combining histologic and clinical data with tailored panels of immunophenotyping reagents, in the context of the 2008 World Health Organization classification. We present data from cases seen at our institution from 2004-8 using this approach, to provide a practical reference for findings seen in daily diagnostic practice. PMID:22820658

  13. The ultrastructural localization of immunoglobulins in human b cells of immunoproliferative diseases.

    PubMed

    Gourdin, M F; Farcet, J P; Reyes, F

    1982-06-01

    The cellular distribution of immunoglobulins in human malignant and normal B cells was investigated by immunoelectron microscopy by direct incubation of fixed cells with electron microscopy by direct incubation of fixed cells with peroxidase-coupled antibody. These conjugates penetrated into the cell, resulting in the simultaneous detection of surface and cytoplasmic immunoglobulins. The latter were seen as specific intracisternal staining of the perinuclear space and endoplasmic reticulum and occasionally of the Golgi complex. Plasma cells were frequently characterized by a heterogeneity of reactivity of the endoplasmic reticulum. Minute amounts of cytoplasmic immunoglobulin were demonstrated in cells without developed secretory organelles, such as lymphoma cells and lymphocytes from chronic lymphocytic leukemia (CLL). The method allowed us to define several subsets of cells according to the expression of surface and cytoplasmic immunoglobulins and thus to determine the stage of maturation of cells involved in monoclonal proliferation. PMID:7044445

  14. Genetic alterations in primary mediastinal B-cell lymphoma: an update.

    PubMed

    Scarpa, A; Moore, P S; Rigaud, G; Menestrina, F

    2001-03-01

    Primary mediastinal B-cell lymphoma (PMBL) is a distinct clinical entity among non-Hodgkin's lymphoma. The malignancy has received little attention from a standpoint of basic research due in part to its rarity. However, based on recent studies consistent trends are beginning to emerge regarding the molecular and chromosomal alterations commonly observed in this disease. By both CGH and AP-PCR, genetic gains involving chromosomes 2, 5, 7, 9p, 12, and Xq are among the most frequently observed events. From a molecular standpoint, alterations in the c-myc, p16(INK4) and p53 genes have been observed in up to 30% of cases. This information along with the well-established histological, immunological, and clinical features should convince the few remaining disbelievers that PMBL is a distinct pathological entity among non-Hodgkin's lymphomas. PMID:11342356

  15. SEOM clinical guidelines for the treatment of diffuse large B-cell lymphoma.

    PubMed

    Gómez Codina, José; Sabín Domínguez, Pilar; Provencio Pulla, Mariano; Rueda Domínguez, Antonio; Isla Casado, Dolores

    2010-11-01

    Diffuse large B-cell non-Hodgkin's lymphoma (LDCGB) is one of the best examples of chemotherapy curable malignant diseases. This "Oncoguía SEOM" summarizes the basic directions of staging and recommended treatment options. The staging study should be thorough and includes clinical, laboratory, diagnostic imaging and nuclear medicine. Treatment depends on patient characteristics and comorbidity and on disease extension and prognostic factors. In localized cases, chemoimmunotherapy (CHOP-R) of short duration, followed by involved-field irradiation is the preferred option. In advanced stages, the association of CHOP-like chemotherapy and Rituximab has been a major breakthrough in terms of cure rate. It is important do not forget the supportive treatment in these patients. PMID:20974570

  16. Primary diffuse large B-cell lymphoma of the left ureter: A case report

    PubMed Central

    Chen, Ping; Jiang, Maoqing; Lin, Yuanwei; Ye, Xianwang; Ruan, Xinzhong; Huang, Qiuli

    2016-01-01

    Diffuse large B-cell lymphoma (DLBCL) is a subtype of non-Hodgkin lymphoma occurring in various sites, but rarely involving the ureters. Primary DLBCL is a rare entity. Imaging studies in a 82-year-old male patient revealed left hydronephrosis and an area of nodular soft tissue density in the upper ureteral wall. On enhanced computed tomography scans, the lesion exhibited early enhancement. As the lesion was considered to be malignant, a left nephroureterectomy was performed for the purpose of pathological diagnosis. Histological analysis and immunohistochemistry revealed DLBCL. Since the surgery, the patient has survived for 16 months without evidence of a relapse. Thus, in cases with ureteral stenosis or obstruction for which the cause is uncertain, the possibility of primary lymphoma of the ureter should be considered and further histopathological examination of bioptic samples should be performed as soon as possible. PMID:27588189

  17. Immune pancytopenia after chemotherapy in a patient with diffuse large B-cell lymphoma.

    PubMed

    Nagashima, Kazuyo; Tanaka, Hiroaki; Nagai, Yurie; Sugita, Yasumasa

    2016-01-01

    During treatment for malignant lymphoma, cytopenia can develop for several reasons. In the treatment of cytopenia, various possibilities should be considered because inadequate treatment causes exacerbation of cytopenia and can lead to fatal conditions, such as infection and bleeding. Herein, we describe immune pancytopenia 3 months after the last exposure to chemotherapy in a patient with diffuse large B-cell lymphoma (DLBCL). She suffered from severe pancytopenia after two courses of rituximab and bendamustine therapy for a second relapse of DLBCL. Immune pancytopenia was diagnosed with bone marrow tests and the presence of autoantibodies; it promptly resolved after initiation of prednisolone therapy. Clinicians should be aware of immune cytopenia and monitor for it carefully, even if patients have already finished chemotherapy treatment. PMID:27651408

  18. Anti-apoptotic role and clinical relevance of neurotrophins in diffuse large B-cell lymphomas

    PubMed Central

    Dubanet, Lydie; Bentayeb, Hafidha; Petit, Barbara; Olivrie, Agnès; Saada, Sofiane; de la Cruz-Morcillo, Miguel A; Lalloué, Fabrice; Gourin, Marie-Pierre; Bordessoule, Dominique; Faumont, Nathalie; Delage-Corre, Manuela; Fauchais, Anne-Laure; Jauberteau, Marie-Odile; Troutaud, Danielle

    2015-01-01

    Background: Diffuse large B-cell lymphoma (DLBCL) is a fatal malignancy that needs to identify new targets for additional therapeutic options. This study aimed to clarify the clinical and biological significance of endogenous neurotrophin (nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF)) in DLBCL biopsy samples and cell lines. Methods: We analysed expression of NGF, BDNF, and their receptors (Trk, p75NTR) in 51 biopsies and cell lines by immunohistochemistry, immunofluorescence, and western blotting. To investigate the biological role of BDNF/TrkB/p75NTR axis, effects of neurotrophin signalling inhibition were determined on tumour cell survival and vascular endothelial growth factor (VEGF) secretion. The pharmacological pan-Trk inhibitor K252a was used for in vitro and in vivo studies. Results: A BDNF/TrkB axis was expressed in all biopsies, which was independent of the germinal centre B-cell (GCB)/non-GCB profile. p75NTR, TrkB, and BDNF tumour scores were significantly correlated and high NGF expression was significantly associated with MUM1/IRF4, and the non-GCB subtype. Diffuse large B-cell lymphoma cell lines co-expressed neurotrophins and their receptors. The full-length TrkB receptor was found in all cell lines, which was also phosphorylated at Tyr-817. p75NTR was associated to Trk and not to its cell death co-receptor sortilin. In vitro, inhibition of neurotrophin signalling induced cell apoptosis. K252a caused cell apoptosis, decreased VEGF secretion, and potentiated rituximab effect, notably in less rituximab-sensitive cells. In vivo, K252a significantly reduced tumour growth and potentiated the effects of rituximab in a GCB-DLBCL xenograft model. Conclusions: This work argues for a pro-survival role of endogenous neurotrophins in DLBCLs and inhibition of Trk signalling might be a potential treatment strategy for rituximab resistant subgroups. PMID:26284337

  19. Clinical Significance of sIL-2R Levels in B-Cell Lymphomas

    PubMed Central

    Yoshida, Noriaki; Oda, Miyo; Kuroda, Yoshiaki; Katayama, Yuta; Okikawa, Yoshiko; Masunari, Taro; Fujiwara, Megumu; Nishisaka, Takashi; Sasaki, Naomi; Sadahira, Yoshito; Mihara, Keichiro; Asaoku, Hideki; Matsui, Hirotaka; Seto, Masao; Kimura, Akiro; Arihiro, Koji; Sakai, Akira

    2013-01-01

    Elevated soluble interleukin-2 receptor (sIL-2R) in sera is observed in patients with malignant lymphoma (ML). Therefore, sIL-2R is commonly used as a diagnostic and prognostic marker for ML, but the mechanisms responsible for the increase in sIL-2R levels in patients with B-cell lymphomas have not yet been elucidated. We first hypothesized that lymphoma cells expressing IL-2R and some proteinases such as matrix metalloproteinases (MMPs) in the tumor microenvironment can give rise to increased sIL-2R in sera. However, flow cytometric studies revealed that few lymphoma cells expressed IL-2R α chain (CD25) in diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL), and most CD25-expressing cells in the tumor were T-cells. Distinct correlations between CD25 expression on B-lymphoma cells and sIL-2R levels were not observed. We then confirmed that MMP-9 plays an important role in producing sIL-2R in functional studies. Immunohistochemical (IHC) analysis also revealed that MMP-9 is mainly derived from tumor-associated macrophages (TAMs). We therefore evaluated the number of CD68 and CD163 positive macrophages in the tumor microenvironment using IHC analysis. A positive correlation between the levels of sIL-2R in sera and the numbers of CD68 positive macrophages in the tumor microenvironment was confirmed in FL and extranodal DLBCL. These results may be useful in understanding the pathophysiology of B-cell lymphomas. PMID:24236041

  20. B-cell prolymphocytic leukemia: a specific subgroup of mantle cell lymphoma.

    PubMed

    van der Velden, Vincent H J; Hoogeveen, Patricia G; de Ridder, Dick; Schindler-van der Struijk, Magdalena; van Zelm, Menno C; Sanders, Mathijs; Karsch, Dennis; Beverloo, H Berna; Lam, King; Orfao, Alberto; Lugtenburg, Pieternella J; Böttcher, Sebastian; van Dongen, Jacques J M; Langerak, Anton W; Kappers-Klunne, Mies; van Lom, Kirsten

    2014-07-17

    B-cell prolymphocytic leukemia (B-PLL) is a rare mature B-cell malignancy that may be hard to distinguish from mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL). B-PLL cases with a t(11;14) were redefined as MCL in the World Health Organization 2008 classification. We evaluated 13 B-PLL patients [7 being t(11;14)-positive (B-PLL+) and 6 negative (B-PLL-)] and compared them with MCL and CLL patients. EuroFlow-based immunophenotyping showed significant overlap between B-PLL+ and B-PLL-, as well as between B-PLL and MCL, whereas CLL clustered separately. Immunogenotyping showed specific IGHV gene usage partly resembling MCL. Gene expression profiling showed no separation between B-PLL+ and B-PLL- but identified 3 subgroups. One B-PLL subgroup clustered close to CLL and another subgroup clustered with leukemic MCL; both were associated with prolonged survival. A third subgroup clustered close to nodal MCL and was associated with short survival. Gene expression profiles of both B-PLL+ and B-PLL- showed best resemblance with normal immunoglobulin M-only B-cells. Our data confirm that B-PLL+ is highly comparable to MCL, indicate that B-PLL- also may be considered as a specific subgroup of MCL, and suggest that B-PLL is part of a spectrum, ranging from CLL-like B-PLL, to leukemic MCL-like B-PLL, to nodal MCL-like B-PLL.

  1. Aggression in Pretend Play and Aggressive Behavior in the Classroom

    ERIC Educational Resources Information Center

    Fehr, Karla K.; Russ, Sandra W.

    2013-01-01

    Research Findings: Pretend play is an essential part of child development and adjustment. However, parents, teachers, and researchers debate the function of aggression in pretend play. Different models of aggression predict that the expression of aggression in play could either increase or decrease actual aggressive behavior. The current study…

  2. Malignant cancer and invasive placentation

    PubMed Central

    D'Souza, Alaric W.; Wagner, Günter P.

    2014-01-01

    Cancer metastasis is an invasive process that involves the transplantation of cells into new environments. Since human placentation is also invasive, hypotheses about a relationship between invasive placentation in eutherian mammals and metastasis have been proposed. The relationship between metastatic cancer and invasive placentation is usually presented in terms of antagonistic pleiotropy. According to this hypothesis, evolution of invasive placentation also established the mechanisms for cancer metastasis. Here, in contrast, we argue that the secondary evolution of less invasive placentation in some mammalian lineages may have resulted in positive pleiotropic effects on cancer survival by lowering malignancy rates. These positive pleiotropic effects would manifest themselves as resistance to cancer cell invasion. To provide a preliminary test of this proposal, we re-analyze data from Priester and Mantel (Occurrence of tumors in domestic animals. Data from 12 United States and Canadian colleges of veterinary medicine. J Natl Cancer Inst 1971;47:1333-44) about malignancy rates in cows, horses, cats and dogs. From our analysis we found that equines and bovines, animals with less invasive placentation, have lower rates of metastatic cancer than felines and canines in skin and glandular epithelial cancers as well as connective tissue sarcomas. We conclude that a link between type of placentation and species-specific malignancy rates is more likely related to derived mechanisms that suppress invasion rather than different degrees of fetal placental aggressiveness. PMID:25324490

  3. Transcription factor networks in B-cell differentiation link development to acute lymphoid leukemia.

    PubMed

    Somasundaram, Rajesh; Prasad, Mahadesh A J; Ungerbäck, Jonas; Sigvardsson, Mikael

    2015-07-01

    B-lymphocyte development in the bone marrow is controlled by the coordinated action of transcription factors creating regulatory networks ensuring activation of the B-lymphoid program and silencing of alternative cell fates. This process is tightly connected to malignant transformation because B-lineage acute lymphoblastic leukemia cells display a pronounced block in differentiation resulting in the expansion of immature progenitor cells. Over the last few years, high-resolution analysis of genetic changes in leukemia has revealed that several key regulators of normal B-cell development, including IKZF1, TCF3, EBF1, and PAX5, are genetically altered in a large portion of the human B-lineage acute leukemias. This opens the possibility of directly linking the disrupted development as well as aberrant gene expression patterns in leukemic cells to molecular functions of defined transcription factors in normal cell differentiation. This review article focuses on the roles of transcription factors in early B-cell development and their involvement in the formation of human leukemia.

  4. Modifying akt signaling in B-cell chronic lymphocytic leukemia cells.

    PubMed

    Hofbauer, Sebastian W; Piñón, Josefina D; Brachtl, Gabriele; Haginger, Lucia; Wang, Wei; Jöhrer, Karin; Tinhofer, Ingeborg; Hartmann, Tanja Nicole; Greil, Richard

    2010-09-15

    Emerging evidence suggests that the survival of B-cell chronic lymphocytic leukemia (CLL) cells is dependent on microenvironmental influences such as antigenic stimulation and support by stromal cells. Akt, also known as protein kinase B, is a central component in prosurvival signaling downstream of these events. We investigated the role of Akt and its modulation by the protooncogene T-cell leukemia 1a (Tcl1a) in the survival pathways of primary CLL samples and CLL-derived prolymphocytic cell lines MEC-1 and MEC-2. Akt activation was increased by the protective presence of human bone marrow stromal cells and B-cell receptor mimicking signals but antagonized by direct Akt blockade with the novel specific inhibitor AiX, with preferential apoptosis induction in CLL cells with an unmutated immunoglobulin status, which predicts poor clinical outcome. In addition, we found a direct interaction of Akt with Tcl1a in an endogenous coimmunoprecipitation assay. Confirming the critical role of Tcl1a in modulating Akt signaling, Akt activation was enhanced by overexpressing Tcl1a in CLL. In contrast, decreasing Tcl1a levels by small interfering RNA reduced Akt activation in the fludarabine-insensitive CLL cell line MEC-2 and sensitized the malignant cells to fludarabine treatment. In summary, our data reveal a significant role for the Akt-Tcl1a axis in CLL survival and propose a further evaluation of this interplay for targeting chemoresistance phenomena.

  5. [Visceral leishmaniasis concurrent with splenic marginal zone B-cell lymphoma].

    PubMed

    Julhakyan, U L; Magomedova, A U; Dvirnyk, V N; Kravchenko, S K

    2016-01-01

    Splenic marginal zone B-cell lymphoma (SMZBCL) is a rare non-Hodgkin B-cell lymphoma that presents with morphologically mature lymphoid cells corresponding in their immunological characteristics to secondary follicular marginal zone lymphocytes. It is clinically characterized by splenomegaly, moderate lymphocytosis, usually focal bone marrow lesion, sometimes moderate of monoclonal immunoglobulin in the serum (generally IgM or IgG) and/or urea, and a relatively benign course. Leishmaniasis is a transmissible natural focal infectious endemic disease that has a great diversity of clinical manifestations. The authors describe Russia's first case of SMZBCL concurrent with visceral leishmaniasis in a 52-year-old female patient admitted to a hematology hospital with weakness, splenomegaly, and lymphadenopathy. The simultaneous detection of lymphoma and leishmaniasis in the same biopsy specimen is extremely rare. Visceral leishmaniasis should be borne in mind as an opportunistic infection in patients with malignancies, particularly in immunocompromised persons who live or have stayed in the endemic areas. PMID:27030189

  6. Malignant sex and aggression: an overview of serial sexual homicide.

    PubMed

    Myers, W C; Reccoppa, L; Burton, K; McElroy, R

    1993-01-01

    Serial murderers have attracted considerable attention in the popular press and criminal justice field, but scientific literature about these individuals is limited. This article provides an overview, from a psychiatric perspective, of serial sexual homicide, one type of serial killing. Characteristics of this type of murder and of these offenders are discussed. Defining qualities and diagnoses applicable to serial sexual killers are reviewed. Various etiologic theories are discussed, with emphasis on the role of fantasy and psychodynamic explanations. Governmental agencies involved in combating this type of crime, along with the role of mental health professionals in criminal profiling, are presented. Finally, the authors explore the reaction of society to this phenomenon.

  7. Malignant sex and aggression: an overview of serial sexual homicide.

    PubMed

    Myers, W C; Reccoppa, L; Burton, K; McElroy, R

    1993-01-01

    Serial murderers have attracted considerable attention in the popular press and criminal justice field, but scientific literature about these individuals is limited. This article provides an overview, from a psychiatric perspective, of serial sexual homicide, one type of serial killing. Characteristics of this type of murder and of these offenders are discussed. Defining qualities and diagnoses applicable to serial sexual killers are reviewed. Various etiologic theories are discussed, with emphasis on the role of fantasy and psychodynamic explanations. Governmental agencies involved in combating this type of crime, along with the role of mental health professionals in criminal profiling, are presented. Finally, the authors explore the reaction of society to this phenomenon. PMID:8054674

  8. B-cell lymphomas with concurrent MYC and BCL2 abnormalities other than translocations behave similarly to MYC/BCL2 double-hit lymphomas.

    PubMed

    Li, Shaoying; Seegmiller, Adam C; Lin, Pei; Wang, Xuan J; Miranda, Roberto N; Bhagavathi, Sharathkumar; Medeiros, L Jeffrey

    2015-02-01

    Large B-cell lymphomas with IGH@BCL2 and MYC rearrangement, known as double-hit lymphoma (DHL), are clinically aggressive neoplasms with a poor prognosis. Some large B-cell lymphomas have concurrent abnormalities of MYC and BCL2 other than coexistent translocations. Little is known about patients with these lymphomas designated here as atypical DHL. We studied 40 patients of atypical DHL including 21 men and 19 women, with a median age of 60 years. Nine (23%) patients had a history of B-cell non-Hodgkin lymphoma. There were 30 diffuse large B-cell lymphoma (DLBCL), 7 B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and Burkitt lymphoma, and 3 DLBCL with coexistent follicular lymphoma. CD10, BCL2, and MYC were expressed in 28/39 (72%), 33/35 (94%), and 14/20 (70%) cases, respectively. Patients were treated with standard (n=14) or more aggressive chemotherapy regimens (n=17). We compared the atypical DHL group with 76 patients with DHLand 35 patients with DLBCL lacking MYC and BCL2 abnormalities. The clinicopathologic features and therapies were similar between patients with atypical and typical DHL. The overall survival of patients with atypical double-hit lymphoma was similar to that of patients with double-hit lymphoma (P=0.47) and significantly worse than that of patients with DLBCL with normal MYC and BCL2 (P=0.02). There were some minor differences. Cases of atypical double-hit lymphoma more often have DLBCL morphology (P<0.01), less frequently expressed CD10 (P<0.01), and patients less often had an elevated serum lactate dehydrogenase level (P=0.01). In aggregate, these results support expanding the category of MYC/BCL2 DHL to include large B-cell lymphomas with coexistent MYC and BCL2 abnormalities other than concurrent translocations. PMID:25103070

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

    SciTech Connect

    Ma, Juan; Usui, Yoshihiko; Takeda, Kazuyoshi; Harada, Norihiro; 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.

  10. B-cell-targeted therapy for systemic lupus erythematosus.

    PubMed

    Sabahi, Ramin; Anolik, Jennifer H

    2006-01-01

    Systemic lupus erythematosus (SLE) is a complex disease characterised by numerous autoantibodies and clinical involvement in multiple organ systems. The immunological events triggering the onset of clinical manifestations have not yet been fully defined, but a central role for B cells in the pathogenesis of this disease has more recently gained prominence as a result of research in both mice and humans. Both antibody-dependent and -independent mechanisms of B cells are important in SLE. Autoantibodies contribute to autoimmunity by multiple mechanisms, including immune complex-mediated type III hypersensitivity reactions, type II antibody-dependent cytotoxicity, and by instructing innate immune cells to produce pathogenic cytokines such as interferon-alpha, tumour necrosis factor and interleukin-1. Suggested autoantibody-independent B-cell functions include antigen presentation, T-cell activation and polarisation, and dendritic-cell modulation. Several of these functions are mediated by the ability of B cells to produce immunoregulatory cytokines, chemokines and lymphangiogenic growth factors, and by their critical contribution to lymphoid tissue development and organisation, including the development of ectopic tertiary lymphoid tissue. Given the large body of evidence implicating abnormalities in the B-cell compartment in SLE, a recent therapeutic focus has been to develop interventions that target the B-cell compartment by multiple mechanisms.Rituximab, a mouse-human chimeric monoclonal antibody against CD20 that specifically depletes B cells, has been studied the most extensively. Although promising open-label data await confirmation in ongoing multicentre placebo-controlled trials, a number of preliminary conclusions can be drawn. The adequacy of peripheral B-cell depletion depends on achieving high and sustained serum rituximab concentrations, pharmacokinetics that can be varied with treatment dose and factors that may affect drug clearance, such as human anti

  11. 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

  12. TRAF3 deficiency promotes metabolic reprogramming in B cells

    PubMed Central

    Mambetsariev, Nurbek; Lin, Wai W.; Wallis, Alicia M.; Stunz, Laura L.; Bishop, Gail A.

    2016-01-01

    The adaptor protein TNF receptor-associated factor 3 (TRAF3) is a critical regulator of B lymphocyte survival. B cell-specific TRAF3 deficiency results in enhanced viability and is associated with development of lymphoma and multiple myeloma. We show that TRAF3 deficiency led to induction of two proteins important for glucose metabolism, Glut1 and Hexokinase 2 (HXK2). This was associated with increased glucose uptake. In the absence of TRAF3, anaerobic glycolysis and oxidative phosphorylation were increased in B cells without changes in mitochondrial mass or reactive oxygen species. Chemical inhibition of glucose metabolism or glucose deprivation substantially attenuated the enhanced survival of TRAF3-deficient B cells, with a decrease in the pro-survival protein Mcl-1. Changes in Glut1 and Mcl-1 levels, glucose uptake and B cell number in the absence of TRAF3 were all dependent upon NF-κB inducing kinase (NIK). These results indicate that TRAF3 deficiency suffices to metabolically reprogram B cells, a finding that improves our understanding of the role of TRAF3 as a tumor suppressor, and suggests potential therapeutic strategies. PMID:27752131

  13. Long noncoding RNAs in B-cell development and activation

    PubMed Central

    Brazão, Tiago F.; Johnson, Jethro S.; Müller, Jennifer; Heger, Andreas; Ponting, Chris P.

    2016-01-01

    Long noncoding RNAs (lncRNAs) are potentially important regulators of cell differentiation and development, but little is known about their roles in B lymphocytes. Using RNA-seq and de novo transcript assembly, we identified 4516 lncRNAs expressed in 11 stages of B-cell development and activation. Most of these lncRNAs have not been previously detected, even in the closely related T-cell lineage. Comparison with lncRNAs previously described in human B cells identified 185 mouse lncRNAs that have human orthologs. Using chromatin immunoprecipitation-seq, we classified 20% of the lncRNAs as either enhancer-associated (eRNA) or promoter-associated RNAs. We identified 126 eRNAs whose expression closely correlated with the nearest coding gene, thereby indicating the likely location of numerous enhancers active in the B-cell lineage. Furthermore, using this catalog of newly discovered lncRNAs, we show that PAX5, a transcription factor required to specify the B-cell lineage, bound to and regulated the expression of 109 lncRNAs in pro-B and mature B cells and 184 lncRNAs in acute lymphoblastic leukemia. PMID:27381906

  14. An analysis of B cell selection mechanisms in germinal centers.

    PubMed

    Meyer-Hermann, Michael E; Maini, Philip K; Iber, Dagmar

    2006-09-01

    Affinity maturation of antibodies during immune responses is achieved by multiple rounds of somatic hypermutation and subsequent preferential selection of those B cells that express B cell receptors with improved binding characteristics for the antigen. The mechanism underlying B cell selection has not yet been defined. By employing an agent-based model, we show that for physiologically reasonable parameter values affinity maturation can be driven by competition for neither binding sites nor antigen--even in the presence of competing secreted antibodies. Within the tested mechanisms, only clonal competition for T cell help or a refractory time for the interaction of centrocytes with follicular dendritic cells is found to enable affinity maturation while generating the experimentally observed germinal centre characteristics and tolerating large variations in the initial antigen density. PMID:16707510

  15. The role of B cells and autoantibodies in neuropsychiatric lupus.

    PubMed

    Wen, Jing; Stock, Ariel D; Chalmers, Samantha A; Putterman, Chaim

    2016-09-01

    The central nervous system manifestations of SLE (neuropsychiatric lupus, NPSLE) occur frequently, though are often difficult to diagnose and treat. Symptoms of NPSLE can be quite diverse, including chronic cognitive and emotional manifestations, as well as acute presentations, such as stroke and seizures. Although the pathogenesis of NPSLE has yet to be well characterized, B-cell mediated damage is believed to be an important contributor. B-cells and autoantibodies may traverse the blood brain barrier promoting an inflammatory environment consisting of glia activation, neurodegeneration, and consequent averse behavioral outcomes. This review will evaluate the various suggested roles of B-cells and autoantibodies in NPSLE, as well as therapeutic modalities targeting these pathogenic mediators.

  16. Induction of Epstein-Barr Virus Oncoprotein LMP1 by Transcription Factors AP-2 and Early B Cell Factor

    PubMed Central

    Noda, Chieko; Narita, Yohei; Watanabe, Takahiro; Yoshida, Masahiro; Ashio, Keiji; Sato, Yoshitaka; Goshima, Fumi; Kanda, Teru; Yoshiyama, Hironori; Tsurumi, Tatsuya; Kimura, Hiroshi

    2016-01-01

    ABSTRACT Latent membrane protein 1 (LMP1) is a major oncogene essential for primary B cell transformation by Epstein-Barr virus (EBV). Previous studies suggested that some transcription factors, such as PU.1, RBP-Jκ, NF-κB, and STAT, are involved in this expression, but the underlying mechanism is unclear. Here, we identified binding sites for PAX5, AP-2, and EBF in the proximal LMP1 promoter (ED-L1p). We first confirmed the significance of PU.1 and POU domain transcription factor binding for activation of the promoter in latency III. We then focused on the transcription factors AP-2 and early B cell factor (EBF). Interestingly, among the three AP-2-binding sites in the LMP1 promoter, two motifs were also bound by EBF. Overexpression, knockdown, and mutagenesis in the context of the viral genome indicated that AP-2 plays an important role in LMP1 expression in latency II in epithelial cells. In latency III B cells, on the other hand, the B cell-specific transcription factor EBF binds to the ED-L1p and activates LMP1 transcription from the promoter. IMPORTANCE Epstein-Barr virus (EBV) latent membrane protein 1 (LMP1) is crucial for B cell transformation and oncogenesis of other EBV-related malignancies, such as nasopharyngeal carcinoma and T/NK lymphoma. Its expression is largely dependent on the cell type or condition, and some transcription factors have been implicated in its regulation. However, these previous reports evaluated the significance of specific factors mostly by reporter assay. In this study, we prepared point-mutated EBV at the binding sites of such transcription factors and confirmed the importance of AP-2, EBF, PU.1, and POU domain factors. Our results will provide insight into the transcriptional regulation of the major oncogene LMP1. PMID:26819314

  17. High-efficiency Generation of Multiple Short Noncoding RNA in B-cells and B-cell-derived Extracellular Vesicles

    PubMed Central

    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

  18. Successful differentiation to T cells, but unsuccessful B-cell generation, from B-cell-derived induced pluripotent stem cells.

    PubMed

    Wada, Haruka; Kojo, Satoshi; Kusama, Chie; Okamoto, Naoki; Sato, Yorino; Ishizuka, Bunpei; Seino, Ken-ichiro

    2011-01-01

    Forced expression of certain transcription factors in somatic cells results in generation of induced pluripotent stem (iPS) cells, which differentiate into various cell types. We investigated T-cell and B-cell lineage differentiation from iPS cells in vitro. To evaluate the impact of iPS cell source, murine splenic B-cell-derived iPS (B-iPS) cells were generated after retroviral transduction of four transcription factors (Oct4, Sox2, Klf4 and c-Myc). B-iPS cells were identical to embryonic stem (ES) cells and mouse embryonic fibroblast (MEF)-derived iPS cells in morphology, ES cell marker expression as well as teratoma and chimera mouse formation. Both B-iPS and MEF-derived iPS cells differentiated into lymphocytes in OP9 co-culture systems. Both efficiently differentiated into T-cell lineage that produced IFN-γ on T-cell receptor stimulation. However, iPS cells including B-iPS cells were relatively resistant to B-cell lineage differentiation. One of the reasons of the failure of B-cell lineage differentiation seemed due to a defect of Pax5 expression in the differentiated cells. Therefore, current in vitro differentiation systems using iPS cells are sufficient for inducing T-cell but not B-cell lineage. PMID:21135032

  19. T-24.B-cell differentiation factor induces immunoglobulin secretion in human B cells without prior cell replication.

    PubMed

    Gallagher, G; Christie, J F; Stimson, W H; Guy, K; Dewar, A E

    1987-04-01

    Stimulation of B lymphocytes from B-cell chronic lymphocytic leukaemia (B-CLL) with 12-0-tetradecanoylphorbol-13-acetate (TPA) has shown that these cells are capable of differentiation (Totterman, Nilsson & Sundstrom, 1980). Increases in the expression of different class II MHC antigens (Guy et al., 1983, 1986) and responsiveness to growth factors (Kabelitz et al., 1985; Suzuki, Butler & Cooper, 1985) have been studied. Supernatant from the human bladder carcinoma line T-24 contains a B-cell differentiation factor (BCDF) able to induce immunoglobulin secretion from CESS cells. We investigated the induction of proliferation and immunoglobulin secretion in human B cells by studying the effects of this factor on B-CLL cells, in both the presence and absence of TPA. We report here that this material (termed T-24.BCDF) causes immunoglobulin secretion to be initiated in these cells, and that this is not accompanied by detectable DNA synthesis. These observations were extended to normal human B cells and demonstrate that human B cells can secrete immunoglobulin in the absence of clonal expansion. PMID:3495482

  20. Regulation of AID, the B-cell genome mutator.

    PubMed

    Keim, Celia; Kazadi, David; Rothschild, Gerson; Basu, Uttiya

    2013-01-01

    The mechanisms by which B cells somatically engineer their genomes to generate the vast diversity of antibodies required to challenge the nearly infinite number of antigens that immune systems encounter are of tremendous clinical and academic interest. The DNA cytidine deaminase activation-induced deaminase (AID) catalyzes two of these mechanisms: class switch recombination (CSR) and somatic hypermutation (SHM). Recent discoveries indicate a significant promiscuous targeting of this B-cell mutator enzyme genome-wide. Here we discuss the various regulatory elements that control AID activity and prevent AID from inducing genomic instability and thereby initiating oncogenesis.

  1. Conjunctival malignant melanoma in a horse.

    PubMed

    Moore, C.P.; Collins, B.K.; Linton, L.L.; Collier, L.L.

    2000-01-01

    A case of malignant melanoma originating from the conjunctiva of a horse is reported. The tumor exhibited locally aggressive behavior as evidenced clinically by recurrence following two treatment episodes including surgical excision on each occasion and one application of cryotherapy. The orbit was subsequently exenterated and histologically malignant conjunctival melanoma was confirmed. Histopathologic features included variable pigmentation with amelanotic sites demonstrating marked cellular and nuclear pleomorphism with high numbers of mitotic figures. Cords of neoplastic cells invaded the sclera and cornea. Following exenteration, the horse exhibited no recurrence of the tumor for five years before being lost to follow-up. To our knowledge, this is the first report of primary malignant conjunctival melanoma in a horse.

  2. Malignant pilomatricoma in the parietal area.

    PubMed

    Kondo, Takeshi; Tanaka, Yoshio

    2006-01-01

    A 27-year-old Japanese woman presented with a 2.5-cm nodular subcutaneous lesion in the parietal area. The nodule was well demarcated and situated in the dermis and subcutis. Histologically, the tumor was diagnosed as malignant pilomatricoma. The tumor was excised, the postoperative course was uneventful, no evidence of local recurrence or distant metastasis was observed, and the patient continues to be under close follow-up. Malignant pilomatricoma, a locally aggressive counterpart of benign pilomatricoma, is also referred to as pilomatrix carcinoma. Most cases are excised as benign tumors; however, when the excision is incomplete local recurrence is likely, and distant metastases have also been reported. Histologically, the diagnosis can be challenging because no clear histologic criteria are available. Because of the rarity of malignant pilomatricoma, no welldefined standards in the surgical management of this neoplasm have been established. Moreover, since distant metastases have been described, close followup of the lesion is requisite.

  3. Targeting B-cell neoplasia with T-cell receptors recognizing a CD20-derived peptide on patient-specific HLA.

    PubMed

    Mensali, Nadia; Ying, Fan; Sheng, Vincent Oei Yi; Yang, Weiwen; Walseng, Even; Kumari, Shraddha; Fallang, Lars-Egil; Kolstad, Arne; Uckert, Wolfgang; Malmberg, Karl Johan; Wälchli, Sébastien; Olweus, Johanna

    2016-05-01

    T cells engineered to express chimeric antigen receptors (CARs) targeted to CD19 are effective in treatment of B-lymphoid malignancies. However, CARs recognize all CD19 positive (pos) cells, and durable responses are linked to profound depletion of normal B cells. Here, we designed a strategy to specifically target patient B cells by utilizing the fact that T-cell receptors (TCRs), in contrast to CARs, are restricted by HLA. Two TCRs recognizing a peptide from CD20 (SLFLGILSV) in the context of foreign HLA-A*02:01 (CD20p/HLA-A2) were expressed as 2A-bicistronic constructs. T cells re-directed with the A23 and A94 TCR constructs efficiently recognized malignant HLA-A2(pos) B cells endogenously expressing CD20, including patient-derived follicular lymphoma and chronic lymphocytic leukemia (CLL) cells. In contrast, a wide range of HLA-A2(pos)CD20(neg) cells representing different tissue origins, and HLA-A2(neg)CD20(pos) cells, were not recognized. Cytotoxic T cells re-directed with CD20p/HLA-A2-specific TCRs or CD19 CARs responded with similar potencies to cells endogenously expressing comparable levels of CD20 and CD19. The CD20p/HLA-A2-specific TCRs recognized CD20p bound to HLA-A2 with high functional avidity. The results show that T cells expressing CD20p/HLA-A2-specific TCRs efficiently and specifically target B cells. When used in context of an HLA-haploidentical allogeneic stem cell transplantation where the donor is HLA-A2(neg) and the patient HLA-A2(pos), these T cells would selectively kill patient-derived B cells and allow reconstitution of the B-cell compartment with HLA-A2(neg) donor cells. These results should pave the way for clinical testing of T cells genetically engineered to target malignant B cells without permanent depletion of normal B cells.

  4. Targeting B-cell neoplasia with T-cell receptors recognizing a CD20-derived peptide on patient-specific HLA.

    PubMed

    Mensali, Nadia; Ying, Fan; Sheng, Vincent Oei Yi; Yang, Weiwen; Walseng, Even; Kumari, Shraddha; Fallang, Lars-Egil; Kolstad, Arne; Uckert, Wolfgang; Malmberg, Karl Johan; Wälchli, Sébastien; Olweus, Johanna

    2016-05-01

    T cells engineered to express chimeric antigen receptors (CARs) targeted to CD19 are effective in treatment of B-lymphoid malignancies. However, CARs recognize all CD19 positive (pos) cells, and durable responses are linked to profound depletion of normal B cells. Here, we designed a strategy to specifically target patient B cells by utilizing the fact that T-cell receptors (TCRs), in contrast to CARs, are restricted by HLA. Two TCRs recognizing a peptide from CD20 (SLFLGILSV) in the context of foreign HLA-A*02:01 (CD20p/HLA-A2) were expressed as 2A-bicistronic constructs. T cells re-directed with the A23 and A94 TCR constructs efficiently recognized malignant HLA-A2(pos) B cells endogenously expressing CD20, including patient-derived follicular lymphoma and chronic lymphocytic leukemia (CLL) cells. In contrast, a wide range of HLA-A2(pos)CD20(neg) cells representing different tissue origins, and HLA-A2(neg)CD20(pos) cells, were not recognized. Cytotoxic T cells re-directed with CD20p/HLA-A2-specific TCRs or CD19 CARs responded with similar potencies to cells endogenously expressing comparable levels of CD20 and CD19. The CD20p/HLA-A2-specific TCRs recognized CD20p bound to HLA-A2 with high functional avidity. The results show that T cells expressing CD20p/HLA-A2-specific TCRs efficiently and specifically target B cells. When used in context of an HLA-haploidentical allogeneic stem cell transplantation where the donor is HLA-A2(neg) and the patient HLA-A2(pos), these T cells would selectively kill patient-derived B cells and allow reconstitution of the B-cell compartment with HLA-A2(neg) donor cells. These results should pave the way for clinical testing of T cells genetically engineered to target malignant B cells without permanent depletion of normal B cells. PMID:27467957

  5. Surrogate light chain is required for central and peripheral B-cell tolerance and inhibits anti-DNA antibody production by marginal zone B cells.

    PubMed

    Ren, Weicheng; Grimsholm, Ola; Bernardi, Angelina I; Höök, Nina; Stern, Anna; Cavallini, Nicola; Mårtensson, Inga-Lill

    2015-04-01

    Selection of the primary antibody repertoire takes place in pro-/pre-B cells, and subsequently in immature and transitional B cells. At the first checkpoint, μ heavy (μH) chains assemble with surrogate light (SL) chain into a precursor B-cell receptor. In mice lacking SL chain, μH chain selection is impaired, and serum autoantibody levels are elevated. However, whether the development of autoantibody-producing cells is due to an inability of the resultant B-cell receptors to induce central and/or peripheral B-cell tolerance or other factors is unknown. Here, we show that receptor editing is defective, and that a higher proportion of BM immature B cells are prone to undergoing apoptosis. Furthermore, transitional B cells are also more prone to undergoing apoptosis, with a stronger selection pressure to enter the follicular B-cell pool. Those that enter the marginal zone (MZ) B-cell pool escape selection and survive, possibly due to the B-lymphopenia and elevated levels of B-cell activating factor. Moreover, the MZ B cells are responsible for the elevated IgM anti-dsDNA antibody levels detected in these mice. Thus, the SL chain is required for central and peripheral B-cell tolerance and inhibits anti-DNA antibody production by MZ B cells.

  6. Canine Lymphoma, More Than a Morphological Diagnosis: What We Have Learned about Diffuse Large B-Cell Lymphoma

    PubMed Central

    Aresu, Luca

    2016-01-01

    Diffuse large B-cell lymphoma (DLBCL) is the most common canine aggressive B-cell lymphoma worldwide, and new recent molecular approaches have shown that DLBCL constitutes a heterogeneous tumor that cannot be unraveled by morphology and immunophenotype. DLBCL behaves aggressively, typically progressing over a short period of time, and the therapy response may be difficult to be predicted. Recently, the rate of bone marrow infiltration by flow cytometry has been demonstrated to be prognostic, but more sensible markers are needed. As the clinical behavior is different, there is vast clinical and basic research devoted to identifying prognostically or biologically distinct DLBCL subgroups. Transcriptomic analysis by gene expression profile, copy number variations by array comparative genomic hybridization and epigenetic perturbations have tentatively described this heterogeneity. Molecular subgroups using oncogenic pathways and target genes have also been correlated to different outcome in a small number of cases. The objectives of this review are to summarize the current knowledge on the biology, clinical, and pathological characteristics of canine DLBCL. To date, DLBCL probably is the most investigated tumor in veterinary medicine, and its relevance as spontaneous model for human DLBCL has been confirmed by these studies. In future, these discoveries will ultimately lead to a better understanding of the underlying disease mechanisms, possibly translating into more effective therapeutic strategies. PMID:27630997

  7. Canine Lymphoma, More Than a Morphological Diagnosis: What We Have Learned about Diffuse Large B-Cell Lymphoma.

    PubMed

    Aresu, Luca

    2016-01-01

    Diffuse large B-cell lymphoma (DLBCL) is the most common canine aggressive B-cell lymphoma worldwide, and new recent molecular approaches have shown that DLBCL constitutes a heterogeneous tumor that cannot be unraveled by morphology and immunophenotype. DLBCL behaves aggressively, typically progressing over a short period of time, and the therapy response may be difficult to be predicted. Recently, the rate of bone marrow infiltration by flow cytometry has been demonstrated to be prognostic, but more sensible markers are needed. As the clinical behavior is different, there is vast clinical and basic research devoted to identifying prognostically or biologically distinct DLBCL subgroups. Transcriptomic analysis by gene expression profile, copy number variations by array comparative genomic hybridization and epigenetic perturbations have tentatively described this heterogeneity. Molecular subgroups using oncogenic pathways and target genes have also been correlated to different outcome in a small number of cases. The objectives of this review are to summarize the current knowledge on the biology, clinical, and pathological characteristics of canine DLBCL. To date, DLBCL probably is the most investigated tumor in veterinary medicine, and its relevance as spontaneous model for human DLBCL has been confirmed by these studies. In future, these discoveries will ultimately lead to a better understanding of the underlying disease mechanisms, possibly translating into more effective therapeutic strategies. PMID:27630997

  8. Canine Lymphoma, More Than a Morphological Diagnosis: What We Have Learned about Diffuse Large B-Cell Lymphoma

    PubMed Central

    Aresu, Luca

    2016-01-01

    Diffuse large B-cell lymphoma (DLBCL) is the most common canine aggressive B-cell lymphoma worldwide, and new recent molecular approaches have shown that DLBCL constitutes a heterogeneous tumor that cannot be unraveled by morphology and immunophenotype. DLBCL behaves aggressively, typically progressing over a short period of time, and the therapy response may be difficult to be predicted. Recently, the rate of bone marrow infiltration by flow cytometry has been demonstrated to be prognostic, but more sensible markers are needed. As the clinical behavior is different, there is vast clinical and basic research devoted to identifying prognostically or biologically distinct DLBCL subgroups. Transcriptomic analysis by gene expression profile, copy number variations by array comparative genomic hybridization and epigenetic perturbations have tentatively described this heterogeneity. Molecular subgroups using oncogenic pathways and target genes have also been correlated to different outcome in a small number of cases. The objectives of this review are to summarize the current knowledge on the biology, clinical, and pathological characteristics of canine DLBCL. To date, DLBCL probably is the most investigated tumor in veterinary medicine, and its relevance as spontaneous model for human DLBCL has been confirmed by these studies. In future, these discoveries will ultimately lead to a better understanding of the underlying disease mechanisms, possibly translating into more effective therapeutic strategies.

  9. Protein kinase c-β-dependent activation of NF-κB in stromal cells is indispensable for the survival of chronic lymphocytic leukemia B cells in vivo.

    PubMed

    Lutzny, Gloria; Kocher, Thomas; Schmidt-Supprian, Marc; Rudelius, Martina; Klein-Hitpass, Ludger; Finch, Andrew J; Dürig, Jan; Wagner, Michaela; Haferlach, Claudia; Kohlmann, Alexander; Schnittger, Susanne; Seifert, Marc; Wanninger, Stefan; Zaborsky, Nadja; Oostendorp, Robert; Ruland, Jürgen; Leitges, Michael; Kuhnt, Toni; Schäfer, Yvonne; Lampl, Benedikt; Peschel, Christian; Egle, Alexander; Ringshausen, Ingo

    2013-01-14

    Tumor cell survival critically depends on heterotypic communication with benign cells in the microenvironment. Here, we describe a survival signaling pathway activated in stromal cells by contact to B cells from patients with chronic lymphocytic leukemia (CLL). The expression of protein kinase C (PKC)-βII and the subsequent activation of NF-κB in bone marrow stromal cells are prerequisites to support the survival of malignant B cells. PKC-β knockout mice are insusceptible to CLL transplantations, underscoring the in vivo significance of the PKC-βII-NF-κB signaling pathway in the tumor microenvironment. Upregulated stromal PKC-βII in biopsies from patients with CLL, acute lymphoblastic leukemia, and mantle cell lymphoma suggests that this pathway may commonly be activated in a variety of hematological malignancies.

  10. Anti-CD20 antibody promotes cancer escape via enrichment of tumor-evoked regulatory B cells expressing low levels of CD20 and CD137L.

    PubMed

    Bodogai, Monica; Lee Chang, Catalina; Wejksza, Katarzyna; Lai, Jinping; Merino, Maria; Wersto, Robert P; Gress, Ronald E; Chan, Andrew C; Hesdorffer, Charles; Biragyn, Arya

    2013-04-01

    The possible therapeutic benefits of B-cell depletion in combating tumoral immune escape have been debated. In support of this concept, metastasis of highly aggressive 4T1 breast cancer cells in mice can be abrogated by inactivation of tumor-evoked regulatory B cells (tBreg). Here, we report the unexpected finding that B-cell depletion by CD20 antibody will greatly enhance cancer progression and metastasis. Both murine and human tBregs express low levels of CD20 and, as such, anti-CD20 mostly enriches for these cells. In the 4T1 model of murine breast cancer, this effect of enriching for tBregs suggests that B-cell depletion by anti-CD20 may not be beneficial at all in some cancers. In contrast, we show that in vivo-targeted stimulation of B cells with CXCL13-coupled CpG oligonucleotides (CpG-ODN) can block cancer metastasis by inhibiting CD20(Low) tBregs. Mechanistic investigations suggested that CpG-ODN upregulates low surface levels of 4-1BBL on tBregs to elicit granzyme B-expressing cytolytic CD8(+) T cells, offering some explanative power for the effect. These findings underscore the immunotherapeutic importance of tBreg inactivation as a strategy to enhance cancer therapy by targeting both the regulatory and activating arms of the immune system in vivo. PMID:23365136

  11. Immunoproliferative Small Intestinal Disease Associated with Overwhelming Polymicrobial Gastrointestinal Infection with Transformation to Diffuse Large B-cell Lymphoma.

    PubMed

    Ewers, Evan C; Sheffler, Robert L; Wang, James; Ngauy, Viseth

    2016-05-01

    Immunoproliferative small intestinal disease (IPSID) is an extra-nodal B-cell lymphoma most commonly described in the Mediterranean, Africa, and Asia. It is associated with poverty and poor sanitation, and is rarely encountered in developed countries. A 26-year-old previously healthy, Marshallese male was transferred to our facility with a 6-month history of watery diarrhea, weakness, and cachexia refractory to multiple short courses of oral antibiotics. Stool cultures grew Campylobacter jejuni and Vibrio fluvialis. Endoscopic evaluation showed histologic evidence of Helicobacter pylori gastritis and gross evidence of whipworm infection found in the colon. Mesenteric lymph node biopsy cultures grew Escherichia coli. Histopathology and immunohistochemical stains of the small intestine were consistent with IPSID. He subsequently transformed to diffuse large B-cell lymphoma (DLBCL) with tonsillar involvement despite treatment with rituximab and an extended course of antibiotics. Systemic chemotherapy with six cycles of rituximab, cyclophosphamide, vincristine, doxorubicin, prednisone, and lenalidomide, resulted in remission of his diffuse B cell lymphoma. This case is illustrative of IPSID developing in a previously healthy individual due to overwhelming polymicrobial gastrointestinal infection by C. jejuni and other enteric pathogens with subsequent transformation to an aggressive DLBCL. IPSID should be considered in residents of developing countries presenting with refractory chronic diarrhea, weight loss, and mesenteric lymphadenopathy. PMID:26903604

  12. DUSP4 deficiency caused by promoter hypermethylation drives JNK signaling and tumor cell survival in diffuse large B cell lymphoma

    PubMed Central

    Schmid, Corina A.; Robinson, Mark D.; Scheifinger, Nicole A.; Müller, Sebastian; Cogliatti, Sergio; Tzankov, Alexandar

    2015-01-01

    The epigenetic dysregulation of tumor suppressor genes is an important driver of human carcinogenesis. We have combined genome-wide DNA methylation analyses and gene expression profiling after pharmacological DNA demethylation with functional screening to identify novel tumor suppressors in diffuse large B cell lymphoma (DLBCL). We find that a CpG island in the promoter of the dual-specificity phosphatase DUSP4 is aberrantly methylated in nodal and extranodal DLBCL, irrespective of ABC or GCB subtype, resulting in loss of DUSP4 expression in 75% of >200 examined cases. The DUSP4 genomic locus is further deleted in up to 13% of aggressive B cell lymphomas, and the lack of DUSP4 is a negative prognostic factor in three independent cohorts of DLBCL patients. Ectopic expression of wild-type DUSP4, but not of a phosphatase-deficient mutant, dephosphorylates c-JUN N-terminal kinase (JNK) and induces apoptosis in DLBCL cells. Pharmacological or dominant-negative JNK inhibition restricts DLBCL survival in vitro and in vivo and synergizes strongly with the Bruton’s tyrosine kinase inhibitor ibrutinib. Our results indicate that DLBCL cells depend on JNK signaling for survival. This finding provides a mechanistic basis for the clinical development of JNK inhibitors in DLBCL, ideally in synthetic lethal combinations with inhibitors of chronic active B cell receptor signaling. PMID:25847947

  13. Aggression in Drosophila.

    PubMed

    Kravitz, Edward A; Fernandez, Maria de la Paz

    2015-10-01

    Aggression is used by essentially all species of animals to gain access to desired resources, including territory, food, and potential mates: Fruit flies are no exception. In Drosophila, both males and females compete in same sex fights for resources, but only males establish hierarchical relationships. Many investigators now study aggression using the fruit fly model, mainly because (a) aggression in fruit flies is a quantifiable well-defined and easily evoked behavior; (b) powerful genetic methods allow investigators to manipulate genes of interest at any place or time during embryonic, larval, pupal or adult life, and while flies are behaving; (c) the growth of the relatively new field of optogenetics makes physiological studies possible at single neuron levels despite the small sizes of neurons and other types of cells in fly brains; and (d) the rearing of fly stocks with their short generation times and limited growth space requirements can easily be performed at relatively low cost in most laboratories. This review begins with an examination of the behavior, both from a historical perspective and then from the birth of the "modern" era of studies of aggression in fruit flies including its quantitative analysis. The review continues with examinations of the roles of genes, neurotransmitters and neurohormones, peptides, nutritional and metabolic status, and surface cuticular hydrocarbons in the initiation and maintenance of aggression. It concludes with suggestions for future studies with this important model system.

  14. Vaccinations in patients with hematological malignancies.

    PubMed

    Tsigrelis, C; Ljungman, P

    2016-03-01

    Patients with hematological malignancies are at risk for a number of infections that are potentially preventable by vaccinations such as pneumococcal infections and influenza. Treatment, especially with anti-B-cell antibodies and hematopoietic stem cell transplantation (HSCT), negatively impacts the response to vaccination for several months. It is therefore recommended that patients be vaccinated before initiating immunosuppressive therapy if possible. The risk of side-effects with inactivated vaccines is low, but care has to be taken with live vaccines, such as varicella-zoster virus vaccine, since severe and fatal complications have been reported. HSCT patients require repeated doses of most vaccines to achieve long-lasting immune responses. New therapeutic options for patients with hematological malignancies that are rapidly being introduced into clinical practice will require additional research regarding the efficacy of vaccinations. New vaccines are also in development that will require well-designed studies to ascertain efficacy and safety.

  15. Clinical Significance of “Double-hit” and “Double-protein” expression in Primary Gastric B-cell Lymphomas

    PubMed Central

    He, Miaoxia; Chen, Keting; Li, Suhong; Zhang, Shimin; Zheng, Jianming; Hu, Xiaoxia; Gao, Lei; Chen, Jie; Song, Xianmin; Zhang, Weiping; Wang, Jianmin; Yang, Jianmin

    2016-01-01

    BACKGROUND AND AIMS: Primary gastric B-cell lymphoma is the second most common malignancy of the stomach. There are many controversial issues about its diagnosis, treatment and clinical management. “Double-hit” and “double-protein” involving gene rearrangement and protein expression of c-Myc and bcl2/bcl6 are the most used terms to describe DLBCL poor prognostic factors in recent years. However, very little is known about the role of these prognostic factors in primary gastric B-cell lymphomas. This study aims to obtain a molecular pathology prognostic model of gastric B-cell lymphoma for clinical stratified management by evaluating how the “double-hit” and “double-protein” in tumor cells as well as microenvironmental reaction of tumor stromal tissue affect clinical outcome in primary gastric B-cell lymphomas. METHODS: Data and tissues of 188 cases diagnosed with gastric B-cell lymphomas were used in this study. Tumor tissue microarray (TMA) of formalin fixed and paraffin embedded (FFPE) tissues was constructed for fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC) analysis with a serial of biomarkers containing MYC, BCL2, BCL6, CD31, SPARC, CD10, MUM1 and Ki-67. Modeled period analysis was used to estimate 3-year and 5-year overall survival (OS) and disease-free survival (DFS) distributions. RESULTS: There was no definite “double-hit” case though the gene rearrangement of c-Myc (5.9%), bcl2 (0.1%) and bcl6 (7.4%) was found in gastric B-cell lymphomas. The gene amplification or copy gains of c-Myc (10.1%), bcl-2 (17.0%) and bcl-6 (0.9%) were present in these lymphomas. There were 12 cases of the lymphomas with the “double-protein” expression of MYC and BCL2/BCL6. All patients with “double-protein” gastric B-cell lymphomas had poor outcome compared with those without. More importantly, “MYC-BCL2-BCL6” negative group of gastric B-cell lymphoma patients had favorable clinical outcome regardless clinical stage

  16. Functional role of regulatory T cells in B cell lymphoma and related mechanisms.

    PubMed

    Wu, Wei; Wan, Jun; Xia, Ruixiang; Huang, Zhenqi; Ni, Jing; Yang, Mingzhen

    2015-01-01

    B cell lymphoma (BCL) has a higher degree of malignancy and complicated pathogenic mechanism. Regulatory T cells (Treg cells) are known to exert certain immune suppression functions, in addition to immune mediating effects. Recent studies have revealed the role of Treg cells in pathogenesis and progression of multiple malignant tumors. This study therefore investigated the functional role and related mechanism of Treg cells in BCL. A cohort of thirty patients who were diagnosed with BCL in our hospital between January 2013 and December 2014. Another thirty healthy individuals were recruited. Peripheral blood mononuclear cells (PBMCs) were separated and analyzed for the ratio of CD4+/CD25+ Treg cells. The mRNA expression levels of Foxp3, transforming growth factor (TGF)-β1 and interleukin (IL)-10 genes were quantified by real-time PCR, while their serum levels were determined by enzyme-linked immunosorbent assay (ELISA). Meanwhile all laboratory indexes for patients were monitored during the complete remission (CR) stage. BCL patients significantly elevated ratio of CD4+/CD25+ Treg cells, which were decreased at CR stage. mRNA levels of Foxp3, TGF-β1 and IL-10, in addition to protein levels of TGF-β1 and IL-10 were potentiated in lymphoma patients but decreased in CR patients (P<0.05 in all cases). CD4+/CD25+ Treg cells exert immune suppressing functions in BCL via regulating cytokines, thereby facilitating the pathogenesis and progression of lymphoma. PMID:26464657

  17. Ebf1 heterozygosity results in increased DNA damage in pro-B cells and their synergistic transformation by Pax5 haploinsufficiency

    PubMed Central

    Prasad, Mahadesh A. J.; Ungerbäck, Jonas; Åhsberg, Josefine; Somasundaram, Rajesh; Strid, Tobias; Larsson, Malin; Månsson, Robert; De Paepe, Ayla; Lilljebjörn, Henrik; Fioretos, Thoas; Hagman, James

    2015-01-01

    Early B-cell factor 1 (Ebf1) is a transcription factor with documented dose-dependent functions in normal and malignant B-lymphocyte development. To understand more about the roles of Ebf1 in malignant transformation, we investigated the impact of reduced functional Ebf1 dosage on mouse B-cell progenitors. Gene expression analysis suggested that Ebf1 was involved in the regulation of genes important for DNA repair and cell survival. Investigation of the DNA damage in steady state, as well as after induction of DNA damage by UV light, confirmed that pro-B cells lacking 1 functional allele of Ebf1 display signs of increased DNA damage. This correlated to reduced expression of DNA repair genes including Rad51, and chromatin immunoprecipitation data suggested that Rad51 is a direct target for Ebf1. Although reduced dosage of Ebf1 did not significantly increase tumor formation in mice, a dramatic increase in the frequency of pro-B cell leukemia was observed in mice with combined heterozygous mutations in the Ebf1 and Pax5 genes, revealing a synergistic effect of combined dose reduction of these proteins. Our data suggest that Ebf1 controls DNA repair in a dose-dependent manner providing a possible explanation to the frequent involvement of EBF1 gene loss in human leukemia. PMID:25838350

  18. Two maturation-associated mouse erythrocyte receptors of human B cells. I. Identification of four human B-cell subsets.

    PubMed Central

    Forbes, I J; Zalewski, P D; Valente, L; Gee, D

    1982-01-01

    Using rosetting tests with untreated mouse erythrocytes (M) and pronase-treated M (pro M), four human B cell subsets can be identified. Three of these, possessing the phenotypes BM+ pro M+, BM- pro M+ or BM- pro M-, constitute 17%, 61% and 22% of normal blood B cells respectively. The fourth subset, BM+ pro M-, does not occur in normal tissues but was found in the pre-B-cell line of Raji cells, indicating that this phenotype may be a marker for early B cells. Some differences in the proportion of each subset were found in cord blood, lymph nodes and tonsils. Surface-immunoglobulin-positive (SIg+) and -negative (SIg-) non-T cells were present in each subset. M and pro-M rosetting tests were applied to cells from blood of 27 cases of chronic lymphocytic leukaemia (CLL) and to cells from involved nodes, spleen or marrow in five cases of non-Hodgkin's lymphoma (NHL). In 15 cases of CLL, there was considerable increase in the BM+ pro M+ subset (BM+ pro M+ type CLL); in seven cases, there was a predominance of BM- pro M+ cells and in another four cases, BM- pro M- cells predominated. All five cases of NHL were greatly enriched in BM- pro M- cells. There was no obvious correlation between rosetting and other surface markers but BM- pro M- clones in CLL or NHL always stained brightly with FITC-anti-Ig. This was not found in BM+ pro M+ or BM- pro M+ clones. Rosette formation of neuraminidase-treated B cells with M identifies the same subset as B-pro-M rosetting in normals and CLL. Evidence is presented that two types of receptors are involved in M and pro-M rosetting, designated R1 and R2, binding to corresponding M ligands L1 and L2. M rosetting is due to R1-L1 binding while R2-L2 binding mediates B-pro-M rosetting. Shifts between subsets within the same clone in some cases of CLL suggest that the subsets are distinct maturational stage of B-cell development rather than families of B cells of different lineage. The following B-cell maturation sequence is proposed: R1+ R2

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

    PubMed Central

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

    1982-01-01

    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. Images Figure 2 Figure 3 Figure 4 Figure 5 Figure 7 PMID:6282131

  20. 324 Facility B-Cell quality process plan

    SciTech Connect

    Carlson, J.L.

    1998-06-10

    B-Cell is currently being cleaned out (i.e., removal of equipment, fixtures and residual radioactive materials) and deactivated. TPA Milestone M-89-02 dictates that all mixed waste and equipment be removed from B-Cell by 5/31/99. The following sections describe the major activities that remain for completion of the TPA milestone. This includes: (1) Size Reduce Tank 119 and Miscellaneous Equipment. This activity is the restart of hotwork in B-Cell to size reduce the remainder of Tank 119 and other miscellaneous pieces of equipment into sizes that can be loaded into a grout container. This activity also includes the process of preparing the containers for shipment from the cell. The specific activities and procedures used are detailed in a table. (2) Load and Ship Low-Level Waste. This activity covers the process of taking a grouted LLW container from B-Cell and loading it into the cask in the REC airlock and Cask Handling Area (CHA) for shipment to the LLBG. The detailed activities and procedures for this part of cell cleanout are included in second table.

  1. Likelihood-Based Inference of B Cell Clonal Families

    PubMed Central

    Ralph, Duncan K.

    2016-01-01

    The human immune system depends on a highly diverse collection of antibody-making B cells. B cell receptor sequence diversity is generated by a random recombination process called “rearrangement” forming progenitor B cells, then a Darwinian process of lineage diversification and selection called “affinity maturation.” The resulting receptors can be sequenced in high throughput for research and diagnostics. Such a collection of sequences contains a mixture of various lineages, each of which may be quite numerous, or may consist of only a single member. As a step to understanding the process and result of this diversification, one may wish to reconstruct lineage membership, i.e. to cluster sampled sequences according to which came from the same rearrangement events. We call this clustering problem “clonal family inference.” In this paper we describe and validate a likelihood-based framework for clonal family inference based on a multi-hidden Markov Model (multi-HMM) framework for B cell receptor sequences. We describe an agglomerative algorithm to find a maximum likelihood clustering, two approximate algorithms with various trade-offs of speed versus accuracy, and a third, fast algorithm for finding specific lineages. We show that under simulation these algorithms greatly improve upon existing clonal family inference methods, and that they also give significantly different clusters than previous methods when applied to two real data sets. PMID:27749910

  2. Regulatory roles of B cells in infectious diseases.

    PubMed

    Fillatreau, Simon

    2016-01-01

    B lymphocytes provide essential mechanisms of protection against infectious diseases. The secretion of specific antibodies by long-lived plasma cells is thought to account for the improved resistance afforded by most successful vaccines against pathogens. Accordingly, a goal in vaccine development is to induce potent B cell responses in order to drive the efficient formation of long-lived antibody-secreting cells. However, the roles of activated B cells are complex in infectious diseases. It was recently observed that activated B cells could also negatively regulate host defence mechanisms, both during primary infection and, after vaccination, upon secondary challenge, via mechanisms involving their production of the anti-inflammatory cytokines interleukin (IL)-10 and IL-35. Remarkably, the B cells expressing IL-10 and IL-35 in vivo were distinct subsets of IgMhiCD19+CD138hi antibody-secreting cells. A better understanding of the diverse roles of these distinct antibody-secreting cell subsets in immunity and immunological memory, as well as of the signals controlling their generation, might help the rational development of better prophylactic and therapeutic vaccines. PMID:27586794

  3. Mucosal B cells: phenotypic characteristics, transcriptional regulation, and homing properties.

    PubMed

    Brandtzaeg, Per; Johansen, Finn-Eirik

    2005-08-01

    Mucosal antibody defense depends on a complex cooperation between local B cells and secretory epithelia. Mucosa-associated lymphoid tissue gives rise to B cells with striking J-chain expression that are seeded to secretory effector sites. Such preferential homing constitutes the biological basis for local production of polymeric immunoglobulin A (pIgA) and pentameric IgM with high affinity to the epithelial pIg receptor that readily can export these antibodies to the mucosal surface. This ultimate functional goal of mucosal B-cell differentiation appears to explain why the J chain is also expressed by IgG- and IgD-producing plasma cells (PCs) occurring at secretory tissue sites; these immunocytes may be considered as 'spin-offs' from early effector clones that through class switch are on their way to pIgA production. Abundant evidence supports the notion that intestinal PCs are largely derived from B cells initially activated in gut-associated lymphoid tissue (GALT). Nevertheless, insufficient knowledge exists concerning the relative importance of M cells, major histocompatibility complex class II-expressing epithelial cells, and professional antigen-presenting cells for the uptake, processing, and presentation of luminal antigens in GALT to accomplish the extensive and sustained priming and expansion of mucosal B cells. Likewise, it is unclear how the germinal center reaction in GALT so strikingly can promote class switch to IgA and expression of J chain. Although B-cell migration from GALT to the intestinal lamina propria is guided by rather well-defined adhesion molecules and chemokines/chemokine receptors, the cues directing preferential homing to different segments of the gut require better definition. This is even more so for the molecules involved in homing of mucosal B cells to secretory effector sites beyond the gut, and in this respect, the role of Waldever's ring (including the palatine tonsils and adenoids) as a regional inductive tissue needs further

  4. 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

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

    PubMed

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

    2015-08-01

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

  6. Translational Mini-Review Series on B cell subsets in disease. Transitional B cells in systemic lupus erythematosus and Sjögren's syndrome: clinical implications and effects of B cell-targeted therapies.

    PubMed

    Vossenkämper, A; Lutalo, P M K; Spencer, J

    2012-01-01

    Systemic lupus erythematosus (SLE) and Sjögren's syndrome are autoimmune disorders which are characterized by a disturbed B cell homeostasis which leads ultimately to dysfunction of various organs. One of the B cell subsets that appear in abnormal numbers is the population of transitional B cells, which is increased in the blood of patients with SLE and Sjögren's syndrome. Transitional B cells are newly formed B cells. In mice, transitional B cells undergo selection checks for unwanted specificity in the bone marrow and the spleen in order to eliminate autoreactive B cells from the circulating naive B cell population. In humans, the exact anatomical compartments and mechanisms of the specificity check-points for transitional B cells remain unclear, but appear to be defective in SLE and Sjögren's syndrome. This review aims to highlight the current understanding of transitional B cells and their defects in the two disorders before and after B cell-targeted therapies.

  7. B cell autophagy mediates TLR7-dependent autoimmunity and inflammation

    PubMed Central

    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 Atg5f/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

  8. 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.

  9. Tet1 is a tumor suppressor of hematopoietic malignancy

    PubMed Central

    Cimmino, Luisa; Dawlaty, Meelad M.; Ndiaye-Lobry, Delphine; Yap, Yoon Sing; Bakogianni, Sofia; Yu, Yiting; Bhattacharyya, Sanchari; Shaknovich, Rita; Geng, Huimin; Lobry, Camille; Mullenders, Jasper; King, Bryan; Trimarchi, Thomas; Aranda-Orgilles, Beatriz; Liu, Cynthia; Shen, Steven; Verma, Amit K.; Jaenisch, Rudolf; Aifantis, Iannis

    2015-01-01

    The TET methylcytosine dioxygenase 1 (TET1) enzyme is an important regulator of 5-hydroxymethylcytosine (5hmC) in embryonic stem cells. Decreased expression of TET proteins and loss of 5hmC in many tumors suggests a critical role for the maintenance of this epigenetic modification. Here we show that deletion of Tet1 promoted the development of B cell lymphoma in mice. Tet1 was required for maintaining normal content of 5hmC, preventing DNA hypermethylation and in the regulation of B cell lineage, chromosome maintenance and DNA repair genes. Whole-exome sequencing of Tet1-deficient tumors revealed mutations frequently found in Non-Hodgkin B cell lymphoma, where TET1 was hypermethylated and transcriptionally silenced. These findings provide in vivo evidence of TET1 function as a tumor suppressor of hematopoietic malignancy. PMID:25867473

  10. Neutralization of (NK-cell-derived) B-cell activating factor by Belimumab restores sensitivity of chronic lymphoid leukemia cells to direct and Rituximab-induced NK lysis.

    PubMed

    Wild, J; Schmiedel, B J; Maurer, A; Raab, S; Prokop, L; Stevanović, S; Dörfel, D; Schneider, P; Salih, H R

    2015-08-01

    Natural killer (NK) cells are cytotoxic lymphocytes that substantially contribute to the therapeutic benefit of antitumor antibodies like Rituximab, a crucial component in the treatment of B-cell malignancies. In chronic lymphocytic leukemia (CLL), the ability of NK cells to lyse the malignant cells and to mediate antibody-dependent cellular cytotoxicity upon Fc receptor stimulation is compromised, but the underlying mechanisms are largely unclear. We report here that NK-cells activation-dependently produce the tumor necrosis factor family member 'B-cell activating factor' (BAFF) in soluble form with no detectable surface expression, also in response to Fc receptor triggering by therapeutic CD20-antibodies. BAFF in turn enhanced the metabolic activity of primary CLL cells and impaired direct and Rituximab-induced lysis of CLL cells without affecting NK reactivity per se. The neutralizing BAFF antibody Belimumab, which is approved for treatment of systemic lupus erythematosus, prevented the effects of BAFF on the metabolism of CLL cells and restored their susceptibility to direct and Rituximab-induced NK-cell killing in allogeneic and autologous experimental systems. Our findings unravel the involvement of BAFF in the resistance of CLL cells to NK-cell antitumor immunity and Rituximab treatment and point to a benefit of combinatory approaches employing BAFF-neutralizing drugs in B-cell malignancies.

  11. Malignant melanoma in a Eurasian otter (Lutra lutra).

    PubMed

    Weber, H; Mecklenburg, L

    2000-03-01

    An 11-yr-old female Eurasian otter (Lutra lutra) presented with multiple cutaneous nodules identified histologically as malignant melanomas of spindle cell and epithelioid cell type. Metastases were detected in lymph nodes and liver, and the tumor, which was derived from melanocytes, showed aggressive biological behavior. Only occasional reports exist of neoplastic disease in otters. PMID:10884131

  12. Induction of heme oxygenase-1 in normal and malignant B lymphocytes by 15-deoxy-Δ12, 14-prostaglandin J2 requires Nrf2

    PubMed Central

    Bancos, Simona; Baglole, Carolyn J.; Rahman, Irfan; Phipps, Richard P.

    2011-01-01

    Heme-oxygenase-1 (HO-1) is induced in response to oxidative stress and is believed to be a cytoprotective and anti-inflammatory enzyme. It is unknown whether normal or malignant human B lineage cells express HO-1. 15-deoxy-Δ12, 14-prostaglandin J2 (15d-PGJ2) is an interesting electrophilic lipid mediator able to increase oxidative stress in B cells. Here, we tested normal and malignant human B lineage cells for their ability to express HO-1 in response to 15d-PGJ2, as well as the signaling pathways required for HO-1 expression. 15d-PGJ2 potently induced HO-1 protein expression in normal and malignant B cells. Malignant B cells exhibited a greater induction of HO-1 protein compared to normal B lymphocytes. Using siRNA directed against the transcription factor Nrf2 and B cells isolated from Nrf2-deficient mice, we show that HO-1 induction by 15d-PGJ2 is dependent on Nrf2. These results show that, compared to normal B lymphocytes, malignant B cells have a greater capacity to increase their HO-1 protein levels in response to 15d-PGJ2. We speculate that the ability to highly express HO-1 by malignant B cells could confer a survival advantage. PMID:20064636

  13. Induction of heme oxygenase-1 in normal and malignant B lymphocytes by 15-deoxy-Delta(12,14)-prostaglandin J(2) requires Nrf2.

    PubMed

    Bancos, Simona; Baglole, Carolyn J; Rahman, Irfan; Phipps, Richard P

    2010-01-01

    Heme-oxygenase-1 (HO-1) is induced in response to oxidative stress and is believed to be a cytoprotective and anti-inflammatory enzyme. It is unknown whether normal or malignant human B-lineage cells express HO-1. 15-deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)) is an interesting electrophilic lipid mediator able to increase oxidative stress in B cells. Here, we tested normal and malignant human B-lineage cells for their ability to express HO-1 in response to 15d-PGJ(2), as well as the signaling pathways required for HO-1 expression. 15d-PGJ(2) potently induced HO-1 protein expression in normal and malignant B cells. Malignant B cells exhibited a greater induction of HO-1 protein compared to normal B lymphocytes. Using siRNA directed against the transcription factor Nrf2 and B cells isolated from Nrf2-deficient mice, we show that HO-1 induction by 15d-PGJ(2) is dependent on Nrf2. These results show that, compared to normal B lymphocytes, malignant B cells have a greater capacity to increase their HO-1 protein levels in response to 15d-PGJ(2). We speculate that the ability to highly express HO-1 by malignant B cells could confer a survival advantage.

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

    PubMed Central

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

    2015-01-01

    Protective antibodies in Plasmodium falciparum malaria are only acquired after years of repeated infections. Chronic malaria exposure is associated with a large increase in atypical memory B cells (MBCs) that resemble B cells expanded in a variety of persistent viral infections. Understanding the function of atypical MBCs and their relationship to classical MBCs will be critical to developing effective vaccines for malaria and other chronic infections. We show that VH gene repertoires and somatic hypermutation rates of atypical and classical MBCs are indistinguishable indicating a common developmental history. Atypical MBCs express an array of inhibitory receptors and B cell receptor (BCR) signaling is stunted in atypical MBCs resulting in impaired B cell responses including proliferation, cytokine production and antibody secretion. Thus, in response to chronic malaria exposure, atypical MBCs appear to differentiate from classical MBCs becoming refractory to BCR-mediated activation and potentially interfering with the acquisition of malaria immunity. DOI: http://dx.doi.org/10.7554/eLife.07218.001 PMID:25955968

  15. Aberrant immunoglobulin class switch re