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Sample records for b-cell lymphoproliferative disorders

  1. Membrane phenotypic studies in B cell lymphoproliferative disorders.

    PubMed Central

    Scott, C S; Limbert, H J; MacKarill, I D; Roberts, B E

    1985-01-01

    A total of 398 cases of B cell lymphoproliferative disease were phenotypically characterised by membrane mouse red blood cell (MRBC) receptor, surface immunoglobulin, common acute lymphoblastic leukaemia (CALLA), and FMC7 and T1 monoclonal antibody studies. Relations between chronic lymphocytic leukaemia (CLL), prolymphocytic leukaemia (PLL), and "prolymphocytoid" CLL variants were examined with particular reference to the expression of FMC7. In addition, the reactivity of TU1 monoclonal antibody with B cell disorders was established. The results suggest that despite some heterogeneity most cases may be characterised by their phenotypic patterns and that these investigations provide a reproducible basis for classification. PMID:2413082

  2. 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

  3. B-cell Lymphoproliferative Disorders Associated with Primary and Acquired Immunodeficiency.

    PubMed

    Low, Lawrence K; Song, Joo Y

    2016-03-01

    The diagnosis of lymphoproliferative disorders associated with immunodeficiency can be challenging because many of these conditions have overlapping clinical and pathologic features and share similarities with their counterparts in the immunocompetent setting. There are subtle but important differences between these conditions that are important to recognize for prognostic and therapeutic purposes. This article provides a clinicopathologic update on how understanding of these B-cell lymphoproliferations in immunodeficiency has evolved over the past decade.

  4. BCA-1, A B-cell chemoattractant signal, is constantly expressed in cutaneous lymphoproliferative B-cell disorders.

    PubMed

    Mori, M; Manuelli, C; Pimpinelli, N; Bianchi, B; Orlando, C; Mavilia, C; Cappugi, P; Maggi, E; Giannotti, B; Santucci, M

    2003-07-01

    We analysed the immunophenotypic and molecular expression of BCA-1 (B-cell-specific chemokine) and CXCR5 (BCA-1 receptor) in normal skin and different cutaneous lymphoproliferative disorders (cutaneous T-cell lymphoma (CTCL); cutaneous B-cell lymphoma (CBCL); cutaneous B-cell pseudolymphoma (PCBCL)), with the aim of investigating their possible involvement in the pathogenesis of cutaneous B-cell disorders. BCA-1 and CXCR5 were constantly expressed in CBCL and PCBCL, but not in normal skin and CTCL. BCA-1 and CXCR5 were constantly coexpressed by CD22+ B-cells, while CD35+ follicular dendritic cells coexpressed BCA-1 in PCBCL cells only. In low grade CBCL, as compared with high grade CBCL, the intensity of CXCR5 expression on neoplastic CD22+ cells was lower than that of BCA-1. The image analysis of reverse transcriptase-polymerase chain reaction (RT-PCR) products showed a significant quantitative difference between PCBCL/low grade CBCL and high grade CBCL. The above findings, although only observed in a small series of patients, are in keeping with findings in MALT gastric and gastric MALT lymphomas, adding further evidence of the close similarities between CBCL and MALT lymphomas.

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

    PubMed Central

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

    2014-01-01

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

  6. Hepatitis C virus upregulates B-cell receptor signaling: a novel mechanism for HCV-associated B-cell lymphoproliferative disorders

    PubMed Central

    Dai, B; Chen, A Y; Corkum, C P; Peroutka, R J; Landon, A; Houng, S; Muniandy, P A; Zhang, Y; Lehrmann, E; Mazan-Mamczarz, K; Steinhardt, J; Shlyak, M; Chen, Q C; Becker, K G; Livak, F; Michalak, T I; Talwani, R; Gartenhaus, R B

    2016-01-01

    B-cell receptor (BCR) signaling is essential for the development of B cells and has a critical role in B-cell neoplasia. Increasing evidence indicates an association between chronic hepatitis C virus (HCV) infection and B-cell lymphoma, however, the mechanisms by which HCV causes B-cell lymphoproliferative disorder are still unclear. Herein, we demonstrate the expression of HCV viral proteins in B cells of HCV-infected patients and show that HCV upregulates BCR signaling in human primary B cells. HCV nonstructural protein NS3/4A interacts with CHK2 and downregulates its activity, modulating HuR posttranscriptional regulation of a network of target mRNAs associated with B-cell lymphoproliferative disorders. Interestingly, the BCR signaling pathway was found to have the largest number of transcripts with increased association with HuR and was upregulated by NS3/4A. Our study reveals a previously unidentified role of NS3/4A in regulation of host BCR signaling during HCV infection, contributing to a better understanding of the molecular mechanisms underlying HCV-associated B-cell lymphoproliferative disorders. PMID:26434584

  7. A Novel, Non-canonical Splice Variant of the Ikaros Gene Is Aberrantly Expressed in B-cell Lymphoproliferative Disorders

    PubMed Central

    Mancarelli, Maria Michela; Verzella, Daniela; Fischietti, Mariafausta; Di Tommaso, Ambra; Maccarone, Rita; Plebani, Sara; Di Ianni, Mauro; Gulino, Alberto; Alesse, Edoardo

    2013-01-01

    The Ikaros gene encodes a Krüppel-like zinc-finger transcription factor involved in hematopoiesis regulation. Ikaros has been established as one of the most clinically relevant tumor suppressors in several hematological malignancies. In fact, expression of dominant negative Ikaros isoforms is associated with adult B-cell acute lymphoblastic leukemia, myelodysplastic syndrome, acute myeloid leukemia and adult and juvenile chronic myeloid leukemia. Here, we report the isolation of a novel, non-canonical Ikaros splice variant, called Ikaros 11 (Ik11). Ik11 is structurally related to known dominant negative Ikaros isoforms, due to the lack of a functional DNA-binding domain. Interestingly, Ik11 is the first Ikaros splice variant missing the transcriptional activation domain. Indeed, we demonstrated that Ik11 works as a dominant negative protein, being able to dimerize with Ikaros DNA-binding isoforms and inhibit their functions, at least in part by retaining them in the cytoplasm. Notably, we demonstrated that Ik11 is the first dominant negative Ikaros isoform to be aberrantly expressed in B-cell lymphoproliferative disorders, such as chronic lymphocytic leukemia. Aberrant expression of Ik11 interferes with both proliferation and apoptotic pathways, providing a mechanism for Ik11 involvement in tumor pathogenesis. Thus, Ik11 could represent a novel marker for B-cell lymphoproliferative disorders. PMID:23874502

  8. Expression of SHP-1 phosphatase indicates post-germinal center cell derivation of B-cell posttransplant lymphoproliferative disorders.

    PubMed

    Paessler, Michele; Kossev, Plamen; Tsai, Donald; Raghunath, Puthiaveetil; Majewski, Miroslaw; Zhang, Qian; Ramalingam, Preetha; Schuster, Stephen; Tomaszewski, John; Arber, Daniel A; Hsi, Eric; Wasik, Mariusz A

    2002-11-01

    SHP-1 tyrosine phosphatase acts as a negative regulator of signaling by receptors for growth factors, cytokines, and chemokines and by receptors involved in immune response. Our recent study showed that SHP-1 is tightly regulated at various stages of B-cell differentiation and is expressed in the mantle and marginal zones, interfollicular B cells, and plasma cells, whereas it is nondetectable in germinal center cells. In this study we evaluated expression of SHP-1 in vitro and in vivo in nine cell lines representing three different types of EBV+ B-cell populations closely resembling or derived from posttransplant lymphoproliferative disorders (PTLDs). Furthermore, we examined tissue samples from 58 patients with B-cell PTLDs, both EBV+ (85% of the cases analyzed) and EBV- (15%). SHP-1 protein was strongly expressed in all cell lines and PTLD cases. In addition, the PTLD cases were essentially negative for germinal center B-cell markers: none expressed CD10 and only one expressed BCL-6. More than 40% expressed a late post-germinal B-cell marker, CD138. The universal expression of SHP-1, lack of expression of CD10 and BCL-6, and frequent expression of CD138 suggest that PTLDs are derived from post-germinal center B cells regardless of the EBV cell infection status. Based on the immunophenotype, B-cell PTLDs could be divided into two broad categories corresponding to the early (CD10-/BCL-6-/SHP-1+/CD138-) and late (CD10-/BCL-6-/SHP-1+/CD138+) post-germinal center cells. By being expressed earlier, SHP-1 is a more sensitive marker of post-germinal center B cells than CD138, which is seen on the terminally differentiated immunoblasts and plasma cells.

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

    PubMed

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

    2015-01-23

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

  10. Metachronous EBV-associated B-cell and T-cell posttransplant lymphoproliferative disorders in a heart transplant recipient.

    PubMed

    Morovic, Anamarija; Jaffe, Elaine S; Raffeld, Mark; Schrager, Jeffrey A

    2009-01-01

    Posttransplant lymphoproliferative disorders (PTLDs) may occur as a complication of immunosuppression in patients who have received solid organ or bone marrow allografts. Most PTLDs are of B-cell lineage, whereas T-cell proliferations are rare. The majority of B-cell lesions are associated with Epstein-Barr virus infection. The occurrence of both B-cell and T-cell PTLDs in the same patient is extremely rare and only 6 cases have been previously published. We report a case of a 63-year-old man who developed 2 metachronous Epstein-Barr virus-related PTLDs beginning 10 years after heart transplantation. A polymorphic B-cell PTLD developed first that completely regressed after immunosuppressive therapy was partially withdrawn. Then, a monomorphic T-cell PTLD developed 31 months later. The patient died 17 months later owing to disease progression. We highlight the diagnostic challenge of this case that required numerous ancillary studies for lineage assessment and classification. Such studies are often needed in patients with a history of immunosuppression.

  11. Age-related EBV-associated B-cell lymphoproliferative disorders: diagnostic approach to a newly recognized clinicopathological entity.

    PubMed

    Shimoyama, Yoshie; Asano, Naoko; Kojima, Masaru; Morishima, Satoko; Yamamoto, Kazuhito; Oyama, Takashi; Kinoshita, Tomohiro; Nakamura, Shigeo

    2009-12-01

    EBV is prevalent among healthy individuals, and is implicated in numerous reactive and neoplastic processes in the immune system. The authors originally identified a series of senile or age-related EBV-associated B-cell lymphoproliferative disorders (LPD) bearing a resemblance to immunodeficiency-associated ones, which may be associated with immune senescence in the elderly and which are now incorporated into the 2008 World Health Organization lymphoma classification as EBV-positive diffuse large B-cell lymphoma (DLBCL) of the elderly. This newly described disease is pathologically characterized by a proliferation of atypical large B cells including Reed-Sternberg-like cells with reactive components, which pose a diagnostic problem for pathologists. Clinically, this disease may present with lymphadenopathy, and is often extranodal, frequently involving the skin, gastrointestinal tract, or lung. Onset is usually after the age of 50; the median patient age is 70-79 years, and incidence continues to increase with age, providing additional support to the nosological term of EBV+ DLBCL of the elderly. These patients have a worse prognosis than those with EBV-negative DLBCL or EBV+ classical Hodgkin lymphoma (CHL). The aim of the present review was to summarize the clinicopathological profile of age-related EBV+ LPD and EBV+ Hodgkin lymphoma to facilitate diagnostic approach.

  12. Posttransplant lymphoproliferative disorders.

    PubMed

    Ibrahim, Hazem A H; Naresh, Kikkeri N

    2012-01-01

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

  13. Age-related Epstein-Barr virus (EBV)-associated B-cell lymphoproliferative disorders: comparison with EBV-positive classic Hodgkin lymphoma in elderly patients.

    PubMed

    Asano, Naoko; Yamamoto, Kazuhito; Tamaru, Jun-Ichi; Oyama, Takashi; Ishida, Fumihiro; Ohshima, Koichi; Yoshino, Tadashi; Nakamura, Naoya; Mori, Shigeo; Yoshie, Osamu; Shimoyama, Yoshie; Morishima, Yasuo; Kinoshita, Tomohiro; Nakamura, Shigeo

    2009-03-19

    Age-related Epstein-Barr virus-associated B-cell lymphoproliferative disorder (aEBVLPD) is a disease group characterized by EBV-associated large B-cell lymphoma in elderly without predisposing immunodeficiency. In nearly one- third of cases, aEBVLPD occurs as a polymorphous subtype with reactive cell-rich components, bearing a morphologic similarity to classic Hodgkin lymphoma (cHL). The aim of this study was to clarify clinicopathologic differences between the polymorphic subtype of aEBVLPD (n = 34) and EBV(+) cHL (n = 108) in patients aged 50 years or older. Results showed that aEBVLPD was more closely associated with aggressive clinical parameters than cHL, with a higher age at onset (71 vs 63 years); lower male predominance (male-female ratio, 1.4 vs 3.3); and a higher rate of involvement of the skin (18% vs 2%), gastrointestinal tract (15% vs 4%), and lung (12% vs 2%). aEBVLPD was histopathologically characterized by a higher ratio of geographic necrosis, greater increase (> 30%) in cytotoxic T cells among background lymphocytes, higher positivity for CD20 and EBNA2, and absence of CD15 expression. As predicted by the clinical profile, aEBVLPD had a significantly poorer prognosis than EBV(+) cHL (P < .001). The polymorphous subtype of aEBVLPD constitutes an aggressive group with an immune response distinct from EBV(+) cHL, and requires the development of innovative therapeutic strategies.

  14. Posttransplant lymphoproliferative disorder in a kidney-pancreas transplanted recipient: simultaneous development of clonal lymphoid B-cell proliferation of host and donor origin.

    PubMed

    Heyny-von Haussen, Roland; Klingel, Karin; Riegel, Werner; Kandolf, Reinhard; Mall, Gerhard

    2006-07-01

    Posttransplant lymphoproliferative disorders (PTLDs) are lymphoid proliferations or lymphomas that develop as a consequence of immunosuppression after solid organ or bone marrow transplantation and are mostly associated with an Epstein-Barr virus infection. The morphologic categories include different types of benign and malignant lymphoid proliferations. The majority of PTLDs is of B-cell origin with clonal rearrangements of the immunoglobulin genes. The PTLDs in solid organ transplants are reported to be either of host or of donor origin. Donor-related PTLDs frequently involve the allograft. We report a case of a 52-year-old woman recipient who developed simultaneously PTLDs in several organs 5 month after receiving a sex-mismatched renal and pancreas allograft. Immunosuppression regimen comprised antithymocyte globulin, tacrolimus, mycophenolate mofetil, and steroids. Pathologic features appeared as polymorphic PTLDs in the renal allograft, liver, and central nervous system (CNS). Molecular genetic studies revealed different clonal immunoglobulin heavy chain gene rearrangements in all 3 organs as determined by polymerase chain reaction (PCR). Epstein-Barr virus were detected by nested PCR and in situ hybridization in all 3 tumors. The PTLDs in liver and CNS were of host origin whereas the allograft kidney PTLD was found to originate from the male donor as shown by the simultaneous detection of female and male sex chromosomes by PCR and fluorescence in situ hybridization. The recipient died in consequence of the CNS involvement, after intracerebral hemorrhage with uncal and tonsillar herniation.

  15. Epstein-Barr virus infection and gene promoter hypermethylation in rheumatoid arthritis patients with methotrexate-associated B cell lymphoproliferative disorders.

    PubMed

    Ejima-Yamada, Kozue; Oshiro, Yumi; Okamura, Seiichi; Fujisaki, Tomoaki; Mihashi, Yasuhito; Tamura, Kazuo; Fukushige, Tomoko; Kojima, Masaru; Shibuya, Kazutoshi; Takeshita, Morishige

    2017-02-01

    We analyzed CpG-island hypermethylation status in 12 genes of paraffin-embedded tissues from 38 rheumatoid arthritis (RA) patients with methotrexate (MTX)-associated large B cell lymphoproliferative disorder (BLPD), 11 RA patients with non-MTX-associated BLPD (non-MTX-BLPD), 22 controls with diffuse large B cell lymphoma (DLBCL), and 10 controls with Epstein-Barr virus (EBV)(+) DLBCL. Among them, tumor cells from EBV(+) MTX-BLPD patients and control EBV(+) DLBCL patients had significantly lower median incidence of CpG island methylator phenotype (CIMP) than those from non-MTX-BLPD and control DLBCL groups (2.3 and 1.7 vs. 4.3 and 4.4; P < 0.01 for each). In the MTX-BLPD group, EBV(+) patients showed lower median CIMP than EBV(-) patients (2.3 vs. 3.2); they also had significantly lower hypermethylation incidence in four apoptosis-related genes, especially death-associated protein kinase (14 vs. 55 %), higher incidence of massive tumor necrosis (86 vs. 27 %), and lower BCL2 protein expression (19 vs. 86 %) than did the control DLBCL group (P < 0.01 for all). In all clinical stages, EBV(+) MTX-BLPD patients had better prognoses than the EBV(-) MTX-BLPD (P = 0.011), non-MTX-BLPD (P = 0.002), and control DLBCL groups (P = 0.015). MTX-BLPD patients without hypermethylated RAS-associated domain family-1A (RASSF1A) or O (6) -methyl guanine-DNA methyltransferase (MGMT) had significantly better prognosis than those with hypermethylation of those genes (P = 0.033). We conclude that in RA patients with MTX-BLPD, EBV infection is associated with a lower incidence of CIMP, apoptosis-related gene hypermethylation, and BCL2 expression, which can induce tumor regression by MTX withdrawal and lead to better prognoses.

  16. Cytotoxic activity of the amphibian ribonucleases onconase and r-amphinase on tumor cells from B cell lymphoproliferative disorders.

    PubMed

    Smolewski, Piotr; Witkowska, Magdalena; Zwolinska, Malgorzata; Cebula-Obrzut, Barbara; Majchrzak, Agata; Jeske, Aleksandra; Darzynkiewicz, Zbigniew; Ardelt, Wojciech; Ardelt, Barbara; Robak, Tadeusz

    2014-07-01

    Although major advancements in antitumor treatment have been observed, several B cell-derived malignancies still remain incurable. A promising approach that involves targeting RNA either by the use of specific antisense oligonucleotides or cytostatic/cytotoxic ribonucleases (RNases) is being promoted. Two amphibian RNases, onconase (ONC; ranpirnase) and, more recently, r-amphinase (r-Amph), have already been tested, but thus far, mostly on solid tumors. In this study, for the first time we provide comprehensive data on ex vivo and in vivo cytotoxic activity of ONC or r-Amph against cancer cells from different B cell lymphoid malignancies, together with their detailed mode of antitumor action. Our data revealed strong pro-apoptotic activity of ONC and r-Amph in both chronic lymphocytic leukemia and aggressive B cell lymphomas, with less impact on acute lymphoblastic leukemia or multiple myeloma cells. Moreover, the antitumor action of ONC and r-Amph was markedly selective against neoplastic cells sparing normal, healthy control‑derived lymphocytes.

  17. Chronic Lymphocytic Leukemia and Other Lymphoproliferative Disorders.

    PubMed

    Wall, Sarah; Woyach, Jennifer A

    2016-02-01

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

  18. Post-transplant lymphoproliferative disorders.

    PubMed

    Dharnidharka, Vikas R; Webster, Angela C; Martinez, Olivia M; Preiksaitis, Jutta K; Leblond, Veronique; Choquet, Sylvain

    2016-01-28

    Post-transplant lymphoproliferative disorders (PTLDs) are a group of conditions that involve uncontrolled proliferation of lymphoid cells as a consequence of extrinsic immunosuppression after organ or haematopoietic stem cell transplant. PTLDs show some similarities to classic lymphomas in the non-immunosuppressed general population. The oncogenic Epstein-Barr virus (EBV) is a key pathogenic driver in many early-onset cases, through multiple mechanisms. The incidence of PTLD varies with the type of transplant; a clear distinction should therefore be made between the conditions after solid organ transplant and after haematopoietic stem cell transplant. Recipient EBV seronegativity and the intensity of immunosuppression are among key risk factors. Symptoms and signs depend on the localization of the lymphoid masses. Diagnosis requires histopathology, although imaging techniques can provide additional supportive evidence. Pre-emptive intervention based on monitoring EBV levels in blood has emerged as the preferred strategy for PTLD prevention. Treatment of established disease includes reduction of immunosuppression and/or administration of rituximab (a B cell-specific antibody against CD20), chemotherapy and EBV-specific cytotoxic T cells. Despite these strategies, the mortality and morbidity remains considerable. Patient outcome is influenced by the severity of presentation, treatment-related complications and risk of allograft loss. New innovative treatment options hold promise for changing the outlook in the future.

  19. Oral Lesions and Lymphoproliferative Disorders

    PubMed Central

    Castellarin, P.; Pozzato, G.; Tirelli, G.; Di Lenarda, R.; Biasotto, M.

    2010-01-01

    Lymphoproliferative disorders are heterogeneous malignancy characterized by the expansion of a lymphoid clone more or less differentiated. At the level of the oral cavity, the lymphoproliferative disorder can occur in various ways, most commonly as lymphoid lesions with extranodal externalization, but sometimes, oral lesions may represent a localization of a disease spread. With regard to the primary localizations of lymphoproliferative disorders, a careful examination of the head and neck, oral, and oropharyngeal area is necessary in order to identify suspicious lesions, and their early detection results in a better prognosis for the patient. Numerous complications have been described and frequently found at oral level, due to pathology or different therapeutic strategies. These complications require precise diagnosis and measures to oral health care. In all this, oral pathologists, as well as dental practitioners, have a central role in the treatment and long-term monitoring of these patients. PMID:20871659

  20. Concurrent classical Hodgkin lymphoma and plasmablastic lymphoma in a patient with chronic lymphocytic leukemia/small lymphocytic lymphoma treated with fludarabine: a dimorphic presentation of iatrogenic immunodeficiency-associated lymphoproliferative disorder with evidence suggestive of multiclonal transformability of B cells by Epstein-Barr virus.

    PubMed

    Foo, Wen-Chi; Huang, Qin; Sebastian, Siby; Hutchinson, Charles B; Burchette, Jim; Wang, Endi

    2010-12-01

    A small fraction of patients with chronic lymphocytic leukemia/small lymphocytic lymphoma develop Epstein-Barr virus-positive B-cell lymphoproliferative disorders. These Epstein-Barr virus-B-cell lymphoproliferative disorders are thought to be related to immune suppression induced by fludarabine/other chemotherapeutic regimens. As in other immunodeficiency-associated lymphoproliferative disorders, these disorders demonstrate a heterogeneous histological spectrum that ranges from polymorphic to monomorphic to classical Hodgkin lymphoma-like lesions. We report a case of concurrent classical Hodgkin lymphoma and plasmablastic lymphoma in a patient with chronic lymphocytic leukemia/small lymphocytic lymphoma treated with fludarabine. Both classical Hodgkin lymphoma and plasmablastic lymphoma were positive for Epstein-Barr virus-encoded RNA, whereas classical Hodgkin lymphoma was also positive for Epstein-Barr virus- latent membrane protein 1, suggesting a different viral latency. Immunoglobulin gene rearrangement studies demonstrated distinct clones in the plasmablastic lymphoma and chronic lymphocytic leukemia/small lymphocytic lymphoma. These findings suggest biclonal secondary lymphomas associated with iatrogenic immunodeficiency. Epstein-Barr virus-B-cell lymphoproliferative disorders in the setting of chronic lymphocytic leukemia/small lymphocytic lymphoma, in particular those arising after chemotherapy, should be separated from true Richter's transformation, and be categorized as (iatrogenic) immunodeficiency-associated lymphoproliferative disorder.

  1. Cutaneous EBV-related lymphoproliferative disorders.

    PubMed

    Gru, Alejandro A; Jaffe, Elaine S

    2017-01-01

    This article will focus on the cutaneous lymphoproliferative disorders associated with EBV, with an emphasis on the upcoming changes in the revised 4th Edition of the WHO classification of tumors of the hematopoietic system, many of which deal with cutaneous disorders derived from NK-cells or T-cells. Extranodal NK/T-cell lymphoma usually presents in the upper aerodigestive tract, but can involve the skin secondarily. EBV-associated T- and NK-cell lymphoproliferative disorders (LPD) in the pediatric age group include the systemic diseases, chronic active EBV infection (CAEBV) and systemic EBV+ T-cell lymphoma of childhood. Hydroa vacciniforme (HV)-like LPD is a primarily cutaneous form of CAEBV and encompasses the lesions previously referred to as HV and HV-like lymphoma (HVLL). All the T/NK-cell-EBV-associated diseases occur with higher frequency in Asians, and indigenous populations from Central and South America and Mexico. Among the B-cell EBV-associated LPD two major changes have been introduced in the WHO. The previously designated EBV-positive diffuse large B-cell lymphoma (EBV-DLBCL) of the elderly, has been changed to EBV-DLBCL with 'not otherwise specified' as a modifier (NOS). A new addition to the WHO system is the more recently identified EBV+ mucocutaneous ulcer, which involves skin and mucosal-associated sites.

  2. Molecular histogenesis of posttransplantation lymphoproliferative disorders.

    PubMed

    Capello, Daniela; Cerri, Michaela; Muti, Giuliana; Berra, Eva; Oreste, Pierluigi; Deambrogi, Clara; Rossi, Davide; Dotti, Giampietro; Conconi, Annarita; Viganò, Mario; Magrini, Umberto; Ippoliti, Giovanbattista; Morra, Enrica; Gloghini, Annunziata; Rambaldi, Alessandro; Paulli, Marco; Carbone, Antonino; Gaidano, Gianluca

    2003-11-15

    Posttransplantation lymphoproliferative disorders (PTLDs) represent a serious complication of solid organ transplantation. This study assessed the molecular histogenesis of 52 B-cell monoclonal PTLDs, including 12 polymorphic PTLDs (P-PTLDs), 36 diffuse large B-cell lymphomas (DLBCLs), and 4 Burkitt/Burkitt-like lymphomas (BL/BLLs). Somatic hypermutation (SHM) of immunoglobulin variable (IgV) genes documented that most monoclonal B-cell PTLDs (75% P-PTLDs, 91.3% DLBCLs, 100% BL/BLLs) derive from germinal center (GC)-experienced B cells. B-cell lymphoma 6 (BCL6) mutations occurred in 25% P-PTLDs, 60.6% DLBCLs, and 75.0% BL/BLLs. A first histogenetic category of PTLDs (31.2% DLBCLs) express the BCL6+/multiple myeloma oncogene-1 protein (MUM1-/+)/CD138- profile and mimic B cells experiencing the GC reaction, as also suggested by ongoing SHM in a fraction of these cases. A second subset of PTLDs (66.7% P-PTLDs and 31.2% DLBCLs) display the BCL6-/MUM1+/CD138- phenotype and mimic B cells that have concluded the GC reaction. A third histogenetic category of PTLDs (25.0% P-PTLDs and 31.2% DLBCLs) shows the BCL6-/MUM1+/CD138+ profile, consistent with preterminally differentiated post-GC B cells. Crippling mutations of IgV heavy chain (IgVH) and/or IgV light chain (IgVL) genes, leading to sterile rearrangements and normally preventing cell survival, occur in 4 DLBCLs and 1 BL/BLL that may have been rescued from apoptosis through expression of Epstein-Barr virus (EBV)-encoded latent membrane protein 1 (LMP1). Overall, the histogenetic diversity of monoclonal B-cell PTLDs may help define biologically homogeneous categories of the disease.

  3. Automated pattern-guided principal component analysis vs expert-based immunophenotypic classification of B-cell chronic lymphoproliferative disorders: a step forward in the standardization of clinical immunophenotyping

    PubMed Central

    Costa, E S; Pedreira, C E; Barrena, S; Lecrevisse, Q; Flores, J; Quijano, S; Almeida, J; del Carmen García- Macias, M; Bottcher, S; Van Dongen, J J M; Orfao, A

    2010-01-01

    Immunophenotypic characterization of B-cell chronic lymphoproliferative disorders (B-CLPD) is becoming increasingly complex due to usage of progressively larger panels of reagents and a high number of World Health Organization (WHO) entities. Typically, data analysis is performed separately for each stained aliquot of a sample; subsequently, an expert interprets the overall immunophenotypic profile (IP) of neoplastic B-cells and assigns it to specific diagnostic categories. We constructed a principal component analysis (PCA)-based tool to guide immunophenotypic classification of B-CLPD. Three reference groups of immunophenotypic data files—B-cell chronic lymphocytic leukemias (B-CLL; n=10), mantle cell (MCL; n=10) and follicular lymphomas (FL; n=10)—were built. Subsequently, each of the 175 cases studied was evaluated and assigned to either one of the three reference groups or to none of them (other B-CLPD). Most cases (89%) were correctly assigned to their corresponding WHO diagnostic group with overall positive and negative predictive values of 89 and 96%, respectively. The efficiency of the PCA-based approach was particularly high among typical B-CLL, MCL and FL vs other B-CLPD cases. In summary, PCA-guided immunophenotypic classification of B-CLPD is a promising tool for standardized interpretation of tumor IP, their classification into well-defined entities and comprehensive evaluation of antibody panels. PMID:20844562

  4. A case of age-related EBV-associated B-cell lymphoproliferative disorder metachronously showing two distinct morphologic appearances, one of a polymorphic disease resembling classical Hodgkin lymphoma, and the other of a large-cell lymphoma.

    PubMed

    Murase, Tadashi; Fujita, Ayumi; Ueno, Hironori; Park, Jae-Won; Yano, Takahiro; Hoshikawa, Masahiro; Takagi, Masayuki; Kuramochi, Shigeru

    2009-01-01

    We report a case of age-related EBV-associated B-cell lymphoproliferative disorder (age-related EBV+ B-cell LPD) metachronously showing two distinct morphologic appearances: one of a polymorphic disease resembling classical Hodgkin lymphoma (CHL), and the other of a large-cell lymphoma. A 71-year-old man was admitted to the St. Marianna University Hospital because of fever and generalized lymphadenopathy. Right axillary lymph node biopsy revealed mixed cellularity classical Hodgkin lymphoma (MCHL). The patient was referred to the Tokyo Medical Center, where he was treated with chemotherapy and obtained CR. One year later, the patient again developed fever and generalized lymphadenopathy. Biopsy of the right cervical mass revealed a diagnosis of diffuse large B-cell lymphoma. The patient was treated with salvage chemotherapies and obtained the second CR. Two years later, the patient developed acute myeloid leukemia (AML). Although CR was achieved with chemotherapy, AML relapsed 5 months later and proved to be refractory. Two and a half years later, the patient developed right cervical lymph node enlargement. The biopsy again revealed diagnosis of MCHL. The patient died 2 months later. On reviewing all of the biopsy specimens, including the findings of immunohistochemistry and in situ hybridization, possibility of CHL was ruled out, because neoplastic giant cells resembling Hodgkin and Reed-Sternberg (HRS) cells were positive for both Oct2 and BOB.1, which has not been reported in CHL. Both HRS-like cells at the time of diagnosis of Hodgkin lymphoma and lymphoma cells at the time of diagnosis of non-Hodgkin lymphoma were positive for CD20 and EBV-encoded small RNAs. This case was finally diagnosed as having age-related EBV+ B-cell LPD. We report the case here as it underscores the difficulty in diagnosing age-related EBV+ B-cell LPDs and also suggests an important role of EBV in the pathogenesis of lymphoid neoplasms.

  5. Flow cytometric immunophenotyping in posttransplant lymphoproliferative disorders.

    PubMed

    Dunphy, Cherie H; Gardner, Laura J; Grosso, Leonard E; Evans, H Lance

    2002-01-01

    We studied the flow cytometric immunophenotyping (FCI) and genotypic data of 11 specimens from 10 transplant recipients and categorized them based on a scheme for posttransplant lymphoproliferative disorders (PTLDs). Specimens had been analyzed by polymerase chain reaction and/or Southern blot for T-cell and B-cell (immunoglobulin heavy chain and light chain genes) gene rearrangements (BGR). The categories for PTLDs were as follows: 1, 1; 2, 6; and 3, 4. The plasmacytic and polymorphic B-cell hyperplasias (PBCHs) revealed no monoclonal/aberrant cells by FCI or genotypic studies (GS). Three of 4 polymorphic B-cell lymphomas (PBCLs) revealed monoclonal or aberrant (no surface light chain) B cells by FCI; 1 of 3 revealed a BGR. However, the 1 case with no monoclonal/aberrant B cells by FCI revealed a BGR. Both immunoblastic lymphomas revealed monoclonal or aberrant B cells by FCI; 1 revealed a BGR. Both multiple myelomas revealed monoclonal plasma cells by FCI; 1 revealed a BGR. In the 4 PTLDs with monoclonal/aberrant B cells by FCI and no clonality detected by GS, the GS were performed on fresh and paraffin-embedded tissue samples. FCI of the plasmacytic and PBCHs supported no clonal process by GS. FCI defined a clonal process in 2 PBCLs, I immunoblastic lymphoma, and 1 multiple myeloma that were negative by GS. However, 1 PBCL that was polyclonal by FCI was monoclonal by GS. Thus, FCI is useful for identifying a clonal process in PTLDs with negative results by GS; FCI and GS should be performed routinely in PTLDs to detect a clonal process.

  6. Complement-mediated cell death induced by rituximab in B-cell lymphoproliferative disorders is mediated in vitro by a caspase-independent mechanism involving the generation of reactive oxygen species.

    PubMed

    Bellosillo, B; Villamor, N; López-Guillermo, A; Marcé, S; Esteve, J; Campo, E; Colomer, D; Montserrat, E

    2001-11-01

    Mechanisms involving the in vitro effect of rituximab in cells from 55 patients with B-cell lymphoproliferative disorders were investigated. No cytotoxic effect was observed when cells were incubated with rituximab alone, but in the presence of human AB serum rituximab induced complement-dependent cell death (R-CDC). A cytotoxic effect was observed in cells from 9 of 33 patients with B-cell chronic lymphocytic leukemia, 16 of 16 patients with mantle-cell lymphoma, 4 of 4 patients with follicular lymphoma, and 2 of 2 patients with hairy-cell leukemia. R-CDC was observed in cells from patients expressing more than 50 x 10(3) CD20 molecules per cell, and directly correlated with the number of CD20 molecules per cell. Preincubation with anti-CD59 increased the cytotoxic effect of rituximab and sensitized cells from nonsensitive cases. Neither cleavage of poly-ADP ribose polymerase (PARP) nor activation of caspase-3 was observed in R-CDC. In addition, no cells with a hypodiploid DNA content were detected and R-CDC was not prevented by a broad-spectrum caspase inhibitor, suggesting a caspase-independent mechanism. Incubation with rituximab in the presence of AB serum induced a rapid and intense production of reactive oxygen species (ROS). R-CDC was blocked by the incubation of cells with N-acetyl-L-cysteine (NAC) or Tiron, 2 ROS scavengers, indicating that the cytotoxic effect was due to the generation of superoxide (O) radicals. In conclusion, the results of the present study suggest that CD20, CD59, and complement have a role in the in vitro cytotoxic effect of rituximab, which is mediated by a caspase-independent process that involves ROS generation.

  7. Posttransplant Lymphoproliferative Disorders in Neuronal Xenotransplanted Macaques.

    PubMed

    Cavicchioli, L; Ferraresso, S; Westmoreland, S; Kaliyaperumal, S; Knight, H; Crossan, C; Scobie, L; Danesi, A; Vadori, M; Trez, D; Badin, R Aron; Hantraye, P; Cozzi, E

    2017-03-01

    Posttransplant lymphoproliferative disorders (PTLDs) are a heterogeneous group of lymphoid proliferations that occur in the setting of depressed T-cell function due to immunosuppressive therapy used following solid organ transplantation, hematopoietic stem cell transplantation, and also xenotransplantation. In the present study, 28 immunosuppressed parkinsonian Macaca fascicularis were intracerebrally injected with wild-type or CTLA4-Ig transgenic porcine xenografts to identify a suitable strategy to enable long-term cell survival, maturation, and differentiation. Nine of 28 (32%) immunosuppressed primates developed masses compatible with PTLD, located mainly in the gastrointestinal tract and/or nasal cavity. The masses were classified as monomorphic PTLD according to the World Health Organization classification. Immunohistochemistry and polymerase chain reaction (PCR) analyses revealed that the PTLDs were associated with macaca lymphocryptovirus as confirmed by double-labeling immunohistochemistry for CD20 and Epstein-Barr nuclear antigen 2 (EBNA-2), where the viral protein was located within the CD20+ neoplastic B cells. In sera from 3 distinct phases of the experimental life of the primates, testing by quantitative PCR revealed a progression of the viral load that paralleled the PTLD progression and no evidence of zoonotic transmission of porcine lymphotropic herpesvirus through xenoneuronal grafts. These data suggest that monitoring the variation of macaca lymphocryptovirus DNA in primates could be used as a possible early diagnostic tool for PTLD progression, allowing preemptive treatment such as immunosuppression therapy reduction.

  8. EBV-associated lymphoproliferative disorders: classification and treatment.

    PubMed

    Carbone, Antonino; Gloghini, Annunziata; Dotti, Giampietro

    2008-05-01

    Since its discovery as the first human tumor virus, Epstein-Barr virus (EBV) has been implicated in the development of a wide range of B-cell lymphoproliferative disorders, including Burkitt's lymphoma, classic Hodgkin's lymphoma, and lymphomas arising in immunocompromised individuals (post-transplant and HIV-associated lymphoproliferative disorders). T-cell lymphoproliferative disorders that have been reported to be EBV associated include a subset of peripheral T-cell lymphomas, angioimmunoblastic T-cell lymphoma, extranodal nasal type natural killer/T-cell lymphoma, and other rare histotypes. EBV encodes a series of products interacting with or exhibiting homology to a wide variety of antiapoptotic molecules, cytokines, and signal transducers, hence promoting EBV infection, immortalization, and transformation. However, the exact mechanism by which EBV promotes oncogenesis is an area of active debate. The focus of this review is on the pathology, diagnosis, classification, and pathogenesis of EBV-associated lymphomas. Recent advances in EBV cell-based immunotherapy, which is beginning to show promise in the treatment of EBV-related disorders, are discussed.

  9. Deregulated expression of HDAC9 in B cells promotes development of lymphoproliferative disease and lymphoma in mice

    PubMed Central

    Gil, Veronica S.; Howell, Louise; Zhang, Jiyuan; Kim, Chae H.; Stengel, Sven; Vega, Francisco; Zelent, Arthur

    2016-01-01

    ABSTRACT Histone deacetylase 9 (HDAC9) is expressed in B cells, and its overexpression has been observed in B-lymphoproliferative disorders, including B-cell non-Hodgkin lymphoma (B-NHL). We examined HDAC9 protein expression and copy number alterations in primary B-NHL samples, identifying high HDAC9 expression among various lymphoma entities and HDAC9 copy number gains in 50% of diffuse large B-cell lymphoma (DLBCL). To study the role of HDAC9 in lymphomagenesis, we generated a genetically engineered mouse (GEM) model that constitutively expressed an HDAC9 transgene throughout B-cell development under the control of the immunoglobulin heavy chain (IgH) enhancer (Eμ). Here, we report that the Eμ-HDAC9 GEM model develops splenic marginal zone lymphoma and lymphoproliferative disease (LPD) with progression towards aggressive DLBCL, with gene expression profiling supporting a germinal center cell origin, as is also seen in human B-NHL tumors. Analysis of Eμ-HDAC9 tumors suggested that HDAC9 might contribute to lymphomagenesis by altering pathways involved in growth and survival, as well as modulating BCL6 activity and p53 tumor suppressor function. Epigenetic modifications play an important role in the germinal center response, and deregulation of the B-cell epigenome as a consequence of mutations and other genomic aberrations are being increasingly recognized as important steps in the pathogenesis of a variety of B-cell lymphomas. A thorough mechanistic understanding of these alterations will inform the use of targeted therapies for these malignancies. These findings strongly suggest a role for HDAC9 in B-NHL and establish a novel GEM model for the study of lymphomagenesis and, potentially, preclinical testing of therapeutic approaches based on histone deacetylase inhibitors. PMID:27799148

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

    PubMed

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

    2013-04-18

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

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

    PubMed Central

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

    2013-01-01

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

  12. Primary central nervous system posttransplant lymphoproliferative disorders.

    PubMed

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

    2004-02-01

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

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

    PubMed Central

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

    2011-01-01

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

  14. T-cells fighting B-cell lymphoproliferative malignancies: the emerging field of CD19 CAR T-cell therapy.

    PubMed

    Heijink, D M; Kater, A P; Hazenberg, M D; Hagenbeek, A; Kersten, M J

    2016-05-01

    CAR T-cells are autologous T-cells transduced with a chimeric antigen receptor (CAR). The CAR contains an antigen recognition part (originating from an antibody), a T-cell receptor transmembrane and cytoplasmic signalling part, and one or more co-stimulatory domains. While CAR T-cells can be directed against any tumour target, most experience thus far has been obtained with targeting of the B-cell antigen CD19 that is expressed by B-cell acute lymphocytic leukaemia, chronic lymphocytic leukaemia and other B-cell lymphomas. The first clinical results are promising, although there are profound differences in response between patients with different haematological malignancies. Treatment-related side effects have been observed that require specific management. This review will explain the mechanism of action, summarise the experience to date and point out future directions for this hopeful new addition to the therapeutic armamentarium in the treatment of lymphoproliferative B-cell malignancies.

  15. EBV-associated polymorphic posttransplant lymphoproliferative disorder presenting as gingival ulcers.

    PubMed

    León, Jorge Esquiche; Takahama Júnior, Ademar; Vassallo, José; Soares, Fernando Augusto; de Almeida, Oslei Paes; Lopes, Márcio Ajudarte

    2011-04-01

    Posttransplant lymphoproliferative disorders (PTLDs) present a wide clinicopathological spectrum, varying from the usual Epstein-Barr virus (EBV)-driven infectious mononucleosis-type polyclonal proliferations to EBV-positive or EBV-negative proliferations indistinguishable from overt lymphomas that occur in immunocompetent individuals. PTLDs characteristically have a predilection for extranodal sites and association with EBV.These disorders are usually B-cell type, although T-cell and rare cases involving both T- and B-cell types have also been described. The initial treatment consists in decreasing the immnosupressive therapy, usually with favorable results. The authors report on a rare case of a 19-year-old girl, with post-renal transplantation EBV-associated polymorphic lymphoproliferative gingival ulcerated lesions. To the best of their knowledge, this is the first case described in the English-language literature of polymorphic PTLD involving both B-cell and T-cell lineages, with an unusual immunoprofile affecting the mouth. The authors warn that this condition could be easily misdiagnosed as malignant lymphoma if not properly recognized.

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

    PubMed Central

    Dierickx, Daan; Cardinaels, Nina

    2015-01-01

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

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

    PubMed

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

    2009-05-14

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

  18. Pure red cell aplasia and lymphoproliferative disorders: an infrequent association.

    PubMed

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

    2012-01-01

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

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

    PubMed Central

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

    1996-01-01

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

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

    SciTech Connect

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

    2014-09-10

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

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

    PubMed

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

    2014-09-10

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

  2. T-cell post-transplantation lymphoproliferative disorders after cardiac transplantation: a single institutional experience.

    PubMed

    Draoua, H Y; Tsao, Lawrence; Mancini, Donna M; Addonizio, Linda J; Bhagat, Govind; Alobeid, Bachir

    2004-11-01

    Post-transplantation lymphoproliferative disorders (PTLDs) are a well-recognized and potentially life-threatening complication of solid organ transplantation. While the vast majority of PTLDs are B-cell lymphoproliferations, T-cell PTLDs are rarely seen. Among 898 patients receiving cardiac transplants between 1990 and 2003, 34 patients (3.8%) developed PTLDs with two (0.2%) T-cell PTLDs, 31 (3.5%) B-cell PTLDs and one (0.1%) natural killer cell PTLD. An additional three cases of T-cell PTLD were identified among all cardiac transplant patients followed at our institution. These T-cell PTLDs comprised a heterogeneous group of Epstein-Barr virus negative lymphoproliferations that developed late after transplantation and followed an aggressive course.

  3. Forced miR-146a expression causes autoimmune lymphoproliferative syndrome in mice via downregulation of Fas in germinal center B cells.

    PubMed

    Guo, Qiuye; Zhang, Jinjun; Li, Jingyi; Zou, Liyun; Zhang, Jinyu; Xie, Zunyi; Fu, Xiaolan; Jiang, Shan; Chen, Gang; Jia, Qingzhu; Li, Fei; Wan, Ying; Wu, Yuzhang

    2013-06-13

    By inhibiting target gene expression, microRNAs (miRNAs) play major roles in various physiological and pathological processes. miR-146a, a miRNA induced upon lipopolysaccharide (LPS) stimulation and virus infection, is also highly expressed in patients with immune disorders such as rheumatoid arthritis, Sjögren's syndrome, and psoriasis. Whether the high level of miR-146a contributes to any of these pathogenesis-related processes remains unknown. To elucidate the function of miR-146a in vivo, we generated a transgenic (TG) mouse line overexpressing miR-146a. Starting at an early age, these TG mice developed spontaneous immune disorders that mimicked human autoimmune lymphoproliferative syndrome (ALPS) with distinct manifestations, including enlarged spleens and lymph nodes, inflammatory infiltration in the livers and lungs, increased levels of double-negative T cells in peripheral blood, and increased serum immunoglobulin G levels. Moreover, with the adoptive transfer approach, we found that the B-cell population was the major etiological factor and that the expression of Fas, a direct target of miR-146a, was significantly dampened in TG germinal center B cells. These results indicate that miR-146a may be involved in the pathogenesis of ALPS by targeting Fas and may therefore serve as a novel therapeutic target.

  4. Epigenetic Control of B Cell Development and B-Cell-Related Immune Disorders.

    PubMed

    Bao, Yan; Cao, Xuetao

    2016-06-01

    B lymphocytes are generally recognized as the essential component of humoral immunity and also a regulator of innate immunity. The development of B cells is precisely regulated by a variety of factors via different mechanisms, including cytokine/cytokine receptors, signal transduction molecules, and transcription factors. Recent findings suggest that epigenetic factors, such as DNA methylation, histone modification, and non-coding RNA, play critical roles in establishing B cell lineage-specific gene expression profiles to define and sustain B cell identity and function. Epigenetic modifications are also sensitive to external stimuli and might bridge genetic and environmental factors in the pathogenesis or control of B-cell-related immune disorders, such as autoimmune diseases, lymphoma, and leukemia. Better understanding of the epigenetic mechanisms for regulating B cell development and involving B cell abnormal differentiation and function will shed light on the design of new therapeutic approaches to B-cell-related diseases, and potential candidates of epigenetic modulators may be identified to target epigenetic pathways to prevent or treat B cell disorders. We summarize the relevance of epigenetic marks and landscapes in the stages of B cell development, discuss the interaction of the transcriptional networks and epigenetic changes, and review the involvement of epigenetic risk in the pathogenesis of B-cell-related diseases. Understanding how specific epigenetic alterations contribute to the development of B-cell-related autoimmunity and malignancies is instrumental to control B cell disorders.

  5. Aggressive angiomyxoma of transplanted kidney mimicking posttransplant lymphoproliferative disorder.

    PubMed

    Gorsi, Ujjwal; Naranje, Priyanka; Rathi, Manish; Nada, Ritambhara; Khandelwal, Niranjan

    2017-01-01

    Angiomyxoma is a scarce neoplasm arising from the soft tissues of perineum and pelvis, more commonly seen in the females. For such a tumor to arise in a renal allograft is rare and has previously been reported only in few case. We report a case of aggressive angiomyxoma arising de novo in the renal allograft nine-year posttransplantation. We describe its imaging features on ultrasound and computed tomography which closely mimic the more usual tumor of the transplanted kidney, posttransplant lymphoproliferative disorder and suggest that angiomyxoma may be considered as a differential diagnosis in a case of soft tissue mass arising within the renal allograft.

  6. Hematopoietic Neoplasias in Horses: Myeloproliferative and Lymphoproliferative Disorders

    PubMed Central

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

    2010-01-01

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

  7. A case of multiple hepatic lesions associated with methotrexate-associated lymphoproliferative disorder.

    PubMed

    Matsumoto, Ruby; Numata, Kazushi; Doba, Nobutaka; Hara, Koji; Chuma, Makoto; Fukuda, Hiroyuki; Nozaki, Akito; Tanaka, Katsuaki; Ishii, Yoshimi; Maeda, Shin

    2016-10-01

    Patients receiving methotrexate (MTX) for the treatment of autoimmune disease are at a high risk of developing lymphoproliferative disorders (LPD), the so-called methotrexate-associated lymphoproliferative disorders (MTX-LPD). We recently performed abdominal ultrasonography (US) in a patient with rheumatoid arthritis (RA) who had developed hepatic dysfunction during the course of MTX therapy; the examination revealed multiple well-demarcated hepatic tumors with slightly irregular borders, the largest one measuring 9 cm in diameter. In view of the finding of portal and hepatic veins perforating the tumor, we suspected a diagnosis of malignant lymphoma and performed a hepatic tumor biopsy. Histopathological examination of the biopsy specimens revealed a diagnosis of diffuse large B-cell lymphoma, and we made a final diagnosis of MTX-LPD. MTX treatment was discontinued, which resulted in rapid resolution of the lesions. Resolution of MTX-LPD can be obtained just by discontinuation of MTX treatment. In patients receiving MTX therapy who are found to have hepatic tumors perforated by the portal vein and/or hepatic vein on abdominal US, it is advisable to perform hepatic tumor biopsy to facilitate differential diagnosis of MTX-LPD and enable a definite diagnosis.

  8. A Rare Presentation of Isolated CNS Posttransplantation Lymphoproliferative Disorder

    PubMed Central

    Smith, Casey; Streicher, Andrew; Magnuson, Allison; Newman, Susan; Bertoli, Robert

    2017-01-01

    Posttransplantation lymphoproliferative disorder (PTLD) is a recognized and extremely morbid complication of solid organ transplantation, but central nervous system involvement, particularly in isolation, is rare. There are no standardized treatment strategies for PTLD, though commonly used strategies include reduction of immunosuppression, chemotherapy, rituximab, radiation, and surgery. We present a case of an unusual morphologic variant of primary central nervous system PTLD with successful response to rituximab and cranial radiation. A 69-year-old Asian male, who underwent postrenal transplant nine years earlier, presented with a one-month history of new onset seizure activity. His evaluation revealed multiple brain lesions on magnetic resonance imaging (MRI), as well as serologic and cerebrospinal fluid studies which were positive for Epstein-Barr Virus (EBV) infection. Ultimately, he underwent craniotomy with tissue biopsy with the final pathology report showing posttransplant lymphoproliferative disorder, polymorphic type. The patient was managed with reduction in immunosuppression, rituximab therapy, and cranial radiation treatments. He had demonstrated marked improvement in his neurologic function and was ultimately discharged to inpatient rehabilitation facility. PMID:28116196

  9. Molecular etiology of an indolent lymphoproliferative disorder determined by whole-genome sequencing

    PubMed Central

    Parker, Jeremy D.K.; Shen, Yaoqing; Pleasance, Erin; Li, Yvonne; Schein, Jacqueline E.; Zhao, Yongjun; Moore, Richard; Wegrzyn-Woltosz, Joanna; Savage, Kerry J.; Weng, Andrew P.; Gascoyne, Randy D.; Jones, Steven; Marra, Marco; Laskin, Janessa; Karsan, Aly

    2016-01-01

    In an attempt to assess potential treatment options, whole-genome and transcriptome sequencing were performed on a patient with an unclassifiable small lymphoproliferative disorder. Variants from genome sequencing were prioritized using a combination of comparative variant distributions in a spectrum of lymphomas, and meta-analyses of gene expression profiling. In this patient, the molecular variants that we believe to be most relevant to the disease presentation most strongly resemble a diffuse large B-cell lymphoma (DLBCL), whereas the gene expression data are most consistent with a low-grade chronic lymphocytic leukemia (CLL). The variant of greatest interest was a predicted NOTCH2-truncating mutation, which has been recently reported in various lymphomas. PMID:27148583

  10. Isolated cerebral post-transplant lymphoproliferative disorder in a lymphoma recipient.

    PubMed

    Tang, Tzung-Chih; Chuang, Wen-Yu; Chang, Hung

    2013-01-01

    Post-transplant lymphoproliferative disorder (PTLD) can occur after solid organ transplantation (SOT) or hematopoietic stem cell transplantation (HSCT). The majority of PTLDs are related to the reactivation of Epstein-Barr virus (EBV) in the lymphoid organs. PLTDs in HSCT recipients tend to present with systemic involvement, and isolated PTLD in these patients is rare. Only 14 isolated cerebral PTLDs have been reported in HSCT recipients, and none have been reported in lymphoma patients. When diagnosing PTLD in a lymphoma patient, it is challenging to discriminate between a PTLD that originated from previous disease and a newly developed clone and to distinguish between donor and recipient origin. In this report, we present the first case of a B-cell lymphoma patient who developed isolated PTLD in the CNS, and we confirmed that the PTLD originated in a distinct clone and from a different origin. Furthermore, the role of EBV-DNA monitoring in such patients is discussed.

  11. EBV-positive mucocutaneous ulcer in organ transplant recipients: a localized indolent posttransplant lymphoproliferative disorder.

    PubMed

    Hart, Melissa; Thakral, Beenu; Yohe, Sophia; Balfour, Henry H; Singh, Charanjeet; Spears, Michael; McKenna, Robert W

    2014-11-01

    Epstein-Barr virus (EBV)-positive mucocutaneous ulcer (EBV MCU) is a B-cell lymphoproliferative disorder occurring in elderly or iatrogenic immunocompromised patients. It has not been reported in solid organ transplant recipients. We observed 7 patients with EBV MCU in a cohort of 70 transplant recipients with EBV posttransplant lymphoproliferative disorder (PTLD). Transplants included: 5 renal, 1 heart, and 1 lung. Median patient age was 61; 5 were male. EBV MCU was observed in oral mucosa in 4 and gastrointestinal tract in 3. Duration of immunosuppressive therapy before EBV MCU was 0.6 to 13 years. Ulcers were undermined by inflammatory cells and polymorphic or monomorphic large cell lymphoproliferation. Reed-Sternberg-like cells were present in 5/7. Large B cells were CD20, CD30, and EBV-encoded RNA positive in all cases. Diagnosis in 3 recent patients was EBV MCU; 4 patients diagnosed before familiarity with EBV MCU were classified as monomorphic large cell (n=3) and polymorphic (n=1) PTLD. None of the patients had EBV DNA in their blood (<1000 copies/mL) at diagnosis or follow-up versus 35/44 transplant patients with systemic PTLD (P<0.001). All lesions resolved with reduced immunosuppression (7/7), change in immunosuppression (2/7), and rituximab (3/7). Five patients are living: 4 healthy, 1 awaiting second renal transplant. Two patients died 3 and 5 years after resolution of EBV MCU. No patient recurred with EBV MCU or other PTLDs. EBV MCU mimics more aggressive categories of PTLD but lacks EBV DNA in blood, which may be a useful distinguishing feature. Lesions are likely to resolve with conservative management. Awareness of EBV MCU in the posttransplant setting is necessary for appropriate diagnosis and treatment.

  12. Post-transplant lymphoproliferative disorder subtypes correlate with different recurring chromosomal abnormalities.

    PubMed

    Djokic, Miroslav; Le Beau, Michelle M; Swinnen, Lode J; Smith, Sonali M; Rubin, Charles M; Anastasi, John; Carlson, Katrin M

    2006-03-01

    Although cytogenetic analysis advanced the understanding of the pathogenesis of primary non-Hodgkin lymphoma and led to improved clinical management, there have been no large cytogenetic studies of post-transplant lymphoproliferative disorder (PTLD). We examined the karyotypes of 36 PTLD cases and correlated them with clinical, laboratory, and pathologic findings. The cases included 2 early lesions, 13 polymorphic PTLDs, and 21 monomorphic PTLDs (18 B-cell and 3 T-cell proliferations). Cytogenetic abnormalities were identified in 72% of monomorphic B-cell PTLDs and in all T-cell PTLDs, but in only 15% of polymorphic PTLDs and in no early lesions. The most frequent clonal abnormalities in monomorphic PTLD were trisomies 9 and/or 11 (5 cases), followed by rearrangements of 8q24.1 (4 cases), 3q27 (2 cases), and 14q32 (2 cases). MYC rearrangement (8q24.1) and T-cell-associated chromosomal abnormalities correlated with poor outcome and short survival. PTLD with trisomy 9 and/or 11 developed early after transplant, presenting as Epstein-Barr virus-positive large B-cell lymphoma with prolonged survival.

  13. Posttransplant Lymphoproliferative Disorder Manifesting as Intestinal Epstein-Barr Virus-Positive Anaplastic Large-Cell Lymphoma in an Adult Renal Transplant Recipient.

    PubMed

    Börcek, Pelin; Özdemir, B Handan; Özgün, Gonca; Haberal, Mehmet

    2016-11-01

    Posttransplant lymphoproliferative disorder is a relatively common posttransplant malignancy affecting as many as 10% of all solid-organ recipients. Most cases of posttransplant lymphoproliferative disorder are of B-cell origin, with common Epstein-Barr virus association. Posttransplant lymphoproliferative disorders of T-cell origin are much rarer and less frequently associated with Epstein-Barr virus. Here, we report an unusual case of Epstein-Barr virus-positive anaplastic large-cell lymphoma causing an intestinal perforation in an adult renal transplant recipient. A 52-year-old male patient with renal allograft developed cryptogenic end-stage liver failure and was accepted as a candidate for liver transplant. Before transplant, he was admitted with severe abdominal pain, which turned out to result from ileal perforation. Pathologic evaluation of the intestinal resection showed diffuse malignant lymphoid infiltration of the ileum, consistent with anaplastic large-cell lymphoma. The tumor was positive for Epstein-Barr virus genome. Anaplastic large-cell lymphoma is a rare form of T-cell posttransplant lymphoproliferative disorder that is infrequently associated with Epstein-Barr virus. The occurrence of this extraordinary form of post transplant lymphoproliferative disorder, its late onset, intestinal localization, and Epstein-Barr virus as sociation represent a unique clinical rarity.

  14. 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

    2017-01-04

    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

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

    PubMed Central

    Matos, Daniel Mazza; Furtado, Felipe Magalhães; Falcão, Roberto Passetto

    2015-01-01

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

  16. Molecular characterization of post-transplant lymphoproliferative disorders of donor origin occurring in liver transplant recipients.

    PubMed

    Capello, Daniela; Rasi, Silvia; Oreste, Pierluigi; Veronese, Silvio; Cerri, Michaela; Ravelli, Erika; Rossi, Davide; Minola, Ernesto; Colosimo, Anna; Gambacorta, Marcello; Muti, Giuliana; Morra, Enrica; Gaidano, Gianluca

    2009-08-01

    Post-transplant lymphoproliferative disorders (PTLDs) represent a frequent complication of solid organ transplantation. Although most PTLDs arise from recipient lymphoid cells, a considerable fraction of cases may arise from donor B-cells. In an attempt to clarify the histogenesis and pathogenesis of PTLDs derived from donor B-cells, monoclonal PTLDs occurring in liver transplant recipients were chosen as a model to compare donor (D-PTLDs) versus recipient PTLDs (R-PTLDs). The tumour panel included nine D-PTLDs and six R-PTLDs. D-PTLDs were early-onset, EBV-infected lymphoproliferations classified as polymorphic PTLD (P-PTLD; n = 7) or diffuse large B-cell lymphoma (DLBCL; n = 2) with tumour localization confined to the hepatic hilum. All R-PTLDs were late-onset DLBCLs and showed extrahepatic localization. A BCL-6(-)/MUM1(+)/CD138(+/-) phenotype, consistent with a post-germinal centre (GC) stage of pre-terminal B-cell differentiation, was observed in all D-PTLDs and in 2/6 R-PTLDs, whereas a BCL6(+)/MUM1(-)/CD138(-) profile, reminiscent of GC B-cells, was detected in 4/6 R-PTLDs. The presence of somatic IGHV hypermutation was observed in 6/9 D-PTLDs and in 4/6 R-PTLDs, suggesting derivation from antigen-experienced B-cells. IGHV4-39 was the IGHV gene most frequently encountered, being rearranged in 3/9 D-PTLDs. Among IGHV-mutated PTLDs, a mutational profile suggesting antigen stimulation and/or selection was observed in 4/6 D-s and in 2/4 R-PTLDs. The presence of ongoing IGHV mutations was detected in 2/4 D-PTLDs. Aberrant SHM was detected in 10/15 (66.7%) PTLDs, including 6/9 D-PTLDs and 4/6 R-PTLDs. Our findings suggest that (i) D-PTLDs show a clinical presentation distinct from R-PTLDs; (ii) immunophenotypic and genetic features of D-PTLDs are consistent with mature, GC-experienced B-cells; (iii) transformed donor-derived B-cells may experience antigen-driven stimulation and selection, and may acquire genetic lesions during neoplastic expansion in the recipient

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

    PubMed

    Cabras, Maria Giuseppina; Angelucci, Emanuele

    2015-01-01

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

  18. Circulating antibody free light chains and risk of posttransplant lymphoproliferative disorder.

    PubMed

    Engels, E A; Preiksaitis, J; Zingone, A; Landgren, O

    2012-05-01

    Posttransplant lymphoproliferative disorder (PTLD) is a major complication of solid-organ transplantation. With human immunodeficiency virus infection (an analogous immunosuppressive state), elevated kappa and lambda immunoglobulin free light chains (FLCs) in peripheral blood are associated with increased risk of lymphoma. To assess the role of B-cell dysfunction in PTLD, we measured circulating FLCs among Canadian transplant recipients, including 29 individuals with PTLD and 57 matched transplant recipients who were PTLD-free. Compared with controls, PTLD cases had higher kappa FLCs (median 1.53 vs. 1.07 times upper limit of normal) and lambda FLCs (1.03 vs. 0.68). Using samples obtained on average 3.5 months before PTLD diagnosis, cases were more likely to have polyclonal FLC elevations (i.e. elevated kappa and/or lambda with normal kappa/lambda ratio: odds ratio [OR] 4.2, 95%CI 1.1-15) or monoclonal elevations (elevated kappa and/or lambda with abnormal ratio: OR 3.0, 95%CI 0.5-18). Strong FLC-PTLD associations were also observed at diagnosis/selection. Among recipients with Epstein-Barr virus (EBV) DNA measured in blood, EBV DNAemia was associated with FLC abnormalities (ORs 6.2 and 3.2 for monoclonal and polyclonal elevations). FLC elevations are common in transplant recipients and associated with heightened PTLD risk. FLCs likely reflect B-cell dysfunction, perhaps related to EBV-driven lymphoproliferation.

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

    PubMed Central

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

    2015-01-01

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

  20. Plasmacytoma-like posttransplant lymphoproliferative disorder following orthotopic liver transplantation: a case report.

    PubMed

    Vishnu, P; Jiang, L; Cortese, C; Menke, D M; Tun, H W

    2011-09-01

    Posttransplant lymphoproliferative disorders (PTLDs) are among the most serious and potentially fatal complications of both stem-cell and solid-organ transplantation. Most monomorphic PTLDs are of B-cell origin and frequently associated with Epstein-Barr virus (EBV) infection in the setting of pharmacological immunosuppression posttransplantation. The majority of monomorphic PTLDs commonly resemble diffuse large B-cell or Burkitt's lymphoma; plasmacytoma-like PTLDs are very rare. We report a case of plasmacytoma-like PTLD arising in the allograft in a 66-year-old male diagnosed 2 months following an orthotopic liver transplant for alcohol-related end-stage liver disease. The liver biopsy revealed marked infiltration of atypical plasma cells with lambda light chain restriction and positivity for EBV by in situ hybridization confirming the diagnosis. Also noted was a remarkable increase of tissue eosinophils. Reduction of immunosuppression led to improvement in his clinical condition, and also resolution of the hepatic lesions and abdominal lymphadenopathy noted on imaging studies. While a few cases of plasmacytoma-like PTLDs have been described in literature, to our knowledge, this is the first reported case of early onset plasmacytoma-like PTLD in a liver transplant recipient occurring in the allograft with associated lymphadenopathy having distinct histopathologic features including tissue eosinophilia. Timely recognition of such an entity is critical in order to initiate early and appropriate intervention.

  1. Mouse model of Epstein-Barr virus LMP1- and LMP2A-driven germinal center B-cell lymphoproliferative disease.

    PubMed

    Minamitani, Takeharu; Ma, Yijie; Zhou, Hufeng; Kida, Hiroshi; Tsai, Chao-Yuan; Obana, Masanori; Okuzaki, Daisuke; Fujio, Yasushi; Kumanogoh, Atsushi; Zhao, Bo; Kikutani, Hitoshi; Kieff, Elliott; Gewurz, Benjamin E; Yasui, Teruhito

    2017-03-28

    Epstein-Barr virus (EBV) is a major cause of immunosuppression-related B-cell lymphomas and Hodgkin lymphoma (HL). In these malignancies, EBV latent membrane protein 1 (LMP1) and LMP2A provide infected B cells with surrogate CD40 and B-cell receptor growth and survival signals. To gain insights into their synergistic in vivo roles in germinal center (GC) B cells, from which most EBV-driven lymphomas arise, we generated a mouse model with conditional GC B-cell LMP1 and LMP2A coexpression. LMP1 and LMP2A had limited effects in immunocompetent mice. However, upon T- and NK-cell depletion, LMP1/2A caused massive plasmablast outgrowth, organ damage, and death. RNA-sequencing analyses identified EBV oncoprotein effects on GC B-cell target genes, including up-regulation of multiple proinflammatory chemokines and master regulators of plasma cell differentiation. LMP1/2A coexpression also up-regulated key HL markers, including CD30 and mixed hematopoietic lineage markers. Collectively, our results highlight synergistic EBV membrane oncoprotein effects on GC B cells and provide a model for studies of their roles in immunosuppression-related lymphoproliferative diseases.

  2. The accuracy of positron emission tomography in the detection of posttransplant lymphoproliferative disorder.

    PubMed

    Dierickx, Daan; Tousseyn, Thomas; Requilé, Annelies; Verscuren, Raf; Sagaert, Xavier; Morscio, Julie; Wlodarska, Iwona; Herreman, An; Kuypers, Dirk; Van Cleemput, Johan; Nevens, Frederik; Dupont, Lieven; Uyttebroeck, Anne; Pirenne, Jacques; De Wolf-Peeters, Christiane; Verhoef, Gregor; Brepoels, Lieselot; Gheysens, Olivier

    2013-05-01

    We investigated sensitivity, specificity, positive predictive value, negative predictive value and accuracy of 18F-fluorodeoxyglucose-positron emission tomography in 170 cases with suspected or biopsy-proven posttransplant lymphoproliferative disorder. All solid organ and hematopoietic stem cell transplant recipients who underwent an 18F-fluorodeoxyglucose-positron emission tomography scan between 2003 and 2010 in our center for the indication posttransplant lymphoproliferative disorder, were retrospectively reviewed and results were compared with tissue biopsy whenever possible. One hundred and seventy positron emission tomography scans in 150 patients were eligible for evaluation. In 45 cases, the patient had a biopsy-confirmed posttransplant lymphoproliferative disorder before positron emission tomography scanning and positron emission tomography was performed for staging purposes. In the remaining 125 cases, positron emission tomography was performed to differentiate between posttransplant lymphoproliferative disorder and other diseases. 18F-fluorodeoxyglucose-uptake was quantitatively expressed by calculation of maximum and mean standardized uptake value in the most intense lesion or, in the absence of attenuation corrected positron emission tomography scans, by comparing uptake in target lesion to liver and mediastinal uptake. We found an overall sensitivity of 89%, specificity of 89%, positive predictive value of 91% and negative predictive value of 87% for posttransplant lymphoproliferative disorder detection by 18F-fluorodeoxyglucose-positron emission tomography. In a subanalysis of the 125 scans performed for differentiating posttransplant lymphoproliferative disorder from other diseases, sensitivity, specificity, positive predictive value and negative predictive value were 90%, 89%, 85% and 93%, respectively. 18F-fluorodeoxyglucose-uptake in posttransplant lymphoproliferative disorder was generally high with a median mean and maximum standardized uptake

  3. The accuracy of positron emission tomography in the detection of posttransplant lymphoproliferative disorder

    PubMed Central

    Dierickx, Daan; Tousseyn, Thomas; Requilé, Annelies; Verscuren, Raf; Sagaert, Xavier; Morscio, Julie; Wlodarska, Iwona; Herreman, An; Kuypers, Dirk; Van Cleemput, Johan; Nevens, Frederik; Dupont, Lieven; Uyttebroeck, Anne; Pirenne, Jacques; De Wolf-Peeters, Christiane; Verhoef, Gregor; Brepoels, Lieselot; Gheysens, Olivier

    2013-01-01

    We investigated sensitivity, specificity, positive predictive value, negative predictive value and accuracy of 18F-fluorodeoxyglucose-positron emission tomography in 170 cases with suspected or biopsy-proven posttransplant lymphoproliferative disorder. All solid organ and hematopoietic stem cell transplant recipients who underwent an 18F-fluorodeoxyglucose-positron emission tomography scan between 2003 and 2010 in our center for the indication posttransplant lymphoproliferative disorder, were retrospectively reviewed and results were compared with tissue biopsy whenever possible. One hundred and seventy positron emission tomography scans in 150 patients were eligible for evaluation. In 45 cases, the patient had a biopsy-confirmed posttransplant lymphoproliferative disorder before positron emission tomography scanning and positron emission tomography was performed for staging purposes. In the remaining 125 cases, positron emission tomography was performed to differentiate between posttransplant lymphoproliferative disorder and other diseases. 18F-fluorodeoxyglucose-uptake was quantitatively expressed by calculation of maximum and mean standardized uptake value in the most intense lesion or, in the absence of attenuation corrected positron emission tomography scans, by comparing uptake in target lesion to liver and mediastinal uptake. We found an overall sensitivity of 89%, specificity of 89%, positive predictive value of 91% and negative predictive value of 87% for posttransplant lymphoproliferative disorder detection by 18F-fluorodeoxyglucose-positron emission tomography. In a subanalysis of the 125 scans performed for differentiating posttransplant lymphoproliferative disorder from other diseases, sensitivity, specificity, positive predictive value and negative predictive value were 90%, 89%, 85% and 93%, respectively. 18F-fluorodeoxyglucose-uptake in posttransplant lymphoproliferative disorder was generally high with a median mean and maximum standardized uptake

  4. T-cell and NK-cell posttransplantation lymphoproliferative disorders.

    PubMed

    Swerdlow, Steven H

    2007-06-01

    Posttransplantation lymphoproliferative disorders (PTLDs) of T-cell or natural killer (NK)-cell origin are an uncommon heterogeneous group of lymphoid proliferations that fulfill the criteria for one of the T- or NK-cell lymphomas/leukemias. This report summarizes 130 T/NK-cell PTLDs reported in the literature or presented at the Society for Hematopathology/European Association for Haematopathology Workshop on T/NK-cell malignancies. The T/NK-cell PTLDs occur at a median of 66 months following transplantation and are usually extranodal. The most common types reported are peripheral T-cell lymphoma, unspecified, and hepatosplenic T-cell lymphoma. Approximately one third are Epstein-Barr virus (EBV)+. The median survival is 6 months. EBV+ cases have a significantly longer survival than EBV- cases, even when indolent T-cell large granular lymphocytic leukemias are included among the EBV- cases. Many T/NK-cell PTLDs have been treated with chemotherapy, often together with decreased immunosuppression, but there are infrequent patients who have done well without chemotherapy or radiation.

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

    PubMed

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

    2011-04-21

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

  6. 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

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

    PubMed Central

    Capello, Daniela; Gaidano, Gianluca

    2009-01-01

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

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

    PubMed

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

    2014-06-01

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

  9. EBV-associated B- and T-cell posttransplant lymphoproliferative disorders following primary EBV infection in a kidney transplant recipient.

    PubMed

    Yin, C Cameron; Medeiros, L Jeffrey; Abruzzo, Lynne V; Jones, Dan; Farhood, Anwar I; Thomazy, Vilmos A

    2005-02-01

    Posttransplant lymphoproliferative disorders (PTLDs) usually are of B-cell lineage and associated with Epstein-Barr virus (EBV). PTLDs of T-cell lineage are much less common and infrequently associated with EBV. We report a rare case of a girl in whom B-cell and T-cell PTLDs developed following 2 EBV-negative kidney transplants. Within 2 years of the second transplantation, the originally EBV-negative patient developed both an EBV-associated clonal B-cell PTLD involving lymph nodes and an EBV-positive T-cell PTLD involving bone marrow and liver. These proliferations occurred concurrently with evidence of primary EBV infection and high plasma viral load. The patient eventually died of multiorgan failure 5 years after the initial transplant (3 years after the second transplant). To our knowledge, only 4 cases of both B-cell and T-cell PTLDs have been reported. Only 2 cases have been proven to be monoclonal and EBV-associated, as in this case, the first following kidney transplantation.

  10. The Immune Response to Epstein Barr Virus and Implications for Posttransplant Lymphoproliferative Disorder.

    PubMed

    Martinez, Olivia M; Krams, Sheri M

    2017-04-04

    Posttransplant lymphoproliferative disorder (PTLD) is a serious complication in organ transplant recipients and is most often associated with the Epstein Barr virus (EBV). EBV is a common gammaherpes virus with tropism for B lymphocytes and infection in immunocompetent individuals is typically asymptomatic and benign. However, infection in immunocompromised or immunosuppressed individuals can result in malignant B cell lymphoproliferations such as PTLD. EBV+ PTLD can arise following primary EBV infection, or because of reactivation of a prior infection, and represents a leading malignancy in the transplant population. The incidence of EBV+ PTLD is variable depending on the organ transplanted and whether the recipient has preexisting immunity to EBV but can be as high as 20%. It is generally accepted that impaired immune function due to immunosuppression is a primary cause of EBV+ PTLD. In this overview, we review the EBV life cycle and discuss our current understanding of the immune response to EBV in healthy, immunocompetent individuals, in transplant recipients, and in PTLD patients. We review the strategies that EBV utilizes to subvert and evade host immunity and discuss the implications for the development of EBV+ PTLD.

  11. HHV8/EBV Coinfection Lymphoproliferative Disorder: Rare Entity with a Favorable Outcome

    PubMed Central

    Chelly, Beya; Kilani, Houda; Charfi, Lamia; Douggaz, Amel; Chatti, Samia; Chelbi, Emna

    2017-01-01

    HHV8/EBV-associated germinotropic lymphoproliferative disorder (GLD) is a challenging diagnosis given its rarity, the particular clinical presentation, and the lack of expression of markers usually used in establishing hematopoietic lineage. We report a new case of HHV8/EBV GLD in an immunocompetent 78-year-old woman. The diagnosis was made in an incidentally discovered lymphadenopathy. Histological examination showed a nodular lymphoid proliferation centered by aggregates of atypical plasmablastic cells admixed with small lymphoid cells. Tumor cells were strongly positive with EMA, HHV8, LMP1, CD38, CD138, and kappa light chains. They were negative with common lymphoma-associated markers (CD20, CD3, CD15, CD30, CD10, and bcl2). In situ hybridization confirmed the monotypic kappa light chains and the EBV infection (EBER+). A polyclonal pattern of Ig gene rearrangement was detected by PCR analysis. In the adjacent lymph node parenchyma, some germinal centers mimicked Castleman disease. In this case, the differential diagnosis was discussed with an early stage of large B-cell lymphoma arising in HHV8-associated multicentric Castleman disease. The clinical presentation, the immunophenotype, and the molecular results helped to make the accurate diagnosis. Through the review of the nine previously reported cases in literature, we discuss the clinical and pathologic features and the differential diagnosis of HHV8/EBV GLD. PMID:28280640

  12. Post-Transplant Lymphoproliferative Disorder Following Clinical Islet Transplantation: Report of the First Two Cases.

    PubMed

    Peters, Anthea; Olateju, Tolu; Deschenes, Jean; Shankarnarayan, Santosh H; Chua, Neil; Shapiro, A M James; Senior, Peter

    2017-04-08

    We report the first two cases of post-transplant lymphoproliferative disorder (PTLD) in recipients of islet transplants worldwide. First, a 44-year old recipient of 3 islet infusions developed PTLD 80 months after his initial transplant, presenting with abdominal pain and diffuse terminal ileum thickening on imaging. He was treated with surgical excision, reduction of immunosuppression and rituximab. Seven months later he developed central nervous system PTLD, presenting with vertigo and diplopia; immunosuppression was discontinued, resulting in graft loss, and he was given high-dose methotrexate and consolidative autologous stem cell transplant. He remains in remission 37 months after initial diagnosis. Second, a 58-year old female recipient of 2 islet infusions developed PTLD 24 months after initial islet infusion, presenting with pancytopenia secondary to extensive bone marrow involvement. Immunosuppression was discontinued, resulting in graft loss, and she received rituximab and chemotherapy, achieving complete remission. Both cases were monomorphic B-cell PTLD subtype by histology and negative for EBV in tissue or blood. These cases document the first occurrences of this rare complication in islet transplant, likely secondary to prolonged, intensive immunosuppression, and highlight the variable clinical manifestations of PTLD. Further studies are needed to determine incidence rate and risk factors in islet transplantation. This article is protected by copyright. All rights reserved.

  13. Post-transplantation lymphoproliferative disorders: diagnosis, prognosis, and current approaches to therapy.

    PubMed

    Evens, Andrew M; Roy, Rupali; Sterrenberg, Danielle; Moll, Michelle Z; Chadburn, Amy; Gordon, Leo I

    2010-11-01

    Post-transplantation lymphoproliferative disorders (PTLD) are a heterogenous group of abnormal lymphoid proliferations that occur after solid organ transplant (SOT) or hematopoietic transplantation. PTLDs consist of a disease spectrum ranging from hyperplasia to aggressive lymphomas with 60-70% being Epstein-Barr virus positive. The majority of cases are B-cell, although 10-15% are of T-cell origin or rarely Hodgkin lymphoma. Recent SOT series suggest PTLD occurs at a median of 36-40 months after transplant. Clinically, extra-nodal disease is common (up to 75-85%) including CNS involvement, which is seen in 10-15% of all cases. Since the first report over 40 years ago, PTLD has remained one of the most morbid complications associated with SOT. However, recent data suggests improved survival in the modern era, especially with the integration of early rituximab-based therapy. These studies utilized first line rituximab (+/- chemotherapy) together with reduced immune suppression (RI) for monomorphic and polymorphic PTLD. It will be critical in future studies to determine which PTLDs are most amenable to initial therapy with RI alone, versus RI/rituximab, versus RI/rituximab/chemotherapy. Additionally, novel therapeutics, such as adoptive immunotherapy, should continue to be explored.

  14. Genetic landscape of T- and NK-cell post-transplant lymphoproliferative disorders

    PubMed Central

    Margolskee, Elizabeth; Jobanputra, Vaidehi; Jain, Preti; Chen, Jinli; Ganapathi, Karthik; Nahum, Odelia; Levy, Brynn; Morscio, Julie; Murty, Vundavalli; Tousseyn, Thomas; Alobeid, Bachir

    2016-01-01

    Post-transplant lymphoproliferative disorders of T- or NK-cell origin (T/NK-PTLD) are rare entities and their genetic basis is unclear. We performed targeted sequencing of 465 cancer-related genes and high-resolution copy number analysis in 17 T-PTLD and 2 NK-PTLD cases. Overall, 377 variants were detected, with an average of 20 variants per case. Mutations of epigenetic modifier genes (TET2, KMT2C, KMT2D, DNMT3A, ARID1B, ARID2, KDM6B, n=11). and inactivation of TP53 by mutation and/or deletion(n=6) were the most frequent alterations, seen across disease subtypes, followed by mutations of JAK/STAT pathway genes (n=5). Novel variants, including mutations in TBX3 (n=3), MED12 (n=3) and MTOR (n=1), were observed as well. High-level microsatellite instability was seen in 1 of 14 (7%) cases, which had a heterozygous PMS2 mutation. Complex copy number changes were detected in 8 of 16 (50%) cases and disease subtype-specific aberrations were also identified. In contrast to B-cell PTLDs, the molecular and genomic alterations observed in T/NK-PTLD appear similar to those reported for peripheral T-cell lymphomas occurring in immunocompetent hosts, which may suggest common genetic mechanisms of lymphoma development. PMID:27203213

  15. Extramedullary plasmacytoma-like posttransplantation lymphoproliferative disorders: clinical and pathologic features.

    PubMed

    Richendollar, Bill G; Hsi, Eric D; Cook, James R

    2009-10-01

    Most monomorphic posttransplantation lymphoproliferative disorders (PTLDs) resemble diffuse large B-cell lymphoma or Burkitt lymphoma. Rare cases of PTLD resembling extramedullary plasmacytomas have also been described. This report describes the clinical, histologic, phenotypic, and genotypic findings in 4 cases of plasmacytoma-like PTLD (2 nodal, 1 adenoidal, and 1 cutaneous) and compares the findings with extramedullary involvement by plasma cell neoplasms arising in immunocompetent patients. Plasmacytoma-like PTLDs characteristically arise late after transplantation (mean, 7.0 years), show a variable association with Epstein-Barr virus (2/4 cases positive), and demonstrate histologic and phenotypic findings that overlap with immunocompetent extramedullary plasma cell neoplasms. None of the patients with plasmacytoma-like PTLD developed lytic bone lesions, and 3 of 4 patients had complete responses (>2 years) to reduction of immunosuppression, confirming the role of immunosuppression in the pathogenesis of these lesions. This report, which represents the first case series of plasmacytoma-like PTLD, clarifies the features of this rare subtype of PTLD.

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

    PubMed

    Vase, Maja Ølholm; Maksten, Eva Futtrup; Bendix, Knud; Hamilton-Dutoit, Stephen; Andersen, Claus; Møller, Michael Boe; Sørensen, Søren Schwartz; Jespersen, Bente; Kampmann, Jan; Søndergård, Esben; Nielsen, Patricia Switten; D'amore, Francesco

    2015-06-01

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

  17. Donor or recipient origin of posttransplant lymphoproliferative disorders following solid organ transplantation.

    PubMed

    Kinch, A; Cavelier, L; Bengtsson, M; Baecklund, E; Enblad, G; Backlin, C; Thunberg, U; Sundström, C; Pauksens, K

    2014-12-01

    Previous studies of donor or recipient origin of posttransplant lymphoproliferative disorders (PTLDs) following solid organ transplantation (SOT) have either been small or with selected patient groups. We studied tumor origin in a population-based cohort of 93 patients with PTLD following SOT. Tumor origin of PTLD tissue was analyzed by fluorescence in situ hybridization of the sex chromosomes in cases of sex mismatch between donor and recipient (n = 41), or HLA genotyping in cases of identical sex but different HLA type (n = 52). Tumor origin of PTLD could be determined in 67 of the 93 cases. All 67 PTLDs were of recipient origin. They were found in recipients of kidney (n = 38), liver (n = 12), heart (n = 10) and lung (n = 7). The most common recipient-derived lymphomas were monomorphic B-cell PTLDs (n = 45), monomorphic T cell PTLDs (n = 9), indolent lymphomas (n = 6), and polymorphic PTLD (n = 4). Half of the recipient-derived PTLDs were Epstein-Barr virus-positive. Twelve of the recipient-derived PTLDs were located in the grafts: in four cases exclusively and in eight cases in combination with disseminated disease outside the graft. Tumor origin was indeterminable in 26 cases, probably due to low DNA quality. We conclude that the vast majority of PTLDs after SOT was of recipient origin.

  18. Challenges and opportunities for checkpoint blockade in T-cell lymphoproliferative disorders.

    PubMed

    Phillips, Tycel; Devata, Sumana; Wilcox, Ryan A

    2016-01-01

    The T-cell lymphoproliferative disorders are a heterogeneous group of non-Hodgkin's lymphomas (NHL) for which current therapeutic strategies are inadequate, as most patients afflicted with these NHL will succumb to disease progression within 2 years of diagnosis. Appreciation of the genetic and immunologic landscape of these aggressive NHL, including PD-L1 (B7-H1, CD274) expression by malignant T cells and within the tumor microenvironment, provides a strong rationale for therapeutic targeting this immune checkpoint. While further studies are needed, the available data suggests that responses with PD-1 checkpoint blockade alone will unlikely approach those achieved in other lymphoproliferative disorders. Herein, we review the unique challenges posed by the T-cell lymphoproliferative disorders and discuss potential strategies to optimize checkpoint blockade in these T-cell derived malignancies.

  19. Epstein-Barr virus-positive T/NK-cell lymphoproliferative disorders.

    PubMed

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

    2015-01-23

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

  20. Epstein–Barr virus-positive T/NK-cell lymphoproliferative disorders

    PubMed Central

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

    2015-01-01

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

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

    PubMed Central

    Hernández, Luis; Gattei, Valter

    2015-01-01

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

  2. Lymphoproliferative Disorders in Patients with Chronic Myeloid Leukemia: A Single-Center Case Series.

    PubMed

    Alshehry, Nawal F; Al-Huneini, Mohammed; Lipton, Jeffrey H; Michelis, Fotios V

    2015-01-01

    Lymphoproliferative disorders presenting simultaneously with or subsequent to the occurrence of chronic myeloid leukemia (CML) have rarely been reported. Herein, we report 8 cases of a variety of lymphoproliferative conditions associated with CML at different times during the course of the disease. All 8 patients were treated with tyrosine kinase inhibitors at some point during the course of their illness. The literature regarding the uncommon association of these apparently unrelated disorders is reviewed as well as the possible underlying mechanisms that could be associated with this phenomenon.

  3. SV40 and p53 as team players in childhood lymphoproliferative disorders.

    PubMed

    Heinsohn, Susanne; Scholz, Roswitha; Kabisch, Hartmut

    2011-05-01

    Simian virus 40 (SV40) is known to be potently oncogenic and can induce several types of tumours, such as lymphoma. p53 was discovered as a cellular partner of the SV40 large T-antigen, the oncoprotein of this virus. There have not been many studies on SV40 and p53 in lymphomas and the ones that exist, are controversial. A comparison of these two components in lymphoma has not been reported previously. We examined 91 lymphomas [60 B-cell non-Hodgkin's lymphomas (B-NHLs), 19 B-cell acute lymphoblastic leukemias (B-ALLs), 7 B-cell precursor acute lymphoblastic leukemias and 5 T-cell acute lymphoblastic leukemias] for the presence of SV40. Overall, 40 samples from 12 B-NHL/19 B-ALL patients were additionally investigated for p53 mutation in the hot-spot exons 5 to 8. Overall, we found 62/91 lymphomas to be SV40-positive, among them 16/19 B-ALLs and 38/60 B-NHLs. SV40 was absent in 147 of the 149 blood control samples. We found 11 p53 mutations in 19 B-ALL patients: 5 in exon 5 (codons 132, 141, 143, 155 and 181), 4 in exon 7 (codons 236, 238 and 248), 2 in exon 8 (codon 273). In B-NHL patients we found p53-mutations in 9/12 samples: 6 of these in 3 lymph nodes (LNs). One LN harboured 3 different p53 mutations: Exon 5 (codon 132), exon 6 (codon 213) and exon 8 (codon 288). Another LN showed 2 different p53 mutations: Exon 6 (codon 213) and exon 8 (codon 285). Except for 1 nonsense mutation in an LN of a B-NHL patient, all 20 mutations were missense mutations, 2 were homozygous, both found in B-NHL-samples, and one of these (codon 175) is known to cause the global denaturation of p53. All occur in the DNA-binding domain of p53. All specimens showing a p53 mutation, were SV40-positive. p53 mutaions found in LNs of B-NHL patients harbour high SV40 copy numbers. Our data strongly support an important role for SV40, as well as a strong association of SV40 and p53 in childhood lympho-proliferative disorders.

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

    ClinicalTrials.gov

    2013-01-24

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

  5. Pesticide exposure as a risk factor for lymphoproliferative disorders in adults.

    PubMed

    Salem, E A; Hegazy, M M; El Khouley, E A

    2014-06-18

    In view of the widespread use of pesticides in Egypt and the increasing incidence of leukaemia and lymphoma we aimed to assess pesticide exposure and other selected variables as risk factors for lymphoproliferative disorders (leukaemia and non-Hodgkin lymphoma). In a hospital-based, retrospective, case-control study in 2011-2012, adult cases of lymphoproliferative disorders (n = 130) were recruited from outpatient clinics in Menoufia, Egypt, while controls (n = 130) were age- and sex-matched fracture patients. Family history of cancer, exposure to X-rays, smoking and use of hair dyes were not risk factors for lymphoproliferative disorders in univariate analysis. History of exposure to pesticides and HCV infection were significant risk factors for lymphoproliferative disorders in multivariate analysis (OR = 2.24; 95% CI: 1.22-4.11 and OR = 2.67; 95% CI: 1.50-4.80 respectively). The risk was significant for cases of non-Hodgkin lymphoma but not chronic lymphocytic leukaemia.

  6. Early post-transplant smooth muscle neoplasia of the colon presenting as diminutive polyps: a case complicating post-transplant lymphoproliferative disorder.

    PubMed

    Medlicott, S A C; Devlin, S; Helmersen, D S; Yilmaz, A; Mansoor, A

    2006-04-01

    A 44-year-old woman, 3 years post-transplant for pulmonary sarcoidosis, developed abdominal pain and diarrhea 13 months subsequent to an eradicated diffuse large B-cell-type, post-transplant lymphoproliferative disorder (PTLD) of the cecal region. Endoscopic examination identified multiple pale tan 5-to-9 mm rubbery nodules of the transverse and right colon in an otherwise unremarkable mucosa. Histology was characterized by bland smooth muscle proliferations, focally pushing into the mucosa. Immunohistochemistry (IHC), in situ hybridization (ISH), and polymerase chain reaction (PCR) of the sampled nodules confirmed Epstein-Barr virus (EBV) infection of neoplastic cells. To our knowledge, this is the first reported case of EBV-related post-transplant lymphoproliferative and smooth muscle neoplasms (PTSN) having distinct tropism for the colon. Endoscopic features of early PTSN, which in this case presented as diminutive polypoid lesions, have not been described previously.

  7. Precursors to Lymphoproliferative Malignancies

    PubMed Central

    Goldin, Lynn R.; McMaster, Mary L.; Caporaso, Neil E.

    2013-01-01

    We review monoclonal B-cell lymphocytosis (MBL) as a precursor to chronic lymphocytic leukemia and monoclonal gammopathy of undetermined significance (MGUS) as a precursor to plasma cell disorders. These conditions are present in the general population and increase with age. These precursors aggregate with lymphoproliferative malignancies in families suggesting shared inheritance. MBL and MGUS may share some of the same risk factors as their related malignancies but data are limited. While these conditions are characterized by enhanced risk for the associated malignancy, the majority of individuals with these conditions do not progress to malignancy. A key focus for current work is to identify markers that predict progression to malignancy. PMID:23549397

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

    PubMed Central

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

    2015-01-01

    Immunosuppressive agents, such as thiopurines, methotrexate, and biologics, have revolutionized the treatment of inflammatory bowel disease (IBD). However, a number of case reports, case control studies and retrospective studies over the last decade have identified a concerning link between immunosuppression and lymphoproliferative disorders (LPDs), the oncological phenomenon whereby lymphocytes divide uncontrollably. These LPDs have been associated with Epstein-Barr virus (EBV) infection in which the virus provides the impetus for malignant transformation while immunosuppression hampers the immune system’s ability to detect and clear these malignant cells. As such, the use of immunosuppressive agents may come at the cost of increased risk of developing LPD. While little is known about the LPD risk in IBD, more is known about immunosuppression in the post-transplantation setting and the development of EBV associated post-transplantation lymphoproliferative disorders (PTLD). In review of the PTLD literature, evidence is available to demonstrate that certain immune suppressants such as cyclosporine and T-lymphocyte modulators in particular are associated with an increased risk of PTLD development. As well, high doses of immunosuppressive agents and multiple immunosuppressive agent use are also linked to increased PTLD development. Here, we discuss these findings in context of IBD and what future studies can be taken to understand and reduce the risk of EBV-associated LPD development from immunosuppression use in IBD. PMID:26600976

  9. Epstein-Barr virus-negative post-transplant lymphoproliferative disorders: a distinct entity?

    PubMed

    Nelson, B P; Nalesnik, M A; Bahler, D W; Locker, J; Fung, J J; Swerdlow, S H

    2000-03-01

    Post-transplant lymphoproliferative disorders (PTLDs) are usually but not invariably associated with Epstein-Barr virus (EBV). The reported incidence, however, of EBV-negative PTLDs varies widely, and it is uncertain whether they should be considered analogous to EBV-positive PTLDs and whether they have any distinctive features. Therefore, the EBV status of 133 PTLDs from 80 patients was determined using EBV-encoded small ribonucleic acid (EBER) in situ hybridization stains with or without Southern blot EBV terminal repeat analysis. The morphologic, immunophenotypic, genotypic, and clinical features of the EBV-negative PTLDs were reviewed, and selected features were compared with EBV-positive cases. Twenty-one percent of patients had at least one EBV-negative PTLD (14% of biopsies). The initial EBV-negative PTLDs occurred a median of 50 months post-transplantation compared with 10 months for EBV-positive cases. Although only 2% of PTLDs from before 1991 were EBV negative, 23% of subsequent PTLDs were EBV negative (p <0.001). Of the EBV-negative PTLDs, 67% were of monomorphic type (M-PTLD) compared with 42% of EBV-positive cases (p <0.05). The other EBV-negative PTLDs were of infectious mononucleosis-like, plasma cell-rich (n = 2), small B-cell lymphoid neoplasm, large granular lymphocyte disorder (n = 4) and polymorphic (P) types. B-cell clonality was established in 14 specimens and T-cell clonality was established in three (two patients). None of the remaining specimens were studied with Southern blot analysis and some had no ancillary studies. Rearrangement of c-MYC was identified in two M-PTLDs with small noncleaved-like features, and rearrangement of BCL-2 was found in one large noncleaved-like M-PTLD. Ten patients were alive at 3 to 63 months (only three patients received chemotherapy). Seven patients, all with M-PTLDs, are dead at 0.3 to 6 months. Therefore, EBV-negative PTLDs have distinct features, but some do respond to decreased immunosuppression, similar

  10. Lymphoproliferative disorders after solid organ transplantation-classification, incidence, risk factors, early detection and treatment options.

    PubMed

    Végso, Gyula; Hajdu, Melinda; Sebestyén, Anna

    2011-09-01

    Posttransplant lymphoproliferative disorder (PTLD) is a heterogeneous disease group of benign and malignant entities. The new World Health Organisation classification introduced in 2008 distinguishes early lesions, polymorphic, monomorphic and classical Hodgkin lymphoma-type PTLD. Based on the time of appearance, early and late forms can be identified.PTLDs are the second most frequent posttransplantation tumors in adulthood, and the most frequent ones in childhood. The incidence varies with the transplanted organ-from 1%-2% following kidney transplantation to as high as 10% following thoracic organ transplantation-due to different intensities in immunosuppression. Immunocompromised state and Epstein-Barr virus (EBV) infection are the two major risk factors.In Europe and the US approximately 85% of PTLDs are of B-cell origin, and the majority are EBV-associated. Symptoms are often unspecific; extranodal, organ manifestations and central nervous system involvement is common. Early lesions respond well to a decrease in immunosuppression. Malignant entities are treated with rituximab, chemotherapy, radiotherapy and surgical therapy. Adoptive T-cell transfer represents a promising therapeutic approach. The prognosis is favorable in early PTLD, and poor in late PTLD. Five-year survival is 30% for high-grade lymphomas. The prognosis of EBV-negative lymphomas is worse.Lowering the risk of PTLD may be achieved by low dose maintenance immunosuppression, immunosuppressive drugs inhibiting cell proliferation, and special immunotherapy (e.g. interleukin-2 inhibitors). Early detection is especially important for high risk-e.g. EBV-negative-patients, where the appearance of EBV-DNA and the increase in its titer may help.

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

    PubMed Central

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

    2014-01-01

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

  12. CD30+ Primary Cutaneous Post-transplant Lymphoproliferative Disorder with Signet-ring Cell Features

    PubMed Central

    Malviya, Neeta; Wickless, Heather

    2016-01-01

    We report a case of primary cutaneous CD30+ post-transplant lymphoproliferative disorder with an uncommon finding of signet ring cell features in a heart transplant patient. The neoplastic cells were CD4 and CD30 positive, and negative for S-100, pancytokeratin, myeloperoxidase, and CD56. In situ hybridization for Epstein Barr Virus (EBV) was negative, even though the patient did have EBV viremia. PMID:27499836

  13. Clinicopathologic spectrum and EBV status of post-transplant lymphoproliferative disorders after allogeneic hematopoietic stem cell transplantation.

    PubMed

    Chen, Ding-Bao; Song, Qiu-Jing; Chen, Yun-Xin; Chen, Yu-Hong; Shen, Dan-Hua

    2013-01-01

    Post-transplant lymphoproliferative disorders (PTLDs) are serious, life-threatening complications of solid-organ transplantation (SOT) and bone marrow transplantation, and are associated with high mortality. PTLDs represent a heterogeneous group of lymphoproliferative diseases, which show a spectrum of clinical, morphologic, and molecular genetic features ranging from reactive polyclonal lesions to frank lymphomas. We describe clinicopathologic features of 17 cases of PTLD after allogeneic hematopoietic stem cell transplantation (allo-HSCT), which were analyzed by in situ hybridization for EBV and a panel of antibodies directed against numerous antigens, including CD20, PAX5, CD3, bcl-6, CD10, MUM-1/IRF4, CD138, Kappa, Lambda, CD30, CD15, and Ki67. The cases included 13 males and 4 females with a median age of 31 years (range 9-49 years) and the PTLDs developed 1.5-19 months post-transplant (mean 4.7 months). The histological types indicated five cases of early lesions, two of plasmacytic hyperplasia and three of infectious mononucleosis-like PTLD. Eight cases were polymorphic PTLD, and four were monomorphic PTLD, including three of diffuse large B cell lymphoma, and one of plasmablastic lymphoma. Foci and sheets of necrosis were observed in five cases. The infected ratio of EBV was 88.2 %. Some cases were treated by reduction of immunosuppression, antiviral therapy, donor lymphocyte infusion, or anti-CD20 monoclonal rituximab. Eight cases died. The first half year after allo-HSCT is very important for the development of PTLD. The diagnosis of PTLD relies on morphology and immunohistochemistry, and EBV plays an important role in the pathogenesis of PTLD. The prognosis of PTLD is poor, and, notably, PTLD after allo-HSCT exhibits some features different from those of PTLD after SOT.

  14. Array-CGH predicts prognosis in plasma cell post-transplantation lymphoproliferative disorders.

    PubMed

    Sarkozy, Clémentine; Kaltenbach, Sophie; Faurie, Pierre; Canioni, Danielle; Berger, Françoise; Traverse-Glehen, Alexandra; Ghesquieres, Hervé; Salles, Gilles; Bachy, Emmanuel; Alyanakian, Marie-Alexandra; Hermine, Olivier; Neven, Bénédicte; Macintyre, Elizabeth; Romana, Serge; Molina, Thierry Jo; Suarez, Felipe; Asnafi, Vahid; Bruneau, Julie

    2017-03-01

    Plasma-cell post-transplantation lymphoproliferative disorder (PC-PTLD) is a rare monomorphic PTLD entity divided into plasma cell myeloma (PCM) and plasmacytoma-like lesion (PLL) PTLD. To date, there are no exhaustive published cytogenetic data on PC-PTLD. We report array-based comparative genomic hybridization (aCGH) of 10 cases of PCM and PLL-PTLD. Patients had received kidney (n = 6), heart (n = 2), lung (n = 1) or bone marrow (n = 1) transplantation. There were six men and median age at time of PTLD was 56.5 years (3-74). We identified two different cytological features, plasmacytic and plasmablastic, among six PLL and three PCM PTLD. Eight cases were associated with EBV. First line treatment was heterogeneous: rituximab alone (n = 5), CHOP-like (n = 3) and multiple myeloma-like (n = 1). One patient died before any treatment. After a median follow-up of 19.5 months (0-150), five patients died (four from PTLD) and five were alive without evidence of disease. By aCGH, 5/10 demonstrated a complex profile. The most frequent abnormalities were +7q (5/10), +16q (5/10), +17q (5/10), +17p (4/10), +5q (4/10), t7 (4/10), t9 (3/10), del1p (3/10). No del17p13 (TP53) were observed. Del1p32.3 (CDKN2C) was observed in 2 cases. On univariate prognostic analysis, a complex aCGH was associated with a shorter OS. Thus, cytogenetic abnormalities seem to be closely related to those reported in multiple myeloma or diffuse large B cell lymphoma. Complex aCGH constitutes an unfavorable prognostic marker and aCGH should be integrated in the evaluation of patients with PLL/PCM-PTLD. © 2016 Wiley Periodicals, Inc.

  15. HCV Infection and B-Cell Lymphomagenesis

    PubMed Central

    Ito, Masahiko; Kusunoki, Hideki; Mochida, Keiko; Yamaguchi, Kazunari; Mizuochi, Toshiaki

    2011-01-01

    Hepatitis C virus (HCV) has been recognized as a major cause of chronic liver diseases worldwide. It has been suggested that HCV infects not only hepatocytes but also mononuclear lymphocytes including B cells that express the CD81 molecule, a putative HCV receptor. HCV infection of B cells is the likely cause of B-cell dysregulation disorders such as mixed cryoglobulinemia, rheumatoid factor production, and B-cell lymphoproliferative disorders that may evolve into non-Hodgkin's lymphoma (NHL). Epidemiological data indicate an association between HCV chronic infection and the occurrence of B-cell NHL, suggesting that chronic HCV infection is associated at least in part with B-cell lymphomagenesis. In this paper, we aim to provide an overview of recent literature, including our own, to elucidate a possible role of HCV chronic infection in B-cell lymphomagenesis. PMID:21789042

  16. Prevalence of occult hepatitis C virus infection in Iranian patients with lymphoproliferative disorders.

    PubMed

    Farahani, Maryam; Bokharaei-Salim, Farah; Ghane, Masood; Basi, Ali; Meysami, Parisa; Keyvani, Hossein

    2013-02-01

    Occult HCV infection is a form of chronic HCV infection characterized by absence of detectable anti-HCV antibodies or plasma HCV-RNA but presence of HCV-RNA in liver biopsy and/or peripheral blood mononuclear cells (PBMCs). The aim of this study was to determine the presence of HCV-RNA in PBMCs of patients with lymphoproliferative disorders. One hundred and four consecutive patients with lymphoproliferative disorders admitted to Firouzgar Hospital from January 2010 to March 2011 were recruited in this cross-sectional study. A 6-ml sample of whole blood was taken from the patients, the total RNA was extracted from the samples after the separation of plasma and PBMCs. The HCV-RNA of the samples was amplified by reverse transcriptase-nested polymerase chain reaction (RT-nested PCR). The HCV genotypes of the positive samples were tested using the INNO-LiPA™ HCV II kit, and the HCV genotypes were then confirmed by sequencing of the 5'-UTR fragments after the PCR products were cloned into a pJET1.2/blunt cloning vector. The mean age of the patients was 48.3 ± 1.76 years (range: 16-83). HCV-RNA was found in PBMCs from 2 (1.9%) of the 104 patients. Genotyping showed that the patients were infected with HCV subtype 1a. One patient suffered non-Hodgkin's lymphoma and the other suffered chronic lymphocytic leukemia. Patients with lymphoproliferative disorders with negative anti-HCV antibodies and negative plasma HCV-RNA may have occult HCV infection. Therefore, in the absence of a liver biopsy, the testing of PBMCs for the detection of genomic HCV-RNA may be beneficial.

  17. Extranodal Marginal Zone Lymphoma of the Lung: Evolution from an Underlying Reactive Lymphoproliferative Disorder.

    PubMed

    Rubenstein, Jon Nicholas; Beatty, Colleen; Kinkade, Zoe; Bryan, Cara; Hogg, Jeffery Paul; Gibson, Laura F; Vos, Jeffrey A

    2015-02-01

    Extranodal Marginal Zone Lymphoma (ENMZL) of Mucosa-Associated Lymphoid Tissue (MALT) is a problematic and sometimes controversial diagnosis. While commonly seen in the stomach in the setting of chronic Helicobacter pylori infection, other extranodal sites, such as the lung, may also present with disease. ENMZL is clinically and morphologically heterogeneous; however, regardless of presentation, the etiology lies in the accumulation of lymphoid tissue in non-traditional sites. This phenomenon is typically secondary to an underlying inflammatory stimulus such as chronic infection or autoimmune states. The current case report details the clinical history of a patient with Sjögren syndrome over a four year period who eventually developed ENMZL. The patient initially presented with an atypical, but polyclonal, lymphoproliferative process diagnosed as lymphocytic interstitial pneumonia. Over time, the patient showed evolution to a monoclonal process with associated radiologic progression of disease. This evolution manifested as a dense lymphoid infiltrate with prominent plasmacytic differentiation and the development of a lung mass radiologically. This case contributes to the growing body of knowledge that suggests ENMZL lies along a biological spectrum of lymphoproliferative disorders whereby a benign, reactive process may eventually undergo malignant transformation. This evolution likely represents the acquisition of genetic abnormalities that allow autonomous proliferation in the absence of the initial immune stimulus. In practice, determining when this event occurs and, thus, distinguishing between reactive and neoplastic disorders within this spectrum may be difficult as no single clinicopathologic feature may be present to establish the diagnosis. This case further illustrates the importance of correlating the clinical, radiologic and pathologic data to evaluate patients with atypical pulmonary lymphoproliferative disorders and to allow the optimal management of

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

    PubMed

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

    2009-09-03

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

  19. Epstein-Barr virus-related lymphoproliferative disorders following bone marrow transplantation: an immunologic and genotypic analysis.

    PubMed

    Davey, D D; Kamat, D; Laszewski, M; Goeken, J A; Kemp, J D; Trigg, M E; Purtilo, D T; Davis, J; Dick, F R

    1989-01-01

    Four patients from 1.5 to 18 yr of age who had received partially matched T-cell-depleted bone marrow transplants for acute leukemia succumbed to a widespread lymphoproliferative disorder (LPD) at 56 to 147 days after transplant. Premortem diagnosis of LPD was suggested in two because plasmacytoid cells were observed in the blood and bone marrow, and in the cerebrospinal fluid of one of these patients. Serum clonal immunoglobulins (Igs) were also demonstrated in these two patients premortem, while the other two had clonal Igs in serum obtained at autopsy. Autopsies revealed a plasmacytoid infiltrate or immunoblastic lymphoma involving lymph nodes, spleen, liver, lungs, gastrointestinal tract, and kidneys. Immunoglobulin gene rearrangement studies performed in three revealed B-cell clonality. Both immunohistochemical and DNA gene rearrangement studies were useful in differentiating the LPD from the pretransplant leukemia. Epstein-Barr virus (EBV) genome was found in the tissues of the three patients studied. The diagnosis of EBV-induced LPD must be considered in bone marrow transplant patients who deteriorate and who exhibit serum clonal Igs or prominent plasmacytoid cells in laboratory specimens.

  20. Age-related Epstein-Barr Virus-positive lymphoproliferative disorders of the orbit and maxillary sinus : a case report.

    PubMed

    Mitsui, Takeki; Mawatari, Momoko; Koiso, Hiromi; Yokohama, Akihiko; Uchiumi, Hideki; Saitoh, Takayuki; Handa, Hiroshi; Hirato, Junko; Karasawa, Masamitsu; Murakami, Hirokazu; Kojima, Masaru; Nakamura, Shigeo; Nojima, Yoshihisa; Tsukamoto, Norifumi

    2012-01-01

    We report a rare case of age-related Epstein-Barr virus (EBV)-positive B-cell lymphoproliferative disorder (aEBVBLPD) primarily involving the orbit and maxillary sinus. Lesions in the left orbit and maxillary sinus were observed in a 59-year-old man presenting with pain in the left orbit and maxilla. Owing to the presence of Reed-Sternberg-like cells, the initial diagnosis was nodular sclerosis-type Hodgkin's lymphoma. Clinical stage was IIAE, and response to chemotherapy and radiotherapy was favorable. Further immunohistochemical and in situ hybridization analyses of the Reed-Sternberg-like giant cells revealed CD30, CD15, CD20, Bob-1, Oct-2, EBV-encoded RNAs (EBERs) and latent membrane protein-1 (LMP-1) expression. The characteristics of the present case, which included immunohistochemical findings, sites of primary lesions, absence of other lymph node lesions and relatively old age, suggested aEBVBLPD. Owing to the similarity in morphology, higher frequency at extranodal sites and poor prognosis, aEBVBLPD represents a differential diagnostic issue from classical Hodgkin's lymphoma when Reed-Sternberg cells are positive for EBV.

  1. Gene expression profiling reveals clear differences between EBV-positive and EBV-negative posttransplant lymphoproliferative disorders.

    PubMed

    Morscio, J; Dierickx, D; Ferreiro, J F; Herreman, A; Van Loo, P; Bittoun, E; Verhoef, G; Matthys, P; Cools, J; Wlodarska, I; De Wolf-Peeters, C; Sagaert, X; Tousseyn, T

    2013-05-01

    Posttransplant patients are at risk of developing a potentially life-threatening posttransplantation lymphoproliferative disorder (PTLD), most often of diffuse large B cell lymphoma (DLBCL) morphology and associated with Epstein-Barr Virus (EBV) infection. The aim of this study was to characterize the clinicopathological and molecular-genetic characteristics of posttransplant DLBCL and to elucidate whether EBV(+) and EBV(-) posttransplant DLBCL are biologically different. We performed gene expression profiling studies on 48 DLBCL of which 33 arose posttransplantation (PT-DLBCL; 72% EBV+) and 15 in immunocompetent hosts (IC-DLBCL; none EBV+). Unsupervised hierarchical analysis showed clustering of samples related to EBV-status rather than immune status. Except for decreased T cell signaling these cases were inseparable from EBV(-) IC-DLBCL. In contrast, a viral response signature clearly segregated EBV(+) PT-DLBCL from EBV(-) PT-DLBCL and IC-DLBCL cases that were intermixed. The broad EBV latency profile (LMP1+/EBNA2+) was expressed in 59% of EBV(+) PT-DLBCL and associated with a more elaborate inflammatory response compared to intermediate latency (LMP1+/EBNA2-). Inference analysis revealed a role for innate and tolerogenic immune responses (including VSIG4 and IDO1) in EBV(+) PT-DLBCL. In conclusion we can state that the EBV signature is the most determining factor in the pathogenesis of EBV(+) PT-DLBCL.

  2. EBV-associated post-transplant lymphoproliferative disorder after umbilical cord blood transplantation in adults with hematological diseases.

    PubMed

    Sanz, J; Arango, M; Senent, L; Jarque, I; Montesinos, P; Sempere, A; Lorenzo, I; Martín, G; Moscardó, F; Mayordomo, E; Salavert, M; Cañigral, C; Boluda, B; Salazar, C; López-Hontangas, J L; Sanz, M A; Sanz, G F

    2014-03-01

    We analyzed the incidence, clinicopathological features, risk factors and prognosis of patients with EBV-associated post-transplant lymphoproliferative disorder (EBV-PTLD) in 288 adults undergoing umbilical cord blood transplantation (UCBT) at a single institution. Twelve patients developed proven EBV-PTLD at a median time of 73 days (range, 36-812). Three-year cumulative incidence (CI) of EBV-PTLD was 4.3% (95% CI: 1.9-6.7). All patients presented with extranodal involvement. Most frequently affected sites were the liver, spleen, central nervous system (CNS), Waldeyer's ring and BM in 7, 6, 4, 3 and 3 patients, respectively. One patient had polymorphic and 11 had monomorphic EBV-PTLD (7 diffuse large B-cell lymphomas not otherwise specified, 4 plasmablastic lymphomas). We confirmed donor origin and EBV infection in all histological samples. EBV-PTLD was the cause of death in 11 patients at a median time of 23 days (range, 1-84). The 3-year CI of EBV-PTLD was 12.9% (95% CI: 3.2-22.5) and 2.6% (95% CI: 0.5-4.7) for patients receiving reduced-intensity conditioning (RIC) and myeloablative conditioning, respectively (P<0.0001). In conclusion, adults with EBV-PTLD after UCBT showed frequent visceral and CNS involvement. The prognosis was poor despite routine viral monitoring and early intervention. An increased risk of EBV-PTLD was noted among recipients of RIC regimens.

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

    PubMed Central

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

    2016-01-01

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

  4. Complete absence of KSHV/HHV-8 in posttransplant lymphoproliferative disorders: an immunohistochemical and molecular study of 52 cases.

    PubMed

    Chen, Wei; Huang, Qin; Zuppan, Craig W; Rowsell, Edward H; Cao, Jeffrey D; Weiss, Lawrence M; Wang, Jun

    2009-05-01

    Posttransplant lymphoproliferative disorders (PTLDs), a heterogeneous group of monoclonal or polyclonal lesions, occur in immunosuppressed patients after solid organ or bone marrow transplantation. Although most PTLDs are Epstein-Barr virus (EBV)+ and seem to represent EBV-induced proliferations of monoclonal (or less often polyclonal) B, T, or plasma cells, a subset of PTLDs is EBV-. Because Kaposi sarcoma-associated herpesvirus/human herpesvirus 8 (KSHV/HHV-8) has been described in association with the development of hematolymphoid and nonhematolymphoid neoplasms in HIV+ patients, we investigated whether there is an association between KSHV/HHV-8 and PTLDs. Formalin-fixed, paraffin-embedded tissue from 52 confirmed PTLD cases were analyzed immunohistochemically for expression of KSHV/HHV-8 latent nuclear antigen (LNA)-1 protein and by polymerase chain reaction-hybridization analysis for the KSHV/HHV-8 genome. The PTLD subtypes included 12 with early lesions (1 plasmacytic hyperplasia and 11 infectious mononucleosis-like), 10 polymorphic, 23 monomorphic (5 Burkitt, 14 diffuse large B-cell lymphoma, 1 plasmacytoma, 1 multiple myeloma, and 2 T-cell), 1 Hodgkin lymphoma (HL), 5 HL-like lesions, and 1 unclassified or other. None of the 51 tested specimens showed expression of KSHV/HHV-8 LNA-1. Furthermore, all 46 specimens tested demonstrated complete absence of the KSHV/HHV-8 genome. Our data clearly indicated that KSHV/HHV-8 is not associated with PTLDs.

  5. Unusual Indolent Course of a Chronic Active Epstein-Barr Virus-Associated Natural Killer Cell Lymphoproliferative Disorder

    PubMed Central

    Al-Riyami, Arwa Z.; Al-Farsi, Khalil; Al-Khabori, Murtadha; Al-Huneini, Mohammed; Al-Hadabbi, Ibrahim

    2016-01-01

    Natural killer (NK) cell lymphoproliferative disorders are uncommon and the Epstein-Barr virus (EBV) plays an important aetiological role in their pathogenesis. We report a 20-year-old male with a chronic active EBV infection associated with a NK cell lymphoproliferative disorder which had an unusual indolent course. He presented to the Sultan Qaboos University Hospital in Muscat, Oman, in December 2011 with a history of intermittent fever and coughing. Examinations revealed generalised lymphadenopathy, hepatosplenomegaly, leukocytosis, transaminitis, diffuse bilateral lung infiltrates and bone marrow lymphocyte involvement. A polymerase chain reaction (PCR) test revealed a high EBV viral load in the peripheral blood cells. The patient received a course of piperacillin-tazobactam for Klebsiella pneumoniae, but no active treatment for the lymphoproliferative disorder. However, his lymphocyte count, serum lactate dehydrogenase and liver enzymes dropped spontaneously. In addition, EBV PCR copies fluctuated and then decreased significantly. He remained clinically asymptomatic over the following four years. PMID:27226916

  6. Pityriasis lichenoides: a clonal T-cell lymphoproliferative disorder.

    PubMed

    Magro, Cynthia; Crowson, A Neil; Kovatich, Al; Burns, Frank

    2002-08-01

    Pityriasis lichenoides (PL) is a papulosquamous disorder often considered a form of reactive dermatosis and classified with small plaque parapsoriasis (digitate dermatosis). However, some patients with PL have developed large plaque parapsoriasis (LPP) and mycosis fungoides (MF), and lymphoid atypia and T-cell clonality have been reported in lesions of PL. We set out to explore the possibility that PL is a form of T-cell dyscrasia. Cases were selected by natural language search from an outpatient dermatopathology database; 35 cases were reviewed and clinicians and patients were contacted. Hematoxylin and eosin-stained sections were examined and immunophenotyping was carried out on paraffin-embedded, formalin-fixed tissue using antibodies to CD2, CD3, CD4, CD5, CD7, CD8, CD20, CD30, and CD56. In paraffin-embedded tissue, T-cell receptor (TCR)-gamma chain rearrangement was sought through polymerase chain reaction single stranded conformational polymorphism analysis. There were 14 males and 21 females with a mean age of 40 years held clinically to have PL chronica (PLC) (28 cases) and/or PL et varioliformis acuta (PLEVA) (7 cases). Five patients developed large atrophic poikilodermatous and/or annular plaques compatible with MF and/or LPP in a background of typical PLC. All biopsies showed tropism of lymphocytes to an epidermis manifesting psoriasiform hyperplasia, dyskeratosis, parakeratosis, and intraepithelial collections of Langerhans' cells and lymphocytes mimicking Pautrier's microabascesses. Epidermal atrophy, dermal fibroplasia, poikilodermatous alterations, and a dominance of intraepidermal cerebriform cells were seen only in patients with chronic persistent disease (i.e., PLC) and in some cases corresponded with clinical progression to MF. All cases had a T cell-dominant infiltrate, with a CD7 deletion in 21 of 32 biopsies examined; the CD7-negative cells were typically the largest and most atypical forms, often in a cohesive array within the upper layers of

  7. Prevalence of occult hepatitis C virus in egyptian patients with chronic lymphoproliferative disorders.

    PubMed

    Youssef, Samar Samir; Nasr, Aml S; El Zanaty, Taher; El Rawi, Rasha Sayed; Mattar, Mervat M

    2012-01-01

    Background. Occult hepatitis C virus infection (OCI) was identified as a new form of Hepatitis C virus (HCV), characterized by undetectable HCV antibodies and HCV RNA in serum, while HCV RNA is detectable in liver and peripheral blood cells only. Aim. The aim of this study was to investigate the occurrence of OCI in Egyptian patients with lymphoproliferative disorders (LPDs) and to compare its prevalence with that of HCV in those patients. Subjects and Methods. The current study included 100 subjects, 50 of them were newly diagnosed cases having different lymphoproliferative disorders (patients group), and 50 were apparently healthy volunteers (controls group). HCV antibodies were detected by ELISA, HCV RNA was detected in serum and peripheral blood mononuclear cells (PBMCs) by reverse transcription polymerase chain reaction(RT-PCR), and HCV genotype was detected by INNO-LiPA. Results. OCI was detected in 20% of patients group, compared to only 4% OCI in controls group. HCV was detected in 26% of patients group with a slightly higher prevalence. There was a male predominance in both HCV and OCI. All HCV positive patients were genotype 4. Conclusion. Our data revealed occurrence of occult HCV infection in Egyptian LPD patients at a prevalence of 20% compared to 26% of HCV.

  8. Understanding Drug Resistance to Targeted Therapeutics in Malignant B-Cell Lymphoproliferative Disorders (B-LPDs)

    DTIC Science & Technology

    2014-10-01

    Ibrutinib for Frontline CLL Therapy? The Duke Debates in Hematological Malignancies, regional Duke CME activity. The Mills House, Charleston, SC, March 14...Hematological Malignancies: Ibrutinib for Frontline CLL Therapy? The Mills House, Charleston, SC, March 14-16th, 2014. Grand Rounds and Institutional...18451242 8. David A. Rizzieri, Robert Storms, Dong-Feng Chen, Gwynn Long, Daniel A. Nikcevich, Cristina Gasparetto, Mitchell Horwitz, John Chute, Keith

  9. Successful treatment of immunodeficiency-associated EBV-negative lymphoproliferative disorders in rheumatoid arthritis by methotrexate withdrawal and prevention of its relapse by rituximab administration.

    PubMed

    Kawano, Noriaki; Ono, Nobuyuki; Yoshida, Shuro; Kuriyama, Takuro; Yamashita, Kiyoshi; Beppu, Kiichiro; Shimao, Yoshiya; Marutsuka, Kosuke; Ueda, Yuji; Ueda, Akira

    2012-01-01

    Immunodeficiency-associated lymphoproliferative disorders (LPD) in rheumatoid arthritis are a rare, aggressive, and life-threatening clinical entity. We describe a 60-year-old man who had rheumatoid arthritis that was treated with methotrexate. Eight months after the treatment, the case was diagnosed as Epstein-Barr virus-negative LPD (diffuse large B-cell lymphoma) with abdominal bulky mass and clinical stage IVB at high risk in the international prognostic index. Immediate withdrawal of methotrexate led the patient to achieve complete remission, and 8 subsequent courses of rituximab treatment for the prevention of relapse kept the patient disease-free for 29 months. Our case suggests that these treatments may be an effective, safe, and feasible strategy for immunodeficiency-associated LPD in rheumatoid arthritis.

  10. Post-transplant lymphoproliferative disorder presenting with skin ulceration in a renal transplant recipient who achieved sustained remission with rituximab therapy: A case report

    PubMed Central

    Law, Man Fai; Chan, Hay Nun; Lai, Ho Kei; Ha, Chung Yin; Ng, Celia; Yeung, Yiu Ming; Yip, Sze Fai

    2016-01-01

    Post-transplant lymphoproliferative disorder (PTLD) is associated with a variety of clinical presentations, but rarely involves the skin. We herein report a case of PTLD presenting with skin ulceration in a renal transplant recipient. A biopsy of the ulcer confirmed the diagnosis of diffuse large B-cell lymphoma. The patient was initially treated with immunosuppression reduction, but the skin ulcer persisted. He was then treated with two courses of chemotherapy, but his condition was complicated with cryptococcal infection. Antifungal agents were administered to control the fungal infection. The patient later developed lymphoma recurrence and was successfully treated with single-agent rituximab. The patient remains well 6 years after treatment, with no evidence of disease relapse. Therefore, PTLD may manifest as skin lesions and physicians must be aware of this rare presentation. PMID:27900097

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

    PubMed

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

    2013-03-01

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

  12. The autoimmune lymphoproliferative syndrome: A rare disorder providing clues about normal tolerance.

    PubMed

    Turbyville, Joseph C; Rao, V Koneti

    2010-05-01

    The autoimmune lymphoproliferative syndrome (ALPS) is characterized by chronic, non-malignant lymphoproliferation, autoimmunity often manifesting as multilineage cytopenias, and an increased risk of lymphoma. While considered a rare disease, there are currently over 250 patients with ALPS being followed at the National Institutes of Health in Bethesda, Maryland. Most of these patients have a mutation in the gene for the TNF receptor-family member Fas (CD 95, Apo-1), and about one-third have an unknown defect or mutations affecting function of other signaling proteins involved in the apoptotic pathway. While ALPS is one of the few autoimmune diseases with a known genetic defect, there remain unanswered questions regarding how a defect in apoptosis results in the observed phenotype. In addition to shedding light on the pathophysiology of this rare and fascinating condition, studying ALPS may improve our understanding of normal tolerance and more common, sporadic autoimmune disorders.

  13. Surgical Management of Perforated Gastrointestinal Posttransplantation Lymphoproliferative Disorder After Heart Transplantation

    PubMed Central

    Osawa, Hideki; Uemura, Mamoru; Nishimura, Junichi; Hata, Taishi; Takemasa, Ichiro; Mizushima, Tsunekazu; Yamamoto, Hirofumi; Doki, Yuichiro; Mori, Masaki

    2015-01-01

    Posttransplantation lymphoproliferative disorder (PTLD) is a relatively rare and life-threatening complication after organ transplantation. From 1999 to 2012, 45 adult patients underwent heart transplantation at our hospital. Two of the patients developed PTLD after transplantation and required emergency surgery due to intestinal perforation. These cases were informative regarding the adequate surgical management of such cases. Both cases revealed Epstein-Barr virus-related PTLD. The optimal treatment of PTLD remains controversial, and PTLD with gastrointestinal perforation could be critical because the patients are already debilitated and immunocompromised after transplantation. Therefore, the nonspecific abdominal symptoms can be diagnostic for PTLD, and proper surgical intervention should be performed immediately. We present these two suggestive and rare cases in regard to the management of perforation with PTLD and a review of literature. PMID:25692442

  14. Are T-LGL Leukemia and NK-Chronic Lymphoproliferative Disorder Really Two Distinct Diseases?

    PubMed Central

    Zambello, Renato; Teramo, Antonella; Gattazzo, Cristina; Semenzato, Gianpietro

    2014-01-01

    Mature Large Granular lymphocytes (LGL) disorders include a spectrum of conditions, ranging from polyclonal to clonal indolent and/or overt leukemic LGL proliferations. Most cases are represented by clonal expansions of TCRα/β+ LGL displaying a CD8+ phenotype with expression of cytotoxic T-cell antigens (CD57, CD16, TIA-1, perforin and granzyme B). Proliferations of CD3-CD16+ NK cells with a restricted patter of NK receptors are less common, usually comprising 15% of the cases. Main features are cytopenias, splenomegaly and autoimmune phenomena. Morphology, immunophenotyping and molecular analyses are crucial to establish a correct diagnosis of disease. According to the 2008 WHO classification, two separate entities account for the majority of cases, T-LGL leukemia and Chronic Lymphoproliferative Disease of NK cell (this latter still provisional). Although these disorders are characterized by the expansion of different cells types i.e. T and NK cells, with specific genetic features and abnormalities, compelling evidence supports the hypothesis that a common pathogenic mechanism would be involved in both disorders. As a matter of fact, a foreign antigen driven clonal selection is considered the initial step in the mechanism ultimately leading to generation of both conditions. In this chapter we will discuss recent advances on the pathogenesis of chronic T and NK disorders of granular lymphocytes, challenging the current WHO classification on the opportunity to separate T and NK disorders, which are likely to represent two sides of the same coin. PMID:24778993

  15. Treatment of post-transplantation lymphoproliferative disorders after kidney transplant with rituximab and conversion to m-TOR inhibitor.

    PubMed Central

    Nieto-Rios, John Fredy; Gómez de los Ríos, Sandra Milena; Ocampo-Kohn, Catalina; Aristizabal-Alzate, Arbey; Gálvez-Cárdenas, Kenny Mauricio; Zuluaga-Valencia, Gustavo Adolfo

    2016-01-01

    Abstract Background: Post-transplantation lymphoproliferative disorders are serious complications of organ transplantation which treatment is not yet standardized. Objective: To describe the clinical response, overall and graft survival of patients in our center with this complication after kidney transplantation, which received rituximab as part of their treatment as well as conversion to m-TOR. Methods: Retrospective study, which included patients, diagnosed with post-transplant lymphoproliferative disorders after kidney transplantation from January 2011 to July 2014. Results: Eight cases were found with a wide spectrum of clinical presentations. Most had monomorphic histology, 85% were associated with Epstein-Barr virus, 25% of patients had tumor involvement of the renal graft, and 12.5% ​​had primary central nervous system lymphoma. All patients were managed with reduction of immunosuppression, conversion to m-TOR (except one who lost the graft at diagnosis) and rituximab-based therapy. The overall response rate was 87.5% (62.5% complete response, 25% partial response). Survival was 87.5% with a median follow-up of 34 months. An additional patient lost the graft, with chronic nephropathy already known. All the remaining patients had stable renal function. Conclusions: There are no standardized treatment regimens for lymphoproliferative disorders after kidney transplantation, but these patients can be managed successfully with reduction of immunosuppression, conversion to m-TOR and rituximab-based schemes. PMID:28293043

  16. KU HAPLOINSUFFIENCY CAUSES A LYMPHOPROLIFERATIVE DISORDER OF IMMATURE T-CELL PRECURSORS DUE TO IKAROS MALFUNCTION

    PubMed Central

    Ozer, Zahide; Qazi, Sanjive; Ishkhanian, Rita; Hasty, Paul; Ma, Hong; Uckun, Fatih M.

    2013-01-01

    Ikaros (IK) malfunction has been implicated in the pathogenesis of acute lymphoblastic leukemia (ALL), the most common form of childhood cancer. Therefore, a stringent regulation of IK activity is very important. Here we provide unique genetic and biochemical evidence that the Ku protein components Ku70 and Ku80 act as positive regulators of IK function via formation of IK-Ku70 and IK-Ku80 heterodimers with augmented sequence-specific DNA binding activity. siRNA-mediated depletion of Ku70 or Ku80 reduced the sequence-specific DNA binding activity of IK in EMSA as well as the RT-PCR measured IK target gene expression levels in human cells. The interaction of Ku components with IK likely contributes to the anti-leukemic effects of IK as a tumor suppressor, because Ku70 as well as Ku80 haploinsuffiency in mice caused development of a lymphoproliferative disorder (LPD) involving CD2+CD4+CD8+CD1+IL7R+ thymic T-cell precursors with functional IK deficiency. PMID:24478815

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

    PubMed

    Rao, V Koneti

    2015-01-01

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

  18. Serum free light chains and post-transplant lymphoproliferative disorder in patients with renal transplant.

    PubMed

    Fernando, Rodrigo C; Rizzatti, Edgar G; Braga, Walter M T; Santos, Melina G; de Oliveira, Mariana B; Pestana, José O M; Baiocchi, Otavio C G; Colleoni, Gisele W B

    2013-10-01

    The aim of the present study was to determine whether there is an association between serum free light chains (sFLC) quantification and the development of post-transplant lymphoproliferative disorder (PTLD), using serum samples from a nested case-control cohort of patients with renal transplant. Ten new cases of PTLD and 46 controls were enrolled. Additional comparison groups consisted of five human immunodeficiency virus (HIV)-infected individuals, five with untreated Hodgkin lymphoma and six normal individuals. Serum κ and λ FLC concentrations were measured by nephelometry and compared with reference ranges (normal and renal ranges). κ and/or λ were above the normal range in 90% of cases and in 65% of matched controls. There was no statistically significant difference between all groups, except for λ FLC concentrations between cases of PTLD and normal individuals (p = 0.016). The κ/λ sFLC ratios of cases and controls were within the renal range and normal range. Our results suggest that sFLC are not useful to predict PTLD development in renal transplant recipients.

  19. Influence of Posttransplant Lymphoproliferative Disorder on Survival in Children After Heart Transplantation.

    PubMed

    Hayes, Don; Breuer, Christopher K; Horwitz, Edwin M; Yates, Andrew R; Tobias, Joseph D; Shinoka, Toshiharu

    2015-12-01

    The influence of posttransplant lymphoproliferative disorder (PTLD) on long-term survival in children after heart transplantation (HTx) is not well studied. The United Network for Organ Sharing database was queried from 1987 to 2013 for data on PTLD in relation to induction immunosuppression and recipient Epstein-Barr virus status in children (<18 years of age) who underwent HTx. Of 6818 first-time pediatric heart transplants, 5169 had follow-up data on posttransplant malignancy, with 360 being diagnosed with PTLD. Univariate Cox analysis identified diminished survival after PTLD onset using a time-varying measure of PTLD (HR 2.208; 95 % CI 1.812, 2.689; p < 0.001), although Kaplan-Meier survival functions found no difference in survival between the group ever diagnosed with PTLD and the non-PTLD reference group (log-rank test: χ 1 (2)  = 0.02; p = 0.928). A multivariate Cox model found a greater mortality hazard associated with the development of PTLD after adjusting for recipient EBV seronegativity and other covariates (HR 3.024; 95 % CI 1.902, 4.808; p < 0.001). Induction immunosuppression at time of HTx did not significantly influence posttransplant mortality. The development of PTLD adversely influenced long-term survival in children after HTx after adjusting for confounding variables.

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

    PubMed

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

    2015-07-01

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

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

    PubMed Central

    Geng, Lingyun; Wang, Xin

    2015-01-01

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

  2. Post-transplant lymphoproliferative disorder following kidney transplantation: a population-based cohort study.

    PubMed

    Maksten, Eva Futtrup; Vase, Maja Ølholm; Kampmann, Jan; d'Amore, Francesco; Møller, Michael Boe; Strandhave, Charlotte; Bendix, Knud; Bistrup, Claus; Thiesson, Helle Charlotte; Søndergaard, Esben; Hamilton-Dutoit, Stephen; Jespersen, Bente

    2016-04-01

    Post-transplant lymphoproliferative disorder (PTLD) incidence is difficult to determine, mainly because both early and other lesions may go unrecognized and unregistered. Few studies have included systematic pathology review to maximize case identification and decide more accurately PTLD frequency after long-term post-transplantation follow-up. A retrospective population-based cohort study including all kidney transplant recipients at two Danish centres (1990-2011; population covered 3.1 million; 2175 transplantations in 1906 patients). Pathology reports were reviewed for all patient biopsies to identify possible PTLDs. Candidate PTLDs underwent histopathological review and classification. Seventy PTLD cases were identified in 2175 transplantations (3.2%). The incidence rate (IR) after first transplantation was 5.4 cases per 1000 patient-years (95% CI: 4.0-7.3). Most PTLDs were monomorphic (58.5%), or early lesions (21.5%). Excluding early lesions and patients <18 years, IR was 3.7 (95% CI: 2.9-5.5). Ten patients with PTLD were retransplanted, 2 developing further PTLDs. Post-transplant patient survival was inferior in patients with PTLD, while death-censored graft survival was not. Using registry data together with extensive pathological review and long follow-up, a rather high incidence of PTLD was found.

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

    PubMed Central

    Rao, V. Koneti

    2015-01-01

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

  4. Virus and Autoantigen-Specific CD4+ T Cells Are Key Effectors in a SCID Mouse Model of EBV-Associated Post-Transplant Lymphoproliferative Disorders

    PubMed Central

    Linnerbauer, Stefanie; Behrends, Uta; Adhikary, Dinesh; Witter, Klaus; Bornkamm, Georg W.; Mautner, Josef

    2014-01-01

    Polyclonal Epstein-Barr virus (EBV)-infected B cell line (lymphoblastoid cell lines; LCL)-stimulated T-cell preparations have been successfully used to treat EBV-positive post-transplant lymphoproliferative disorders (PTLD) in transplant recipients, but function and specificity of the CD4+ component are still poorly defined. Here, we assessed the tumor-protective potential of different CD4+ T-cell specificities in a PTLD-SCID mouse model. Injection of different virus-specific CD4+ T-cell clones showed that single specificities were capable of prolonging mouse survival and that the degree of tumor protection directly correlated with recognition of target cells in vitro. Surprisingly, some CD4+ T-cell clones promoted tumor development, suggesting that besides antigen recognition, still elusive functional differences exist among virus-specific T cells. Of several EBV-specific CD4+ T-cell clones tested, those directed against virion antigens proved most tumor-protective. However, enriching these specificities in LCL-stimulated preparations conferred no additional survival benefit. Instead, CD4+ T cells specific for unknown, probably self-antigens were identified as principal antitumoral effectors in LCL-stimulated T-cell lines. These results indicate that virion and still unidentified cellular antigens are crucial targets of the CD4+ T-cell response in this preclinical PTLD-model and that enriching the corresponding T-cell specificities in therapeutic preparations may enhance their clinical efficacy. Moreover, the expression in several EBV-negative B-cell lymphoma cell lines implies that these putative autoantigen(s) might also qualify as targets for T-cell-based immunotherapy of virus-negative B cell malignancies. PMID:24853673

  5. Occurrence of Epstein-Barr virus-associated plasmacytic lymphoproliferative disorder after antithymocyte globulin therapy for aplastic anemia: a case report with review of the literature.

    PubMed

    Nakanishi, Ryota; Ishida, Mitsuaki; Hodohara, Keiko; Okuno, Hiroko; Yoshii, Miyuki; Horinouchi, Akiko; Shirakawa, Ayaka; Harada, Ayumi; Iwai, Muneo; Yoshida, Keiko; Kagotani, Akiko; Yoshida, Takashi; Okabe, Hidetoshi

    2014-01-01

    It is well established that patients with immunosuppression have a higher risk of development of lymphoproliferative disorders (LPDs), and Epstein-Barr virus (EBV) is associated with development of LPDs. Aplastic anemia (AA) is an immune-mediated hematological disorder, and immunosuppression therapy (IST), such as antithymocyte globulin (ATG), is widely used for treatment of AA. However, occurrence of LPD without bone marrow transplantation has been extremely rarely documented in patients with IST for AA. Herein, we report the 6th documented case of EBV-associated LPD after IST for AA and review the clinicopathological features of this extremely rare complication. A 46-year-old Japanese female was admitted for evaluation of progressive pancytopenia. Bone marrow biopsy revealed fatty marrow with marked decrease of trilineage cells, and bone marrow aspiration demonstrated no dysplastic changes. IST with rabbit ATG was administered, after which, she developed high fever. Bone marrow aspiration showed increase of atypical plasma cells with mildly enlarged nuclei and irregular nuclear contour. These atypical plasma cells were EBER-positive. Accordingly, a diagnosis of EBV-positive plasmacytic LPD was made. Most cases of LPDs are B-cell origin, and plasmacytic LPD is a rare subtype. The current report is the second case of plasmacytic LPD in patients with IST for AA. Therefore, detailed histopathological and immunohistochemical analyses are needed for correct diagnosis and treatment, and additional studies are needed to clarify the clinicopathological features of EBV-LPD after IST for AA.

  6. Subsequent development of diffuse large B-cell lymphomas and Hodgkin lymphoma associated with primary immune disorder in a 6-year-old female: a case report and review of the literature.

    PubMed

    Bautista-Quach, Marnelli A; Bedros, Antranik; Wang, Jun

    2011-10-01

    Neoplastic lymphoid proliferation may arise from immune deficiency or disordered regulation of the immune system. Often the neoplasms are associated with viral agents, such as Epstein-Barr virus, human immunodeficiency virus, or human herpes virus 8. Lymphoproliferative diseases have been documented in a variety of primary immune disorders. The most commonly encountered neoplastic lesion is diffuse large B-cell lymphoma (DLBCL), although Hodgkin lymphoma (HL), Burkitt lymphoma, and peripheral T-cell lymphomas and/or leukemias have also been documented in rare instances. We report a case of a 6-year-old girl with unclassifiable primary immunodeficiency diagnosed with 2 different clones of DLBCLs and subsequently developed lymphocyte-depleted, classical HL. Both neoplasms were associated with Epstein-Barr virus. To the best of our knowledge, this is the first reported occurrence of primary immune disorder-associated lymphoproliferative disease with sequential development of DLBCLs and HL in a pediatric patient. Thorough surveillance is paramount for accurate assessment of the associated lymphoproliferative disease and in ascertaining likely transformation to, or de novo evolution of a different lymphoid neoplasm. This is also important in evaluating treatment response with appropriate therapeutic adjustments if clinically indicated.

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

    PubMed Central

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

    2014-01-01

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

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

    PubMed

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

    2015-03-01

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

  9. Post-transplant lymphoproliferative disorder after pancreas transplantation: a United Network for Organ Sharing database analysis.

    PubMed

    Jackson, K; Ruppert, K; Shapiro, R

    2013-01-01

    There are not a great deal of data on post-transplant lymphoproliferative disorder (PTLD) following pancreas transplantation. We analyzed the United Network for Organ Sharing national database of pancreas transplants to identify predictors of PTLD development. A univariate Cox model was generated for each potential predictor, and those at least marginally associated (p < 0.15) with PTLD were entered into a multivariable Cox model. PTLD developed in 43 patients (1.0%) of 4205 pancreas transplants. Mean follow-up time was 4.9 ± 2.2 yr. In the multivariable Cox model, recipient EBV seronegativity (HR 5.52, 95% CI: 2.99-10.19, p < 0.001), not having tacrolimus in the immunosuppressive regimen (HR 6.02, 95% CI: 2.74-13.19, p < 0.001), recipient age (HR 0.96, 95% CI: 0.92-0.99, p = 0.02), non-white ethnicity (HR 0.11, 95% CI: 0.02-0.84, p = 0.03), and HLA mismatching (HR 0.80, 95% CI: 0.67-0.97, p = 0.02) were significantly associated with the development of PTLD. Patient survival was significantly decreased in patients with PTLD, with a one-, three-, and five-yr survival of 91%, 76%, and 70%, compared with 97%, 93%, and 88% in patients without PTLD (p < 0.001). PTLD is an uncommon but potentially lethal complication following pancreas transplantation. Patients with the risk factors identified should be monitored closely for the development of PTLD.

  10. Posttransplantation lymphoproliferative disorder after pediatric solid organ transplantation: experiences of 20 years in a single center

    PubMed Central

    Jeong, Hyung Joo; Ahn, Yo Han; Park, Eujin; Choi, Youngrok; Yi, Nam-Joon; Ko, Jae Sung; Min, Sang Il; Ha, Jong Won; Ha, Il-Soo; Cheong, Hae Il

    2017-01-01

    Purpose To evaluate the clinical spectrum of posttransplantation lymphoproliferative disorder (PTLD) after solid organ transplantation (SOT) in children. Methods We retrospectively reviewed the medical records of 18 patients with PTLD who underwent liver (LT) or kidney transplantation (KT) between January 1995 and December 2014 in Seoul National University Children's Hospital. Results Eighteen patients (3.9% of pediatric SOTs; LT:KT, 11:7; male to female, 9:9) were diagnosed as having PTLD over the last 2 decades (4.8% for LT and 2.9% for KT). PTLD usually presented with fever or gastrointestinal symptoms in a median period of 7 months after SOT. Eight cases had malignant lesions, and all the patients except one had evidence of Epstein-Barr virus (EBV) involvement, assessed by using in situ hybridization of tumor tissue or EBV viral load quantitation of blood. Remission was achieved in all patients with reduction of immunosuppression and/or rituximab therapy or chemotherapy, although 1 patient had allograft kidney loss and another died from complications of chemotherapy. The first case of PTLD was encountered after the introduction of tacrolimus for pediatric SOT in 2003. The recent increase in PTLD incidence in KT coincided with modification of clinical practice since 2012 to increase the tacrolimus trough level. Conclusion While the outcome was favorable in that all patients achieved complete remission, some patients still had allograft loss or mortality. To prevent PTLD and improve its outcome, monitoring for EBV infection is essential, which would lead to appropriate modification of immunosuppression and enhanced surveillance for PTLD. PMID:28392824

  11. HLA Associations and Risk of Posttransplant Lymphoproliferative Disorder in a Danish Population-Based Cohort

    PubMed Central

    Vase, Maja Ølholm; Maksten, Eva Futtrup; Strandhave, Charlotte; Søndergaard, Esben; Bendix, Knud; Hamilton-Dutoit, Stephen; Andersen, Claus; Møller, Michael Boe; Sørensen, Søren Schwartz; Kampmann, Jan; Eiskjær, Hans; Iversen, Martin; Weinreich, Ilse Duus; Møller, Bjarne; Jespersen, Bente; d'Amore, Francesco

    2015-01-01

    Background Posttransplant lymphoproliferative disorder (PTLD) is a feared complication to organ transplantation, associated with substantial morbidity and inferior survival. Risk factors for PTLD include T cell–depleting induction therapy and primary infection or reactivation of Epstein-Barr virus. Possible associations between certain HLA types and the risk of developing PTLD have been reported by other investigators; however, results are conflicting. Methods We conducted a retrospective, population-based study on 4295 Danish solid organ transplant patients from the Scandiatransplant database. Having identified 93 PTLD patients in the cohort, we investigated the association of HLA types with PTLD, Epstein-Barr virus status and time to PTLD onset. The outcomes survival and PTLD were evaluated using Cox regression; mismatching, and the PTLD-specific mortality were evaluated in a competing risk analysis. Results Risk of PTLD was associated with male sex (odds ratio, 1.70; 95% confidence interval, 1.07-2.71), and, in women, HLA-DR13 conferred an increased risk (odds ratio, 3.22; 95% confidence interval, 1.41-7.31). In multivariate analysis, HLA-B45 and HLA-DR13 remained independent predictive factors of PTLD. Mismatching in the B locus was associated with a reduced risk of PTLD (P < 0.001). Overall survival was poor after a PTLD diagnosis and was significantly worse than that in the remaining transplant cohort (P < 0.001). Conclusions Our data indicate risk-modifying HLA associations, which can be clinically useful after transplantation in personalized monitoring schemes. Given the strong linkage disequilibrium in the HLA region, the associations must be interpreted carefully. The large size, virtually complete ascertainment of cases and no loss to follow-up remain important strengths of the study. PMID:27500227

  12. Post-transplant lymphoproliferative disorders: implications for acquired immunodeficiency syndrome-associated malignancies.

    PubMed

    Swinnen, L J

    2001-01-01

    Post-transplant lymphoproliferative disorders (PTLDs) comprise a histologic spectrum, ranging from hyperplastic-appearing lesions to frank non-Hodgkin's lymphoma or multiple myeloma histology. Multiple clones may coexist, each representing a discrete lymphomagenic event, a situation that is unique to immunodeficiency states. The incidence varies from 1% in renal recipients to 5% in heart recipients, but can be markedly increased by the use of anti-T-cell therapies or by T-cell depletion in bone marrow transplantation. PTLD continues to arise, even many years after transplantation, and late T-cell lymphomas have recently been recognized. Pretransplant Epstein-Barr virus (EBV) seronegativity increases risk to as high as 30%-50%. PTLD has a highly variable clinical picture; certain patterns are, however, seen. Reversibility of PTLD with reduction in immunosuppressives has long been recognized. Predicting reversibility has been difficult. The presence or absence of bcl-6 mutations has recently been identified as being of predictive value. Surgical resection can be curative. Cytotoxics, although problematic, can also be curative. Long-term remission has been achieved with anti CD21 and CD24 antibodies; efficacy has been reported for interferon alfa and for rituximab. In vitro expanded EBV-specific T cells have been effective as treatment and as prophylaxis in the setting of bone marrow transplantation. EBV viral load measured in blood appears to associate with the emergence of PTLD and may facilitate prophylactic studies. PTLD is a model of immunodeficiency-related EBV lymphomagenesis. Pathogenetic, therapeutic, and prophylactic insights gained from the study of PTLD are likely to be applicable to the acquired immunodeficiency syndrome setting.

  13. Primary cutaneous CD30+ lymphoproliferative disorders: new insights into biology and therapy.

    PubMed

    Querfeld, Christiane; Kuzel, Timothy M; Guitart, Joan; Rosen, Steven T

    2007-05-01

    The spectrum of CD30+ lymphoproliferative diseases of the skin includes CD30+ cutaneous anaplastic large cell lymphoma, lymphomatoidpapulosis, as well as borderline cases. These entities constitute the second most common group of cutaneous lymphomas according to the newly revised World Health Organization and European Organisation for Research and Treatment of Cancer consensus classification. Recent progress in immune and molecular biology, and identification of therapeutic targets have increased our understanding of these diseases and have led to novel treatment approaches. This review will provide an update on recent findings of immunologic, molecular, cytogenetic features and treatment strategies for patients with CD30+ lymphoproliferative diseases.

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

    PubMed

    Krasuska-Sławińska, Ewa; Minko-Chojnowska, Izabela; Pawłowska, Joanna; Dembowska-Bagińska, Bożenna; Pronicki, Maciej; Olczak-Kowalczyk, Dorota

    2015-08-18

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

  15. Role of diffusion weighted imaging in diagnosis of post transplant lymphoproliferative disorders: Case reports and review of literature

    PubMed Central

    Singh, A.; Das, C. J.; Gupta, A. K.; Bagchi, S.

    2016-01-01

    Post transplant lymphoproliferative disorder include a spectrum of conditions occurring in immunosuppressed post transplant recipients, lymphoma being the most ominous. 18F-fludeoxyglucose positron emission tomography with computed tomography CT) is the current imaging gold standard for lymphoma imaging as it allows both morphological and functional assessment. CT and/or conventional magnetic resonance imaging (MRI) are used for morphological evaluation in transplant recipients. Integrating diffusion weighted imaging with apparent diffusion coefficient analysis in MRI protocol enhances its sensitivity and may prove invaluable in response assessment in transplant recipients. PMID:27194838

  16. EBV-positive extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue in the posttransplant setting: a distinct type of posttransplant lymphoproliferative disorder?

    PubMed

    Gibson, Sarah E; Swerdlow, Steven H; Craig, Fiona E; Surti, Urvashi; Cook, James R; Nalesnik, Michael A; Lowe, Chris; Wood, Katrina M; Bacon, Chris M

    2011-06-01

    The 2008 World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues defines monomorphic posttransplant lymphoproliferative disorders (M-PTLDs) as lymphoid or plasmacytic proliferations that fulfill the criteria for one of the B-cell or T/NK-cell neoplasms recognized in immunocompetent patients. However, indolent B-cell lymphomas, such as extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma), are specifically excluded from this category. In this study, we describe the clinicopathologic features of 4 posttransplant lymphoma-like proliferations that were Epstein-Barr virus (EBV) positive, but were otherwise completely typical for a MALT lymphoma. The 4 patients (age, 12 to 71 y) had received solid organ transplants (2 hearts, 1 kidney, 1 kidney/pancreas) at a median of 116 months before presentation, and had been maintained on varying immunosuppressive regimens that included cyclosporine, azathioprine, tacrolimus, and sirolimus. Three of the 4 patients presented with solitary subcutaneous masses, whereas the fourth patient presented with a solitary orbital soft tissue mass. All the 4 cases were morphologically typical for MALT lymphoma, demonstrated plasmacytic differentiation with IgA heavy chain restriction (3 cases κ positive, 1 case λ positive), and were diffusely EBV-encoded small RNA positive. Patients were followed for a median of 44.9 months, and all achieved a complete response following various regimens that included reduced immunosuppression with or without antiviral therapy, local surgical excision, rituximab, or local radiation therapy. The uniform EBV positivity and response to immune reconstitution in some cases suggest that EBV-positive MALT lymphomas arising in the posttransplant setting should be included among PTLDs. Whether their distinctive subcutaneous/soft tissue localization and IgA positivity are uniform features will require identification of additional cases.

  17. Methotrexate-related Epstein-Barr virus-associated lymphoproliferative disorder occurring in the gingiva of a patient with rheumatoid arthritis.

    PubMed

    Ishida, Mitsuaki; Hodohara, Keiko; Yoshii, Miyuki; Okuno, Hiroko; Horinouchi, Akiko; Nakanishi, Ryota; Harada, Ayumi; Iwai, Muneo; Yoshida, Keiko; Kagotani, Akiko; Yoshida, Takashi; Okabe, Hidetoshi

    2013-01-01

    It is well recognized that patients with immunodeficiency have a high risk of development of lymphoproliferative disorders (LPDs), and Epstein-Barr virus (EBV) is associated with the occurrence of LPDs. Methotrexate (MTX) is one of the common cause of iatrogenic-associated LPD, and approximately 40-50% of MTX-related LPD cases occur in extranodal sites. However, the occurrence of MTX-related LPD in the gingiva is extremely rare. Herein, we report the fourth documented case of MTX-related EBV-associated LPD occurring in the gingiva of a patient with rheumatoid arthritis (RA). A 76-year-old Japanese female with a 10-year history of RA, who was treated with MTX and infliximab, presented with a tumorous lesion in the gingiva. Biopsy of the gingiva tumor revealed diffuse proliferation of large-sized lymphoid cells with cleaved nuclei containing conspicuous nucleoli. These lymphoid cells were CD20- and EBER-positive. Therefore, a diagnosis of MTX-related EBV-associated LPD showing features of diffuse large B-cell lymphoma (DLBCL) that occurred in the gingiva was made. Although the occurrence of LPD in the oral region, as seen in the present case, is rare, the prevalence of this disorder may be on the rise due to the increased number of patients undergoing immunosuppression therapy. Moreover, immunosenescence can also be a cause of EBV-associated LPD. Therefore, recognition of the occurrence of this disorder in the oral cavity and consideration of the clinical history can facilitate the correct diagnosis.

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

    PubMed Central

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

    2008-01-01

    Epidermal keratinocytes form a highly organized stratified epithelium and sustain a competent barrier function together with dermal and hematopoietic cells. The Notch signaling pathway is a critical regulator of epidermal integrity. Here, we show that keratinocyte-specific deletion of total Notch signaling triggered a severe systemic B-lymphoproliferative disorder, causing death. RBP-j is the DNA binding partner of Notch, but both RBP-j–dependent and independent Notch signaling were necessary for proper epidermal differentiation and lipid deposition. Loss of both pathways caused a persistent defect in skin differentiation/barrier formation. In response, high levels of thymic stromal lymphopoietin (TSLP) were released into systemic circulation by Notch-deficient keratinocytes that failed to differentiate, starting in utero. Exposure to high TSLP levels during neonatal hematopoiesis resulted in drastic expansion of peripheral pre- and immature B-lymphocytes, causing B-lymphoproliferative disorder associated with major organ infiltration and subsequent death, a previously unappreciated systemic effect of TSLP. These observations demonstrate that local skin perturbations can drive a lethal systemic disease and have important implications for a wide range of humoral and autoimmune diseases with skin manifestations. PMID:18507503

  19. Epstein-Barr virus-associated lymphoproliferative disorder developed following autologous peripheral blood stem cell transplantation for relapsing Hodgkin's lymphoma.

    PubMed

    Izumiya, Sakura; Ishida, Mitsuaki; Hodohara, Keiko; Yoshida, Takashi; Okabe, Hidetoshi

    2012-06-01

    Post-transplant lymphoproliferative disorders (PTLDs) are lymphoid or plasmacytic proliferations that develop as a consequence of immunosuppression in a recipient of a solid organ, bone marrow or stem cell allograft. The development of PTLDs is usually associated with Epstein-Barr virus (EBV) and the disorder is also termed EBV-associated lymphoproliferative disorder (LPD). The development of PTLD is a rare complication in autologous bone marrow/peripheral blood stem cell transplantation. In the present study, we report a case of EBV-associated LPD which developed following autologous peripheral blood stem cell transplantation for relapsing Hodgkin's lymphoma. A 51-year-old male presented with swelling of the left cervical lymph nodes. A biopsy revealed nodular sclerosis classical Hodgkin's lymphoma. Following four courses of ABVd (adriamycin, bleomycin, vinblastine, dacarbazine) therapy, the Hodgkin's lymphoma relapsed. CHASE (cyclophosphamide, etoposide, cytarabine, dexamethasone) therapy and autologous peripheral blood stem cell transplantation were performed. In the 128 days following the transplantation, lymph node swelling was noted and a biopsy specimen demonstrated EBV-associated LPD. The serum copy number of EBV-DNA was 2.7×10(3) copies/ml. The occurrence of EBV-associated LPD may be on the rise due to the increased number of patients undergoing immunosuppression therapy. The measurement of the serum EBV-DNA copy number and the detection of EBV-infected atypical lymphocytes using in situ hybridization are significant in establishing an early accurate diagnosis and initiating the correct treatment for EBV-associated LPD in patients with immunosuppression.

  20. Methotrexate-associated lymphoproliferative disorder arising in the retromolar triangle and lung of a patient with rheumatoid arthritis.

    PubMed

    Kudoh, Masanori; Harada, Hiroyuki; Matsumoto, Koshi; Sato, Yuriko; Omura, Ken; Ishii, Yoshimasa

    2014-10-01

    We report an extremely rare case of massive methotrexate-associated lymphoproliferative disorder (MTX-LPD) arising in the retromolar triangle and lung of a patient with rheumatoid arthritis. The patient was a 75-year-old woman who was referred to our department because of severe pain associated with a unilateral ulcer on the left retromolar triangle. The tumor had an extranodal location in the retromolar triangle and in the right lung. A clinicopathologic examination found a lymphocytic infiltrate with increasingly atypical histopathologic features. Atypical large cells were strongly positive in Epstein-Barr virus-encoded small RNA in situ hybridization and in staining with CD20 antibodies. MTX-LPD was diagnosed based on the medical history and histopathologic results. The lesion responded well to withdrawal of MTX followed by R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) chemotherapy. There have been no signs of recurrence for 4 years since withdrawal of MTX.

  1. A Literature Revision in Primary Cutaneous B-cell Lymphoma

    PubMed Central

    Selva, R La; Violetti, S Alberti; Delfino, C; Grandi, V; Cicchelli, S; Tomasini, C; Fierro, M T; Berti, E; Pimpinelli, N; Quaglino, P

    2017-01-01

    The term “Primary Cutaneous B-Cell Lymphoma” (PCBCL) comprehends a variety of lymphoproliferative disorders characterized by a clonal proliferation of B-cells primarily involving the skin. The absence of evident extra-cutaneous disease must be confirmed after six-month follow-up in order to exclude a nodal non-Hodgkin's lymphoma (NHL) with secondary cutaneous involvement, which may have a completely different clinical behavior and prognosis. In this article, we have summarized the clinico-pathological features of main types of PCBCL and we outline the guidelines for management based on a review of the available literature.

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

    PubMed

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

    2016-02-01

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

  3. T-gamma-lymphoproliferative disorder arising in a background of autoimmune disease and terminating in plasma cell dyscrasia with primary amyloidosis.

    PubMed

    Amparo, E; Kaplan, L; Rosenbloom, B; Lee, S

    1991-01-01

    T-gamma-lymphoproliferative disorder, a syndrome of T-cell lymphocytosis with neutropenia has been described in patients with various autoimmune disorders, especially rheumatoid arthritis. We report a case of T-gamma-lymphoproliferative disorder occurring in a 42-year-old white woman with a long history of dermatitis herpetiformis and subsequent development of Coomb's positive autoimmune hemolytic anemia and polymyositis. The peripheral blood lymphocytes showed the T-suppressor cell phenotype (CD2-, CD3-, CD8-, and CD4-). DNA analysis of the peripheral blood lymphocytes revealed a T-cell receptor beta-chain gene rearrangement and an immunoglobulin heavy-chain gene rearrangement. The patient's course was marked by numerous bouts of infection. The unique factor in this patient was the development of a plasma cell dyscrasia and amyloidosis prior to death.

  4. An unusual manifestation of post-transplant lymphoproliferative disorder in the lip after pediatric heart transplantation.

    PubMed

    Chen, C; Akanay-Diesel, S; Schuster, F R; Klee, D; Schmidt, K G; Donner, B C

    2012-11-01

    PTLD is a serious and frequently observed complication after solid organ transplantation. We present a six-yr-old girl with a rapidly growing, solid tumor of the lip four yr after orthotopic heart transplantation, which was classified as monomorphic PTLD with the characteristics of a diffuse large B-cell lymphoma. Treatment with reduction in immunosuppression, ganciclovir, and anti B-cell monoclonal antibody (rituximab) resulted in full remission since 12 months. To the best of our knowledge, this report is the first description of PTLD in the lip in a pediatric patient after heart transplantation in the English literature.

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

    ClinicalTrials.gov

    2016-07-29

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

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

    PubMed Central

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

    2015-01-01

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

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

    PubMed

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

    2015-03-27

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

  8. Cytogenetics in the management of lymphomas and lymphoproliferative disorders in adults and children: an update by the Groupe francophone de cytogénétique hématologique (GFCH).

    PubMed

    Lefebvre, Christine; Callet-Bauchu, Evelyne; Chapiro, Elise; Nadal, Nathalie; Penther, Dominique; Poirel, Hélène-Antoine

    2016-10-01

    Non-Hodgkin's lymphomas and lymphoproliferative disorders include a high number of heterogeneous entities, described in the 2008 WHO classification. This classification reflects the crucial role of a multidisciplinary approach which integrates cytogenetic results both for the notion of clonality and for differential diagnosis between these entities. The prognostic impact of some cytogenetic abnormalities or genome complexity is also confirmed for many of these entities. Novel provisional entities have been described, such as BCLU (B-cell lymphoma unclassifiable with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma) for which karyotype is critical to distinguish BCLU from Burkitt's lymphoma. The karyotype can be established from any tumour or liquid infiltrated by lymphoma cells. Recent adaptations of technics for cellular cultures according to the subtype of known (or suspected) lymphoma have significantly improved the percentage of informative karyotypes. Conventional karyotypes remain the best technical approach recommended for most of these subtypes. Interphase and/or metaphase FISH also represents a solid and rapid approach, because of the significant number of recurrent (sometimes specific) rearrangements of these entities. Next generation sequencing technologies contribute to enrich genomic data and substantially improve the understanding of oncogenic mechanisms underlying these lymphoid malignancies. Some molecular biomarkers are already part of the diagnostic process (for example, somatic mutation of MYD88 in Waldenström disease) thus reinforcing the essential principle of a multidisciplinary approach for the diagnosis of all the mature lymphoid malignancies.

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

    PubMed

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

    2014-09-01

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

  10. Emerging therapeutic strategies for Epstein-Barr virus+ post-transplant lymphoproliferative disorder.

    PubMed

    Hatton, Olivia; Martinez, Olivia M; Esquivel, Carlos O

    2012-05-01

    De novo malignancies represent an increasing concern in the transplant population, particularly as long-term graft and patient survival improves. EBV-associated B-cell lymphoma in the setting of PTLD is the leading malignancy in children following solid organ transplantation. Therapeutic strategies can be categorized as pharmacologic, biologic, and cell-based but the variable efficacy of these approaches and the complexity of PTLD suggest that new treatment options are warranted. Here, we review current therapeutic strategies for treatment of PTLD. We also describe the life cycle of EBV, addressing the viral mechanisms that contribute to the genesis and persistence of EBV+ B-cell lymphomas. Specifically, we focus on the oncogenic signaling pathways activated by the EBV LMP1 and LMP2a to understand the underlying mechanisms and mediators of lymphomagenesis with the goal of identifying novel, rational therapeutic targets for the treatment of EBV-associated malignancies.

  11. Posttransplantation lymphoproliferative disease involving the pituitary gland.

    PubMed

    Meriden, Zina; Bullock, Grant C; Bagg, Adam; Bonatti, Hugo; Cousar, John B; Lopes, M Beatriz; Robbins, Mark K; Cathro, Helen P

    2010-11-01

    Posttransplantation lymphoproliferative disorders (PTLD) are heterogeneous lesions with variable morphology, immunophenotype, and molecular characteristics. Multiple distinct primary lesions can occur in PTLD, rarely with both B-cell and T-cell characteristics. Lesions can involve both grafted organs and other sites; however, PTLD involving the pituitary gland has not been previously reported. We describe a patient who developed Epstein-Barr virus-negative PTLD 13 years posttransplantation involving the terminal ileum and pituitary, which was simultaneously involved by a pituitary adenoma. Immunohistochemistry of the pituitary lesion showed expression of CD79a, CD3, and CD7 with clonal rearrangements of both T-cell receptor gamma chain (TRG@) and immunoglobulin heavy chain (IGH@) genes. The terminal ileal lesion was immunophenotypically and molecularly distinct. This is the first report of pituitary PTLD and illustrates the potentially complex nature of PTLD.

  12. Posttransplant lymphoproliferative disease in liver transplant patients.

    PubMed

    Hartmann, Christina; Schuchmann, Marcus; Zimmermann, Tim

    2011-02-01

    Posttransplant lymphoproliferative disorders (PTLD) are a life-threatening complication following solid organ transplantation. Many posttransplant lymphomas develop from the uncontrolled proliferation of Epstein-Barr virus (EBV)-infected B-cells, whereas EBV-negative PTLDs were increasingly recognized within the past decade. Major risk factors for the development of PTLDs after liver transplantation are immunosuppressive therapy and the type of underlying disease: viral hepatitis, autoimmune liver disease, or alcoholic liver cirrhosis contribute to an increased risk for PTLD. Therapeutic regimens include reduction of immunosuppression, the anti-CD20 antibody rituximab, and chemotherapy, as well as new approaches using interferon-α and anti-interleukin-6 antibodies. Despite the different therapeutic regimens, mortality from PTLD remains high. Therefore, it is of major importance to identify patients at risk at an early stage of the disease. In this review, risk factors for PTLD development after liver transplantation, clinical presentation, diagnosis, and therapy are discussed.

  13. Fc Receptor-Like Proteins in Pathophysiology of B-cell Disorder

    PubMed Central

    Capone, Mollie; Bryant, John Matthew; Sutkowski, Natalie; Haque, Azizul

    2016-01-01

    Members of the family of Fc receptor-like (FcRL) proteins, homologous to FcγRI, have been identified by multiple research groups. Consequently, they have been described using multiple nomenclatures including Fc receptor homologs (FcRH), immunoglobulin superfamily receptor translocation-associated genes (IRTA), immunoglobulin-Fc-gp42-related genes (IFGP), Src homology 2 domain-containing phosphatase anchor proteins (SPAP), and B cell cross-linked by anti-immunoglobulin M-activating sequences (BXMAS). They are now referred to under a unified nomenclature as FCRL. Eight different human FCRL genes have been identified, all of which appear to be related to the genes of the immunoglobulin superfamily (IgSF) of cellular adhesion molecules. These type 1 transmembrane glycoproteins are composed of different combinations of 5 types of immunoglobulin-like domains, with each protein consisting of 3 to 9 domains, and no individual domain type conserved throughout all of the FCRL proteins. Ligands for the majority of the FCRLs remain unknown. In general, FCRL expression is restricted to lymphocytes and is primarily expressed in B-lymphocytes, supporting FCRL’s involvement in a variety of immune disorders. Most FCRLs functionally repress B-cell activation; however, they might have dual roles in lymphocyte functions as these proteins often possess immunoreceptor tyrosine activation (ITAM) and inhibitory (ITIM) motif elements. The biological functions of these newly recognized FCRL proteins are just beginning to emerge, and might provide the insight necessary for understanding pathophysiology of lymphocyte disorders and treating different immune diseases. PMID:27446638

  14. Effect of anti-CD 20 antibody rituximab in patients with post-transplant lymphoproliferative disorder (PTLD).

    PubMed

    Oertel, S H K; Verschuuren, E; Reinke, P; Zeidler, K; Papp-Váry, M; Babel, N; Trappe, R U; Jonas, S; Hummel, M; Anagnostopoulos, I; Dörken, B; Riess, H B

    2005-12-01

    Post-transplant lymphoproliferative disorders (PTLD) are a life-threatening complication following solid organ transplantation. Treatment with rituximab, a humanized anti-CD20 monoclonal antibody, has proved to be a promising approach and shown a low toxicity profile. Between February 1999 and April 2002, we conducted a multicentre phase II trial investigating rituximab as single agent in 17 patients with PTLD. Transplanted organs were heart (n = 5), kidney (n = 4), lung (n = 4) and liver (n = 4). Patients were treated with four weekly doses of 375 mg/m(2) of rituximab. The mean follow-up time is 24.2 months. Histology was distributed in 10 diffuse large cell-, 2 marginal zone-, 1 Burkitt-like lymphoma, 1 Hodgkin-like PTLD and 3 polymorphic lymphoproliferations. Therapy was well tolerated and no severe adverse events were observed. The mean overall survival period is 37.0 months with 11 patients still living. In total, 9 patients (52.9%) achieved a complete remission, with a mean duration of 17.8 months. Partial remission was observed in 1 patient, minor remission in 2 patients, no change in 3 patients and 1 patient experienced progressive disease. Two patients relapsed, at intervals 3 and 5 months after obtaining complete remission. Rituximab proved to be well tolerated and effective in the treatment of PTLD.

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

    PubMed Central

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

    2015-01-01

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

  16. Comprehensive polymerase chain reaction assay for detection of pathogenic DNA in lymphoproliferative disorders of the ocular adnexa

    PubMed Central

    Usui, Yoshihiko; Rao, Narsing A.; Takase, Hiroshi; Tsubota, Kinya; Umazume, Kazuhiko; Diaz-Aguilar, Daniel; Kezuka, Takeshi; Mochizuki, Manabu; Goto, Hiroshi; Sugita, Sunao

    2016-01-01

    Infectious agents have been identified as a major cause of specific types of human cancers worldwide. Several microorganisms have been identified as potential aggravators of ocular adnexal neoplasms; however, given the rarity of these neoplasms, large epidemiological studies are difficult to coordinate. This study aimed to conduct an exhaustive search for pathogenic DNA in lymphoproliferative disorders (LPD) of the ocular adnexa in a total of 70 patients who were diagnosed with LPD of the ocular adnexa between 2008 and 2013. Specimens were screened for bacterial, viral, fungal, and parasitic DNA by multiplex polymerase chain reaction (PCR) and quantitative real-time PCR. Among cases of conjunctival mucosa-associated lymphoid tissue lymphoma, human herpes virus (HHV)-6, HHV-7, chlamydia, Epstein-Barr virus (EBV) and bacterial 16S ribosomal DNA were detected. In cases of IgG4-related ocular disease, similar pathogens were detected but in a larger number of patients. Our PCR assays detected DNAs of various infectious agents in tumor specimens, especially HHV6, HHV7, and EBV, with different positive rates in various types of LPD. Chronic inflammatory stimulation or activation of oncogenes from these infectious agents might be involved in the pathogenesis of LPD of the ocular adnexa. PMID:27830722

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

    PubMed

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

    2015-12-15

    Currently, the lack of a universal and specific marker of clonality hampers the diagnosis and classification of chronic expansions of natural killer (NK) cells. Here we investigated the utility of flow cytometric detection of aberrant/altered NK-cell phenotypes as a surrogate marker for clonality, in the diagnostic work-up of chronic lymphoproliferative disorders of NK cells (CLPD-NK). For this purpose, a large panel of markers was evaluated by multiparametric flow cytometry on peripheral blood (PB) CD56(low) NK cells from 60 patients, including 23 subjects with predefined clonal (n = 9) and polyclonal (n = 14) CD56(low) NK-cell expansions, and 37 with CLPD-NK of undetermined clonality; also, PB samples from 10 healthy adults were included. Clonality was established using the human androgen receptor (HUMARA) assay. Clonal NK cells were found to show decreased expression of CD7, CD11b and CD38, and higher CD2, CD94 and HLADR levels vs. normal NK cells, together with a restricted repertoire of expression of the CD158a, CD158b and CD161 killer-associated receptors. In turn, NK cells from both clonal and polyclonal CLPD-NK showed similar/overlapping phenotypic profiles, except for high and more homogeneous expression of CD94 and HLADR, which was restricted to clonal CLPD-NK. We conclude that the CD94(hi)/HLADR+ phenotypic profile proved to be a useful surrogate marker for NK-cell clonality.

  18. Post-transplant lymphoproliferative disorder after liver transplantation: Incidence, long-term survival and impact of serum tacrolimus level

    PubMed Central

    Eshraghian, Ahad; Imanieh, Mohammad Hadi; Dehghani, Seyed Mohsen; Nikeghbalian, Saman; Shamsaeefar, Alireza; Barshans, Frouzan; Kazemi, Kourosh; Geramizadeh, Bita; Malek-Hosseini, Seyed Ali

    2017-01-01

    AIM To investigate incidence and survival of post-transplant lymphoproliferative disorder (PTLD) patients after liver transplantation. METHODS A cross-sectional survey was conducted among patients who underwent liver transplantation at Shiraz Transplant Center (Shiraz, Iran) between August 2004 and March 2015. Clinical and laboratory data of patients were collected using a data gathering form. RESULTS There were 40 cases of PTLD in the pediatric age group and 13 cases in the adult group. The incidence of PTLD was 6.25% in pediatric patients and 1.18% in adult liver transplant recipients. The post-PTLD survival of patients at 6 mo was 75.1% ± 6%, at 1 year was 68.9% ± 6.5% and at 5 years was 39.2% ± 14.2%. Higher serum tacrolimus level was associated with lower post-PTLD survival in pediatric patients (OR = 1.07, 95%CI: 1.006-1.15, P = 0.032). A serum tacrolimus level over 11.1 ng/mL was predictive of post PTLD survival (sensitivity = 90%, specificity = 52%, area under the curve = 0.738, P = 0.035). CONCLUSION Incidence of PTLD in our liver transplant patients is comparable to other centers. Transplant physicians may consider adjustment of tacrolimus dose to maintain its serum level below this cutoff point. PMID:28275302

  19. Partial Least Squares Based Gene Expression Analysis in EBV- Positive and EBV-Negative Posttransplant Lymphoproliferative Disorders.

    PubMed

    Wu, Sa; Zhang, Xin; Li, Zhi-Ming; Shi, Yan-Xia; Huang, Jia-Jia; Xia, Yi; Yang, Hang; Jiang, Wen-Qi

    2013-01-01

    Post-transplant lymphoproliferative disorder (PTLD) is a common complication of therapeutic immunosuppression after organ transplantation. Gene expression profile facilitates the identification of biological difference between Epstein-Barr virus (EBV) positive and negative PTLDs. Previous studies mainly implemented variance/regression analysis without considering unaccounted array specific factors. The aim of this study is to investigate the gene expression difference between EBV positive and negative PTLDs through partial least squares (PLS) based analysis. With a microarray data set from the Gene Expression Omnibus database, we performed PLS based analysis. We acquired 1188 differentially expressed genes. Pathway and Gene Ontology enrichment analysis identified significantly over-representation of dysregulated genes in immune response and cancer related biological processes. Network analysis identified three hub genes with degrees higher than 15, including CREBBP, ATXN1, and PML. Proteins encoded by CREBBP and PML have been reported to be interact with EBV before. Our findings shed light on expression distinction of EBV positive and negative PTLDs with the hope to offer theoretical support for future therapeutic study.

  20. Post-transplant lymphoproliferative disorders: determination of donor/recipient origin in a large cohort of kidney recipients.

    PubMed

    Olagne, J; Caillard, S; Gaub, M P; Chenard, M P; Moulin, B

    2011-06-01

    Although in previous studies most post-transplant lymphoproliferative disorders (PTLD) were reported to derive from recipient cells, some cases derived from donor lymphocytes have been reported. To provide a better description of the features and outcome of PTLD according to the origin of the lymphoma, we performed histologic and molecular studies of PTLD in kidney recipients. Forty-three specimens were analyzed by histochemistry, fluorescent hybridization of the Y chromosome and analysis of multiple short tandem repeat microsatellite loci. Sixteen tumors were shown to be of donor origin and 27 of recipient origin. Time to PTLD was shorter in donor-derived PTLDs (20 ± 27 vs. 69 ± 67 months, p = 0.013). Ten-year patient survival was similar among patients with recipient- and donor-derived PTLD, but when PTLD-related mortality was analyzed, there was a trend to better survival in patients with donor lymphomas. Among the 21 PTLDs localized in the allograft, 14 lymphomas were of donor origin and seven of recipient origin. No difference was found between the two groups. Our analysis of the origin of PTLDs in the largest cohort studied to date with a description of the clinical and histological characteristics of donor and recipient PTLDs should lead to a better understanding of lymphomagenesis.

  1. Clinical and pathological prognostic markers for survival in adult patients with post-transplant lymphoproliferative disorders in solid transplant.

    PubMed

    Oton, Ana B; Wang, Hong; Leleu, Xavier; Melhem, Mona F; George, Diane; Lacasce, Ann; Foon, Kenneth; Ghobrial, Irene M

    2008-09-01

    We sought to determine the clinical and immunohistopathological prognostic factors for overall survival (OS) in adult patients with post-transplant lymphoproliferative disorders (PTLDs). Eighty-four patients diagnosed with PTLDs between 1980 and 2004 at the University of Pittsburgh Medical Center were identified. Immunohistochemical staining was performed on tumor tissue at the time of diagnosis for the following proteins: Bcl-2, Bcl-6, c-myc and p53. The median survival for all patients was 20.8 months, 95% CI: (7.4-77.6). On univariate analysis for OS, the following poor prognostic factors were identified: age at transplant >60 years (p = 0.024), multiorgan transplant (p = 0.019), ECOG > 2 (p < 0.0001), grafted organ involvement (p < 0.0001), extranodal disease (p = 0.011), early (<1 year) PTLDs (p < 0.0001), stage IV (p = 0.0017), EBV positive (p = 0.012) and elevated white blood count (p = 0.010). Good prognostic factors included ECOG<2 (p < 0.0001), late (>1 year) PTLDs (p = 0.002), early stage at diagnosis (stages I and II, p = 0.005), nodal disease (p = 0.0053), monomorphic disease (0.0034), initial immunosuppression reduction (p = 0.0015) and use of rituximab (p = 0.045). Bcl-2 but not Bcl-6, c-myc, or p53 correlated with poor survival, p = 0.0036. This study identifies new clinical and pathological markers for poor survival in PTLDs.

  2. Post-transplant lymphoproliferative disorders: clinicopathological analysis of 43 cases in a single center, 1990-2009.

    PubMed

    Yoon, Sun Och; Yu, Eunsil; Cho, Yong Mee; Suh, Cheolwon; Kim, Kyung Mo; Han, Duck Jong; Lee, Seung Gyu; Huh, Jooryung

    2012-01-01

    Post-transplant lymphoproliferative disorders (PTLDs) are a heterogeneous set of complications of organ transplantation associated with poor patient prognosis. We analyzed the clinicopathological features of PTLDs in 43 adult and pediatric recipients of solid organ or bone marrow transplantation at a large transplant service in the Republic of Korea between 1990 and 2009. Of 4545 solid organ and 747 bone marrow transplant recipients, 37 (0.81%) and 6 (0.8%), respectively, developed heterogeneous types of PTLDs. The cumulative incidences of PTLDs during this period were 1.79% (4/223) for heart transplant recipients, 0.78% (17/2192) for kidney transplant recipients, and 0.77% (16/2067) for liver transplant recipients. The patterns of disease onset, histology, and patient survival were associated with the types of organs transplanted. There is a trend for shorter overall survival (OS) in recipients with early-onset PTLDs and monomorphic PTLD histology, while kidney transplant recipients showed favorable OS. This study may be the first comprehensive analysis of the characteristics of PTLDs in Korean patients.

  3. Localization of post-transplant lymphoproliferative disorders to the stomach might be associated with favorable outcome: a systematic review.

    PubMed

    Khedmat, Hossein; Ghamar-Chehreh, Mohammad Ebrahim; Amini, Mohsen; Agah, Shahram; Taheri, Saeed

    2014-03-01

    Gastric localization of post-transplant lymphoproliferative disorders (PTLDs) is very rare. In this study, we aimed to accumulate existing data in the current literature to reveal the clinical, histopathological and prognostic specificities associated with gastric PTLDs and to find the best treatment strategies in this patient population. A comprehensive search was conducted for the available data in the current literature using Pubmed and Google scholar search engines for reports on gastric PTLD in renal transplant recipients. Data of different studies were standardized and entered into a database and analyzed. No statistically significant difference was found between gastric and non-gastric PTLD. Gastric PTLD was relatively more prevalent in female patients (P = 0.08) and showed a trend toward better outcome (P = 0.1) and less metastasis (P = 0.07). Surgical intervention and rituximab therapy were associated with a more favorable outcome (17% mortality). Our study showed that organ transplant recipients having gastric PTLD develop metastasis less frequently and tend to have a relatively more favorable outcome. Prospective studies with larger patient populations are needed to confirm or modify our results.

  4. Posttransplant lymphoproliferative disorders in lung transplant patients: the Cleveland Clinic experience.

    PubMed

    Ramalingam, P; Rybicki, L; Smith, M D; Abrahams, N A; Tubbs, R R; Pettay, J; Farver, C F; Hsi, E D

    2002-06-01

    PTLD is a well-recognized complication of organ transplantation. Large series of heart, renal, and liver transplants have been examined for the incidence and behavior of PTLD. However, reports of the incidence and characteristics of PTLDs in lung transplant (LTx) patients are few. We report our experience with PTLDs in a large series of LTx recipients at a single institution and compare them to other solid organ transplant recipient PTLDs seen at our institution. Twenty-eight patients were found to have PTLD, of whom 8 were lung transplant recipients. We evaluated nine PTLD specimens from these 8 patients for their histology, immunophenotype (CD20, CD3, EBV-LMP1), EBER status by in situ hybridization, and clinical features. The incidence of PTLD was 3.3% (8/244 patients). The time to development of PTLD, after transplant, was short (median time, 7 mo). All were of B-cell lineage. Overall, EBV was demonstrated in 77.7% (7 of 9 specimens) of PTLDs. All specimens tested for clonality were found to be monoclonal. Five patients died, with a median time to death of only 4.6 months. PTLDs in LTx patients are EBV-associated B-cell, predominantly monoclonal lymphoid lesions similar to other solid organ transplant PTLDs. Compared with other solid organ transplant recipients with PTLD at our institution, PTLDs in LTx patients have a propensity to involve the transplanted organ (P =.001, Fisher's exact test), occur earlier after transplant (P =.003, Wilcoxon test), and have a shorter survival (P =.002, log rank test). Reasons for this may include the relatively higher level of immunosuppression required in these patients and limited options in decreasing it. Although the incidence is low, careful early monitoring of lung transplantation patients is warranted because of the poor prognosis of patients developing this complication.

  5. Epstein-Barr virus-associated posttransplantation lymphoproliferative disorder after high-dose immunosuppressive therapy and autologous CD34-selected hematopoietic stem cell transplantation for severe autoimmune diseases.

    PubMed

    Nash, Richard A; Dansey, Roger; Storek, Jan; Georges, George E; Bowen, James D; Holmberg, Leona A; Kraft, George H; Mayes, Maureen D; McDonagh, Kevin T; Chen, Chien-Shing; Dipersio, John; Lemaistre, C Fred; Pavletic, Steven; Sullivan, Keith M; Sunderhaus, Julie; Furst, Daniel E; McSweeney, Peter A

    2003-09-01

    High-dose immunosuppressive therapy followed by autologous hematopoietic stem cell transplantation (HSCT) is currently being evaluated for the control of severe autoimmune diseases. The addition of antithymocyte globulin (ATG) to high-dose chemoradiotherapy in the high-dose immunosuppressive therapy regimen and CD34 selection of the autologous graft may induce a higher degree of immunosuppression compared with conventional autologous HSCT for malignant diseases. Patients may be at higher risk of transplant-related complications secondary to the immunosuppressed state, including Epstein-Barr virus (EBV)-associated posttransplantation lymphoproliferative disorder (PTLD), but this is an unusual complication after autologous HSCT. Fifty-six patients (median age, 42 years; range, 23-61 years) with either multiple sclerosis (n = 26) or systemic sclerosis (n = 30) have been treated. The median follow-up has been 24 months (range, 2-60 months). Two patients (multiple sclerosis, n = 1; systemic sclerosis, n = 1) had significant reactivations of herpesvirus infections early after HSCT and then developed aggressive EBV-PTLD and died on days +53 and +64. Multiorgan clonal B-cell infiltrates that were EBV positive by molecular studies or immunohistology were identified at both autopsies. Both patients had positive screening skin tests for equine ATG (Atgam) and had been converted to rabbit ATG (Thymoglobulin) from the first dose. Of the other 54 patients, 2 of whom had partial courses of rabbit ATG because of a reaction to the intravenous infusion of equine ATG, only 1 patient had a significant clinical reactivation of a herpesvirus infection (herpes simplex virus 2) early after HSCT, and none developed EBV-PTLD. The T-cell count in the peripheral blood on day 28 was 0/microL in all 4 patients who received rabbit ATG; this was significantly less than in patients who received equine ATG (median, 174/microL; P =.001; Mann-Whitney ranked sum test). Although the numbers are limited

  6. Epstein–Barr Virus-Positive T/NK-Cell Lymphoproliferative Disorders Manifested as Gastrointestinal Perforations and Skin Lesions

    PubMed Central

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

    2016-01-01

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

  7. Three Rwandan Children With Massive Splenomegaly and Epstein-Barr Virus-associated Lymphoproliferative Disorders: Case Presentations and the Literature Review.

    PubMed

    Friedman-Klabanoff, DeAnna; Ball, Allison; Rutare, Samuel; McCall, Natalie; Blackall, Douglas P

    2016-07-01

    This report describes 3 Rwandan children with massive splenomegaly and pancytopenia who underwent splenectomy. Each was diagnosed with Epstein-Barr virus-associated lymphoproliferative disorder (EBV LPD) based on lymphocyte morphology, lymphocyte immunophenotype, and the results of EBV in situ hybridization studies. The differential diagnosis of splenomegaly, with a special emphasis on the sub-Saharan African context, is discussed along with EBV and associated disorders. These cases serve as a call to consider EBV LPD in the differential diagnosis of splenomegaly in children in whom common causes have been ruled out.

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

    PubMed Central

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

    2014-01-01

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

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

    PubMed

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

    2014-01-01

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

  10. The radiological spectrum of pulmonary lymphoproliferative disease

    PubMed Central

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

    2012-01-01

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

  11. No evidence of HTLV-I proviral integration in lymphoproliferative disorders associated with cutaneous T-cell lymphoma.

    PubMed

    Wood, G S; Schaffer, J M; Boni, R; Dummer, R; Burg, G; Takeshita, M; Kikuchi, M

    1997-02-01

    Several recent studies have reported detection of HTLV-I genetic sequences in patients with cutaneous T-cell lymphoma (CTCL) including mycosis fungoides and Sezary syndrome. The purpose of this study was to determine whether HTLV-I was detectable in lesional tissues of patients suffering from diseases known to be associated with CTCL. Thirty-five cases were obtained from diverse geographical locations including Ohio, California, Switzerland, and Japan. Six of them had concurrent CTCL. Cases were analyzed using a combination of genomic polymerase chain reaction (PCR)/ Southern blot, dot blot, and Southern blot analyses. All assays were specific for HTLV-I provirus. Sensitivity ranged from approximately 10(-6) for PCR-based studies to 10(-2) for unamplified genomic blotting. Lesional DNA from patients with lymphomatoid papulosis (fourteen cases), Hodgkin's disease (twelve cases), and CD30+ large-cell lymphoma (nine cases) was tested for the HTLV-I proviral pX region using a genomic PCR assay followed by confirmatory Southern blot analysis with a nested oligonucleotide pX probe. All cases were uniformly negative. All of the Hodgkin's disease cases, eight of the large-cell lymphoma cases, and six of the lymphomatoid papulosis cases were then subjected to dot blot analysis of genomic DNA using a full-length HTLV-I proviral DNA probe that spans all regions of the HTLV-I genome. Again, all cases were negative. Finally, eleven of the Hodgkin's disease cases were also subjected to Southern blot analysis of EcoRI-digested genomic DNA using the same full-length HTLV-I probe. Once again, all cases were negative. These findings indicated that, despite utilization of a variety of sensitive and specific molecular biological methods, HTLV-I genetic sequences were not detectable in patients with CTCL-associated lymphoproliferative disorders. These results strongly suggest that the HTLV-I retrovirus is not involved in the pathogenesis of these diseases.

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

    PubMed Central

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

    2015-01-01

    Abstract To investigate the chest computed tomography (CT) and F-18 fluoro-2-deoxy-d-glucose positron emission tomographic (FDG-PET) findings of posttransplant lymphoproliferative disorder (PTLD) in the thorax. From November 2004 to February 2013, the cases of 12 adult patients (3 female and 9 male, age range 34–68, and median age 46 years) with proven PTLD were retrospectively reviewed. The transplanted organs included the kidney (5/12), liver (4/12), heart (1/12), combined kidney and pancreas (1/12), and hematopoietic stem cell (1/12). We investigated the relationship of the Epstein–Barr virus (EBV) to the patients’ long-term follow-up, and evaluated the characteristics of the lesions on the chest CT and FDG-PET. The lesions were classified into 2 patterns: that of lymph node and lung involvement. The interval between the transplantation and the onset of PTLD was 2 to 128 months (median, 49). Positive EBV-encoded RNA in the pathologic specimens was found in 10 patients (83.3%). Eight patients were positive for EBV PCR in their blood, and 3 patients showed seroconversion without antiviral therapy. The responses to treatment were complete in 7 cases (58.3%), partial remission in 4 cases (33.3%), and undetermined in 1 case (8.3%). The more common chest CT patterns showed lymph node involvement (10/12) rather than lung involvement (3/12). The median maximum-standardized uptake value on the FDG-PET scans was 7.7 (range, 2.7–25.5). In patients with PTLD involving the thorax, lymphadenopathy was the more common manifestation on the chest CT rather than lung involvement. The lesions showed hypermetabolism on FDG-PET. PMID:26252295

  13. Mapping the x-linked lymphoproliferative syndrome

    SciTech Connect

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

    1987-04-01

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

  14. Autoimmune Lymphoproliferative Syndrome with Red Cell Aplasia.

    PubMed

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

    2015-12-01

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

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

    PubMed Central

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

    2014-01-01

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

  16. Circulating regulatory B cell subsets in patients with neuromyelitis optica spectrum disorders.

    PubMed

    Han, Jinming; Sun, Li; Wang, Zhongkun; Fan, Xueli; Wang, Lifang; Song, Yang-Yang; Zhu, Jie; Jin, Tao

    2017-04-07

    This study analyzed the populations of three different subsets of regulatory B cells (Bregs) in the peripheral blood mononuclear cells (PBMCs) of patients with neuromyelitis optica spectrum disorders (NMOSDs) and explored the relationship between the changes in these subsets of Bregs and the severity of NMOSD. A total of 22 patients with relapsed NMOSDs before treatment were recruited in our study, along with 20 age and gender-matched healthy controls, from May 2015 to March 2016. The percentages and numbers for three different subsets of Bregs including the CD19(+)CD24(hi)CD38(hi), CD19(+)CD24(hi)CD27(+), and CD19(+)CD5(+)CD1d(hi) populations were evaluated in parallel by flow cytometry. Afterwards, correlations between the change of three different subsets of Bregs and disease severity were analyzed. We found significantly lower percentages of CD19(+)CD24(hi)CD38(hi) and CD19(+)CD5(+)CD1d(hi) Bregs in NMOSDs patients than in healthy individuals. In contrast, the CD19(+)CD24(hi)CD27(+) Bregs population was significantly higher in NMOSDs patients than in healthy individuals. However, the three different Bregs subsets showed no significant correlation with expanded disability status scale (EDSS) or annualized relapse rate (ARR). Our findings suggest that the subsets of Bregs may play complex roles in the pathogenesis of NMOSDs and are not correlated with clinical disease severity. Further insights into the potential role of subsets of Bregs could increase our basic knowledge of NMOSDs pathogenesis.

  17. Primary cardiac B cell lymphoma: Manifestation of Felty's syndrome or TNFα antagonist.

    PubMed

    Benzerdjeb, Nazim; Ameur, Fatima; Ikoli, Jean-Fortune; Sevestre, Henri

    2016-12-01

    Primary cardiac B cell lymphoma is rare. To date, fewer than 90 cases have been described in the literature. We report a 67-year-old woman with a 30-year history of rheumatoid arthritis, who had received treatment with leflunomide for 10 years and infliximab for 2 years. Secondary Felty's syndrome appeared. She was admitted to the hospital for abdominal pain. Investigations disclosed a 5cm cardiac mass in the right atrium. Histopathologic examination of tissue specimens obtained at surgical myocardial biopsy demonstrated primary cardiac B cell lymphoma. The other iatrogenic lymphoproliferative disorders are reviewed. This lesion might be a manifestation of long term TNFα antagonists treatment.

  18. Atypical methotrexate ulcerative stomatitis with features of lymphoproliferative like disorder: Report of a rare ciprofloxacin-induced case and review of the literature

    PubMed Central

    Katsoulas, Nikolaos; Piperi, Evangelia; Levidou, Georgia; Sklavounou-Andrikopoulou, Alexandra

    2016-01-01

    Methotrexate (MTX) is an established immunomodulating agent used in low doses (LDMTX) to treat several autoimmune diseases. Ulcerative stomatitis (US) may be observed as a long-term LDMTX adverse effect showing a wide histopathologic spectrum. A 73-year old female presented with painful oral ulcers of 5 days duration. The patient had been under treatment for rheumatoid arthritis with LDMTX, while one week before presentation she was prescribed ciprofloxacin for a urinary infection. Histopathologic examination of a lingual ulcer revealed a polymorphous lymphohistiocytic proliferation with scattered binucleated atypical lymphocytes. Immunohistochemically, most cells were of T-cell lineage while the EBER test was negative and a diagnosis of MTX-induced reactive ulceration was rendered. MTX cessation resulted in complete resolution of the ulcers with no recurrences reported so far. The clinical and histopathologic features of MTX-induced oral ulcers are not always diagnostic and a detailed history and an extensive clinicopathologic investigation may be needed to exclude a lymphoproliferative disorder. Key words:Atypical oral ulcers, ciprofloxacin, lymphoproliferative disorders, methotrexate. PMID:27957282

  19. Idelalisib therapy of indolent B-cell malignancies: chronic lymphocytic leukemia and small lymphocytic or follicular lymphomas

    PubMed Central

    Madanat, Yazan F; Smith, Mitchell R; Almasan, Alexandru; Hill, Brian T

    2016-01-01

    Chronic lymphocytic leukemia, small lymphocytic lymphoma, and follicular lymphoma are indolent B-cell lymphoproliferative disorders that mainly affect an older population. Although the majority of patients in need of treatment derive significant benefit from conventional chemotherapeutic agents as well as monoclonal antibodies, less toxic and more effective treatments are needed. Novel agents that inhibit the B-cell receptor signaling pathway have shown promising outcomes in these disorders. Idelalisib is a potent selective oral inhibitor of phosphatidylinositol 3-kinase delta and has shown significant clinical activity in B-cell malignancies. In this review, we summarize the clinical trial data using idelalisib as monotherapy or in combination with rituximab for the treatment of relapsed/refractory disease. The adverse effect profile includes autoimmune disorders such as transaminitis, colitis, and pneumonitis. Given the efficacy and manageable toxicity profile of idelalisib, it is being increasingly incorporated into the management of indolent B-cell malignancies. PMID:27375364

  20. Management of Epstein-Barr Virus infections and post-transplant lymphoproliferative disorders in patients after allogeneic hematopoietic stem cell transplantation: Sixth European Conference on Infections in Leukemia (ECIL-6) guidelines

    PubMed Central

    Styczynski, Jan; van der Velden, Walter; Fox, Christopher P.; Engelhard, Dan; de la Camara, Rafael; Cordonnier, Catherine; Ljungman, Per

    2016-01-01

    Epstein-Barr virus-related post-transplant lymphoproliferative disorders are recognized as a significant cause of morbidity and mortality in patients undergoing hematopoietic stem cell transplantation. To better define current understanding of post-transplant lymphoproliferative disorders in stem cell transplant patients, and to improve its diagnosis and management, a working group of the Sixth European Conference on Infections in Leukemia 2015 reviewed the literature, graded the available quality of evidence, and developed evidence-based recommendations for diagnosis, prevention, prophylaxis and therapy of post-transplant lymphoproliferative disorders exclusively in the stem cell transplant setting. The key elements in diagnosis include non-invasive and invasive methods. The former are based on quantitative viral load measurement and imaging with positron emission tomography; the latter with tissue biopsy for histopathology and detection of Epstein-Barr virus. The diagnosis of post-transplant lymphoproliferative disorder can be established on a proven or probable level. Therapeutic strategies include prophylaxis, preemptive therapy and targeted therapy. Rituximab, reduction of immunosuppression and Epstein-Barr virus-specific cytotoxic T-cell therapy are recommended as first-line therapy, whilst unselected donor lymphocyte infusions or chemotherapy are options as second-line therapy; other methods including antiviral drugs are discouraged. PMID:27365460

  1. Management of Epstein-Barr Virus infections and post-transplant lymphoproliferative disorders in patients after allogeneic hematopoietic stem cell transplantation: Sixth European Conference on Infections in Leukemia (ECIL-6) guidelines.

    PubMed

    Styczynski, Jan; van der Velden, Walter; Fox, Christopher P; Engelhard, Dan; de la Camara, Rafael; Cordonnier, Catherine; Ljungman, Per

    2016-07-01

    Epstein-Barr virus-related post-transplant lymphoproliferative disorders are recognized as a significant cause of morbidity and mortality in patients undergoing hematopoietic stem cell transplantation. To better define current understanding of post-transplant lymphoproliferative disorders in stem cell transplant patients, and to improve its diagnosis and management, a working group of the Sixth European Conference on Infections in Leukemia 2015 reviewed the literature, graded the available quality of evidence, and developed evidence-based recommendations for diagnosis, prevention, prophylaxis and therapy of post-transplant lymphoproliferative disorders exclusively in the stem cell transplant setting. The key elements in diagnosis include non-invasive and invasive methods. The former are based on quantitative viral load measurement and imaging with positron emission tomography; the latter with tissue biopsy for histopathology and detection of Epstein-Barr virus. The diagnosis of post-transplant lymphoproliferative disorder can be established on a proven or probable level. Therapeutic strategies include prophylaxis, preemptive therapy and targeted therapy. Rituximab, reduction of immunosuppression and Epstein-Barr virus-specific cytotoxic T-cell therapy are recommended as first-line therapy, whilst unselected donor lymphocyte infusions or chemotherapy are options as second-line therapy; other methods including antiviral drugs are discouraged.

  2. Resveratrol Prevents EBV Transformation and Inhibits the Outgrowth of EBV-Immortalized Human B Cells

    PubMed Central

    Espinoza, J. Luis; Takami, Akiyoshi; Trung, Ly Quoc; Kato, Shunichi; Nakao, Shinji

    2012-01-01

    Background Epstein Barr virus-associated lymphoproliferative disease is an increasing complication in patients with immunosuppressive conditions. Although the current therapies for this disorder are effective, they are also associated with significant toxicity. In an attempt to identify newer therapeutic agents, this study investigated the effects of Resveratrol, a naturally occurring polyphenolic compound, on the EBV transformation of human B cells. Methodology/Principal Findings This study demonstrates that resveratrol prevents EBV transformation in human B cells. These effects are mediated by specific cytotoxic activities of resveratrol against EBV-infected B cells that are associated with the downregulation of the anti-apoptotic proteins Mcl-1 and survivin. This occurs as a consequence of the inhibition of EBV-induced NFκB and STAT-3 signaling pathways and a resveratrol-induced decrease in the expression of the oncogenic viral product LMP1 in EBV-infected B cells. In addition, resveratrol decreased the expression of miR-155 and miR-34a in EBV-infected B cells, blocked the expression of the anti-apoptotic viral gene BHRF1, and thus interrupted events that are critical for EBV transformation and the survival of EBV-transformed cells. Conclusions/Significance These results suggest that resveratrol may therefore be a potentially effective therapeutic alternative for preventing EBV-associated lymphoproliferative diseases in immune compromised patients. PMID:23251493

  3. Differences in HTLV-I integration patterns between skin lesions and peripheral blood lymphocytes of HTLV-I seropositive patients with cutaneous lymphoproliferative disorders.

    PubMed

    Hamada, T; Setoyama, M; Katahira, Y; Furuno, T; Fujiyoshi, T; Sonoda, S; Tashiro, M

    1992-09-01

    We examined HTLV-I integration patterns in nine cases of HTLV-I-seropositive patients with cutaneous lymphoproliferative disorders. The Southern blot on EcoRI digests of DNA revealed a discrete band of HTLV-I provirus (monoclonal integration) in either skin lesions or peripheral blood lymphocytes (PBL). Four cases showed the monoclonal integration of HTLV-I provirus only in skin lesions: one case showed only in PBL and two cases showed in both skin and PBL. The Southern blot on PstI digests of DNA revealed a 2.4 Kb band of the internal construct of HTLV-I provirus (polyclonal integration) in the PBL of EcoRI-negative samples. The difference in HTLV-I integration patterns between skin lesions and PBL in these cases suggests that the monoclonal outgrowth of HTLV-I-infected cells in the skin is causatively associated with the pathogenesis of cutaneous ATL.

  4. Oral cyclophosphamide was effective for Coombs-negative autoimmune hemolytic anemia in CD16+CD56- chronic lymphoproliferative disorder of NK-cells.

    PubMed

    Sekiguchi, Nodoka; Nishina, Sayaka; Kawakami, Toru; Sakai, Hitoshi; Senoo, Noriko; Senoo, Yasushi; Ito, Toshiro; Saito, Hiroshi; Nakazawa, Hideyuki; Koizumi, Tomonobu; Ishida, Fumihiro

    2016-12-27

    An 84-year-old woman was referred to our hospital presenting anemia. Her hemoglobin level was 5.8 g/dL, and white blood cell count was 9400/μL, consisting of 82% lymphocytes. Given the lymphocyte phenotype (CD2+, CD3-, CD16+, and CD56-) and negative whole blood EBV viral load, we made a diagnosis of chronic lymphoproliferative disorder of NK cells (CLPD-NK). We suspected hemolytic anemia because of the high levels of reticulocytes in the peripheral blood and the low haptoglobin value. Although the direct Coombs test was negative and there was no cold agglutination, we examined her red-blood-cell-bound IgG (RBC-IgG), which was elevated. She was diagnosed as having as Coombs-negative autoimmune hemolytic anemia (AIHA). We report the effectiveness of oral cyclophosphamide for Coombs-negative autoimmune hemolytic anemia in CLPD-NK.

  5. CD4(+) memory T cells retain surface expression of CD31 independently of thymic function in patients with lymphoproliferative disorders following autologous hematopoietic stem-cell transplantation.

    PubMed

    Batorov, Egor V; Tikhonova, Marina A; Kryuchkova, Irina V; Sergeevicheva, Vera V; Sizikova, Svetlana A; Ushakova, Galina Y; Batorova, Dariya S; Gilevich, Andrey V; Ostanin, Alexander A; Shevela, Ekaterina Y; Chernykh, Elena R

    2017-03-14

    High-dose chemotherapy with autologous hematopoietic stem-cell transplantation (AHSCT) causes severe and long-lasting immunodeficiency in patients with lymphoproliferative disorders. The thymus begins to restore the T-cell repertoire approximately from the sixth month post-transplant. We assessed the dynamics of post-transplant recovery of CD4(+)CD45RA(+)CD31(+) T cells, "recent thymic emigrants" (RTEs), and a poorly described subtype of CD4(+)CD45RA(-)CD31(+) T cells in 90 patients with lymphoproliferative disorders following high-dose chemotherapy with AHSCT. Relative and absolute counts of CD4(+)CD31(+) naïve and memory T cells were evaluated before AHSCT, at the day of engraftment, and 6- and 12-month post-transplant. The pre-transplant count of CD4(+)CD45RA(+)CD31(+) T cells was lower than in healthy controls, and did not reach donors' values during the 12-month period. The pre-transplant number of CD4(+)CD45RA(-)CD31(+) T cells was higher than in healthy controls and was restored rapidly following AHSCT. Post-transplant mediastinal radiotherapy reduced counts of RTEs and elongated recovery period. Non-thymic tissue irradiation did not reduce this subset. The obtained data indicate that homeostatic proliferation may decrease the significance of CD31 expression on CD4(+)CD45RA(+) T cells as a marker of RTEs, and suggest that evaluation of RTEs recovery by flow cytometry requires an accurate gating strategy to exclude CD31(+) memory T cells.

  6. Development of B-lineage predominant lentiviral vectors for use in genetic therapies for B cell disorders.

    PubMed

    Sather, Blythe D; Ryu, Byoung Y; Stirling, Brigid V; Garibov, Mikhail; Kerns, Hannah M; Humblet-Baron, Stéphanie; Astrakhan, Alexander; Rawlings, David J

    2011-03-01

    Sustained, targeted, high-level transgene expression in primary B lymphocytes may be useful for gene therapy in B cell disorders. We developed several candidate B-lineage predominant self-inactivating lentiviral vectors (LV) containing alternative enhancer/promoter elements including: the immunoglobulin β (Igβ) (B29) promoter combined with the immunoglobulin µ enhancer (EµB29); and the endogenous BTK promoter with or without Eµ (EµBtkp or Btkp). LV-driven enhanced green fluorescent protein (eGFP) reporter expression was evaluated in cell lines and primary cells derived from human or murine hematopoietic stem cells (HSC). In murine primary cells, EµB29 and EµBtkp LV-mediated high-level expression in immature and mature B cells compared with all other lineages. Expression increased with B cell maturation and was maintained in peripheral subsets. Expression in T and myeloid cells was much lower in percentage and intensity. Similarly, both EµB29 and EµBtkp LV exhibited high-level activity in human primary B cells. In contrast to EµB29, Btkp and EµBtkp LV also exhibited modest activity in myeloid cells, consistent with the expression profile of endogenous Bruton's tyrosine kinase (Btk). Notably, EµB29 and EµBtkp activity was superior in all expression models to an alternative, B-lineage targeted vector containing the EµS.CD19 enhancer/promoter. In summary, EµB29 and EµBtkp LV comprise efficient delivery platforms for gene expression in B-lineage cells.

  7. Persistent polyclonal B-cell lymphocytosis with splenomegaly: histologic description of 2 cases.

    PubMed

    Martinez-Lopez, Azahara; Montes-Moreno, Santiago; Mazorra, Francisco; Miranda-Vallina, Cesar; Ulibarrena, Carlos; Martin, Juan Luis Alfonso; Bosch, Jose Miguel; Peri, Valeria; Burdaspal, Ana; Fernandez-Alvarez, Montse; Sanchez-Verde, Lidia; Piris, Miguel A

    2013-07-01

    Persistent polyclonal B-cell lymphocytosis is a rare, benign lymphoproliferative disorder characterized by a stable, polyclonal CD19-positive CD5-negative lymphocytosis, the presence of binucleated lymphocytes in peripheral blood, and a polyclonal increase in serum immunoglobulin-M that may occasionally be accompanied by splenomegaly. Histopathologic diagnosis of these splenectomy specimens is difficult because of the massive spleen infiltration and the rarity of the descriptions of this condition. We describe the histopathologic findings from 2 splenectomy specimens. These included a partially preserved architecture with infiltration of the red pulp by small lymphocytes and partial replacement of the white pulp. Suggestions for identifying the disorder are made.

  8. Bone marrow findings in autoimmune lymphoproliferative syndrome with germline FAS mutation.

    PubMed

    Xie, Yi; Pittaluga, Stefania; Price, Susan; Raffeld, Mark; Hahn, Jamie; Jaffe, Elaine S; Rao, V Koneti; Maric, Irina

    2017-02-01

    Autoimmune lymphoproliferative syndrome is a rare genetic disorder characterized by defective FAS-mediated apoptosis, autoimmune disease, accumulation of mature T-cell receptor alpha/beta positive, CD4 and CD8 double-negative T cells and increased risk of lymphoma. Despite frequent hematologic abnormalities, literature is scarce regarding the bone marrow pathology in autoimmune lymphoproliferative syndrome. We retrospectively reviewed 3l bone marrow biopsies from a cohort of 240 patients with germline FAS mutations. All biopsies were performed for the evaluation of cytopenias or to rule out lymphoma. Clinical information was collected and morphological, immunohistochemical, flow cytometric and molecular studies were performed. Bone marrow lymphocytosis was the predominant feature, present in 74% (23/31) of biopsies. The lymphoid cells showed several different patterns of infiltration, most often forming aggregates comprising T cells in 15 cases, B cells in one and a mixture of T and B cells in the other seven cases. Double-negative T cells were detected by immunohistochemistry in the minority of cases (10/31; 32%); significantly, all but one of these cases had prominent double-negative T-lymphoid aggregates, which in four cases diffusely replaced the marrow space. One case showed features of Rosai-Dorfman disease, containing scattered S-100(+) cells with emperipolesis and double-negative T cells. No clonal B or T cells were detected by polymerase chain reaction in any evaluated cases. Classical Hodgkin lymphoma was identified in three cases. Our results demonstrate that infiltrates of T cells, or rarely B cells, can be extensive in patients with autoimmune lymphoproliferative syndrome, mimicking lymphoma. A multi-modality approach, integrating clinical, histological, immunohistochemical as well as other ancillary tests, can help avoid this diagnostic pitfall. This study is registered at Clinicaltrials.gov ID # NCT00001350.

  9. Bone marrow findings in autoimmune lymphoproliferative syndrome with germline FAS mutation

    PubMed Central

    Xie, Yi; Pittaluga, Stefania; Price, Susan; Raffeld, Mark; Hahn, Jamie; Jaffe, Elaine S.; Rao, V. Koneti; Maric, Irina

    2017-01-01

    Autoimmune lymphoproliferative syndrome is a rare genetic disorder characterized by defective FAS-mediated apoptosis, autoimmune disease, accumulation of mature T-cell receptor alpha/beta positive, CD4 and CD8 double-negative T cells and increased risk of lymphoma. Despite frequent hematologic abnormalities, literature is scarce regarding the bone marrow pathology in autoimmune lymphoproliferative syndrome. We retrospectively reviewed 3l bone marrow biopsies from a cohort of 240 patients with germline FAS mutations. All biopsies were performed for the evaluation of cytopenias or to rule out lymphoma. Clinical information was collected and morphological, immunohistochemical, flow cytometric and molecular studies were performed. Bone marrow lymphocytosis was the predominant feature, present in 74% (23/31) of biopsies. The lymphoid cells showed several different patterns of infiltration, most often forming aggregates comprising T cells in 15 cases, B cells in one and a mixture of T and B cells in the other seven cases. Double-negative T cells were detected by immunohistochemistry in the minority of cases (10/31; 32%); significantly, all but one of these cases had prominent double-negative T-lymphoid aggregates, which in four cases diffusely replaced the marrow space. One case showed features of Rosai-Dorfman disease, containing scattered S-100+ cells with emperipolesis and double-negative T cells. No clonal B or T cells were detected by polymerase chain reaction in any evaluated cases. Classical Hodgkin lymphoma was identified in three cases. Our results demonstrate that infiltrates of T cells, or rarely B cells, can be extensive in patients with autoimmune lymphoproliferative syndrome, mimicking lymphoma. A multi-modality approach, integrating clinical, histological, immunohistochemical as well as other ancillary tests, can help avoid this diagnostic pitfall. This study is registered at Clinicaltrials.gov ID # NCT00001350 PMID:27846610

  10. Immunophenotypic features by multiparameter flow cytometry can help distinguish low grade B-cell lymphomas with plasmacytic differentiation from plasma cell proliferative disorders with an unrelated clonal B-cell process.

    PubMed

    Rosado, Flavia G; Morice, William G; He, Rong; Howard, Matthew T; Timm, Michael; McPhail, Ellen D

    2015-05-01

    Highly sensitive flow cytometry studies may incidentally identify B cell clones when used to assess plasma cell clonality in bone marrows. Clinical history, which can help differentiate related clones (low grade B cell lymphoma with plasmacytic differentiation/LBCL-PD) from unrelated ones (plasma cell proliferative disorder (PCPD) with an unrelated B cell clone), is often unavailable in referred specimens. We sought to identify morphologic or phenotypic features that would help predict the significance of these clones in the absence of history. We included only cases with identical light chain B and plasma cell clones, as determined by 6-color flow cytometry with additional DNA ploidy analysis, in which the relationship between clones could be established by review of medical records. There were 26 cases; 18 were related (14 were Waldenstrom macroglobulinemia) and eight were unrelated (seven multiple myeloma). Features seen exclusively in LBCL-PD include CD19+/CD45+ clonal plasma cell phenotype (66·7%, P = 0·0022) and morphologic features such as paratrabecular bone marrow involvement, increased mast cells, and plasma cells surrounding B-cell nodules. Aneuploidy was identified exclusively in PCPD cases (75%, P = 0·000028). We conclude that CD19+/CD45+ clonal plasma cell phenotype and aneuploidy are useful in distinguishing related clones (LBCL-PD) from unrelated clones (PCPD).

  11. Epstein-Barr virus-related post-transplant lymphoproliferative disorder occurring after bone marrow transplantation for aplastic anemia in Down's syndrome.

    PubMed

    Furuya, Aya; Ishida, Mitsuaki; Hodohara, Keiko; Yoshii, Miyuki; Okuno, Hiroko; Horinouchi, Akiko; Nakanishi, Ryota; Harada, Ayumi; Iwai, Muneo; Yoshida, Keiko; Kagotani, Akiko; Yoshida, Takashi; Okabe, Hidetoshi

    2014-01-01

    It is well established that Down's syndrome exhibits a predisposition to development of leukemia, however, association between aplastic anemia and Down's syndrome is exceptional. Herein, we describe a case of aplastic anemia occurring in Down's syndrome following post-transplant lymphoproliferative disorder (PTLD) after bone marrow transplantation (BMT). A 27-year-old Japanese male with Down's syndrome presented with a headache. Laboratory tests revealed severe pancytopenia, and bone marrow biopsy demonstrated hypocellular bone marrow with decrease of trilineage cells, which led to a diagnosis of aplastic anemia. One year after diagnosis, he was incidentally found to have an anterior mediastinal tumor, which was histopathologically diagnosed as seminoma. Subsequently, he received BMT from a female donor, and engraftment was observed. Three months after transplantation, he experienced cough and high fever. Biopsy specimen from the lung revealed diffuse proliferation of large-sized lymphoid cells expressing CD20 and EBER. These lymphoid cells had XY chromosomes. Thus, a diagnosis of EBV-associated PTLD was made. This is the seventh documented case of aplastic anemia occurring in Down's syndrome. Association between aplastic anemia and Down's syndrome has not been established, therefore, additional clinicopathological studies are needed. Moreover, this is the first case to undergo BMT for aplastic anemia in Down's syndrome. Although engraftment was observed, he developed EBV-positive PTLD. The neoplastic cells of the present case were considered to be of recipient origin, although the majority of PTLD cases with BMT are of donor origin.

  12. Clinicopathological characteristics of posttransplant lymphoproliferative disorders of T-cell origin: single-center series of nine cases and meta-analysis of 147 reported cases.

    PubMed

    Herreman, An; Dierickx, Daan; Morscio, Julie; Camps, Jordi; Bittoun, Emilie; Verhoef, Gregor; De Wolf-Peeters, Christiane; Sagaert, Xavier; Tousseyn, Thomas

    2013-10-01

    T-cell or natural killer (NK)-cell posttransplant lymphoproliferative disorder (T-PTLD) is a rare but severe complication after transplant. Here we present the clinicopathological features of a single-center series of nine cases. Additionally, we summarize the clinicopathological findings of 147 cases of T/NK-cell PTLD reported in the literature in an attempt to define subtype-specific characteristics. T/NK-cell PTLD occurs in patients of all ages, usually extranodally, and most frequently after kidney transplant. Organ specific incidence, however, is highest following heart transplant. Approximately one-third of T-cell PTLDs are Epstein-Barr virus (EBV)-related, with peripheral T-cell lymphoma, not otherwise specified (PTCL, NOS) being the most prevalent EBV-associated T-cell PTLD. A male predominance is observed, which is most striking in the EBV(+) group, particularly in PTCL, NOS. With a median posttransplant interval of 72 months, T-cell PTLDs are among the late-occurring PTLDs. Of the most common T-cell PTLDs, anaplastic large cell lymphoma (ALCL) has the best prognosis, whereas PTCL, NOS and hepatosplenic T-cell lymphoma (HSTCL) have the worst prognosis. EBV(+) cases seem to have a longer survival than EBV(-) cases, suggesting a different pathogenetic mechanism.

  13. Risk factors for early-onset and late-onset post-transplant lymphoproliferative disorder in kidney recipients in the United States.

    PubMed

    Quinlan, Scott C; Pfeiffer, Ruth M; Morton, Lindsay M; Engels, Eric A

    2011-02-01

    Solid-organ transplant recipients have an elevated risk for some malignancies because of the requirement for immunosuppression [1]. In particular, non-Hodgkin's lymphoma (NHL) is common and comprises one end of a spectrum of post-transplant lymphoproliferative disorder (PTLD) ranging from benign hyperplasia to lymphoid malignancy [2]. PTLD risk is influenced by the type of organ transplanted, the age and Epstein-Barr virus (EBV) serostatus of the transplant recipient, and the intensity of immunosuppression [3-9]. PTLD incidence is high immediately after transplantation, decreases subsequently, and then rises again 4-5 years from transplantation [10,11]. This incidence pattern suggests the presence of separate early-onset and late-onset PTLD subtypes. Early-onset PTLDs tend to be EBV-positive and, when extranodal, are more likely than late-onset PTLDs to be localized to the transplanted organ [12,13]. Late-onset PTLD is less likely to be associated with EBV and, overall, is more likely than early-onset PTLD to be extranodal [13,14]. The Scientific Registry of Transplant Recipients (SRTR) includes data on a large number of solid-organ transplant recipients in the United States and information on malignancies diagnosed post-transplantation. We used these data to conduct a retrospective cohort study among kidney transplant recipients to examine differences in risk factors between early-onset PTLD and late-onset PTLD.

  14. Epstein-Barr virus (EBV) load and interleukin-10 in EBV-positive and EBV-negative post-transplant lymphoproliferative disorders.

    PubMed

    Muti, Giuliana; Klersy, Catherine; Baldanti, Fausto; Granata, Simonetta; Oreste, Pierluigi; Pezzetti, Laura; Gatti, Marta; Gargantini, Livio; Caramella, Marianna; Mancini, Valentina; Gerna, Guiseppe; Morra, Enrica

    2003-09-01

    Post-transplant lymphoproliferative disorders (PTLDs) are heterogeneous severe complications occurring in 1-10% of transplanted patients. In most cases, PTLDs are associated with Epstein-Barr virus (EBV) infection but, recently, some clinical studies have reported an increasing number of EBV-negative PTLDs. Several studies have emphasized the critical role of the early identification of patients at risk for PTLD, in prompting the adoption of either pre-emptive strategies or timely treatment. To this purpose, monitoring of EBV DNA load in peripheral blood mononuclear cells is considered to be a useful test. Moreover, recently, the role of interleukin (IL)-10 in EBV-related diseases has been remarked, and high levels of IL-10 have been detected in PTLD patients. In this study, both EBV load and IL-10 were monitored in 38 PTLD patients at diagnosis and during follow-up, as well as in a control group, in order to establish the diagnostic role of the two tests, their relationship with the different PTLD subsets (EBV-positive and EBV-negative) and their behaviour during treatment. Results of our study suggest that the usefulness of IL-10 assay for early diagnosis of PTLD is similar to that of EBV load quantification, and its clinical diagnostic value is lower in EBV-negative than in EBV-positive PTLDs.

  15. Detection of bone marrow involvement in newly diagnosed post-transplant lymphoproliferative disorder: (18)F-fluorodeoxyglucose positron emission tomography/computed tomography versus bone marrow biopsy.

    PubMed

    Gheysens, Olivier; Thielemans, Sanne; Morscio, Julie; Boeckx, Nancy; Goffin, Karolien E; Deroose, Christophe M; Sagaert, Xavier; Wlodarska, Iwona; Verhoef, Gregor; Dierickx, Daan; Tousseyn, Thomas

    2016-10-01

    Detecting bone marrow involvement (BMI) in lymphoma is important as it adversely affects stage. Bone marrow biopsy (BMB) remains the standard to detect BMI but is prone to sampling error. We retrospectively investigated whether (18)F-fluorodeoxyglucose positron emission tomography with computed tomography ((18)F-FDG-PET/CT) could identify BMI in patients with post-transplant lymphoproliferative disorder (PTLD) with sufficient accuracy in comparison with staging BMB. Twenty-five patients diagnosed with PTLD who underwent (18)F-FDG-PET/CT and BMB within one month were evaluated. Based on our criteria, six patients (24%) were considered positive for BMI on (18)F-FDG-PET/CT compared to one by BMB. Although we cannot completely exclude false positive results on (18)F-FDG-PET/CT, our data indicate a significantly higher sensitivity of (18)F-FDG-PET/CT compared to BMB (100% vs 17%) but similar specificity. These data confirm the high diagnostic performance of (18)F-FDG-PET/CT for detecting BMI, but prospective studies are needed to determine whether (18)F-FDG-PET/CT could indeed replace staging BMB in PTLD.

  16. Rapamycin modulated brain-derived neurotrophic factor and B-cell lymphoma 2 to mitigate autism spectrum disorder in rats

    PubMed Central

    Zhang, Jie; Liu, Li-Ming; Ni, Jin-Feng

    2017-01-01

    The number of children suffered from autism spectrum disorder (ASD) is increasing dramatically. However, the etiology of ASD is not well known. This study employed mammalian target of rapamycin inhibitor rapamycin to explore its effect on ASD and provided new therapeutic strategies for ASD. ASD rat model was constructed and valproic acid (VPA) was injected intraperitoneally into rats on pregnancy day 12.5. Offspring from VPA group were divided into ASD group and ASD + rapamycin (ASD + RAPA) group. Compared with normal group, the frequency and duration of social behavior and straight times of ASD group were shortened, but the grooming times were extended. Meanwhile, in ASD group, the average escape latency and the frequency of crossing plates were decreased, the apoptotic index (AI) detected by TUNEL assay was increased, and the expression of brain-derived neurotrophic factor (BDNF) and B-cell lymphoma 2 (Bcl-2) analyzed was decreased with great difference compared with normal group (P<0.01). However, rapamycin treatment in ASD rats mitigated the ASD-like social behavior, such as the frequencies of straight and grooming. Furthermore, rapamycin shortened the average escape latency, but increased the frequency of crossing plates of ASD rats. In hippocampus, rapamycin decreased the AI, but increased the levels of BDNF and Bcl-2 (P<0.01) of ASD rats. These findings revealed that rapamycin significantly mitigated the social behavior by enhancing the expression of BDNF and Bcl-2 to suppress the hippocampus apoptosis in VPA-induced ASD rats. PMID:28360521

  17. Methotrexate-associated primary cutaneous CD30-positive cutaneous T-cell lymphoproliferative disorder: a case illustration and a brief review

    PubMed Central

    Claudino, Wederson M; Gibson, Bradley; Tse, William; Krem, Maxwell; Grewal, Jaspreet

    2016-01-01

    Methotrexate (MTX) is a commonly used anti-metabolite agent. Increased risk of lymphoproliferative disorders (LPD) in patients with rheumatoid arthritis (RA) has been documented with the prolonged use of immunosuppressive medications such as MTX. This is thought to be the result of immune dysregulation and/or chronic immune stimulation. Most cases of LPDs regress following withdrawal of the offending immunosuppressive agent. We present an interesting and rare case of CD30 and EBV positive CD8 primary cutaneous anaplastic large cell lymphoma (PC-ALCL) in a 66-year-old African American woman. Patient had been on MTX for rheumatoid arthritis (RA) which was stopped after the patient was evaluated at our institution. Patient had an incredible response to stopping immunosuppression with spontaneous regression of skin lesions and disappearance of clonal malignant cell population as evidenced on serial biopsy specimens. Primary cutaneous CD30+ LPDs constitute about 30% of the primary cutaneous T-cell lymphomas (CTLs) and includes entities such as lymphomatoid papulosis (LyP), primary cutaneous anaplastic large cell lymphoma (PC-ALCL) and other CD30+ borderline LPDs. Histopathological criteria in addition to CD30 positivity is important for identification of these conditions. Treatment options include “wait and see”, phototherapy, radiotherapy, topical agents, systemic therapy and surgical resection. Prognosis is excellent and most cases resolve spontaneously on withdrawal of immunosuppression. Refractory cases may require aggressive local treatment or systemic therapy. Brentuximab Vedontin, an anti-CD30 antibody drug conjugate (ADC), may provide additional therapeutic option in refractory cases. PMID:27335685

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

    PubMed Central

    2014-01-01

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

  19. Next-generation sequencing of miRNAs in clinical samples of Epstein-Barr virus-associated B-cell lymphomas.

    PubMed

    Sakamoto, Kouta; Sekizuka, Tsuyoshi; Uehara, Taeko; Hishima, Tsunekazu; Mine, Sohtaro; Fukumoto, Hitomi; Sato, Yuko; Hasegawa, Hideki; Kuroda, Makoto; Katano, Harutaka

    2017-03-01

    Epstein-Barr virus (EBV) encodes 49 microRNAs (miRNAs) in the BART and BHRF1 regions of its genome. Although expression profiles of EBV-encoded miRNAs have been reported for EBV-positive cell lines and nasopharyngeal carcinoma, to date there is little information about total miRNA expression, including cellular and viral miRNAs, in the primary tumors of EBV-associated B-lymphoproliferative disorders. In this study, next-generation sequencing and quantitative real-time reverse transcription-PCR were used to determine the expression profiles of miRNAs in EBV-infected cell lines and EBV-associated B-cell lymphomas, including AIDS-related diffuse large B-cell lymphoma (DLBCL), pyothorax-associated lymphoma, methotrexate-associated lymphoproliferative disorder, EBV-positive DLBCL of the elderly, and Hodgkin lymphoma. Next-generation sequencing revealed that EBV-encoded miRNAs accounted for up to 34% of total annotated miRNAs in these cases. Expression of three miR-BHRF1s was significantly higher in AIDS-related DLBCL and pyothorax-associated lymphoma compared with methotrexate-associated lymphoproliferative disorder and EBV-positive DLBCL of the elderly, suggesting the association of miR-BHRF1s expression with latency III EBV infection. Heat map/clustering analysis of expression of all miRNAs, including cellular and EBV miRNAs, by next-generation sequencing demonstrated that each EBV tumor, except methotrexate-associated lymphoproliferative disorder, formed an isolated cluster. Principal component analysis based on the EBV-encoded miRNA expression showed that each EBV tumor formed a distinguished cluster, but AIDS-related DLBCL and pyothorax-associated lymphoma formed larger clusters than other tumors. These data suggest that expression of miRNAs, including EBV-encoded miRNAs, is associated with the tumor type and status of virus infection in these tumors.

  20. Immunodeficiency disorders.

    PubMed

    Cooper, Max D; Lanier, Lewis L; Conley, Mary Ellen; Puck, Jennifer M

    2003-01-01

    Hematological complications occur frequently in patients with both primary and secondary immunodeficiency disorders. Anemia, thrombocytopenia or leukopenias may bring these individuals to the attention of hematologists. Conversely, evidence suggesting a lymphoproliferative disorder may be the cause for referral. This session will provide an update on the diagnosis and treatment of immunodeficiency diseases ranging from isolated defects in antibody production to the severe combined immunodeficiencies (SCID). Immunodeficiency diseases have traditionally been defined as defects in the development and function of T and B cells, the primary effector cells of specific cellular and humoral immunity. However, it has become increasingly evident that innate immune mechanisms contribute greatly to host defense, either through acting alone or by enhancing specific T and B cell responses. In Section I, Dr. Lewis Lanier reviews the burgeoning information on the extensive families of activating and inhibitory immunoreceptors that are expressed on NK cells, dendritic cells, T and B cells, and phagocytic cells. He provides an overview on the biological functions of these receptors in host defense. In Section II, Dr. Mary Ellen Conley defines the spectrum of antibody deficiency disorders, the most frequently occurring types of primary immunodeficiencies. She covers the different defects in B-cell development and function that lead to antibody deficiencies, and includes diagnosis and therapy of these disorders. In Section III, Dr. Jennifer Puck discusses the diagnosis and treatment of the different types of SCID. She describes the genetic basis for SCID, and the benefits, pitfalls, and complications of gene therapy and bone marrow transplantation in SCID patients.

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

    ClinicalTrials.gov

    2016-11-21

    B-cell Adult Acute Lymphoblastic Leukemia; B-cell Childhood Acute Lymphoblastic Leukemia; B-cell Chronic Lymphocytic Leukemia; Childhood Burkitt Lymphoma; Childhood Diffuse Large Cell Lymphoma; Childhood Immunoblastic Large Cell Lymphoma; Cutaneous B-cell Non-Hodgkin Lymphoma; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Intraocular Lymphoma; Nodal Marginal Zone B-cell Lymphoma; Post-transplant Lymphoproliferative Disorder; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Grade III Lymphomatoid Granulomatosis; Recurrent Adult Hodgkin Lymphoma; Recurrent Adult Immunoblastic Large Cell Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Childhood Acute Lymphoblastic Leukemia; Recurrent Childhood Grade III Lymphomatoid Granulomatosis; Recurrent Childhood Large Cell Lymphoma; Recurrent Childhood Lymphoblastic Lymphoma; Recurrent Childhood Small Noncleaved Cell Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Small Lymphocytic Lymphoma; Recurrent/Refractory Childhood Hodgkin Lymphoma; Refractory Chronic Lymphocytic Leukemia; Refractory Hairy Cell Leukemia; Small Intestine Lymphoma; Splenic Marginal Zone Lymphoma; Testicular Lymphoma; Waldenström Macroglobulinemia

  2. Autoimmune lymphoproliferative syndrome misdiagnosed as hemophagocytic lymphohistiocytosis.

    PubMed

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

    2013-11-01

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

  3. Autoimmune lymphoproliferative syndrome (ALPS): a rare cause of immune cytopenia.

    PubMed

    John, M Joseph; Rajasekhar, Reena; Mathews, Vikram

    2008-02-01

    Autoimmune Lymphoproliferative syndrome (ALPS) is an inherited disorder manifesting with autoimmune cytopenia, lymphadenopathy and splenomegaly. The differential diagnosis includes infections, autoimmune disorders or malignancies. The disease is characterized by accumulation of double negative (CD3+ CD4- CD8-) T cells (DNT) in the peripheral blood. We describe a case and review the literature.

  4. Transgenic mouse model of IgM+ lymphoproliferative disease mimicking Waldenström macroglobulinemia

    PubMed Central

    Tompkins, V S; Sompallae, R; Rosean, T R; Walsh, S; Acevedo, M; Kovalchuk, A L; Han, S-S; Jing, X; Holman, C; Rehg, J E; Herms, S; Sunderland, J S; Morse, H C; Janz, S

    2016-01-01

    Waldenström macroglobulinemia (WM) is a low-grade incurable immunoglobulin M+ (IgM+) lymphoplasmacytic lymphoma for which a genetically engineered mouse model of de novo tumor development is lacking. On the basis of evidence that the pro-inflammatory cytokine, interleukin 6 (IL6), and the survival-enhancing oncoprotein, B cell leukemia 2 (BCL2), have critical roles in the natural history of WM, we hypothesized that the enforced expression of IL6 and BCL2 in mice unable to perform immunoglobulin class switch recombination may result in a lymphoproliferative disease that mimics WM. To evaluate this possibility, we generated compound transgenic BALB/c mice that harbored the human BCL2 and IL6 transgenes, EμSV-BCL2-22 and H2-Ld-hIL6, on the genetic background of activation-induced cytidine deaminase (AID) deficiency. We designated these mice BCL2+IL6+AID− and found that they developed—with full genetic penetrance (100% incidence) and suitably short latency (93 days median survival)—a severe IgM+ lymphoproliferative disorder that recapitulated important features of human WM. However, the BCL2+IL6+AID− model also exhibited shortcomings, such as low serum IgM levels and histopathological changes not seen in patients with WM, collectively indicating that further refinements of the model are required to achieve better correlations with disease characteristics of WM. PMID:27813533

  5. Transgenic mouse model of IgM(+) lymphoproliferative disease mimicking Waldenström macroglobulinemia.

    PubMed

    Tompkins, V S; Sompallae, R; Rosean, T R; Walsh, S; Acevedo, M; Kovalchuk, A L; Han, S-S; Jing, X; Holman, C; Rehg, J E; Herms, S; Sunderland, J S; Morse, H C; Janz, S

    2016-11-04

    Waldenström macroglobulinemia (WM) is a low-grade incurable immunoglobulin M(+) (IgM(+)) lymphoplasmacytic lymphoma for which a genetically engineered mouse model of de novo tumor development is lacking. On the basis of evidence that the pro-inflammatory cytokine, interleukin 6 (IL6), and the survival-enhancing oncoprotein, B cell leukemia 2 (BCL2), have critical roles in the natural history of WM, we hypothesized that the enforced expression of IL6 and BCL2 in mice unable to perform immunoglobulin class switch recombination may result in a lymphoproliferative disease that mimics WM. To evaluate this possibility, we generated compound transgenic BALB/c mice that harbored the human BCL2 and IL6 transgenes, EμSV-BCL2-22 and H2-L(d)-hIL6, on the genetic background of activation-induced cytidine deaminase (AID) deficiency. We designated these mice BCL2(+)IL6(+)AID(-) and found that they developed-with full genetic penetrance (100% incidence) and suitably short latency (93 days median survival)-a severe IgM(+) lymphoproliferative disorder that recapitulated important features of human WM. However, the BCL2(+)IL6(+)AID(-) model also exhibited shortcomings, such as low serum IgM levels and histopathological changes not seen in patients with WM, collectively indicating that further refinements of the model are required to achieve better correlations with disease characteristics of WM.

  6. A Unique "Composite" PTLD with Diffuse Large B-Cell and T/Anaplastic Large Cell Lymphoma Components Occurring 17 Years after Transplant.

    PubMed

    La Fortune, Kristin; Zhang, Dahua; Raca, Gordana; Ranheim, Erik A

    2013-01-01

    Posttransplant lymphoproliferative disorder (PTLD) comprises a spectrum ranging from polyclonal hyperplasia to aggressive monoclonal lymphomas. The majority of PTLDs are of B-cell origin while T-cell PTLDs and Hodgkin lymphoma-like PTLDs are uncommon. Here, we report a unique case of a 56-year-old man in whom a lymphoma with two distinct components developed as a duodenal mass seventeen years following a combined kidney-pancreas transplant. This PTLD, which has features not previously reported in the literature, consisted of one component of CD20 positive and EBV negative monomorphic diffuse large B-cell lymphoma. The other component showed anaplastic morphology, expressed some but not all T-cell markers, failed to express most B-cell markers except for PAX5, and was diffusely EBV positive. Possible etiologies for this peculiar constellation of findings are discussed and the literature reviewed for "composite-like" lymphomas late in the posttransplant setting.

  7. Issues in diagnosis of small B cell lymphoid neoplasms involving the bone marrow and peripheral blood. Report on the Bone Marrow Workshop of the XVIIth meeting of the European Association for Haematopathology and the Society for Hematopathology.

    PubMed

    Porwit, Anna; Fend, Falko; Kremer, Marcus; Orazi, Attilio; Safali, Mükerrem; van der Walt, Jon

    2016-09-01

    Small B cell lymphoid neoplasms are the most common lymphoproliferative disorders involving peripheral blood (PB) and bone marrow (BM). The Bone Marrow Workshop (BMW) organized by the European Bone Marrow Working Group (EBMWG) of the European Association for Haematopathology (EAHP) during the XVIIth EAHP Meeting in Istanbul, October 2014, was dedicated to discussion of cases illustrating how the recent advances in immunophenotyping, molecular techniques and cytogenetics provide better understanding and classification of these entities. Submitted cases were grouped into following categories: (i) cases illustrating diagnostic difficulties in chronic lymphocytic leukaemia (CLL); (ii) cases of BM manifestations of small B cell lymphoid neoplasms other than CLL; (iii) transformation of small B cell lymphoid neoplasms in the BM; and (iv) multiclonality and composite lymphomas in the BM. This report summarizes presented cases and conclusions of the BMW and provides practical recommendations for classification of the BM manifestations of small B cell lymphoid neoplasms based on the current state of knowledge.

  8. Advances in autoimmune lymphoproliferative syndromes.

    PubMed

    Madkaikar, Manisha; Mhatre, Snehal; Gupta, Maya; Ghosh, Kanjaksha

    2011-07-01

    Autoimmune lymphoproliferative syndrome (ALPS) is a disorder of lymphocyte homeostasis. It is characterized by non-malignant lymphoproliferation autoimmunity mostly directed toward blood cells and increased risk of lymphoma. Majority of patients with ALPS harbor heterozygous germline mutations in the gene for the TNF receptor-family member Fas (CD 95, Apo-1) which are inherited in an autosomal dominant fashion. Somatic Fas mutations are the second most common genetic etiology of ALPS. Additionally mutations in the genes encoding Fas-ligand (FASLG), caspase 10 (CASP10) and caspase 8 (CASP8), NRAS and KRAS have been identified in a small number of patients with ALPS and related disorders. Approximately one-third of patients with ALPS have yet unidentified defect. ALPS was initially thought to be a very rare disease, but recent studies have shown that it may be more common than previously thought. Testing for ALPS should therefore be considered in patients with unexplained lymphadenopathy, cytopenias, and hepatosplenomegaly. There have been significant advances in the understanding of the pathophysiology of ALPS in last few years which has resulted in the development of new diagnostic criteria and a number of targeted therapies. This review describes the clinical and laboratory manifestations found in patients with ALPS, as well as the molecular basis for the disease and new advances in treatment.

  9. Frequency of monoclonal B-cell lymphocytosis in relatives of patients with chronic lymphocytic leukemia

    PubMed Central

    Franco Alzate, Catalina; Rendón Henao, Javier; Torres Hernández, José Domingo; Jaramillo Arbelaez, Patricia Elena

    2016-01-01

    Introduction: Monoclonal B-cell lymphocytosis is a symptom free condition characterized by the circulation of small clonal population of B lymphocytes in peripheral blood (less than 5x109/L) expressing an immunophenotype similar to chronic lymphocytic leukemia. Different studies based on big hospital series have manifested a higher risk in subjects with monoclonal B-cell lymphocytosis to progress to a chronic lymphocytic leukemia. The behavior of this hematologic entity is unknown therefore its frequency in sporadic chronic lymphocytic leukemia patient relatives was determined. Methods: Transversal descriptive study, 8 color flow cytometry was performed using two of the tubes of the Euro Flow recommended panel, with modifications, for the diagnose of chronic lymphoproliferative disorders of B lymphocytes; besides, a fluorescence in situ hybridization was performed. univariate and bivariate analyses of the information were performed. Results: Monoclonal B-cell lymphocytosis frequency found in 51 analyzed relatives was 2%, it was a female participant, 59 years old, with a total leukocyte count of 7.7x109/L and a B lymphocyte count of 0.124x109/L; from these, 0.04x109/L were clonal cells with restrictions of the kappa light chain. Rearrangements of the IGH gene (14q32) were found. Conclusion: Monoclonal B-cell lymphocytosis was detected in one relative of a patient with sporadic chronic lymphocytic leukemia in a frequency similar to the one reported in general population. PMID:27546929

  10. How I treat autoimmune lymphoproliferative syndrome.

    PubMed

    Rao, V Koneti; Oliveira, João Bosco

    2011-11-24

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

  11. Disturbed B-lymphocyte selection in autoimmune lymphoproliferative syndrome.

    PubMed

    Janda, Ales; Schwarz, Klaus; van der Burg, Mirjam; Vach, Werner; Ijspeert, Hanna; Lorenz, Myriam Ricarda; Elgizouli, Magdeldin; Pieper, Kathrin; Fisch, Paul; Hagel, Joachim; Lorenzetti, Raquel; Seidl, Maximilian; Roesler, Joachim; Hauck, Fabian; Traggiai, Elisabetta; Speckmann, Carsten; Rensing-Ehl, Anne; Ehl, Stephan; Eibel, Hermann; Rizzi, Marta

    2016-05-05

    Fas is a transmembrane receptor involved in the maintenance of tolerance and immune homeostasis. In murine models, it has been shown to be essential for deletion of autoreactive B cells in the germinal center. The role of Fas in human B-cell selection and in development of autoimmunity in patients carrying FAS mutations is unclear. We analyzed patients with either a somatic FAS mutation or a germline FAS mutation and somatic loss-of-heterozygosity, which allows comparing the fate of B cells with impaired vs normal Fas signaling within the same individual. Class-switched memory B cells showed: accumulation of FAS-mutated B cells; failure to enrich single V, D, J genes and single V-D, D-J gene combinations of the B-cell receptor variable region; increased frequency of variable regions with higher content of positively charged amino acids; and longer CDR3 and maintenance of polyreactive specificities. Importantly, Fas-deficient switched memory B cells showed increased rates of somatic hypermutation. Our data uncover a defect in B-cell selection in patients with FAS mutations, which has implications for the understanding of the pathogenesis of autoimmunity and lymphomagenesis of autoimmune lymphoproliferative syndrome.

  12. Rapamycin improves lymphoproliferative disease in murine autoimmune lymphoproliferative syndrome (ALPS).

    PubMed

    Teachey, David T; Obzut, Dana A; Axsom, Kelly; Choi, John K; Goldsmith, Kelly C; Hall, Junior; Hulitt, Jessica; Manno, Catherine S; Maris, John M; Rhodin, Nicholas; Sullivan, Kathleen E; Brown, Valerie I; Grupp, Stephan A

    2006-09-15

    Autoimmune lymphoproliferative syndrome (ALPS) is a disorder of abnormal lymphocyte survival caused by defective Fas-mediated apoptosis, leading to lymphadenopathy, hepatosplenomegaly, and an increased number of double-negative T cells (DNTs). Treatment options for patients with ALPS are limited. Rapamycin has been shown to induce apoptosis in normal and malignant lymphocytes. Since ALPS is caused by defective lymphocyte apoptosis, we hypothesized that rapamycin would be effective in treating ALPS. We tested this hypothesis using rapamycin in murine models of ALPS. We followed treatment response with serial assessment of DNTs by flow cytometry in blood and lymphoid tissue, by serial monitoring of lymph node and spleen size with ultrasonography, and by enzyme-linked immunosorbent assay (ELISA) for anti-double-stranded DNA (dsDNA) antibodies. Three-dimensional ultrasound measurements in the mice correlated to actual tissue measurements at death (r = .9648). We found a dramatic and statistically significant decrease in DNTs, lymphadenopathy, splenomegaly, and autoantibodies after only 4 weeks when comparing rapamycin-treated mice with controls. Rapamycin induced apoptosis through the intrinsic mitochondrial pathway. We compared rapamycin to mycophenolate mofetil, a second-line agent used to treat ALPS, and found rapamycin's control of lymphoproliferation was superior. We conclude that rapamycin is an effective treatment for murine ALPS and should be explored as treatment for affected humans.

  13. Treatment of B-cell disorder improves renal outcome of patients with monoclonal gammopathy-associated C3 glomerulopathy.

    PubMed

    Chauvet, Sophie; Frémeaux-Bacchi, Véronique; Petitprez, Florent; Karras, Alexandre; Daniel, Laurent; Burtey, Stéphane; Choukroun, Gabriel; Delmas, Yahsou; Guerrot, Dominique; François, Arnaud; Le Quintrec, Moglie; Javaugue, Vincent; Ribes, David; Vrigneaud, Laurence; Arnulf, Bertrand; Goujon, Jean Michel; Ronco, Pierre; Touchard, Guy; Bridoux, Frank

    2017-03-16

    The high frequency of monoclonal gammopathy in adult patients with C3 glomerulopathy (C3G) emphasizes the role of monoclonal immunoglobulin (MIg) in the occurrence of renal disease and raises the issue of the therapeutic management. The aim of the study was to evaluate the effect of chemotherapy in a large cohort of patients with MIg-associated C3G. Fifty adult patients with MIg and biopsy-proven C3G were extracted from the French national database of C3G. We retrospectively compared renal outcomes in patients who either received or did not receive chemotherapy targeting the underlying B-cell clone. At diagnosis, renal disease was severe, with nephrotic-range proteinuria in 20/46 (43%) patients and chronic kidney disease stage 3 or above in 42/49 (86%) patients. Monoclonal gammopathy was of IgG type in 47 (94%) patients. Hematological diagnosis was monoclonal gammopathy of renal significance in 30 (60%), multiple myeloma in 17 (34%), and chronic lymphocytic leukemia in 3 (6%) patients. Complement studies showed low C3 level in 22/50 (43%) and elevated soluble C5b-9 level in 27/34 (79%) patients. Twenty-nine patients received chemotherapy (including bortezomib in 22), whereas 8 and 13 patients received various immunosuppressive drugs or symptomatic measures alone, respectively. Patients who achieved hematological response after chemotherapy had higher renal response rates (P = .0001) and median renal survival (hazard ratio, 0.22; 95% confidence interval, 0.05-0.92; P = .009) than those receiving conservative/immunosuppressive therapy. In conclusion, our results suggest that chemotherapy adapted to the B-cell clone may constitute an efficient strategy for C3G in the setting of MIg, as rapid achievement of hematological response appears to result in improved renal survival.

  14. Identification of distinct subgroups of EBV-positive post-transplant diffuse large B-cell lymphoma.

    PubMed

    Morscio, Julie; Finalet Ferreiro, Julio; Vander Borght, Sara; Bittoun, Emilie; Gheysens, Olivier; Dierickx, Daan; Verhoef, Gregor; Wlodarska, Iwona; Tousseyn, Thomas

    2017-03-01

    Post-transplantation lymphoproliferative disorder is an aggressive complication of transplantation, most frequently of diffuse large B-cell lymphoma morphology and associated with Epstein-Barr virus (EBV) infection/reactivation. In this study the microenvironment of EBV(+) (n=23) and EBV(-) (n=9) post-transplant non-germinal center B-cell diffuse large B-cell lymphoma was characterized. Of EBV(+) cases somatic hypermutation analysis, gene expression profiling, and extensive phenotyping were performed. Our results demonstrated variable cytotoxic T-cell infiltration and significantly increased CD163(+) M2 macrophage infiltration in EBV(+) compared with EBV(-) post-transplant diffuse large B-cell lymphoma. On the basis of IgM staining and hypermutation analysis, two EBV(+) post-transplant diffuse large B-cell lymphoma subgroups were identified: IgM(+) tumors lacking somatic hypermutations and IgM(-) tumors harboring somatic hypermutations. IgM(-) tumors arose late following transplantation (median interval: 16 months), mainly in kidney recipients. IgM(+) tumors on the other hand arose early (median interval: 3 months, P-value=0.0032), almost exclusively following stem cell transplantation and were associated with worse outcome (median survival 1 month for IgM(+) versus 41 months for IgM(-) tumors, log-rank/Wilcoxon P-value 0.07/0.04). Notably, IgM(+) tumors were characterized by plasma cell features (monotypic kappa/lambda expression, high MUM1 expression, and partial CD138 expression) and a high proliferation index. Consistent with the plasma cell phenotype, unfolded protein response signaling was upregulated. In contrast, IgM(-) EBV(+) post-transplant diffuse large B-cell lymphoma did not express kappa, lambda, IgD, or CD138 and expressed limited MUM1. In these tumors T-cell signaling was enhanced associated with increased T-cell infiltration compared with IgM(+) cases. Overall, our results allow further molecular classification of EBV(+) post-transplant diffuse

  15. iNKT and memory B-cell alterations in HHV-8 multicentric Castleman disease.

    PubMed

    Sbihi, Zineb; Dossier, Antoine; Boutboul, David; Galicier, Lionel; Parizot, Christophe; Emarre, Amandine; Hoareau, Bénédicte; Dupin, Nicolas; Marcelin, Anne-Geneviève; Oudin, Anne; Fieschi, Claire; Agbalika, Félix; Autran, Brigitte; Oksenhendler, Eric; Carcelain, Guislaine

    2017-02-16

    Human herpesvirus 8 (HHV-8) is the causative agent of Kaposi sarcoma (KS) and multicentric Castleman disease (MCD), a life-threatening, virally induced B-cell lymphoproliferative disorder. HHV-8 is a B-lymphotropic γ-herpesvirus closely related to the Epstein-Barr virus (EBV). Invariant natural killer T (iNKT) cells are innate-like T cells that play a role in antiviral immunity, specifically in controlling viral replication in EBV-infected B cells. Decline of iNKT cells is associated with age or HIV infection, both situations associated with HHV-8-related diseases. We analyzed iNKT cells in both blood (n = 26) and spleen (n = 9) samples from 32 patients with HHV-8 MCD and compared them with patients with KS (n = 24) and healthy donors (n = 29). We determined that both circulating and splenic iNKT cell frequencies were markedly decreased in patients with HHV-8 MCD and were undetectable in 6 of them. Moreover, iNKT cells from patients with HHV-8 MCD displayed a proliferative defect after stimulation with α-galactosylceramide. These iNKT cell alterations were associated with an imbalance in B-cell subsets, including a significant decrease in memory B cells, particularly of marginal zone (MZ) B cells. Coculture experiments revealed that the decrease in iNKT cells contributed to the alterations in the B-cell subset distribution. These observations contribute to a better understanding of the complex interactions between HHV-8 and immune cells that cause HHV-8-related MCD.

  16. Differential and tumor-specific expression of CD160 in B-cell malignancies

    PubMed Central

    Farren, Timothy W.; Giustiniani, Jerome; Liu, Feng-Ting; Tsitsikas, Dimitris A.; Macey, Marion G.; Cavenagh, James D.; Oakervee, Heather E.; Taussig, David; Newland, Adrian C.; Calaminici, Maria; Bensussan, Armand; Jenner, Michael; Gribben, John G.

    2011-01-01

    CD160 is a human natural killer (NK)-cell–activating receptor that is also expressed on T-cell subsets. In the present study, we examined 811 consecutive cases of B-cell lymphoproliferative disorders (B-LPDs), and demonstrated CD160 expression in 98% (590 of 600) of chronic lymphocytic leukemia (CLL) cases, 100% (32 of 32) of hairy cell leukemia (HCL) cases, 15% (5 of 34) of mantle cell lymphoma (MCL) in the leukemic phase, and 16% (23 of 145) of other B-LPD cases. CD160 transcript and protein were absent in the normal B-cell hierarchy, from stem cells, B-cell precursors, maturing B cells in the germinal center, and circulating B cells, including CD5+CD19+ B1 cells in umbilical cord. CD160 positivity was significantly higher in CLL and HCL in terms of percentage (65.9% and 67.8%, respectively, P < .0001) and median fluorescence intensity (552 and 857, respectively, P < .0001) compared with all other B-LPD cases. Lymph node CLL samples were also CD160+. Using the disease-specific expression of CD5, CD23, and CD160, a score of 3 characterized CLL (diagnostic odds ratio, 1430); a score of 0 excluded CLL, MCL, and HCL; and the CD23/CD5 ratio differentiated CLL from leukemic CD23+ MCL. In the B-cell lineage, CD160 is a tumor-specific antigen known to mediate cellular activation signals in CLL, and is a novel target for therapeutic manipulation and monitoring of minimal residual disease. PMID:21715317

  17. [Autoimmune lymphoproliferative syndrome].

    PubMed

    Rodrigues, Vera; Conde, Marta; Figueiredo, António; Vasconcelos, Júlia; Dias, Alexandra

    2011-01-01

    The Autoimmune Lymphoproliferative Syndrome (ALPS) is an impairment of lymphocyte apoptosis expressed by generalized non-malignant lymphoproliferation, lymphadenopathy and/or splenomegaly. This article describes a seven and 14 year old males. The first one was admitted at 3 years of age with fever, bicytopenia and generalized lymphadenopathy. Hystopathological analysis of lymph nodes showed reactive follicular hyperplasia and marked paracortical expansion. He was readmitted three years later presenting herpes zoster and similar clinical features. High levels of IL-10 and increasing tendency of Fas-L in plasma and serum. The second child was admitted at 13 years of age presenting thigh and gluteus cellulitis, anemia and neutropenia. T lymphocytes aß+CD4-CD8- 3,1%. Hystopathological analysis of lymph nodes showed marked paracortical hyperplasia. Both children are treated with mycophenolate mofetil with good response. ALPS is an underestimated entity that must be considered in non malign lymphoproliferation, autoimmunity and expansion of an unusual population of a/ßCD3+CD4-CD8-(double-negative T cells>1%).

  18. 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

  19. Monoclonal B-cell lymphocytosis (MBL, CD4+/CD8 weak T-cell large granular lymphocytic leukemia (T-LGL leukemia) and monoclonal gammopathy of unknown significance (MGUS): molecular and flow cytometry characterization of three concomitant hematological disorders.

    PubMed

    Matos, Daniel Mazza; de Oliveira, Ana Cesarina Vitoriano; Tomé, Maria de Nazaré Amaral; Scrideli, Carlos Alberto

    2012-12-01

    The diagnosis of T-cell large granular lymphocytic leukemia in association with other B-cell disorders is uncommon but not unknown. However, the concomitant presence of three hematological diseases is extraordinarily rare. We report an 88-year-old male patient with three simultaneous clonal disorders, that is, CD4+/CD8(weak) T-cell large granular lymphocytic leukemia, monoclonal gammopathy of unknown significance and monoclonal B-cell lymphocytosis. The patient has only minimal complaints and has no anemia, neutropenia or thrombocytopenia. Lymphadenopathy and hepatosplenomegaly were not present. The three disorders were characterized by flow cytometry analysis, and the clonality of the T-cell large granular lymphocytic leukemia was confirmed by polymerase chain reaction. Interestingly, the patient has different B-cell clones, given that plasma cells of monoclonal gammopathy of unknown significance exhibited a kappa light-chain restriction population and, on the other hand, B-lymphocytes of monoclonal B-cell lymphocytosis exhibited a lambda light-chain restriction population. This finding does not support the antigen-driven hypothesis for the development of multi-compartment diseases, but suggests that T-cell large granular lymphocytic expansion might represent a direct antitumor immunological response to both B-cell and plasma-cell aberrant populations, as part of the immune surveillance against malignant neoplasms.

  20. Clinical and immunological overlap between autoimmune lymphoproliferative syndrome and common variable immunodeficiency.

    PubMed

    Rensing-Ehl, A; Warnatz, K; Fuchs, S; Schlesier, M; Salzer, U; Draeger, R; Bondzio, I; Joos, Y; Janda, A; Gomes, M; Abinun, M; Hambleton, S; Cant, A; Shackley, F; Flood, T; Waruiru, C; Beutel, K; Siepermann, K; Dueckers, G; Niehues, T; Wiesel, T; Schuster, V; Seidel, M G; Minkov, M; Sirkiä, K; Kopp, M V; Korhonen, M; Schwarz, K; Ehl, S; Speckmann, C

    2010-12-01

    Autoimmune lymphoproliferative syndrome (ALPS) is mainly caused by defects in the CD95 pathway. Raised CD3+TCRαβ+CD4-CD8- double negative T cells and impaired T cell apoptosis are hallmarks of the disease. In contrast, the B cell compartment has been less well studied. We found an altered distribution of B cell subsets with raised transitional B cells and reduced marginal zone B cells, switched memory B cells and plasma blasts in most of 22 analyzed ALPS patients. Moreover, 5 out of 66 ALPS patients presented with low IgG and susceptibility to infection revealing a significant overlap between ALPS and common variable immunodeficiency (CVID). In patients presenting with lymphoproliferation, cytopenia, hypogammaglobulinemia and impaired B cell differentiation, serum biomarkers were helpful in addition to apoptosis tests for the identification of ALPS patients. Our observations may indicate a role for apoptosis defects in some diseases currently classified as CVID.

  1. Distribution of lymphocytes with interleukin-2 receptors (TAC antigens) in reactive lymphoproliferative processes, Hodgkin's disease, and non-Hodgkin's lymphomas. An immunohistologic study of 300 cases.

    PubMed Central

    Sheibani, K.; Winberg, C. D.; van de Velde, S.; Blayney, D. W.; Rappaport, H.

    1987-01-01

    The authors investigated the distribution of interleukin-2 receptors (TAC antigen) in the lymph nodes of 300 patients with lymphoproliferative disorders. They used fresh-frozen sections to evaluate a possible correlation between the immunophenotype of specific lymphoid disorders and the presence or absence of TAC expression and to determine whether the TAC positivity of lymphoid cells contributes to the characterization of lymphoproliferative processes. All of the cases had previously been studied with a large screening panel of monoclonal antibodies and polyclonal antisera. Among 85 patients with a variety of benign reactive processes, the lymph nodes from 47 contained TAC-bearing lymphocytes in various patterns of distribution. Of 41 patients with Hodgkin's disease, 37 had TAC-bearing lymphocytes. Of 26 B-cell, well-differentiated lymphocytic lymphomas (WDL), 14 were diffusely TAC-positive and one had TAC-bearing cells in random distribution. Six cases of intermediate lymphocytic lymphoma were also studied, and three showed randomly distributed TAC-bearing lymphocytes. Of 19 patients with follicular or follicular and diffuse, poorly differentiated lymphocytic (PDL) lymphoma, 14 were TAC-positive. All 3 diffuse PDL lymphomas studied were TAC-negative. Among 23 cases of B-cell and 5 cases of T-cell mixed cell lymphoma, 15 and three, respectively, had TAC-positive lymphocytes. Of 39 large cell lymphomas (B-cell, 33; T-cell, 6), 14 were TAC-positive. All 13 cases of hairy cell leukemia were diffusely positive. Of 23 T-lymphoblastic lymphomas, only 1 showed positive TAC reactivity, which was focal. Of 5 cases of cutaneous T-cell lymphoma, 2 had TAC-bearing lymphocytes. Our study indicates that the TAC antigen is not lineage-specific, and that it may be expressed by lymphoid cells regardless of their phenotype. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 PMID:3105322

  2. Hepatitis C virus - associated B cell non-Hodgkin's lymphoma

    PubMed Central

    Mihăilă, Romeo-Gabriel

    2016-01-01

    The hepatitis C virus (HCV) infected patients are prone to develop bone marrow or various tissue infiltrates with monoclonal B cells, monoclonal B lymphocytosis or different types of B cell non-Hodgkin’s lymphoma (BCNHL), of which the most common are splenic marginal zone BCNHL, diffuse large BCNHL and follicular lymphoma. The association between chronic HCV infection and non Hodgkin’s lymphoma has been observed especially in areas with high prevalence of this viral infection. Outside the limitations of some studies that have been conducted, there are also geographic, environmental, and genetic factors that contribute to the epidemiological differences. Various microenvironmental signals, such as cytokines, viral antigenic external stimulation of lymphocyte receptors by HCV antigens, and intercellular interactions contribute to B cell proliferation. HCV lymphotropism and chronic antigenic stimulation are involved in B-lymphocyte expansion, as mixted cryoglobulinemia or monoclonal gammopathy of undetermined significance, which can progress to BCNHL. HCV replication in B lymphocytes has oncogenic effect mediated by intracellular HCV proteins. It is also involved in an important induction of reactive oxygen species that can lead to permanent B lymphocyte damage, as DNA mutations, after binding to surface B-cell receptors. Post-transplant lymphoproliferative disorder could appear and it has a multiclonal potentiality that may develop into different types of lymphomas. The hematopoietic stem cell transplant made for lymphoma in HCV-infected patients can increase the risk of earlier progression to liver fibrosis and cirrhosis. HCV infected patients with indolent BCNHL who receive antiviral therapy can be potentially cured. Viral clearance was related to lymphoma response, fact that highlights the probable involvement of HCV in lymphomagenesis. Direct acting antiviral drugs could be a solution for the patients who did not tolerate or respond to interferon, as they

  3. Epstein-Barr viral load in whole blood of adults with posttransplant lymphoproliferative disorder after solid organ transplantation does not correlate with clinical course.

    PubMed

    Oertel, Stephan; Trappe, Ralf Ulrich; Zeidler, Kristin; Babel, Nina; Reinke, Petra; Hummel, Manfred; Jonas, Sven; Papp-Vary, Matthias; Subklewe, Marion; Dörken, Bernd; Riess, Hanno; Gärtner, Barbara

    2006-07-01

    Posttransplant lymphoproliferative disease (PTLD) is closely linked to primary Epstein-Barr virus (EBV) infection. A defect of EBV specific cellular immunity is postulated to play a pivotal role in the etiology of PTLD, but there is some debate as to whether EBV load in the peripheral blood of transplant patients predicts onset of PTLD or relapse after treatment. The current prospective, single-center study was undertaken to investigate the impact of therapy on EBV load in adult patients with PTLD. Fifteen patients with PTLD after solid organ transplantation were included and of these, seven had EBV-associated PTLD. All 15 patients received Rituximab as primary therapy. In cases of treatment failure or relapse after Rituximab treatment, patients received polychemotherapy according to the cyclophosphamide, vincristine, doxorubicin, and prednisone regimen. At onset of PTLD, the median EBV load in the peripheral blood of patients was higher in EBV-associated PTLD than PTLD with no associated EBV infection. After Rituximab therapy, four of seven patients with EBV-associated PTLD achieved long-lasting complete remissions. However, in two of these patients, EBV load increased to reach levels as high as those recorded at onset of PTLD. Another patient showed a dramatic decline of EBV load after the first dose of Rituximab while suffering from progressive disease. The other patient relapsed after Rituximab monotherapy, but his viral load stayed low. In total, discordance in EBV load and clinical course was observed in five of the seven patients with EBV-associated PTLD. We conclude that in adult patients with PTLD, EBV load does not correlate with treatment response and is not suitable as a predictive marker for PTLD relapse.

  4. Molecular signature of Epstein Barr virus-positive Burkitt lymphoma and post-transplant lymphoproliferative disorder suggest different roles for Epstein Barr virus

    PubMed Central

    Navari, Mohsen; Fuligni, Fabio; Laginestra, Maria A.; Etebari, Maryam; Ambrosio, Maria R.; Sapienza, Maria R.; Rossi, Maura; De Falco, Giulia; Gibellini, Davide; Tripodo, Claudio; Pileri, Stefano A.; Leoncini, Lorenzo; Piccaluga, Pier P.

    2014-01-01

    Epstein Barr virus (EBV) infection is commonly associated with human cancer and, in particular, with lymphoid malignancies. Although the precise role of the virus in the pathogenesis of different lymphomas is largely unknown, it is well recognized that the expression of viral latent proteins and miRNA can contribute to its pathogenetic role. In this study, we compared the gene and miRNA expression profile of two EBV-associated aggressive B non-Hodgkin lymphomas known to be characterized by differential expression of the viral latent proteins aiming to dissect the possible different contribution of such proteins and EBV-encoded miRNAs. By applying extensive bioinformatic inferring and an experimental model, we found that EBV+ Burkitt lymphoma presented with significant over-expression of EBV-encoded miRNAs that were likely to contribute to its global molecular profile. On the other hand, EBV+ post-transplant diffuse large B-cell lymphomas presented a significant enrichment in genes regulated by the viral latent proteins. Based on these different viral and cellular gene expression patterns, a clear distinction between EBV+ Burkitt lymphoma and post-transplant diffuse large B-cell lymphomas was made. In this regard, the different viral and cellular expression patterns seemed to depend on each other, at least partially, and the latency type most probably played a significant role in their regulation. In conclusion, our data indicate that EBV influence over B-cell malignant clones may act through different mechanisms of transcriptional regulation and suggest that potentially different pathogenetic mechanisms may depend upon the conditions of the interaction between EBV and the host that finally determine the latency pattern. PMID:25566237

  5. Epstein-Barr virus-positive cytotoxic T-cell lymphoma followed by chronic active Epstein-Barr virus infection-associated T/NK-cell lymphoproliferative disorder: a case report.

    PubMed

    Kato, Seiichi; Miyata, Tomoko; Takata, Katsuyoshi; Shimada, Satoko; Ito, Yoshinori; Tomita, Akihiro; Elsayed, Ahmed Ali; Takahashi, Emiko; Asano, Naoko; Kinoshita, Tomohiro; Kimura, Hiroshi; Nakamura, Shigeo

    2013-12-01

    A 30-year-old female patient presented with intestinal Epstein-Barr virus (EBV)-positive cytotoxic T-cell lymphoma (EBV+ CTL), which was surgically resected. Fourteen years later, she returned to our hospital with hypersensitivity to mosquito bites and was diagnosed with chronic active EBV infection-associated T/NK-cell lymphoproliferative disorder (CAEBV/TNK-LPD). She developed systemic EBV+ CTL at age 47 years during the 2.5-year clinical course of CAEBV/TNK-LPD, despite multiagent chemotherapy and allogeneic stem cell transplantation. Afterward, she had a rapidly deteriorating clinical course and died at age 48 years. The immunophenotype of the EBV+ CTL was consistently a CD3, CD8, and cytotoxic molecule-positive type with the same clonality in polymerase chain reaction analysis of T-cell receptor-γ chain gene rearrangement. This is the first reported case of EBV+ CTL preceding the clinical presentation of CAEBV/TNK-LPD. The present case was unique in suggesting a close relationship between EBV+ CTL and chronic active EBV infection.

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

    PubMed

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

    2010-10-07

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

  7. T cell-rich lymphoid infiltrates with large B cells: a review of key entities and diagnostic approach.

    PubMed

    Cheng, Chee Leong; O'Connor, Simon

    2017-03-01

    Accurate diagnostic interpretation of a lymphoid population composed predominantly of small T cells, together with smaller numbers of large B cells, with or without a nodular architecture, is a common problem faced by the histopathologist. The differential diagnosis of this histological pattern is wide, ranging from reactive conditions such as drug reactions and viral infections, through borderline entities such as immunodeficiency-related lymphoproliferative disorders to lymphomas. The latter includes entities where the large B cells are primarily neoplastic (classical and nodular lymphocyte-predominant Hodgkin lymphomas and T cell/histiocyte-rich large B cell lymphoma) as well as T cell lymphomas such as angioimmunoblastic T cell lymphoma where the large B cells represent an epiphenomenon and may or may not be neoplastic. Several rare variants of these conditions, and the fact that treatment can significantly modify appearances, add to the diagnostic difficulty of these pathological entities. Unlike monomorphic lymphoid infiltrates, the histological pattern of T cell-rich proliferation with large B cells requires close evaluation of the inter-relationship between B cells and T cells, follicular dendritic cells and sometimes other inflammatory cells. Epstein-Barr virus plays a key role in several of these scenarios, and interpreting not only its presence but also its distribution within cellular subgroups is essential to accurate diagnosis and the avoidance of some important diagnostic pitfalls. An understanding of normal immunoarchitecture and lymphoid maturational pathways is also fundamental to resolving these cases, as is a knowledge of their common patterns of spread, which facilitates correlation with clinical and radiological findings.

  8. How I treat autoimmune lymphoproliferative syndrome

    PubMed Central

    Oliveira, João Bosco

    2011-01-01

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

  9. Childhood polyarteritis nodosa in autoimmune lymphoproliferative syndrome.

    PubMed

    Naumann-Bartsch, Nora; Stachel, Daniel; Morhart, Patrick; Staatz, Gundula; Jüngert, Jörg; Schwarz, Klaus; Holter, Wolfgang

    2010-01-01

    Autoimmune lymphoproliferative syndrome (ALPS) is an uncommon disorder of Fas-mediated apoptosis that results in impaired lymphocyte death and, therefore, disturbed immune homeostasis. Besides presentation with lymphadenopathy and splenomegaly, patients with ALPS have a high incidence of autoimmune phenomena. To our knowledge, this is the first description of polyarteritis nodosa that includes numerous arterial aneurysms in a child with ALPS. Active vasculitis resolved after allogeneic hematopoietic stem cell transplantation. This report of polyarteritis nodosa associated with human ALPS supports previous findings in Fas-deficient mouse models that frequently develop vasculitic manifestations and suggests that apoptotic defects of lymphocytes may play a role in the pathophysiology of systemic vasculitis. Thus, patients with ALPS might be more susceptible to autoimmune vessel inflammation. This case furthermore emphasizes that even rare autoimmune manifestations should be considered and investigated in patients with immunodeficiencies, because that might help in planning treatment strategies for these patients.

  10. B cell helper assays.

    PubMed

    Abrignani, Sergio; Tonti, Elena; Casorati, Giulia; Dellabona, Paolo

    2009-01-01

    Activation, proliferation and differentiation of naïve B lymphocytes into memory B cells and plasma cells requires engagement of the B cell receptor (BCR) coupled to T-cell help (1, 2). T cells deliver help in cognate fashion when they are activated upon recognition of specific MHC-peptide complexes presented by B cells. T cells can also deliver help in a non-cognate or bystander fashion, when they do not find specific MHC-peptide complexes on B cells and are activated by alternative mechanisms. T-cell dependent activation of B cells can be studied in vitro by experimental models called "B cell helper assays" that are based on the co-culture of B cells with activated T cells. These assays allow to decipher the molecular bases for productive T-dependent B cell responses. We show here examples of B cell helper assays in vitro, which can be reproduced with any subset of T lymphocytes that displays the appropriate helper signals.

  11. Proposed categorization of pathological states of EBV-associated T/natural killer-cell lymphoproliferative disorder (LPD) in children and young adults: overlap with chronic active EBV infection and infantile fulminant EBV T-LPD.

    PubMed

    Ohshima, Koichi; Kimura, Hiroshi; Yoshino, Tadashi; Kim, Chul Woo; Ko, Young H; Lee, Seung-Suk; Peh, Suat-Cheng; Chan, John K C

    2008-04-01

    EBV-associated T/natural killer (NK)-cell lymphoproliferative disorder (EBV-T/NK LPD) of children and young adults is generally referred to with the blanket nosological term of severe chronic active EBV infection (CAEBV). This disease is rare, associated with high morbidity and mortality, and appears to be more prevalent in East Asian countries. But because there is no grading or categorization system for CAEBV, pathologists and clinicians often disagree regarding diagnosis and therapy. EBV-T/NK LPD includes polyclonal, oligoclonal, and monoclonal proliferation of cytotoxic T and/or NK cells. Moreover, a unique disease previously described as infantile fulminant EBV-associated T-LPD has been identified and overlaps with EBV-T/NK LPD. In the present review a clinicopathological categorization of EBV-T/NK LPD is proposed, based on pathological evaluation and molecular data, as follows: (i) category A1, polymorphic LPD without clonal proliferation of EBV-infected cells; (ii) category A2, polymorphic LPD with clonality; (iii) category A3, monomorphic LPD (T-cell or NK cell lymphoma/leukemia) with clonality; and (iv) category B, monomorphic LPD (T-cell lymphoma) with clonality and fulminant course. Categories A1, A2, and A3 possibly constitute a continuous spectrum and together are equivalent to CAEBV. Category B is the exact equivalent of infantile fulminant EBV-associated T-LPD. It is expected that this categorization system will provide a guide for the better understanding of this disorder. This proposal was approved at the third meeting of the Asian Hematopathology Association (Nagoya, 2006).

  12. EBV Zta protein induces the expression of interleukin-13, promoting the proliferation of EBV-infected B cells and lymphoblastoid cell lines

    PubMed Central

    Tsai, Shu-Chun; Lin, Sue-Jane; Chen, Po-Wen; Luo, Wen-Yi; Yeh, Te-Huei; Wang, Hsei-Wei; Chen, Chi-Ju

    2009-01-01

    Epstein-Barr virus (EBV) infection can modify the cytokine expression profiles of host cells and determine the fate of those cells. Of note, expression of interleukin-13 (IL-13) may be detected in EBV-associated Hodgkin lymphoma and the natural killer (NK) cells of chronic active EBV-infected patients, but its biologic role and regulatory mechanisms are not understood. Using cytokine antibody arrays, we found that IL-13 production is induced in B cells early during EBV infection. Furthermore, the EBV lytic protein, Zta (also known as the BZLF-1 product), which is a transcriptional activator, was found to induce IL-13 expression following transfection. Mechanistically, induction of IL-13 expression by Zta is mediated directly through its binding to the IL-13 promoter, via a consensus AP-1 binding site. Blockade of IL-13 by antibody neutralization showed that IL-13 is required at an early stage of EBV-induced proliferation and for long-term maintenance of the growth of EBV immortalized lymphoblastoid cell lines (LCLs). Thus, Zta-induced IL-13 production facilitates B-cell proliferation and may contribute to the pathogenesis of EBV-associated lymphoproliferative disorders, such as posttransplantation lymphoproliferative disease (PTLD) and Hodgkin lymphoma. PMID:19417211

  13. First-line use of rituximab correlates with increased overall survival in late post-transplant lymphoproliferative disorders: retrospective, single-centre study.

    PubMed

    Martínez-Calle, Nicolás; Alfonso, Ana; Rifón, José; Herrero, Ignacio; Errasti, Pedro; Rábago, Gregorio; Merino, Juana; Panizo, Ángel; Pardo, Javier; Prósper, Felipe; García-Muñoz, Ricardo; Lecumberri, Ramón; Panizo, Carlos

    2017-01-01

    This retrospective study evaluates the impact of rituximab on PTLD response and survival in a single-centre cohort. PTLD cases between 1984 and 2009, including heart, kidney, liver and lung transplant recipients, were included. Survival was analysed taking into account the type of PTLD (monomorphic vs. polymorphic), EBV infection status, IPI score, Ann Arbor stage and use of rituximab. Among 1335 transplanted patients, 24 developed PTLD. Median age was 54 yr (range 29-69), median time to diagnosis 50 months (range 0-100). PTLD type was predominantly late/monomorphic (79% and 75%), mostly diffuse large B-cell type. Overall response rate (ORR) was 62% (66% rituximab vs. 50% non-rituximab; P = 0.5). R-CHOP-like regimens were used most frequently (72% of patients treated with rituximab). Median overall survival was 64 months (CI 95% 31-96). OS was significantly increased in patients treated with rituximab (P = 0.01; CI 95% rituximab 58-79 months; non-rituximab 1-30 months). Post-transplant immunosuppression regimen had no effect on survival or time to PTLD, except for cyclosporine A (CyA), which associated with increased time to PTLD (P = 0.02). Rituximab was associated with increased survival in our single-centre series, and it should be considered as first-line therapy for PTLD patients. The possible protective effect of CyA for development of PTLD should be prospectively evaluated.

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

    SciTech Connect

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

    1994-09-01

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

  15. MYD88 L265P in Waldenström macroglobulinemia, immunoglobulin M monoclonal gammopathy, and other B-cell lymphoproliferative disorders using conventional and quantitative allele-specific polymerase chain reaction

    PubMed Central

    Xu, Lian; Hunter, Zachary R.; Yang, Guang; Zhou, Yangsheng; Cao, Yang; Liu, Xia; Morra, Enrica; Trojani, Alessandra; Greco, Antonino; Arcaini, Luca; Varettoni, Maria; Brown, Jennifer R.; Tai, Yu-Tzu; Anderson, Kenneth C.; Munshi, Nikhil C.; Patterson, Christopher J.; Manning, Robert J.; Tripsas, Christina K.; Lindeman, Neal I.

    2013-01-01

    By whole-genome and/or Sanger sequencing, we recently identified a somatic mutation (MYD88 L265P) that stimulates nuclear factor κB activity and is present in >90% of Waldenström macroglobulinemia (WM) patients. MYD88 L265P was absent in 90% of immunoglobulin M (IgM) monoclonal gammopathy of undetermined significance (MGUS) patients. We therefore developed conventional and real-time allele-specific polymerase chain reaction (AS-PCR) assays for more sensitive detection and quantification of MYD88 L265P. Using either assay, MYD88 L265P was detected in 97 of 104 (93%) WM and 13 of 24 (54%) IgM MGUS patients and was either absent or rarely expressed in samples from splenic marginal zone lymphoma (2/20; 10%), CLL (1/26; 4%), multiple myeloma (including IgM cases, 0/14), and immunoglobulin G MGUS (0/9) patients as well as healthy donors (0/40; P < 1.5 × 10−5 for WM vs other cohorts). Real-time AS-PCR identified IgM MGUS patients progressing to WM and showed a high rate of concordance between MYD88 L265P ΔCT and BM disease involvement (r = 0.89, P = .008) in WM patients undergoing treatment. These studies identify MYD88 L265P as a widely present mutation in WM and IgM MGUS patients using highly sensitive and specific AS-PCR assays with potential use in diagnostic discrimination and/or response assessment. The finding of this mutation in many IgM MGUS patients suggests that MYD88 L265P may be an early oncogenic event in WM pathogenesis. PMID:23321251

  16. Post-transplantation lymphoproliferative disease of natural killer cell lineage: a clinicopathological and molecular analysis.

    PubMed

    Kwong, Y L; Lam, C C; Chan, T M

    2000-07-01

    Post-transplantation lymphoproliferative disorders (PTLD) occur after solid organ and bone marrow transplantation. They are predominantly of B-cell and occasionally of T-cell lineage. We report a case of PTLD of natural killer (NK) cell lineage. A renal allograft recipient developed progressive pancytopenia 1 year after transplantation. Serial bone marrow biopsies showed an increasing infiltration by large granular lymphoid cells. A subsequent leukaemic phase also developed with systemic infiltration of other organs. Immunophenotyping showed that these cells were CD2+, CD3-, CD3epsilon+, CD56+, CD94+, CD158a- and CD158b-. In situ hybridization showed Epstein-Barr virus (EBV) infection of the neoplastic cells. Genotypical analysis showed the T-cell receptor gene in germline configuration and clonal EBV episomal integration. The overall features were consistent with NK cell lymphoma/leukaemia. The patient did not respond to cessation of immunosuppression or anti-EBV treatment. Combination chemotherapy was given, but the patient died ultimately of disseminated fungal infection. In conclusion, we have demonstrated that NK cell lymphoma is another rare type of PTLD that appears to be highly aggressive and therefore may require early chemotherapy to improve treatment outcome.

  17. Systemic Epstein-Barr virus positive T-cell lymphoproliferative disease of childhood with hemophagocytic syndrome.

    PubMed

    Chen, Guoshu; Chen, Li; Qin, Xiaohua; Huang, Zhuoya; Xie, Xiaoling; Li, Guowei; Xu, Bing

    2014-01-01

    Epstein-Barr virus (EBV) associated lymphoproliferative disease (LPD) are commonly derived from B-cells, however, it is becoming more and more apparently that EBV can also infect T-lymphocytes. Systemic EBV positive T-cell LPD of childhood is rare and characterized by an extremely aggressive course and poor prognosis. Here, we report a 22-year-old female of systemic EBV positive TLPD with acute EBV infection and review the clinical features of this disorder. A 22-year-old previously healthy female without immunocompromised status presented with persisting coach and fever resistant to conventional therapies. Physical examination showed hemorrhage and hepatosplenomegaly. Laboratory examinations revealed severe pancytopenia, disseminated intra-vascular coagulopathy (DIC), and anti-EBV-IgM positivity. Peripheral blood smears and bone marrow investigation identified a number of atypical lymphocytes. Flow cytometry (FCM) did not show any significant evidence of leukemia or lymphoma. The lymph node biopsy showed apparent infiltration of lymphocytes, which expressed CD2+, CD3+, CD7+ and TIA1+. There was no CD20+ or CD56+ cells. EBV early RNA (EBER) was positive. Cytogenetic analysis showed a normal karyotype. T-cell receptor (TCR) gene rearrangement revealed a polyclonal pattern. The patient received prednisolone and IVIG therapy with a transient good condition, and then died of multiorgan failure one week after diagnosis.

  18. Systemic Epstein-Barr virus positive T-cell lymphoproliferative disease of childhood with hemophagocytic syndrome

    PubMed Central

    Chen, Guoshu; Chen, Li; Qin, Xiaohua; Huang, Zhuoya; Xie, Xiaoling; Li, Guowei; Xu, Bing

    2014-01-01

    Epstein-Barr virus (EBV) associated lymphoproliferative disease (LPD) are commonly derived from B-cells, however, it is becoming more and more apparently that EBV can also infect T-lymphocytes. Systemic EBV positive T-cell LPD of childhood is rare and characterized by an extremely aggressive course and poor prognosis. Here, we report a 22-year-old female of systemic EBV positive TLPD with acute EBV infection and review the clinical features of this disorder. A 22-year-old previously healthy female without immunocompromised status presented with persisting coach and fever resistant to conventional therapies. Physical examination showed hemorrhage and hepatosplenomegaly. Laboratory examinations revealed severe pancytopenia, disseminated intra-vascular coagulopathy (DIC), and anti-EBV-IgM positivity. Peripheral blood smears and bone marrow investigation identified a number of atypical lymphocytes. Flow cytometry (FCM) did not show any significant evidence of leukemia or lymphoma. The lymph node biopsy showed apparent infiltration of lymphocytes, which expressed CD2+, CD3+, CD7+ and TIA1+. There was no CD20+ or CD56+ cells. EBV early RNA (EBER) was positive. Cytogenetic analysis showed a normal karyotype. T-cell receptor (TCR) gene rearrangement revealed a polyclonal pattern. The patient received prednisolone and IVIG therapy with a transient good condition, and then died of multiorgan failure one week after diagnosis. PMID:25400806

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

    PubMed

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

    2013-01-01

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

  20. EBV Lymphoproliferative Disease after Hematopoietic Stem Cell Transplant

    PubMed Central

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

    2014-01-01

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

  1. MTHFR C677 T gene polymorphism in lymphoproliferative diseases.

    PubMed

    Deligezer, Ugur; Akisik, Ebru E; Yaman, Fulya; Erten, Nilgün; Dalay, Nejat

    2006-01-01

    Methylenetetrahydrofolate reductase (MTHFR), a key enzyme in folate metabolism, has been implicated in cancer risk. In the present study we used a melting curve analysis to investigate the association of the common MTHFR C677 T polymorphism with lymphoproliferative diseases. Patients (n=117) were compared with age- and sex-matched control subjects (n=154). Our results indicate that the 677 T variant occurred less frequently in patients (26%) than in the control group (33.7%; P=0.05). Investigation of the variant allele (677 T) frequency in the subgroups with Hodgkin's lymphoma (HL) and B-cell neoplasms (BCNs) revealed that this difference was a result of the significantly lower distribution of the variant allele in patients with HL (20.5%; P=0.01). This was accompanied by a significantly higher frequency of the homozygote normal genotype (677CC) among the patients with HL. In patients with BCNs the distribution of the variant allele (30.3%) was comparable to that in the control group (P=0.47). However, the difference between HL (20.5%) and BCNs (30.3%) did not reach statistical significance (P=0.09). Our results suggest that the distribution of the C677 T polymorphism may vary among lymphoproliferative diseases.

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

    PubMed Central

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

    2015-01-01

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

  3. Immune Disorder HSCT Protocol

    ClinicalTrials.gov

    2016-11-01

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

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

    PubMed

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

    2016-02-01

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

  5. Autoimmune lymphoproliferative syndrome with neonatal onset.

    PubMed

    Naveed, Muhammad; Khamis Butt, Umar Bin; Mannan, Jovaria

    2014-05-01

    We describe 2 cases of autoimmune lymphoproliferative syndrome (ALPS), which is a rare disorder of auto-immunity, chronic persistent or recurrent lymphadenopathy, splenomegaly, hepatomegaly and hyper gamma globulinemia (1gG, 1gA). Both cases presented in neonatal period which is a rare age of presentation in this disease. A 20 days old female neonate presented with respiratory symptoms which rapidly progressed needing ventilatory support. There was hepatomegaly and no auscultatory findings in the chest. Serial CBCs (complete blood counts) showed persistent leucocytosis with predominant lymphocytosis. Her chest X-ray showed left sided consolidation which responded poorly to antibiotics. Her prompt clinical response to steroids raised the suspicion of autoimmunity and the diagnosis was established after a negative bone marrow examination for leukemia and a positive result for ALPS on flow cytometry. The second case presented with anemia, thrombocytopenia starting in neonatal period followed by persistent lymphadenopathy, hepatosplenomegaly and recurrent infections which responded poorly to antibiotics. Diagnosis was delayed due to low index of suspicion, and finally achieved with multiple radiological studies, histopathology and flow cytometry.

  6. Pentostatin for treatment of refractory autoimmune lymphoproliferative syndrome.

    PubMed

    Bajwa, Rajinder; Savelli, Stephanie; Gross, Thomas

    2011-08-01

    Autoimmune lymphoproliferative syndrome (ALPS), a disorder of programmed cell death, could be due to a congenital defect in the Fas signaling pathway or other pathways for apoptosis. Most cases present with lymphoproliferation and certain autoimmune features such as thrombocytopenia, neutropenia, and anemia are due to excessive production of antibodies by B lymphocytes. Majority of cases present within the first few years of life. We report a case of ALPS presenting at birth which was refractory to splenectomy and immunosuppressive therapy, but responded to pentostatin followed by hematopoietic stem cell transplantation (HSCT).

  7. Accessory spleen: differential diagnosis for lymphoma in autoimmune lymphoproliferative syndrome.

    PubMed

    Georgin-Lavialle, Sophie; Aouba, Achille; Canioni, Danielle; Rieux-Laucat, Frédéric; Fischer, Alain; Hermine, Olivier

    2010-07-01

    Mutations of Fas or, less frequently, Fas ligand genes result in a rare inherited lymphoid disorder called autoimmune lymphoproliferative syndrome (ALPS) in which lymphoma frequency is increased. We report on a patient with ALPS who had been splenectomized for giant splenomegaly and progressively developed a voluminous abdominal tumor. The histology of the removed tumor revealed that it was an accessory spleen exhibiting typical features of ALPS involvement, as shown by the presence of a large excess of CD3+CD4-CD8- T cells and plasma cells without a detectable monoclonal population. This observation highlights the lymphoma's differential diagnosis in this context.

  8. SAP modulates B cell functions in a genetic background-dependent manner.

    PubMed

    Detre, Cynthia; Yigit, Burcu; Keszei, Marton; Castro, Wilson; Magelky, Erica M; Terhorst, Cox

    2013-06-01

    Mutations affecting the SLAM-associated protein (SAP) are responsible for the X-linked lympho-proliferative syndrome (XLP), a severe primary immunodeficiency syndrome with disease manifestations that include fatal mononucleosis, B cell lymphoma and dysgammaglobulinemia. It is well accepted that insufficient help by SAP-/- CD4+ T cells, in particular during the germinal center reaction, is a component of dysgammaglobulinemia in XLP patients and SAP-/- animals. It is however not well understood whether in XLP patients and SAP-/- mice B cell functions are affected, even though B cells themselves do not express SAP. Here we report that B cell intrinsic responses to haptenated protein antigens are impaired in SAP-/- mice and in Rag-/- mice into which B cells derived from SAP-/- mice together with wt CD4+ T cells had been transferred. This impaired B cells functions are in part depending on the genetic background of the SAP-/- mouse, which affects B cell homeostasis. Surprisingly, stimulation with an agonistic anti-CD40 causes strong in vivo and in vitro B cell responses in SAP-/- mice. Taken together, the data demonstrate that genetic factors play an important role in the SAP-related B cell functions. The finding that anti-CD40 can in part restore impaired B cell responses in SAP-/- mice, suggests potentially novel therapeutic interventions in subsets of XLP patients.

  9. Memory B cells.

    PubMed

    Kurosaki, Tomohiro; Kometani, Kohei; Ise, Wataru

    2015-03-01

    The immune system can remember a previously experienced pathogen and can evoke an enhanced response to reinfection that depends on memory lymphocyte populations. Recent advances in tracking antigen-experienced memory B cells have revealed the existence of distinct classes of cells that have considerable functional differences. Some of these differences seem to be determined by the stimulation history during memory cell formation. To induce rapid recall antibody responses, the contributions of other types of cells, such as memory T follicular helper cells, have also now begun to be appreciated. In this Review, we discuss these and other recent advances in our understanding of memory B cells, focusing on the underlying mechanisms that are required for rapid and effective recall antibody responses.

  10. Cross-sectional imaging of extranodal involvement in abdominopelvic lymphoproliferative malignancies.

    PubMed

    Leite, Nuno Pinto; Kased, Norbert; Hanna, Robert F; Brown, Michele A; Pereira, Jose M; Cunha, Rui; Sirlin, Claude B

    2007-01-01

    Extranodal lymphoproliferative diseases are common, and their prevalence is increasing. Non-Hodgkin lymphomas and Hodgkin disease, in particular, frequently involve extranodal structures in the abdomen and pelvis, including both the solid organs (liver, spleen, kidneys, and pancreas) and the hollow organs of the gastrointestinal tract. Because virtually any abdominopelvic tissue may be involved, many different imaging manifestations are possible, and lymphoproliferative diseases may mimic other disorders. Familiarity with the imaging manifestations that are diagnostically specific for extranodal lymphoproliferative diseases is important because imaging plays an important role in the noninvasive management of disease. However, a definitive diagnosis requires a biopsy (of bone marrow, a lymph node, or a mass), a peripheral blood analysis, and other laboratory tests. In patients with known disease, the goals of imaging are staging, evaluation of response to therapy, and identification of new or recurrent disease or of complications of therapy. In patients without known disease, imaging permits a provisional diagnosis.

  11. Clinical characteristics of patients with lymphoproliferative neoplasms in the setting of systemic autoimmune diseases.

    PubMed

    Suvajdzic, Nada; Djurdjevic, Predrag; Todorovic, Milena; Perunicic, Maja; Stojanović, Roksanda; Novkovic, Aleksandra; Mihaljevic, Biljana

    2012-09-01

    Clinical features of 40 lymphoproliferative neoplasm patients in the setting of systemic autoimmune diseases managed in the Clinic of Hematology during 1994-2006 were analyzed retrospectively. The classification of systemic autoimmune disease patients was as follows: 15 systemic lupus erythematosus--SLE, 11 rheumatoid arthritis--RA, 12 Sjögren's syndrome--SS, 1 scleroderma, and 1 dermatomyositis. Patients comprised 31 women and 9 men of mean age 55 years (range 33-76). Systemic autoimmune diseases preceeded the development of lymphoproliferative neoplasms in 37/40 (92.5%) patients. Mean latency period between the onset of systemic autoimmune diseases and lymphoproliferative neoplasms occurrence was significantly longer in RA (113 months) than in SLE (75 months) and SS patients (65 months)--P < 0.05. The most frequent lymphoproliferative neoplasms were non-Hodgkin's lymphoma--NHL (35/40; 88%), diffuse large B-cell lymphoma (DBCL)--12 (34%), follicular lymphoma (FC)--7 (20%), small lymphocytic (SL), and marginal zone lymphoma (MZL)--5 (14%) each. The primary site of NHL was extranodal in 18/35 (51.5%) cases. Advanced disease on diagnosis (III + IV clinical stages), constitutional symptoms, and bulky disease were diagnosed in 27/35 (77%), 26/35 (74%), and 3/35 (8.5%) patients, respectively. The overall survival (OS) was as follows (months): DBCL-12, FC-63, SLL-60, and MZL-48. There was no association between the lymphoproliferative neoplasm histological subtype and the systemic autoimmune diseases type or antirheumatic treatment P > 0.05. Our findings are in line with earlier reports showing a high proportion of patients with advanced disease, constitutional symptoms, extranodal manifestations, high grade histology, and low OS in the systemic autoimmune diseases setting.

  12. Primary lymphoproliferative conditions of lung.

    PubMed

    Gibbs, A R; Seal, R M

    1978-04-01

    The clinical, laboratory, and pathological features of six primary lymphoproliferative conditions of the lung are described. These comprise two patients with malignant lymphomas, one with pseudolymphoma, one with lymphoid interstitial pneumonia (LIP), one with lymphomatoid granulomatosis, and one with plasma cell granuloma. We recommend that the term 'premalignant lymphoma' be used for pseudolymphoma since the condition, although tending to remain localised, has a malignant potential. A combination of dyspnoea, cough, and pyrexia were the presenting features in our cases of premalignant and malignant lymphoma although they may often be discovered accidentally by chest radiography. The patient with LIP presented with the usual symptoms of dyspnoea and cough. The initial manifestations of the patient with lymphomatoid granulomatosis were skin radh and peripheral neuropathy nine months before the pulmonary symptoms, a not unusual occurrence. Plasma cell granuloma is often asymptomatic but our patient presented with cough, chest pain, haemoptysis. Premalignant lymphoma tends to pursue a benign course although exceptionally it may become disseminated. Malignant lymphoma may remain localised for many years but a significant proportion metastasise. Lymphomatoid granulomatosis and LIP have a varied course but both may terminate in malignant lymphoma. Plasma cell granuloma is always benign. The interrelationships of these conditions and their differential diagnosis are discussed.

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

    PubMed Central

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

    2016-01-01

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

  14. Characterization of antibodies directed against the immunoglobulin light kappa chain variable chain region (VK) of hepatitis C virus-related type-II mixed cryoglobulinemia and B-cell proliferations.

    PubMed

    de Re, Valli; Simula, Maria Paola; Pavan, Alessandro; Garziera, Marica; Marin, Dolores; Dolcetti, Riccardo; de Vita, Salvatore; Sansonno, Domenico; Geremia, Silvano; Toffoli, Giuseppe

    2009-09-01

    Autoimmune type-II cryoglobulinemia (II-MC) is sustained by hepatitis C virus (HCV) infection and B-cell (oligo)clones. This is the reason why the disease may be considered an "indolent B-cell lymphoma (NHL)." B clones show a restricted use of immunoglobulin variable genes (BCR), in particular in the use of the variable kappa (VK)3-20/15 light chain, and show a homology between their BCR functional regions and those of autoimmune rheumatoid factors. We underlined the BCR unique repertoire with frequent rheumatoid factor activity also observed in other autoimmune disorders associated with NHL. The immunoglobulin idiotype is a clonal B-cell marker and an ideal target for immunotherapy. Five monoclonal antibodies were produced in our laboratory toward the VK3-20 of a subject with HCV infection and a II-MC-associated NHL. Epitope determination was performed using the epitope excision approach. Monoclonal antibody reactivity was tested in vitro in ELISA, Western blot, and cytofluorimetry. Data confirmed that a panel of antibodies, reactive against shared idiotypes, can be produced from patients with HCV-associated B-cell lymphoproliferative diseases, thus obviating the need to produce an anti-idiotype antibody for each patient.

  15. Age-related EBV positive clonal B-cell Lymphoid proliferation (EBV+-DLBCL)

    PubMed Central

    Doukas-Alexiou, Marina; Stoufi, Eleana; Kittas, Christos; Pangalis, Gerasimos; Laskaris, George

    2017-01-01

    The Ebstein Barr virus(EBV), herpes virus 5 has been associated with lymphoproliferative disordrers. Age-related EBV+ B-LPD is defined as an EBV+ clonal B-cell lymphoid proliferation or EBV+-DLBCL developing in patients over the age of 40 years in the absence of any known immunodeficiency and without an underlying T-cell lymphoma1. We present a case of EBV+ clonal B-cell lymphoid proliferation. Key words:Oral mucosa ulcer, EBV+-DLBCL, age related. PMID:28149483

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

    PubMed Central

    Badial, Peres R.; Tallmadge, Rebecca L.; Miller, Steven; Stokol, Tracy; Richards, Kristy; Borges, Alexandre S.

    2015-01-01

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

  17. Optimal Management of Autoimmune Lymphoproliferative Syndrome in Children.

    PubMed

    George, Lindsey A; Teachey, David T

    2016-08-01

    Autoimmune lymphoproliferative syndrome (ALPS) is a disorder of abnormal lymphocyte homeostasis, resulting from mutations in the Fas apoptotic pathway. Clinical manifestations include noninfectious and nonmalignant lymphadenopathy, splenomegaly, and autoimmune pathology-most commonly, autoimmune cytopenias. Rarely, and in association with specific genetic mutations, patients with ALPS may go on to develop secondary lymphoid malignancies. Though ALPS is a rare disorder, it should be suspected and ruled out in children presenting with chronic and refractory multilineage cytopenias associated with nonmalignant lymphoproliferation. Revised diagnostic criteria and insights into disease biology have improved both diagnosis and treatment. Sirolimus and mycophenolate mofetil are the best-studied and most effective corticosteroid-sparing therapies for ALPS, and they should be considered first-line therapy for patients who need chronic treatment. This review highlights practical clinical considerations for diagnosis and management of ALPS.

  18. Restoring balance to B cells in ADA deficiency.

    PubMed

    Luning Prak, Eline T

    2012-06-01

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

  19. BCL2 mutation spectrum in B-cell non-Hodgkin lymphomas and patterns associated with evolution of follicular lymphoma.

    PubMed

    Burkhard, Regula; Bhagat, Govind; Cogliatti, Sergio B; Rossi, Davide; Gaidano, Gianluca; Pasqualucci, Laura; Novak, Urban

    2015-03-01

    BCL2 is a target of somatic hypermutation in t(14;18) positive and also in a small fraction of t(14;18) negative diffuse large B-cell lymphoma (DLBCL), suggesting an aberrant role of somatic hypermutation (ASHM). To elucidate the prevalence of BCL2 mutations in lymphomas other than DLBCL, we Sanger-sequenced the hypermutable region of the BCL2 gene in a panel of 69 mature B-cell lymphomas, including Richter's syndrome DLBCL, marginal-zone lymphomas, post-transplant lymphoproliferative disorders, HIV-associated and common-variable immunodeficiency-associated DLBCL, all known to harbour ASHM-dependent mutations in other genes, as well as 16 t(14,18) negative and 21 t(14;18) positive follicular lymphomas (FLs). We also investigated the pattern of BCL2 mutations in longitudinal samples from 10 FL patients relapsing to FL or transforming to DLBCL (tFL). By direct sequencing, we found clonally represented BCL2 mutations in 2/16 (13%) of t(14;18) negative FLs, 2/16 (13%) HIV-DLBCLs, 1/9 (11%) of Richter's syndrome DLBCL, 1/17 (6%) of post-transplant lymphoproliferative disorders and 1/2 (50%) common-variable immunodeficiency-associated DLBCL. The proportion of mutated cases was significantly lower than in FLs carrying the t(14;18) translocation (15/21, 71%). However, the absence of t(14;18) by FISH or PCR and the molecular features of the mutations strongly suggest that BCL2 represents an additional target of ASHM in these entities. Analysis of the BCL2 mutation pattern in clonally related FL/FL and FL/tFL samples revealed two distinct scenarios of genomic evolution: (i) direct evolution from the antecedent FL clone, with few novel clonal mutations acquired by the tFL major clone, and (ii) evolution from a common mutated long-lived progenitor cell, which subsequently acquired distinct mutations in the FL and in the relapsed or transformed counterpart.

  20. Memory B cells in Transplantation

    PubMed Central

    Chong, Anita S.; Sciammas, Roger

    2014-01-01

    Much of the research on the humoral response to allografts has focused on circulating serum antibodies and the long-lived plasma cells that produce these antibodies. In contrast, the interrogation of the quiescent memory B cell compartment is technically more challenging and thus has not been incorporated into the clinical diagnostic or prognostic toolkit. In this review, we discuss new technologies that have allowed this heretofore enigmatic subset of B cells to be identified at quiescence and during a recall response. These technologies in experimental models are providing new insights into memory B cell heterogeneity with respect to their phenotype, cellular function and the antibodies they produce. Similar technologies are also allowing for the identification of comparable memory alloreactive B cells in transplant recipients. While much of the focus in transplant immunology has been on controlling the alloreactive B cell population, long-term transplant patient survival is critically dependent on protection by pathogen-specific memory B cells. Techniques are also available that allow the interrogation of memory B cell response to pathogen re-encounter. Thus we are poised in our ability toinvestigate how immunosuppression affects allo- as well as pathogen-specific memory B cells, and reason that these investigation can yield new insights that will be beneficial for graft as well as patient survival. PMID:25525921

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

    PubMed

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

    2015-01-01

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

  2. Tubulointerstitial nephritis in a patient with probable autoimmune lymphoproliferative syndrome.

    PubMed

    Glerup, Mia; Herlin, Troels; Rittig, Søren; Grønbæk, Kirsten; Hokland, Marianne; Hasle, Henrik

    2013-07-01

    Autoimmune lymphoproliferative syndrome (ALPS) is caused by a nonmalignant defective Fas-mediated apoptosis. The main clinical manifestations are chronic lymphadenopathy, splenomegaly, and autoimmune cytopenia. Most patients with ALPS have a FAS germline mutation. ALPS has occasionally been associated with glomerulonephritis and we present the first report of tubulointerstitial nephritis associated with probable ALPS. A 5-year-old girl presented with fever, vomiting, hypertension, and azotemia. No autoantibodies, viral, or streptococcal antibodies were detected. A renal biopsy showed small-vessel vasculitis with normal glomeruli and inflammation in the interstitium. The patient responded to prednisolone treatment and obtained a full renal recovery. Symptoms of connective tissue disorder supervened and after the development of more pronounced splenomegaly, a diagnosis of ALPS was confirmed.

  3. Diffuse large B-cell lymphoma mimicking advanced basal cell carcinoma.

    PubMed Central

    Akinyemi, Emmanuel; Mai, Le; Matin, Abu; Maini, Archana

    2007-01-01

    Primary cutaneous B-cell lymphomas (PCBCLs) are made up of a heterogenous group of B-cell lymphoproliferative diseases confined to the skin at the time of diagnosis with no evidence of extracutaneous involvement. With early diagnosis and adequate treatment, PCBCLs as a group has excellent prognosis, with about a 95% survival rate at five years. We report a case of diffuse large B-cell lymphoma (DLBCL) in a 52-year-old woman presenting as a fungating skin ulcer mimicking advanced basal cell carcinoma. Review of available literature showed most studies of PCBCLs being done on Europeans with no universally acceptable system of classification. Clinical findings, diagnostic evaluations and treatment outcomes of PCBCLs are discussed with emphasis on comparison of European Organization for Research and Treatment of Cancer (EORTC) and the World Health Organization (WHO) Classification of Neoplasms of the Hematopoietic and Lymphoid Tissue classification systems. Images Figure 1 Figure 2 PMID:17722675

  4. Diffuse large B-cell lymphoma mimicking advanced basal cell carcinoma.

    PubMed

    Akinyemi, Emmanuel; Mai, Le; Matin, Abu; Maini, Archana

    2007-08-01

    Primary cutaneous B-cell lymphomas (PCBCLs) are made up of a heterogenous group of B-cell lymphoproliferative diseases confined to the skin at the time of diagnosis with no evidence of extracutaneous involvement. With early diagnosis and adequate treatment, PCBCLs as a group has excellent prognosis, with about a 95% survival rate at five years. We report a case of diffuse large B-cell lymphoma (DLBCL) in a 52-year-old woman presenting as a fungating skin ulcer mimicking advanced basal cell carcinoma. Review of available literature showed most studies of PCBCLs being done on Europeans with no universally acceptable system of classification. Clinical findings, diagnostic evaluations and treatment outcomes of PCBCLs are discussed with emphasis on comparison of European Organization for Research and Treatment of Cancer (EORTC) and the World Health Organization (WHO) Classification of Neoplasms of the Hematopoietic and Lymphoid Tissue classification systems.

  5. B Cell Subsets in Atherosclerosis

    PubMed Central

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

    2012-01-01

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

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

    PubMed Central

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

    2014-01-01

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

  7. Colonic diffuse large B-cell lymphoma in a liver transplant patient with historically very low tacrolimus levels.

    PubMed

    Moore, Christopher M; Lamzabi, Ihab; Bartels, Anne K; Jakate, Shriram; Van Thiel, David H

    2012-01-01

    Posttransplant lymphoproliferative disorders (PTLDs) comprise a wide spectrum of hematologic malignancies that are found increasingly in orthotopic liver transplant (OLT) patients given the rising frequency of these surgeries and their long-term success. PTLDs are highly correlated with both the Epstein-Barr virus (EBV) infection and the degree of immunosuppression involved. Herein is reported a case of a 53-year-old male with successfully treated hepatitis C virus genotype 4 and hepatocellular carcinoma who underwent OLT and developed symptoms of weakness and poor appetite 4 years later while on tacrolimus 3 mg b.i.d. with historically very low plasma levels. He was found to be anemic and colonoscopy revealed a 4.5 cm cecal diffuse large B-cell lymphoma (DLBCL). Further workup revealed mesenteric lymph node enlargement consistent and nodal DLBCL dissemination. He was treated with cyclophosphamide-hydroxyldaunorubicin-oncovin-prednisone-rituximab (CHOP-R) chemotherapy and his tacrolimus dose was lowered. Additionally, he manifested PTLD-associated cryoglobulinemia leading to acute kidney injury. After a prolonged hospitalization he was discharged with close followup.

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

    PubMed

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

    2014-05-01

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

  9. Treatment of neuromyelitis optica and neuromyelitis optica spectrum disorders with rituximab using a maintenance treatment regimen and close CD19 B cell monitoring. A six-year follow-up.

    PubMed

    Evangelopoulos, M E; Andreadou, E; Koutsis, G; Koutoulidis, V; Anagnostouli, M; Katsika, P; Evangelopoulos, D S; Evdokimidis, I; Kilidireas, C

    2017-01-15

    Neuromyelitis optinca (NMO) represents a serious demyelinating disease of the central nervous system selectively attacking the spinal cord and optic nerve. Early differential diagnosis from multiple sclerosis is of vital importance, as NMO mandates immunosuppressive and not immunomodulatory treatment. Rituximab has been recently introduced as a treatment option for NMO. However, optimal surrogate measures and treatment intervals are still unclear. Five patients (females, mean age 54±10.21years) with NMO and NMO spectrum disorders (NMOSD) were evaluated with respect to disability and relapse rate. All patients were found positive for NMO IgG. All patients (three with NMO and two with NMOSD, 1 patient with recurrent optic neuritis and 1 patient with recurrent myelitis) had received rituximab treatment for six years. One patient with NMOSD received cyclophosphamide prior to rituximab while two were misdiagnosed as multiple sclerosis and had received interferon treatment. All received rituximab infusion of 375mg/m(2) once per week for 4weeks and then every two months for the first two years and then every six months. B-cell counts were measured every two months and were kept in almost undetectable levels. No relapse was noted during the treatment period while EDSS score was improved in all patients. No severe adverse effects occurred during RTX treatment. Rituximab treatment on NMO and NMOSD patients showed significant improvement in disability and relapse-rate without any significant adverse effects.

  10. Lack of evidence of HTLV-I/II infection in T CD8 malignant or reactive lymphoproliferative disorders in France: a serological and/or molecular study of 169 cases.

    PubMed

    Fouchard, N; Flageul, B; Bagot, M; Avril, M F; Hermine, O; Sigaux, F; Merle-Beral, H; Troussard, X; Delfraissy, J F; de Thé, G

    1995-12-01

    Human T lymphotropic virus type II (HTLV-II), originally isolated in 1982 from a patient with a "T hairy cell leukemia", has not yet been proven to be the causative agent of any specific hematological disease. In order to screen for such an event, and because HTLV-II has a preferential tropism for OKT8 (CD8) T cells (both in vivo and in vitro), we searched for the presence of HTLV-II in lymphoproliferative diseases (LP) of CD8+ T cells. We report a serological and/or molecular study of 169 patients with a T CD8 LP, including 76 patients with malignant or reactive T CD8 LP (34 lymphomas, 27 large granular leukemias, three prolymphocytic leukemias, one hairy cell leukemia, 11 reactive T CD8 LP) and 93 HIV-1+ patients with a T CD8 peripheral lymphocytosis ( > 1500/mm3) from a prospective HIV cohort involving 1264 individuals. In the first series, the 40 sera available were all HTLV-I/II negative, except a 67-year-old French Guyanan man, with a cutaneous large T CD8 cell lymphoma, HTLV-I+. Furthermore, the molecular analysis of the 69 available DNA samples by PCR failed to detect any proviral HTLV-I/II sequences, except for the HTLV-I+ patient. The serological study of the 93 HIV-1+ individuals with CD8 lymphocytosis, showed that three patients were HTLV-I+, but none was HTLV-II+. Thus, in contrast to HTLV-I, whose etiological role in adult T cell leukemia is now well established, there is neither epidemiological nor molecular evidence that prototypic HTLV-II may be etiologically associated specifically with any of the CD8+ T cell LP investigated in this report.

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

    PubMed

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

    2015-11-01

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

  12. Evolution of B Cell Immunity

    PubMed Central

    Sunyer, J. Oriol

    2013-01-01

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

  13. Lymphoproliferative disease after lung and heart-lung transplantation: first description in Spain.

    PubMed

    Morales, P; Torres, J; Pérez-Enguix, D; Solé, A; Pastor, A; Segura, A; Zurbano, F

    2005-11-01

    Lymphoproliferative syndromes are the most common tumors in transplant recipients. More than 90% of posttransplantation lymphoproliferative syndromes (PTLS) are considered to be associated with Epstein-Barr virus, and 86% are of the B-cell line. Histopathology ranges from polymorphic-reactive to monomorphic forms. Clonality should be studied using molecular biology techniques. Clinically, a differentiation is usually made between early PTLS (occurring within 1 year after transplantation) and late PTLS, which occur as localized or disseminated nodal lymphomas. In localized forms, immunosuppression should be discontinued or decreased, and the involved area should be subsequently resected or irradiated. In disseminated cases, immunosuppression should be decreased and administration of acyclovir/ganciclovir should be considered. If this is not effective, treatment should be started with anti-CD20 monoclonal antibodies (rituximab). If no response occurs, use of chemotherapy, possibly with interferon, should be considered. Our aim was to report the incidence, clinical signs, and treatment in a series of patients undergoing lung transplantation (LTx).

  14. Expression of the Epstein-Barr virus in lymphoproliferative diseases of the lung.

    PubMed

    Shimakage, Misuzu; Sakamoto, Haruhiko; Harada, Shizuko; Sasagawa, Toshiyuki; Kodama, Ken

    2007-06-01

    There have been few studies regarding the etiology of lymphoproliferative disorders of the lung. To examine the possible involvement of the Epstein-Barr virus (EBV) in these diseases, EBV mRNAs, proteins and DNA, were detected. Two non-Hodgkin's lymphomas (NHL) originating in the lung, 5 mucosal-associated lymphoid tissue lymphomas (MALT lymphoma) of the lung, 1 lymphoid hyperplasia of the lung and 1 lymphoid interstitial pneumonia (LIP), were subjected to mRNA in situ hybridization, indirect immunofluorescence staining and PCR. mRNA in situ hybridization using BamHIW, BamHIY1Y2, the Epstein-Barr virus nuclear antigen (EBNA) and the EBV encoded small non-polyadenylated RNA (EBER1) probe revealed signals in all the examined samples, although some samples showed weak signals by using the EBER1 probe. Indirect immunofluorescence staining using the anti-leader protein, anti-EBNA2, the anti-latent member protein-1 and anti-BamHIZ coding leftward reading frame-1 antibodies showed definitive fluorescence. PCR also revealed EBV DNA in these specimens. EBV infected all the lymphoproliferative diseases of the lung irrespective of the histological or clinical stages. Furthermore, EBV infected not only the atypical lymphocytes but also the macrophages in the tissues of these diseases. These results suggest that the expression of EBV could be involved in the pathogenesis of many lymphoproliferative diseases of the lung.

  15. Memory B cells: total recall.

    PubMed

    Phan, Tri Giang; Tangye, Stuart G

    2017-03-28

    Immunological memory is a cornerstone of adaptive immune responses in higher vertebrates. The remarkable ability to generate memory cells following Ag exposure, in the context of natural infection or immunization, provides long-lived protection against infectious diseases, often for the hosts' lifetime. Indeed, the generation of memory B cells and long-lived plasma cells underpins the success of most vaccines. The concept of immunological memory is not new-it was first proposed nearly 2500 years ago. While our understanding of the complexities of humoral and cell-mediated memory continues to evolve, important aspects of this process remain unresolved. Here, we will provide an overview of recent advances in B-cell memory in mice and humans, and in health and disease.

  16. Epstein-Barr virus-negative, CD5-positive diffuse large B-cell lymphoma developing after treatment with oral tacrolimus for mixed connective tissue disease : a case report and review of the literature.

    PubMed

    Sekiguchi, Yasunobu; Shimada, Asami; Imai, Hidenori; Wakabayashi, Mutsumi; Sugimoto, Keiji; Nakamura, Noriko; Sawada, Tomonori; Komatsu, Norio; Noguchi, Masaaki

    2012-01-01

    A 69-year-old woman, who had been diagnosed as having Sjögren's syndrome at 37 years old and mixed connective tissue disease at 42 years old, was under treatment with oral prednisolone. In 2009, she was diagnosed as having active systemic lupus erythematosus, and started on treatment with tacrolimus at 3 mg/day. In 2010, para-aortic lymphadenopathy and superficial multiple lymphadenopathy were detected. Tacrolimus was discontinued. Axillary lymph node biopsy revealed Epstein-Barr (EB) virus-negative CD5-positive diffuse large B-cell lymphoma (DLBCL). The patient was classified into clinical stage IIIA and as being at high risk according to the international prognostic index. After the discontinuation of tacrolimus, the lymph nodes reduced temporarily in size. In January 2011, the lymphadenopathy increased again, and the patient received a total of 8 courses of therapy with rituximab, pirarubicin, vincristine, cyclophosphamide and prednisolone, followed by intrathecal injection to prevent central nervous system infiltration, which was followed by complete remission. In February 2012, fluorodeoxyglucose positron emission tomography showed relapse in multiple lymph nodes and central nervous system infiltration. The patient was considered to have iatrogenic lymphoproliferative disorder classified as "other iatrogenic immunodeficiency-associated lymphoproliferative disorders" by the WHO, and this is the first reported case of CD5-positive DLBCL and central nervous system infiltration following administration of the drug. The patient was considered to have a poor prognosis as EB virus was negative, discontinuation of tacrolimus was ineffective and there was evidence of central nervous system infiltration.

  17. Autoimmune Lymphoproliferative Syndrome: A Rare Cause of Disappearing HDL Syndrome.

    PubMed

    Sriram, Swetha; Joshi, Avni Y; Rodriguez, Vilmarie; Kumar, Seema

    2016-01-01

    The term disappearing HDL syndrome refers to development of severe high density lipoprotein cholesterol (HDL-C) deficiency in noncritically ill patients with previously normal HDL-C and triglyceride levels. Autoimmune lymphoproliferative syndrome (ALPS) is a disorder of the immune system due to an inability to regulate lymphocyte homeostasis resulting in lymphadenopathy and hepatosplenomegaly. We describe a 17-year-old boy who was evaluated in the lipid clinic for history of undetectable or low HDL-C and low density lipoprotein cholesterol (LDL-C) levels. Past medical history was significant for ALPS IA diagnosed at 10 years of age when he presented with bilateral cervical adenopathy. He was known to have a missense mutation in one allele of the FAS protein extracellular domain consistent with ALPS type 1A. HDL-C and LDL-C levels had been undetectable on multiple occasions, though lipids had not been measured prior to the diagnosis of ALPS. He had been receiving sirolimus for immunosuppression. The HDL-C and LDL-C levels correlated with disease activity and improved to normal levels during times when the activity of ALPS was controlled. This case highlights the importance of considering ALPS as a cause of low HDL-C and LDL-C levels in a child with evidence of lymphoproliferation.

  18. Autoimmune Lymphoproliferative Syndrome: A Rare Cause of Disappearing HDL Syndrome

    PubMed Central

    Sriram, Swetha; Joshi, Avni Y.; Rodriguez, Vilmarie

    2016-01-01

    The term disappearing HDL syndrome refers to development of severe high density lipoprotein cholesterol (HDL-C) deficiency in noncritically ill patients with previously normal HDL-C and triglyceride levels. Autoimmune lymphoproliferative syndrome (ALPS) is a disorder of the immune system due to an inability to regulate lymphocyte homeostasis resulting in lymphadenopathy and hepatosplenomegaly. We describe a 17-year-old boy who was evaluated in the lipid clinic for history of undetectable or low HDL-C and low density lipoprotein cholesterol (LDL-C) levels. Past medical history was significant for ALPS IA diagnosed at 10 years of age when he presented with bilateral cervical adenopathy. He was known to have a missense mutation in one allele of the FAS protein extracellular domain consistent with ALPS type 1A. HDL-C and LDL-C levels had been undetectable on multiple occasions, though lipids had not been measured prior to the diagnosis of ALPS. He had been receiving sirolimus for immunosuppression. The HDL-C and LDL-C levels correlated with disease activity and improved to normal levels during times when the activity of ALPS was controlled. This case highlights the importance of considering ALPS as a cause of low HDL-C and LDL-C levels in a child with evidence of lymphoproliferation. PMID:27579193

  19. Advances in the management and understanding of autoimmune lymphoproliferative syndrome (ALPS).

    PubMed

    Teachey, David T; Seif, Alix E; Grupp, Stephan A

    2010-01-01

    Autoimmune lymphoproliferative syndrome (ALPS) is a disorder of T cell dysregulation caused by defective Fas-mediated apoptosis. Patients with ALPS can develop a myriad of clinical manifestations including lymphadenopathy, hepatosplenomegaly, autoimmunity and increased rates of malignancy. ALPS may be more common that originally thought, and testing for ALPS should be considered in patients with unexplained lymphadenopathy, hepatosplenomegaly, and/or autoimmunity. As the pathophysiology of ALPS is better characterized, a number of targeted therapies are in preclinical development and clinical trials with promising early results. This review describes the clinical and laboratory manifestations found in ALPS patients, as well as the molecular basis for the disease and new advances in treatment.

  20. B-cell tolerance and autoimmunity

    PubMed Central

    Tsubata, Takeshi

    2017-01-01

    Self-reactive B cells are tolerized at various stages of B-cell development and differentiation, including the immature B-cell stage (central tolerance) and the germinal center (GC) B-cell stage, and B-cell tolerance involves various mechanisms such as deletion, anergy, and receptor editing. Self-reactive B cells generated by random immunoglobulin variable gene rearrangements are tolerized by central tolerance and anergy in the periphery, and these processes involve apoptosis regulated by Bim, a pro-apoptotic member of the Bcl-2 family, and regulation of B-cell signaling by various phosphatases, including SHIP-1 and SHP-1. Self-reactive B cells generated by somatic mutations during GC reaction are also eliminated. Fas is not directly involved in this process but prevents persistence of GC reaction that allows generation of less stringently regulated B cells, including self-reactive B cells. Defects in self-tolerance preferentially cause lupus-like disease with production of anti-nuclear antibodies, probably due to the presence of a large potential B-cell repertoire reactive to nucleic acids and the presence of nucleic acid-induced activation mechanisms in various immune cells, including B cells and dendritic cells. A feed-forward loop composed of anti-nuclear antibodies produced by B cells and type 1 interferons secreted from nucleic acid-activated dendritic cells plays a crucial role in the development of systemic lupus erythematosus.

  1. B cell activating factor (BAFF) selects IL-10(-)B cells over IL-10(+)B cells during inflammatory responses.

    PubMed

    Ma, Ning; Zhang, Yu; Liu, Qilin; Wang, Zhiding; Liu, Xiaoling; Zhu, Gaizhi; Yu, Dandan; Han, Gencheng; Chen, Guojiang; Hou, Chunmei; Wang, Tianxiao; Ma, Yuanfang; Shen, Beifen; Li, Yan; Xiao, He; Wang, Renxi

    2017-05-01

    B cell activating factor (BAFF) regulates B cell maturation, survival, function, and plays a critical pathogenic role in autoimmune diseases. It remains unclear how BAFF affects IL-10(-)B cells versus regulatory B cells (Bregs) in inflammatory responses. In this study, we found that IL-10-expressing Bregs decreased in lupus-prone MRL/lpr mice and experimental allergic encephalomyelitis (EAE) mice. On blockade of the effects of BAFF with TACI-IgG, IL-10(+) Bregs were upregulated in MRL/lpr and EAE mice. In addition, BAFF expanded IL-10(+)B cells over IL-10(-)B cells under noninflammatory conditions in vitro, whereas it expanded IL-10(-)B cells over IL-10(+)B cells during inflammatory responses, such as stimulation with autoantigen and LPS. Finally, the selection of IL-10(-)B cells over IL-10(+)B cells by BAFF was dependent on BAFF receptors (BAFFR, TACI, and BCMA) that were upregulated by inflammatory responses. This study suggests that BAFF selects IL-10(-)B cells over IL-10(+) regulatory B cells via BAFF receptors in inflammatory responses.

  2. JAK2 V617F detected in two B-cell chronic lymphocytic leukemia patients without coexisting Philadelphia chromosome-negative myeloproliferative neoplasms: A report of two cases

    PubMed Central

    YANG, YI-NING; QIN, YOU-WEN; WANG, CHUN

    2014-01-01

    The JAK2 V617F mutation has been observed in patients with Philadelphia chromosome-negative myeloproliferative neoplasms (Ph-MPNs), including polycythemia vera, essential thrombocythemia and idiopathic myelofibrosis. This mutation has also been observed in a small number of other myeloid malignancies, such as acute myeloid leukemia, chronic myeloid leukemia and myelodysplastic syndrome. The JAK2 V617F allele has rarely been evaluated in lymphoproliferative disorders. In total, 28 JAK2 V617F-positive B-cell lymphocytic leukemia (B-CLL) patients have previously been reported and all presented with Ph-MPN concomitantly. However, following investigation of the JAK2 V617F mutation in 63 B-CLL patients at the Shanghai First People’s Hospital (Shanghai, China) between January 2008 and December 2012 via allele-specific polymerase chain reaction, two B-CLL patients without a history of Ph-MPN were identified to carry the JAK2 V617F allele. PMID:25013507

  3. High incidence of Kaposi sarcoma-associated herpesvirus infection in HIV-related solid immunoblastic/plasmablastic diffuse large B-cell lymphoma.

    PubMed

    Deloose, S T P; Smit, L A; Pals, F T; Kersten, M-J; van Noesel, C J M; Pals, S T

    2005-05-01

    Kaposi sarcoma-associated herpesvirus (KSHV) is known to be associated with two distinct lymphoproliferative disorders: primary effusion lymphoma (PEL) and multicentric Castleman disease (MCD)/MCD-associated plasmablastic lymphoma. We here report a high incidence of KSHV infection in solid HIV-associated immunoblastic/plasmablastic non-Hodgkin's lymphomas (NHLs), in patients lacking effusions and without evidence of (prior) MCD. Within a cohort of 99 HIV-related NHLs, 10 cases were found to be KSHV positive on the basis of immunostaining for KSHV LNA-1 as well as KSHV-specific polymerase chain reaction. All but one of the tumors coexpressed Epstein-Barr virus. Interestingly, all KSHV-positive cases belonged to a distinctive subgroup of 26 diffuse large B-cell lymphomas characterized by the expression of CD138 (syndecan-1) and plasmablastic/immunoblastic morphology. These KSHV-positive lymphomas were preceded by Kaposi sarcoma in 60% of the patients and involved the gastrointestinal tract in 80%. Our results indicate that KSHV infection is not restricted to PEL and MCD; it is also common (38%) in HIV-related solid immunoblastic/plasmablastic lymphomas.

  4. Impaired humoral immunity in X-linked lymphoproliferative disease is associated with defective IL-10 production by CD4+ T cells

    PubMed Central

    Ma, Cindy S.; Hare, Nathan J.; Nichols, Kim E.; Dupré, Loic; Andolfi, Grazia; Roncarolo, Maria-Grazia; Adelstein, Stephen; Hodgkin, Philip D.; Tangye, Stuart G.

    2005-01-01

    X-linked lymphoproliferative disease (XLP) is an often-fatal immunodeficiency characterized by hypogammaglobulinemia, fulminant infectious mononucleosis, and/or lymphoma. The genetic lesion in XLP, SH2D1A, encodes the adaptor protein SAP (signaling lymphocytic activation molecule–associated [SLAM-associated] protein); however, the mechanism(s) by which mutations in SH2D1A causes hypogammaglobulinemia is unknown. Our analysis of 14 XLP patients revealed normal B cell development but a marked reduction in the number of memory B cells. The few memory cells detected were IgM+, revealing deficient isotype switching in vivo. However, XLP B cells underwent proliferation and differentiation in vitro as efficiently as control B cells, which indicates that the block in differentiation in vivo is B cell extrinsic. This possibility is supported by the finding that XLP CD4+ T cells did not efficiently differentiate into IL-10+ effector cells or provide optimal B cell help in vitro. Importantly, the B cell help provided by SAP-deficient CD4+ T cells was improved by provision of exogenous IL-10 or ectopic expression of SAP, which resulted in increased IL-10 production by T cells. XLP CD4+ T cells also failed to efficiently upregulate expression of inducible costimulator (ICOS), a potent inducer of IL-10 production by CD4+ T cells. Thus, insufficient IL-10 production may contribute to hypogammaglobulinemia in XLP. This finding suggests new strategies for treating this immunodeficiency. PMID:15761493

  5. Antiviral Treatment of HCV-Infected Patients with B-Cell Non-Hodgkin Lymphoma: ANRS HC-13 Lympho-C Study

    PubMed Central

    Alric, Laurent; Besson, Caroline; Lapidus, Nathanael; Jeannel, Juliette; Michot, Jean-Marie; Cacoub, Patrice; Canioni, Danielle; Pol, Stanislas; Davi, Frédéric; Rabiega, Pascaline; Ysebaert, Loic; Bonnet, Delphine; Hermine, Olivier

    2016-01-01

    Hepatitis C virus (HCV) infection is associated with lymphoproliferative disorders and B-cell non-Hodgkin lymphomas (B-NHLs). Evaluation of the efficacy and safety profiles of different antiviral therapies in HCV patients with B-NHL is warranted. Methods: First, we evaluated the sustained virologic response (SVR) and safety of Peg-interferon-alpha (Peg-IFN) + ribavirin +/- first protease inhibitors (PI1s) therapy in 61 HCV patients with B-NHL enrolled in a nationwide observational survey compared with 94 matched HCV-infected controls without B-NHL. In a second series, interferon-free regimens using a newly optimal combination therapy with direct-acting antiviral drugs (DAAs) were evaluated in 10 patients with HCV and B-NHL. Results: The main lymphoma type was diffuse large B-cell lymphoma (38%) followed by marginal zone lymphoma (31%). In the multivariate analysis, patients with B-NHL treated by Peg-IFN-based therapy exhibited a greater SVR rate compared with controls, 50.8% vs 30.8%, respectively, p<0.01, odds ratio (OR) = 11.2 [2.3, 52.8]. B-NHL response was better (p = 0.02) in patients with SVR (69%) than in patients without SVR (31%). Premature discontinuation of Peg-IFN-based therapy was significantly more frequent in the B-NHL group (19.6%) compared with the control group (6.3%), p<0.02. Overall, survival was significantly enhanced in the controls than in the B-NHL group (hazard ratio = 34.4 [3.9, 304.2], p< 0.01). Using DAAs, SVR was achieved in 9/10 patients (90%). DAAs were both well tolerated and markedly efficient. Conclusions: The virologic response of HCV-associated B-NHL is high. Our study provides a comprehensive evaluation of different strategies for the antiviral treatment of B-NHL associated with HCV infection. PMID:27749916

  6. Differential expression of viral agents in lymphoma tissues of patients with ABC diffuse large B-cell lymphoma from high and low endemic infectious disease regions

    PubMed Central

    Högfeldt, Therese; Jaing, Crystal; Loughlin, Kevin Mc; Thissen, James; Gardner, Shea; Bahnassy, Abeer A.; Gharizadeh, Baback; Lundahl, Joachim; Österborg, Anders; Porwit, Anna; Zekri, Abdel-Rahman N.; Khaled, Hussein M.; Mellstedt, Håkan; Moshfegh, Ali

    2016-01-01

    Diffuse large B-cell lymphoma (DLBCL), the most common type of non-Hodgkin's lymphoma (NHL) in adults, accounts for approximately 30–40% of newly diagnosed lymphomas worldwide. Environmental factors, such as viruses and bacteria, may contribute to cancer development through chronic inflammation and the integration of oncogenes, and have previously been indicated in cervical cancer, hepatocellular carcinoma, gastric cancer and lymphoproliferative disorders. In the present study, the presence of microbial agents was analyzed in the lymphoma tissue of patients with activated B-cell like (ABC) DLBCL. The present study compared two groups of patients from geographically varied regions that possess a difference in the prevalence of viral and other microbial agents. The patient populations were from Sweden (a low endemic infectious disease region) and Egypt (a high endemic infectious disease region). A differential expression of several viruses in lymphoma tissues was noted when comparing Swedish and Egyptian patients. JC polyomavirus (JCV) was detected in Swedish and Egyptian patients and, uniquely, the complete hepatitis B virus (HBV) genome was detected only in Egyptian lymphoma patients. None of these viruses were detected in control lymph tissues from Sweden or Egypt. In total, 38% of the Egyptian patients were found to have HBV surface antigens (HBsAgs) in their serum; however, HBsAgs were not found in any of the Swedish patients. The percentage of serum HBsAgs in Egyptian patients with ABC DLBCL was significantly increased compared with the general Egyptian population (P<0.05). The present study may support a notion that viral agents, including JCV and HBV, may be involved in the tumorigenesis of DLBCL in regions of high infectious disease. PMID:27698858

  7. Cytogenetic analysis of B-cell posttransplant lymphoproliferations validates the World Health Organization classification and suggests inclusion of florid follicular hyperplasia as a precursor lesion.

    PubMed

    Vakiani, Efsevia; Nandula, Subhadra V; Subramaniyam, Shivakumar; Keller, Christian E; Alobeid, Bachir; Murty, Vundavalli V; Bhagat, Govind

    2007-02-01

    Cytogenetic abnormalities in B-cell posttransplant lymphoproliferative disorders (PTLD) have not been well characterized. We thus performed cytogenetic analysis of 28 cases of B-cell PTLD, 1 infectious mononucleosis (IM)-like lesion, 9 polymorphic PTLD, 17 monomorphic PTLD, and 1 classical Hodgkin lymphoma (HL), and correlated the karyotypic findings with the phenotype, Epstein-Barr virus infection status, and clinical outcome. Karyotypes of 19 cases of posttransplant florid follicular hyperplasia (FFH) were also analyzed. Informative karyotypes were obtained in 20 (71.4%) of 28 PTLDs and 18 (94.7%) of 19 FFHs. Clonal karyotypic abnormalities were detected in 13 (65%) of 20 PTLDs, including 9 (75%) of 12 monomorphic PTLDs, 2 (33.3%) of 6 polymorphic PTLDs, 1 IM-like lesion, and 1 HL, and 2 (11.1%) of 18 FFHs. Recurrent chromosome breaks at 1q11-21 (n = 6, including 1 FFH), 14q32 (n = 3, including 1 FFH), 16p13 (n = 3), 11q23-24 (n = 2), and 8q24 (c-MYC) (n = 2); gains of chromosome 7 (n = 4), X (n = 3), 2 (n = 3), 12 (n = 2); and loss of chromosome 22 (n = 2, including 1 IM-like lesion) were identified. The presence of cytogenetic abnormalities did not correlate with PTLD phenotype, Epstein-Barr virus infection, or clinical outcome. We describe novel karyotypic aberrations in PTLD and report clonal cytogenetic abnormalities in posttransplant FFH and an IM-like lesion for the first time. Our findings provide validation of the current World Health Organization classification of PTLD and also suggest incorporation of FFH as the earliest recognizable precursor of PTLD.

  8. Junctional adhesion molecule C (JAM-C) distinguishes CD27+ germinal center B lymphocytes from non-germinal center cells and constitutes a new diagnostic tool for B-cell malignancies.

    PubMed

    Ody, C; Jungblut-Ruault, S; Cossali, D; Barnet, M; Aurrand-Lions, M; Imhof, B A; Matthes, T

    2007-06-01

    Differentiation of naïve B cells into plasma cells or memory cells occurs in the germinal centers (GCs) of lymph follicles or alternatively via a GC- and T-cell-independent pathway. It is currently assumed that B-cell lymphomas correlate to normal B-cell differentiation stages, but the precise correlation of several B-cell lymphomas to these two pathways remains controversial. In the present report, we describe the junctional adhesion molecule C (JAM-C), currently identified at the cell-cell border of endothelial cells, as a new B-cell marker with a tightly regulated expression during B-cell differentiation. Expression of JAM-C in tonsils allows distinction between two CD27+ B-cell subpopulations: JAM-C- GC B cells and JAM-C+ non-germinal B cells. The expression of JAM-C in different B-cell lymphomas reveals a disease-specific pattern and allows a clear distinction between JAM-C- lymphoproliferative syndromes (chronic lymphocytic leukemia, mantle cell lymphoma and follicular lymphoma) and JAM-C+ ones (hairy cell leukemia, marginal zone B-cell lymphoma). Therefore, we propose JAM-C as a new identification tool in B-cell lymphoma diagnosis.

  9. B Cell Immunity in Solid Organ Transplantation

    PubMed Central

    Karahan, Gonca E.; Claas, Frans H. J.; Heidt, Sebastiaan

    2017-01-01

    The contribution of B cells to alloimmune responses is gradually being understood in more detail. We now know that B cells can perpetuate alloimmune responses in multiple ways: (i) differentiation into antibody-producing plasma cells; (ii) sustaining long-term humoral immune memory; (iii) serving as antigen-presenting cells; (iv) organizing the formation of tertiary lymphoid organs; and (v) secreting pro- as well as anti-inflammatory cytokines. The cross-talk between B cells and T cells in the course of immune responses forms the basis of these diverse functions. In the setting of organ transplantation, focus has gradually shifted from T cells to B cells, with an increased notion that B cells are more than mere precursors of antibody-producing plasma cells. In this review, we discuss the various roles of B cells in the generation of alloimmune responses beyond antibody production, as well as possibilities to specifically interfere with B cell activation. PMID:28119695

  10. 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.

  11. Rationale for B cell targeting in SLE

    PubMed Central

    Sanz, Iñaki

    2014-01-01

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

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

    Technology Transfer Automated Retrieval System (TEKTRAN)

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

  13. Autoimmune lymphoproliferative syndrome mimicking chronic active Epstein-Barr virus infection.

    PubMed

    Nomura, Keiko; Kanegane, Hirokazu; Otsubo, Keisuke; Wakiguchi, Hiroshi; Noda, Yukihiro; Kasahara, Yoshihito; Miyawaki, Toshio

    2011-06-01

    Chronic active Epstein-Barr virus infection (CAEBV) is defined as a systemic EBV-associated lymphoproliferative disease characterized by fever, lymphadenopathy, and splenomegaly in apparently immunocompetent persons. Recent studies have revealed that EBV infects T or natural killer cells in most patients with CAEBV; the etiology of CAEBV, however, remains unknown. Autoimmune lymphoproliferative disorder (ALPS) is an inherited disorder associated with defects in apoptosis, and clinically characterized by lymphadenopathy, splenomegaly, hypergammaglobulinemia, and autoimmune disease. ALPS is most often associated with mutations in the FAS gene, which is an apoptosis-signaling receptor important for homeostasis of the immune system. Based on the clinical similarity between ALPS and CAEBV with respect to lymphoproliferation, we have examined the possibility of the co-occurrence of ALPS in patients with a diagnosis of CAEBV. In this study, we have identified FAS gene mutations in three Japanese patients with lymphadenopathy, hepatosplenomegaly, and unusual EBV infection, who were diagnosed with CAEBV. These observations, which indicate that the clinical development of ALPS may be associated with EBV infection, alert us to a potential diagnostic pitfall of CAEBV.

  14. Differential radiosensitivity among B cell subpopulations

    SciTech Connect

    Riggs, J.E.

    1988-01-01

    The selective radiosensitivity of sIgM >> sIgD marginal zone B cells is associated with the selective loss of B cell function. The simultaneous restoration of impaired function and recovery of these cells with time supports this premise. B cell recovery, delayed one week after irradiation, is in progress at two weeks, and virtually complete by three weeks. XID mice reveal similar recovery kinetics although there are fewer recovering cells and these bear reduced levels of Ia. This observation represents additional evidence that xid B cells are distinct from those of normal mice. The simultaneous loss, and concurrent recovery, of sIgM >> sIgD B cells and TI-2 responsiveness in irradiated mice suggests the existence of a unique B cell subpopulation possessing both phenotypes. Additional support for this hypothesis is provided by demonstrating that splenocytes, depleted of IgD{sup +} cells adoptively reconstitute this response in XID mice. The peritoneal B cell pool, which, compared to the spleen, consist of increased numbers of sIgM >> sIgD B cells, is shown to be a source of radiosensitive B cells that are TI-2 responsive. These observations represent additional evidence for an association between sIgM >> sIgD B cells and TI-2 responsiveness.

  15. Role of MYC in B Cell Lymphomagenesis.

    PubMed

    Korać, Petra; Dotlić, Snježana; Matulić, Maja; Zajc Petranović, Matea; Dominis, Mara

    2017-04-04

    B cell lymphomas mainly arise from different developmental stages of B cells in germinal centers of secondary lymphoid tissue. There are a number of signaling pathways that affect the initiation and development of B cell lymphomagenesis. The functions of several key proteins that represent branching points of signaling networks are changed because of their aberrant expression, degradation, and/or accumulation, and those events determine the fate of the affected B cells. One of the most influential transcription factors, commonly associated with unfavorable prognosis for patients with B cell lymphoma, is nuclear phosphoprotein MYC. During B cell lymphomagenesis, oncogenic MYC variant is deregulated through various mechanisms, such as gene translocation, gene amplification, and epigenetic deregulation of its expression. Owing to alterations of downstream signaling cascades, MYC-overexpressing neoplastic B cells proliferate rapidly, avoid apoptosis, and become unresponsive to most conventional treatments. This review will summarize the roles of MYC in B cell development and oncogenesis, as well as its significance for current B cell lymphoma classification. We compared communication networks within transformed B cells in different lymphomas affected by overexpressed MYC and conducted a meta-analysis concerning the association of MYC with tumor prognosis in different patient populations.

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

    PubMed

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

    2012-12-01

    Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an extremely rare condition that originates from dendritic cells. We report on the first case of Epstein-Barr virus (EBV)-driven post-transplant lymphoproliferative disorder (PTLD) of donor origin in a BPDC patient post-allogeneic haematopoietic stem cell transplantation (HSCT). Flow cytometry study identified a cell population CD4+/CD56+/CD45RA+/CD123+/TCL1+ suggestive of BPDCN diagnosis, which was confirmed by a lymph node biopsy (cells positive for BCL11a, BDCA-2, CD2AP, CD123, TCL1 and S100). Cytogenetic analysis revealed a complex karyotype: (19 metaphase) 47,XX,t(1;6)(q21;q2?5),-13 + 2mar[11]/47, XX, +21 [3]/46,XX [5]. The patient was started on acute myeloid leukaemia (AML) induction schedule, and subsequently an allogeneic HSCT was performed. On day +36 post-HSCT, bone marrow biopsy/aspirate showed complete morphological remission, and chimerism study showed 100% donor chimera. However, on day +37, the patient was found to have enlarged cervical and supraclavicular lymphoadenopathy, splenomegaly and raised lactic dehydrogenase. EBV-DNA copies in blood were elevated, consistent with a lytic cycle. A lymph node biopsy showed EBV encoded RNA and large atypical B cells (CD45dim-, CD4+/CD56+, monoclonal for k-chain, CD19+/CD20+/CD21+/CD22+/CD38+/CD43+/CD79β-/CD5-/CD10-), consistent with PTLD monomorphic type. Chimerism study showed that PTLD was of donor origin. This case together with the recent literature findings on BPDCN and PTLD are discussed.

  17. Monotypic plasma cells in labial salivary glands of patients with Sjögren's syndrome: prognosticator for systemic lymphoproliferative disease.

    PubMed Central

    Bodeutsch, C; de Wilde, P C; Kater, L; van den Hoogen, F H; Hené, R J; van Houwelingen, J C; van de Putte, L B; Vooijs, G P

    1993-01-01

    AIMS: To determine the prevalence of plasma cell monotypia in labial salivary gland tissue of patients with and without Sjögren's syndrome, and to evaluate its relation to the development of systemic monoclonal lymphoproliferative disorders. METHODS: A quantitative immunohistological study was performed on labial salivary gland tissue of 45 patients with Sjögren's syndrome, 18 with rheumatoid arthritis without Sjögren's syndrome, and 80 healthy controls. In none of the patients with Sjögren's syndrome was there evidence of systemic monoclonal lymphoproliferative disease at the time of biopsy. RESULTS: Monotypic plasma cell populations, defined by a kappa:lambda ratio of > or = 3, were only observed in older patients (above 43 years) with Sjögren's syndrome. In almost all these patients monotypic plasma cell populations were present in multiple labial salivary gland tissues and the IgM/kappa monotypia was observed most frequently. The prevalence of monotypic plasma cell populations in the group with Sjögren's syndrome was 22% (10/45) and there was no significant predilection for primary Sjögren's syndrome. Of special clinical interest was the observation that progression to systemic monoclonal lymphoproliferative disease had occurred exclusively in this subgroup of patients with Sjögren's syndrome, with a prevalence of 30% (3/10). CONCLUSION: Quantitative immunohistological examination of labial salivary gland tissues provides pathologists with a simple method to select those patients with Sjögren's syndrome who have an increased relative risk at the time of biopsy to develop benign or malignant lymphoproliferative disorders. PMID:8459032

  18. Fibrin-associated EBV-positive Large B-Cell Lymphoma: An Indolent Neoplasm With Features Distinct From Diffuse Large B-Cell Lymphoma Associated With Chronic Inflammation.

    PubMed

    Boyer, Daniel F; McKelvie, Penelope A; de Leval, Laurence; Edlefsen, Kerstin L; Ko, Young-Hyeh; Aberman, Zachary A; Kovach, Alexandra E; Masih, Aneal; Nishino, Ha T; Weiss, Lawrence M; Meeker, Alan K; Nardi, Valentina; Palisoc, Maryknoll; Shao, Lina; Pittaluga, Stefania; Ferry, Judith A; Harris, Nancy Lee; Sohani, Aliyah R

    2017-03-01

    Incidental cases of localized fibrin-associated Epstein-Barr virus (EBV)+ large B-cell proliferations have been described at unusual anatomic sites and have been included in the category of diffuse large B-cell lymphoma associated with chronic inflammation (DLBCL-CI) in the WHO Classification. We describe 12 cases and review the literature to define their clinicopathologic spectrum and compare features with typical cases of DLBCL-CI. Median age was 55.5 years with a M:F ratio of 3. In all 12 cases, the lymphoma was an incidental microscopic finding involving atrial myxomas (n=3), thrombi associated with endovascular grafts (n=3), chronic hematomas (n=2), and pseudocysts (n=4). All cases tested were nongerminal center B-cell origin, type III EBV latency, and were negative for MYC rearrangements and alternative lengthening of telomeres by FISH. Most showed high CD30, Ki67, and PD-L1, and low to moderate MYC and p53 expression. Among 11 patients with detailed follow-up, 6 were treated surgically, 3 with cardiac or vascular lesions had persistent/recurrent disease at intravascular sites, and 4 died of causes not directly attributable to lymphoma. Reports of previously published fibrin-associated cases showed similar features, whereas traditional DLBCL-CI cases with a mass lesion had significantly higher lymphoma-associated mortality. Fibrin-associated EBV+ large B-cell lymphoma is clinicopathologically distinct from DLBCL-CI, warranting separate classification. Most cases, particularly those associated with pseudocysts, behave indolently with the potential for cure by surgery alone and may represent a form of EBV+ lymphoproliferative disease rather than lymphoma. However, primary cardiac or vascular disease may have a higher risk of recurrence despite systemic chemotherapy.

  19. Derailed B cell homeostasis in patients with mixed connective tissue disease.

    PubMed

    Hajas, A; Barath, S; Szodoray, P; Nakken, B; Gogolak, P; Szekanecz, Z; Zold, E; Zeher, M; Szegedi, G; Bodolay, E

    2013-07-01

    Mixed connective tissue disease (MCTD) is a systemic autoimmune disorder, characterized by the presence of antibodies to U1-RNP protein. We aimed to determine phenotypic abnormalities of peripheral B cell subsets in MCTD. Blood samples were obtained from 46 MCTD patients, and 20 controls. Using anti-CD19, anti-CD27, anti-IgD and anti-CD38 monoclonal antibodies, the following B cell subsets were identified by flow cytometry: (1) transitional B cells (CD19+CD27-IgD+CD38(high)); (2) naive B cells (CD19+CD27-IgD+CD38(low)); (3) non-switched memory B cells (CD19+CD27+IgD+); (4) switched memory B cells (CD19+CD27+IgD-); (5) double negative (DN) memory B cells (CD19+CD27-IgD-) and (6) plasma cells (CD19+CD27(high)IgD-). The proportion of transitional B cells, naive B cells and DN B lymphocytes was higher in MCTD than in controls. The DN B cells were positive for CD95 surface marker. This memory B cells population showed a close correlation with disease activity. The number of plasma cells was also increased, and there was an association between the number of plasma cells and the anti-U1RNP levels. Cyclophosphamide, methotrexate, and corticosteroid treatment decreased the number of DN and CD27(high) B cells. In conclusion, several abnormalities were found in the peripheral B-cell subsets in MCTD, which reinforces the role of derailed humoral autoimmune processes in the pathogenesis.

  20. Autoimmune Lymphoproliferative Syndrome (ALPS) in a Boy with Massive Lymphadenopathy.

    PubMed

    Kianifar, Hamid Reza; Khalesi, Maryam; Farid, Reza; Badiee, Zahra; Rastin, Maryam; Ahanchian, Hamid

    2010-09-01

    Autoimmune lymphoproliferative syndrome (ALPS) is an uncommon nonmalignant lymphoproliferative disease which is characterized by chronic, persistent or recurrent lymphadenopathy, splenomegaly, hepatomegaly, immune cytopenia , hypergammaglobinemia and increased risk of lymphoma. We report a 2-year old boy with hepatosplenomegaly as first presentation. Petechial and purpuric rashes with massive cervical lymphadenopathies developed 10 months later.In laboratory tests anemia, thrombocytopenia and hypergammaglobinemia were observed. According to flocytometry increased double negative T cells and by apoptosis assay decrease apoptosis of lymphocytes accompanied clinical manifestations, thus diagnosis of ALPS was established. In conclusion; in all patients with massive lymphadenopathy and hepatosplenomegay; especially with cytopenia; ALPS should be considered.

  1. Selection of natural autoreactive B cells.

    PubMed

    Hardy, Richard R; Hayakawa, Kyoko

    2015-01-01

    Natural antibodies produced by CD5+ B1 B cells include anti-thymocyte autoantibody (ATA). Transgenic mice bearing the Ig-μ heavy chain of a prototypic ATA, V(H)3609Vκ21c, demonstrated a critical requirement for self-antigen in the accumulation of ATA B cells and production of high levels of serum ATA. Further work with ATA-μκ transgenic mice revealed that, while development of most B cells were blocked at an immature stage in spleen, some mature ATA B cells were present. ATA-μκ transgenic mice with varying levels of Thy-1 autoantigen showed a clear relationship between BCR crosslinking and B cell fate, with low levels generating marginal zone ATA B cells and complete antigen absence allowing maturation to follicular ATA B cells. Finally, different fates of developing ATA B cells encountering high levels self-antigen may be accounted for by variations in the response of newly formed B cells arising from foetal and adult development.

  2. B-Cell Hematologic Malignancy Vaccination Registry

    ClinicalTrials.gov

    2016-12-28

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

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

    PubMed

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

    2015-07-01

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

  4. 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

  5. Epstein-Barr Virus-Negative Post-Transplant Lymphoproliferative Diseases: Three Distinct Cases from a Single Center

    PubMed Central

    Bakanay, Şule Mine; Kaygusuz, Gülşah; Topçuoğlu, Pervin; Şengül, Şule; Tunçalı, Timur; Keven, Kenan; Kuzu, Işınsu; Uysal, Akın; Arat, Mutlu

    2014-01-01

    Three cases of Epstein-Barr virus (EBV)-negative post-transplant lymphoproliferative disease that occurred 6 to 8 years after renal transplantation are reported. The patients respectively had gastric mucosa-associated lymphoid tissue lymphoma, gastric diffuse large B-cell lymphoma, and atypical Burkitt lymphoma. Absence of EBV in the tissue samples was demonstrated by both in situ hybridization for EBV early RNA and polymerase chain reaction for EBV DNA. Patients were treated with reduction in immunosuppression and combined chemotherapy plus an anti-CD20 monoclonal antibody, rituximab. Despite the reduction in immunosuppression, patients had stable renal functions without loss of graft functions. The patient with atypical Burkitt lymphoma had an abnormal karyotype, did not respond to treatment completely, and died due to disease progression. The other patients are still alive and in remission 5 and 3 years after diagnosis, respectively. EBV-negative post-transplant lymphoproliferative diseases are usually late-onset and are reported to have poor prognosis. Thus, reduction in immunosuppression is usually not sufficient for treatment and more aggressive approaches like rituximab with combined chemotherapy are required. PMID:24764734

  6. Rafting in the membrane. A lesson learnt from lymphoproliferative disorders.

    PubMed

    Svec, A

    2008-10-01

    Lipid rafts are chemically distinct compartments of the plasma membrane. Their integrity is a prerequisite for vital cellular functions particularly for signalling and trafficking. Their perturbation is associated with development of a broad spectrum of diseases. Lipid rafts are also important for therapeutic effects of some drugs. Moreover, some of the raft associated molecules are useful immunohistochemical markers in routine histopathology.

  7. Accumulation of peripheral autoreactive B cells in the absence of functional human regulatory T cells

    PubMed Central

    Kinnunen, Tuure; Chamberlain, Nicolas; Morbach, Henner; Choi, Jinyoung; Kim, Sangtaek; Craft, Joseph; Mayer, Lloyd; Cancrini, Caterina; Passerini, Laura; Bacchetta, Rosa; Ochs, Hans D.; Torgerson, Troy R.

    2013-01-01

    Regulatory T cells (Tregs) play an essential role in preventing autoimmunity. Mutations in the forkhead box protein 3 (FOXP3) gene, which encodes a transcription factor critical for Treg function, result in a severe autoimmune disorder and the production of various autoantibodies in mice and in IPEX (immune dysregulation, polyendocrinopathy, enteropathy, X-linked) patients. However, it is unknown whether Tregs normally suppress autoreactive B cells. To investigate a role for Tregs in maintaining human B-cell tolerance, we tested the reactivity of recombinant antibodies isolated from single B cells isolated from IPEX patients. Characteristics and reactivity of antibodies expressed by new emigrant/transitional B cells from IPEX patients were similar to those from healthy donors, demonstrating that defective Treg function does not impact central B-cell tolerance. In contrast, mature naive B cells from IPEX patients often expressed autoreactive antibodies, suggesting an important role for Tregs in maintaining peripheral B-cell tolerance. T cells displayed an activated phenotype in IPEX patients, including their Treg-like cells, and showed up-regulation of CD40L, PD-1, and inducibl T-cell costimulator (ICOS), which may favor the accumulation of autoreactive mature naive B cells in these patients. Hence, our data demonstrate an essential role for Tregs in the establishment and the maintenance of peripheral B-cell tolerance in humans. PMID:23223361

  8. B cell maturation antigen deficiency exacerbates lymphoproliferation and autoimmunity in murine lupus.

    PubMed

    Jiang, Chao; Loo, William M; Greenley, Erin J; Tung, Kenneth S; Erickson, Loren D

    2011-06-01

    Systemic lupus erythematosus and its preclinical lupus-prone mouse models are autoimmune disorders involving the production of pathogenic autoantibodies. Genetic predisposition to systemic lupus erythematosus results in B cell hyperactivity, survival of self-reactive B cells, and differentiation to autoantibody-secreting plasma cells (PCs). These corrupt B cell responses are, in part, controlled by excess levels of the cytokine BAFF that normally maintains B cell homeostasis and self-tolerance through limited production. B cell maturation Ag (BCMA) is a receptor for BAFF that, under nonautoimmune conditions, is important for sustaining enduring Ab protection by mediating survival of long-lived PCs but is not required for B cell maturation and homeostasis. Through analysis of two different lupus-prone mouse models deficient in BCMA, we identify BCMA as an important factor in regulating peripheral B cell expansion, differentiation, and survival. We demonstrate that a BCMA deficiency combined with the lpr mutation or the murine lupus susceptibility locus Nba2 causes dramatic B cell and PC lymphoproliferation, accelerated autoantibody production, and early lethality. This study unexpectedly reveals that BCMA works to control B cell homeostasis and self-tolerance in systemic autoimmunity.

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

    PubMed

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

    2015-03-01

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

  10. Genetics Home Reference: X-linked lymphoproliferative disease

    MedlinePlus

    ... 59. doi: 10.1007/s12026-008-8048-7. Review. Citation on PubMed GeneReview: Lymphoproliferative Disease, X-Linked ... Clin Immunol. 2007 Dec;7(6):510-4. Review. Citation on PubMed Marsh RA, Madden L, Kitchen ...

  11. Regulatory B cells in autoimmune diseases

    PubMed Central

    Yang, Min; Rui, Ke; Wang, Shengjun; Lu, Liwei

    2013-01-01

    B cells are generally considered to be positive regulators of the immune response because of their capability to produce antibodies, including autoantibodies. The production of antibodies facilitates optimal CD4+ T-cell activation because B cells serve as antigen-presenting cells and exert other modulatory functions in immune responses. However, certain B cells can also negatively regulate the immune response by producing regulatory cytokines and directly interacting with pathogenic T cells via cell-to-cell contact. These types of B cells are defined as regulatory B (Breg) cells. The regulatory function of Breg cells has been demonstrated in mouse models of inflammation, cancer, transplantation, and particularly in autoimmunity. In this review, we focus on the recent advances that lead to the understanding of the development and function of Breg cells and the implications of B cells in human autoimmune diseases. PMID:23292280

  12. Differential radiosensitivity among B cell subpopulations

    SciTech Connect

    Riggs, J.E.; Lussier, A.M.; Lee, S.K.; Appel, M.C.; Woodland, R.T.

    1988-09-15

    We have previously shown that low doses of ionizing radiation selectively impair a functionally defined B cell subpopulation. Normal mice, after exposure to 200 rad of ionizing radiation, have normal or near normal splenic plaque-forming cell responses to thymus-independent type 1 Ag, but reduced responses to thymus-independent type 2 Ag. Here, we confirm and extend the original findings by using hapten-specific serum RIA to demonstrate this differential radiosensitivity is systemic. We also examined splenocytes stained with a panel of lymphocyte surface Ag by FACS analysis to determine if these functional changes are accompanied by a physical alteration of the B cell pool of irradiated mice. Single-parameter FACS analyses demonstrate a diminution in both B cell number and the heterogeneity of membrane Ag expression within the surviving B cell pool after irradiation. In contrast, T cells are relatively radioresistant as the relative percentage of T cells in the irradiated splenocyte pool increases, whereas the heterogeneity of membrane Ag expression remains constant. Multiparameter FACS analyses indicate that B cells with the sIgM much greater than sIgD phenotype are more radiosensitive than B cells of the sIgM much less than sIgD phenotype. In addition, immunohistochemical analysis of splenic sections stained with anti-IgM or anti-IgD reveal the enhanced radiosensitivity of marginal zone B cells.

  13. 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.

  14. Expression of HSV-1 receptors in EBV-associated lymphoproliferative disease determines susceptibility to oncolytic HSV.

    PubMed

    Wang, P-Y; Currier, M A; Hansford, L; Kaplan, D; Chiocca, E A; Uchida, H; Goins, W F; Cohen, J B; Glorioso, J C; van Kuppevelt, T H; Mo, X; Cripe, T P

    2013-07-01

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

  15. FAS haploinsufficiency is a common disease mechanism in the human autoimmune lymphoproliferative syndrome.

    PubMed

    Kuehn, Hye Sun; Caminha, Iusta; Niemela, Julie E; Rao, V Koneti; Davis, Joie; Fleisher, Thomas A; Oliveira, João B

    2011-05-15

    The autoimmune lymphoproliferative syndrome (ALPS) is characterized by early-onset lymphadenopathy, splenomegaly, immune cytopenias, and an increased risk for B cell lymphomas. Most ALPS patients harbor mutations in the FAS gene, which regulates lymphocyte apoptosis. These are commonly missense mutations affecting the intracellular region of the protein and have a dominant-negative effect on the signaling pathway. However, analysis of a large cohort of ALPS patients revealed that ∼30% have mutations affecting the extracellular region of FAS, and among these, 70% are nonsense, splice site, or insertions/deletions with frameshift for which no dominant-negative effect would be expected. We evaluated the latter patients to understand the mechanism(s) by which these mutations disrupted the FAS pathway and resulted in clinical disease. We demonstrated that most extracellular-region FAS mutations induce low FAS expression due to nonsense-mediated RNA decay or protein instability, resulting in defective death-inducing signaling complex formation and impaired apoptosis, although to a lesser extent as compared with intracellular mutations. The apoptosis defect could be corrected by FAS overexpression in vitro. Our findings define haploinsufficiency as a common disease mechanism in ALPS patients with extracellular FAS mutations.

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

    PubMed

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

    2014-03-27

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

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

    PubMed Central

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

    2012-01-01

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

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

    PubMed Central

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

    2014-01-01

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

  19. Identifying autoimmune lymphoproliferative syndrome in children with Evans syndrome: a multi-institutional study.

    PubMed

    Seif, Alix E; Manno, Catherine S; Sheen, Cecilia; Grupp, Stephan A; Teachey, David T

    2010-03-18

    Autoimmune lymphoproliferative syndrome (ALPS) is a disorder of abnormal lymphocyte survival caused by dysregulation of the Fas apoptotic pathway. Clinical manifestations of ALPS include autoimmune cytopenias, organomegaly, and lymphadenopathy. These findings overlap with Evans syndrome (ES), defined by presence of at least 2 autoimmune cytopenias. We hypothesized a subset of patients with ES have ALPS and tested 45 children at 22 institutions, measuring peripheral blood double-negative T cells (DNTs) and Fas-mediated apoptosis. ALPS was diagnosed in 47% of patients tested. Markedly elevated DNTs (> or = 5%) were a strong predictor of ALPS (positive predictive value = 94%), whereas no patients with DNTs less than 2.5% had ALPS on apoptosis testing. Severity of cytopenias and elevated immunoglobulin levels also predicted ALPS. This is the largest published series describing children with ES and documents a high rate of ALPS among pediatric ES patients. These data suggest that children with ES should be screened for ALPS with DNTs.

  20. Report on the X-linked lymphoproliferative disease in an Australian family.

    PubMed

    Turner, A M; Berdoukas, V A; Tobias, V H; Ziegler, J B; Toogood, I R; Mulley, J C; Skare, J; Purtilo, D T

    1992-04-01

    X-linked lymphoproliferative disease is characterized by immune deficiency, particularly to the Epstein-Barr virus and by a tendency to develop fatal infectious mononucleosis, acquired hypogammaglobulinaemia or malignant lymphoma. This disorder has been diagnosed in three boys, two brothers and a maternally related cousin, residing in Australia. The proband presented at 6 years of age with fulminating infectious mononucleosis. His 9 year old male cousin had developed an ileal Burkitt lymphoma one year earlier. Immunological and molecular genetic evidence is presented to support our view that his younger sibling is also affected with this condition. DNA linkage studies using probes to DXS10 and DXS37 provide confirmatory evidence for the diagnosis in the proband's brother and information on carrier status in female family members.

  1. Novel molecular and cellular therapeutic targets in acute lymphoblastic leukemia and lymphoproliferative disease

    PubMed Central

    Seif, Alix E.; Reid, Gregor S. D.; Teachey, David T.; Grupp, Stephan A.

    2010-01-01

    While the outcome for pediatric patients with lymphoproliferative disorders (LPD) or lymphoid malignancies, such as acute lymphoblastic leukemia (ALL), has improved dramatically, patients often suffer from therapeutic sequelae. Additionally, despite intensified treatment, the prognosis remains dismal for patients with refractory or relapsed disease. Thus, novel biologically targeted treatment approaches are needed. These targets can be identified by understanding how a loss of lymphocyte homeostasis can result in LPD or ALL. Herein, we review potential molecular and cellular therapeutic strategies that (i) target key signaling networks (e.g., PI3K/AKT/mTOR, JAK/STAT, Notch1, and SRC kinase family-containing pathways) which regulate lymphocyte growth, survival, and function; (ii) block the interaction of ALL cells with stromal cells or lymphoid growth factors secreted by the bone marrow microenvironment; or (iii) stimulate innate and adaptive immune responses. PMID:18716718

  2. The early history of B cells.

    PubMed

    Cooper, Max D

    2015-03-01

    The separate development of functionally intertwined lineages of lymphocytes known as B cells and T cells is now recognized as a fundamental organizing principle of the adaptive immune system in all vertebrates. Immunologists strive to define the different sublineages of the clonally diverse B cells and T cells, how they interact with each other and how they interact with innate lymphoid cells and other elements of the innate immune system to counter infections, cancer and the development of autoimmune and inflammatory diseases. On the 50th anniversary of the recognition of B cells as a discrete cell lineage, this Timeline article recounts some of the milestones marking the development of the concept that B cells are a functionally and developmentally distinct arm of the adaptive immune system.

  3. IDO2 Modulates T Cell-Dependent Autoimmune Responses through a B Cell-Intrinsic Mechanism.

    PubMed

    Merlo, Lauren M F; DuHadaway, James B; Grabler, Samantha; Prendergast, George C; Muller, Alexander J; Mandik-Nayak, Laura

    2016-06-01

    Mechanistic insight into how adaptive immune responses are modified along the self-nonself continuum may offer more effective opportunities to treat autoimmune disease, cancer, and other sterile inflammatory disorders. Recent genetic studies in the KRN mouse model of rheumatoid arthritis demonstrate that the immunomodulatory molecule IDO2 modifies responses to self-antigens; however, the mechanisms involved are obscure. In this study, we show that IDO2 exerts a critical function in B cells to support the generation of autoimmunity. In experiments with IDO2-deficient mice, adoptive transplant experiments demonstrated that IDO2 expression in B cells was both necessary and sufficient to support robust arthritis development. IDO2 function in B cells was contingent on a cognate, Ag-specific interaction to exert its immunomodulatory effects on arthritis development. We confirmed a similar requirement in an established model of contact hypersensitivity, in which IDO2-expressing B cells are required for a robust inflammatory response. Mechanistic investigations showed that IDO2-deficient B cells lacked the ability to upregulate the costimulatory marker CD40, suggesting IDO2 acts at the T-B cell interface to modulate the potency of T cell help needed to promote autoantibody production. Overall, our findings revealed that IDO2 expression by B cells modulates autoimmune responses by supporting the cross talk between autoreactive T and B cells.

  4. 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.

  5. Autoimmune lymphoproliferative syndrome: response to mycophenolate mofetil and pyrimethamine/sulfadoxine in a 5-year-old child.

    PubMed

    Arora, Sunaina; Singh, Neeraj; Chaudhary, Gurmeet Kaur; John, M Joseph

    2011-06-01

    Autoimmune Lymphoproliferative Syndrome (ALPS) is a rare inherited disorder of disrupted lymphocyte homeostasis characterized by chronic splenomegaly and lymphadenopathy of early onset, hypergammaglobulinemia (Ig G and Ig A), autoimmune phenomena, and expanded populations of TCR-α/β+, CD3+, CD4-, CD8-T cells (Fisher et al. Cell 81:935-946; 1995), called double negative T-cells [(DN) T cells]. We discuss a case of ALPS which showed good response to immunosuppressant drug Mycophenolate-Mofetil in combination with Pyrimethamine/Sulfadoxine.

  6. Use of Sirolimus (Rapamycin) for Treatment of Cytopenias and Lymphoproliferation Linked to Autoimmune Lymphoproliferative Syndrome (ALPS). Two Case Reports.

    PubMed

    Cayrol, Julie; Garrido Colino, Carmen

    2017-02-23

    Autoimmune lymphoproliferative syndrome (ALPS) is a disorder of lymphocyte apoptosis. Children present with chronic nonmalignant lymphadenopathy, hepatosplenomegaly, and autoimmune cytopenias. Recent advances show efficacy of treatment with immunosuppressive drugs. Sirolimus, an mammalian target of rapamycin inhibitor, improves autoimmune cytopenias and lymphoproliferation, with a safe profile. We present 2 patients, a 5-year-old girl and 15-year-old boy, diagnosed with ALPS with initial partial response to steroid treatment. Autoimmune cytopenias and lymphoproliferation then became refractory to treatment, with recurrence of symptoms. In both cases, treatment with sirolimus was started, with a rapid response, complete remission of cytopenias, and resolution of lymphoproliferation, with no significant adverse effects.

  7. MYSM1-dependent checkpoints in B cell lineage differentiation and B cell-mediated immune response.

    PubMed

    Förster, Michael; Farrington, Kyo; Petrov, Jessica C; Belle, Jad I; Mindt, Barbara C; Witalis, Mariko; Duerr, Claudia U; Fritz, Jörg H; Nijnik, Anastasia

    2017-03-01

    MYSM1 is a chromatin-binding histone deubiquitinase. MYSM1 mutations in humans result in lymphopenia whereas loss of Mysm1 in mice causes severe hematopoietic abnormalities, including an early arrest in B cell development. However, it remains unknown whether MYSM1 is required at later checkpoints in B cell development or for B cell-mediated immune responses. We analyzed conditional mouse models Mysm1(fl/fl)Tg.mb1-cre, Mysm1(fl/fl)Tg.CD19-cre, and Mysm1(fl/fl)Tg.CD21-cre with inactivation of Mysm1 at prepro-B, pre-B, and follicular B cell stages of development. We show that loss of Mysm1 at the prepro-B cell stage in Mysm1(fl/fl)Tg.mb1-cre mice results in impaired B cell differentiation, with an ∼2-fold reduction in B cell numbers in the lymphoid organs. Mysm1(fl/fl)Tg.mb1-cre B cells also showed increased expression of activation markers and impaired survival and proliferation. In contrast, Mysm1 was largely dispensable from the pre-B cell stage onward, with Mysm1(fl/fl)Tg.CD19-cre and Mysm1(fl/fl)Tg.CD21-cre mice showing no alterations in B cell numbers and largely normal responses to stimulation. MYSM1, therefore, has an essential role in B cell lineage specification but is dispensable at later stages of development. Importantly, MYSM1 activity at the prepro-B cell stage of development is important for the normal programming of B cell responses to stimulation once they complete their maturation process.

  8. Autoimmune lymphoproliferative syndrome (ALPS). Case report and family history.

    PubMed

    Ries, F; Ferster, A; Rieux-Laucat, F; Biwer, A; Dicato, M

    2010-01-01

    Autoimmune lymphoproliferative syndrome (ALPS) is a rare disease caused by defective lymphocyte apoptosis and is characterized by non-malignant lymphoproliferation, hepatosplenomegaly, autoimmune manifestations and increased risk of both Hodgkin's and non-Hodgkin's lymphoma. Most forms of the disease are due to germ line mutations of the FAS gene and manifest during the first years of life with fluctuating lymphadenopathies, hemolysis, immune thrombocytopenia. During the second decade of life disease manifestations improve spontaneously but autoimmune problems still occur and there is an increased risk of lymphoproliferative malignancy. We describe a typical case of ALPS in a now 44 year old man, followed since the age of 2 for disease manifestations that were unclear at the beginning.

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

    PubMed

    Garrido Colino, C

    2014-02-01

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

  10. Autoimmune lymphoproliferative syndrome (ALPS): a case with congenital onset.

    PubMed

    Kahwash, Samir B; Fung, Bonita; Savelli, Stephanie; Bleesing, Jack J; Qualman, Stephen J

    2007-01-01

    We describe a case of autoimmune lymphoproliferative syndrome (ALPS), which is very unusual with regard to a clinical onset soon after birth, and a clinical picture dominated by splenomegaly, jaundice, and consumptive peripheral blood cytopenias, with minimal lymphadenopathy. Our documented close follow up demonstrated initial involvement of the spleen, followed by involvement of the bone marrow and the peripheral blood. The patient underwent bone marrow transplant and is alive and well 20 months after diagnosis.

  11. B-cell malignancies in microRNA Eμ-miR-17∼92 transgenic mice

    PubMed Central

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

    2013-01-01

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

  12. The proapoptotic benzodiazepine Bz-423 affects the growth and survival of malignant B cells.

    PubMed

    Boitano, Anthony; Ellman, Jonathan A; Glick, Gary D; Opipari, Anthony W

    2003-10-15

    Bz-423 is a novel proapoptotic 1,4-benzodiazepine that induces cell death via a superoxide signal. Previous work has shown that Bz-423 ameliorates disease in animal models of systemic lupus erythematosus that also have features of lymphoproliferative disease. Here we describe the effects of Bz-423 against a group of malignant B-cell lines derived from Burkitt's lymphoma. These experiments demonstrate that Bz-423 has cytotoxic activity against all B-cell lines tested, regardless of EBV status or Bcl-2 and Bcl-x(L) expression levels. In addition to its cytotoxic properties, we found that Bz-423 is also a potent antiproliferative agent that induces a G(1)-phase arrest independent of p53. Mechanistically, both the cytotoxicity and growth arrest are mediated by increased reactive oxygen species levels and appear independent of binding to the peripheral benzodiazepine receptor. This work further defines the biological activities of Bz-423 that are consistent with those of other compounds in clinical development for antineoplastic therapies.

  13. MIF promotes B cell chemotaxis through the receptors CXCR4 and CD74 and ZAP-70 signaling.

    PubMed

    Klasen, Christina; Ohl, Kim; Sternkopf, Marieke; Shachar, Idit; Schmitz, Corinna; Heussen, Nicole; Hobeika, Elias; Levit-Zerdoun, Ella; Tenbrock, Klaus; Reth, Michael; Bernhagen, Jürgen; El Bounkari, Omar

    2014-06-01

    Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine with chemokine-like functions that plays a pivotal role in the pathogenesis of inflammatory diseases by promoting leukocyte recruitment. We showed that MIF promotes the atherogenic recruitment of monocytes and T cells through its receptors CXCR2 and CXCR4. Effects of MIF on B cell recruitment have not been addressed. In this study, we tested the involvement of MIF in B cell chemotaxis and studied the underlying mechanism. We show that MIF promotes primary murine B cell chemotaxis in a dose-dependent manner, comparable to the B cell chemokines CXCL13 and CXCL12. Splenic B cells express CXCR4 and the receptor CD74 but not CXCR2. Inhibition of CXCR4 or CD74 or a genetic deficiency of Cd74 in primary B cells fully abrogated MIF-mediated B cell migration, implying cooperative involvement of both receptors. MIF stimulation of B cells resulted in a rapid increase in intracellular Ca(2+) mobilization and F-actin polymerization. Intriguingly, the tyrosine kinase ZAP-70 was activated upon MIF and CXCL12 treatment in a CXCR4- and CD74-dependent manner. Pharmacological inhibition of ZAP-70 resulted in abrogation of primary B cell migration. Functional involvement of ZAP-70 was confirmed by small interfering RNA-mediated knockdown in Ramos B cell migration. Finally, primary B cells from ZAP-70 gene-deficient mice exhibited ablated transmigration in response to MIF or CXCL12. We conclude that MIF promotes the migration of B cells through a ZAP-70-dependent pathway mediated by cooperative engagement of CXCR4 and CD74. The data also suggest that MIF may contribute to B cell recruitment in vivo (e.g., in B cell-related immune disorders).

  14. Inflammatory monocytes hinder antiviral B cell responses

    PubMed Central

    Sammicheli, Stefano; Kuka, Mirela; Di Lucia, Pietro; de Oya, Nereida Jimenez; De Giovanni, Marco; Fioravanti, Jessica; Cristofani, Claudia; Maganuco, Carmela G.; Fallet, Benedict; Ganzer, Lucia; Sironi, Laura; Mainetti, Marta; Ostuni, Renato; Larimore, Kevin; Greenberg, Philip D.; de la Torre, Juan Carlos; Guidotti, Luca G.; Iannacone, Matteo

    2016-01-01

    Antibodies are critical for protection against viral infections. However, several viruses, such as lymphocytic choriomeningitis virus (LCMV), avoid the induction of early protective antibody responses by poorly understood mechanisms. Here we analyzed the spatiotemporal dynamics of B cell activation to show that, upon subcutaneous infection, LCMV-specific B cells readily relocate to the interfollicular and T cell areas of the draining lymph node where they extensively interact with CD11b+Ly6Chi inflammatory monocytes. These myeloid cells were recruited to lymph nodes draining LCMV infection sites in a type I interferon-, CCR2-dependent fashion and they suppressed antiviral B cell responses by virtue of their ability to produce nitric oxide. Depletion of inflammatory monocytes, inhibition of their lymph node recruitment or impairment of their nitric oxide-producing ability enhanced LCMV-specific B cell survival and led to robust neutralizing antibody production. In conclusion, our results identify inflammatory monocytes as critical gatekeepers that prevent antiviral B cell responses and suggest that certain viruses take advantage of these cells to prolong their persistence within the host. PMID:27868108

  15. Receptor Dissociation and B-Cell Activation.

    PubMed

    Yang, Jianying; Reth, Michael

    2016-01-01

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

  16. Human norovirus culture in B cells

    PubMed Central

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

    2015-01-01

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

  17. Transitional B cells are the target of negative selection in the B cell compartment

    PubMed Central

    1995-01-01

    B lymphocytes recognize antigen through membrane-bound antigen- receptors, membrane IgM and IgD (mIgM and mIgD). Binding to foreign antigens initiates a cascade of biochemical events that lead to activation and differentiation. In contrast, binding to self-antigens leads to death or to inactivation. It is commonly believed that the B cells acquire the ability to discriminate between self and nonself in the early phases of development. We report here that immature B cells, which have just emerged from the mIgMneg, B220pos pool, are not deleted upon binding of self-antigen. In vivo, developing B cells become sensitive to tolerance induction in a relatively late window of differentiation, when they are in transition from the immature (HSAbright, B220dull) to the mature (HSAdull, B220bright) stage. In the transitional B cells, early markers of differentiation such as Pgp1 (CD44) and ThB reach the highest level of expression, while the expression of CD23 and mIgD, late markers of differentiation, and expression of class II MHC, progressively increases. Most of the transitional B cells, but only few of the mature and of the immature B cells, express the fas antigen, while mature B cells, but not immature and transitional B cells, express bcl-2 protein. mIgM is present in low amounts in immature B cells, reaches the highest level of expression in transitional B cells and is down-regulated in mature resting B cells, where it is coexpressed with mIgD. The high expression of mIgM, the presence of the fas antigen and the absence of bcl-2 protein is compatible with the high sensitivity of transitional B cells to negative selection. In vitro, immature B cells die rapidly by apoptosis after cross-linking of mIgM. This result, combined with the resistance of immature B cells to elimination in vivo, suggests that early in development the stroma cell microenvironment modulates signals transduced through mIgM. The functional and phenotypic division of IgMpos bone marrow B cells in

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

    PubMed Central

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

    1995-01-01

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

  19. B cell suppression in primary glomerular disease.

    PubMed

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

    2014-03-01

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

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

    PubMed Central

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

    2013-01-01

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

  1. Expression of CD45RO on circulating CD19+ B-cells in Crohn's disease.

    PubMed Central

    Yacyshyn, B R; Pilarski, L M

    1993-01-01

    Crohn's disease is an immunoregulatory disorder of the intestine that can be associated with systemic manifestations. This study analysed B-cell differentiation antigens to identify B-cell subpopulations unique to patients with Crohn's disease. CD45 isoform expression was used as an indicator of B-cell differentiation stage. This work shows that B-cells in blood and gut of patients with Crohn's disease are at an advanced stage of differentiation based on their unusual presentation of transitional (RA+ RO+) and late stage (RO+)CD45 isoforms on lamina propria lymphocytes, whereas normal intestinal lamina propria lymphocytes B-cells express primarily CD45RA. Crohn's disease patients had heightened expression of the CD45RO isoform on CD19+ lamina propria lymphocytes, and was found in a statistically significant proportion of Crohn's peripheral blood mononuclear cells (PBMC) where CD19+ PBMC had an expression pattern affecting an unexpectedly high proportion of these differentiated or late stage CD45RO+ B-cells. The expression of CD45RO varied greatly among CD19+ PBMC from patients with Crohn's disease, so multiple regression analysis was performed between these CD45 isoforms and several clinical parameters. After grouping high and low CD45RO expression on CD19+ B-cells, a significant statistical difference was found between high Crohn's disease activity index (CDAI) and low CDAI Crohn's disease patients respectively. PMID:7506695

  2. VNAR single-domain antibodies specific for BAFF inhibit B cell development by molecular mimicry.

    PubMed

    Häsler, Julien; Flajnik, Martin F; Williams, Gareth; Walsh, Frank S; Rutkowski, J Lynn

    2016-07-01

    B cell-activating factor (BAFF) plays a dominant role in the B cell homeostasis. However, excessive BAFF promotes the development of autoreactive B-cells and several antibodies have been developed to block its activity. Bispecific antibodies with added functionality represent the next wave of biologics that may be more effective in the treatment of complex autoimmune disease. The single variable domain from the immunoglobulin new antigen receptor (VNAR) is one of the smallest antibody recognition units that could be combined with monospecific antibodies to develop bispecific agents. We isolated a panel of BAFF-binding VNARs with low nM potency from a semi-synthetic phage display library and examined their functional activity. The anti-BAFF VNARs blocked the binding of BAFF to all three of its receptors (BR3, TACI and BCMA) and the presence of the conserved DXL receptor motif found in the CDR3 regions suggests molecular mimicry as the mechanism of antagonism. One clone was formatted as an Fc fusion for functional testing and it was found to inhibit both mouse and human BAFF with equal potency ex vivo in a splenocyte proliferation assay. In mice, subchronic administration reduced the number of immature and transitional intermediates B cells and mature B cell subsets. These results indicate that VNAR single domain antibodies function as selective B-cell inhibitors and offer an alternative molecular format for targeting B-cell disorders.

  3. Autoimmune Lymphoproliferative Syndrome and Epstein-Barr Virus-Associated Lymphoma: An Adjunctive Diagnostic Role for Monitoring EBV Viremia?

    PubMed

    Pace, Romina; Vinh, Donald C

    2013-01-01

    Background. Autoimmune lymphoproliferative syndrome (ALPS) is a genetic disorder of lymphocyte homeostasis due to defects in FAS-mediated apoptosis. ALPS is characterized by childhood onset of chronic lymphadenopathy and splenomegaly, autoimmunity, an expanded population of double-negative T cells (DNTCs), and an increased risk of lymphoma. This propensity for lymphoma in ALPS is not well understood. It is possible that lymphomagenesis in some of these patients may result from Epstein-Barr virus (EBV) infection exploiting the defective T-cell surveillance resulting from impaired FAS-mediated apoptosis. Case Presentation. We report the first case, to our knowledge, of lymphoma in a patient with ALPS that was clinically heralded by progressively increasing EBV viremia. We discuss its practical implications and the possible immune pathways involved in the increased risk for EBV-associated lymphoproliferative disorders in ALPS patients. Conclusion. In patients with ALPS, distinguishing chronic lymphadenopathy from emerging lymphoma is difficult, with few practical recommendations available. This case illustrates that, at least for some patients, monitoring for progressively increasing EBV viremia may be useful.

  4. Human adipose tissue-derived mesenchymal stem cells abrogate plasmablast formation and induce regulatory B cells independently of T helper cells.

    PubMed

    Franquesa, M; Mensah, F K; Huizinga, R; Strini, T; Boon, L; Lombardo, E; DelaRosa, O; Laman, J D; Grinyó, J M; Weimar, W; Betjes, M G H; Baan, C C; Hoogduijn, M J

    2015-03-01

    Mesenchymal or stromal stem cells (MSC) interact with cells of the immune system in multiple ways. Modulation of the immune system by MSC is believed to be a therapeutic option for autoimmune disease and transplant rejection. In recent years, B cells have moved into the focus of the attention as targets for the treatment of immune disorders. Current B-cell targeting treatment is based on the indiscriminate depletion of B cells. The aim of this study was to examine whether human adipose tissue-derived MSC (ASC) interact with B cells to affect their proliferation, differentiation, and immune function. ASC supported the survival of quiescent B cells predominantly via contact-dependent mechanisms. Coculture of B cells with activated T helper cells led to proliferation and differentiation of B cells into CD19(+) CD27(high) CD38(high) antibody-producing plasmablasts. ASC inhibited the proliferation of B cells and this effect was dependent on the presence of T cells. In contrast, ASC directly targeted B-cell differentiation, independently of T cells. In the presence of ASC, plasmablast formation was reduced and IL-10-producing CD19(+) CD24(high) CD38(high) B cells, known as regulatory B cells, were induced. These results demonstrate that ASC affect B cell biology in vitro, suggesting that they can be a tool for the modulation of the B-cell response in immune disease.

  5. Nonrandon X chromosome inactivation in B cells from carriers of X chromosome-linked severe combined immunodeficiency

    SciTech Connect

    Conley, M.E.; Lavoie, A.; Briggs, C.; Brown, P.; Guerra, C.; Puck, J.M.

    1988-05-01

    X chromosome-linked sever combined immunodeficiency (XSCID) is characterized by markedly reduced numbers of T cells, the absence of proliferative responses to mitogens, and hypogammaglobulinemia but normal or elevated number of B cells. To determine if the failure of the B cells to produce immunoglobulin might be due to expression of the XSCID gene defect in B-lineage cells as well as T cells, the authors analyzed patterns of X chromosome inactivation in B cells from nine obligate carriers of this disorder. A series of somatic cell hybrids that selectively retained the active X chromosome was produced from Epstein-Barr virus-stimulated B cells from each woman. To distinguish between the two X chromosome, the hybrids from each woman were analyzed using an X-linked restriction fragment length polymorphism for which the woman in question was heterozygous. In all obligate carriers of XSCID, the B-cell hybrids demonstrated preferential use of a single X chromosome, the nonmutant X, as the active X. To determine if the small number of B-cell hybrids that contained the mutant X were derived from an immature subset of B cells, lymphocytes from three carriers were separated into surface IgM positive and surface IgM negative B cells prior to exposure to Epstein-Barr virus and production of B-cell hybrids. The results demonstrated normal random X chromosome inactivation in B-cell hybrids derived from the less mature surface IgM positive B cells. These results suggest that the XSCID gene product has a direct effect on B cells as well as T cells and is required during B-cell maturation.

  6. Targeting B cells with biologics in SLE

    PubMed Central

    La Cava, Antonio

    2010-01-01

    Importance of the field The use of biologics as immune modulators in several autoimmune diseases has provided new tools to the physician's therapeutic armamentiarium and has led to improved patients' outcomes and quality of life. By producing autoantibodies, B cells in SLE are key players in the pathogenesis of the disease and in its clinical manifestations. Therefore, biologics that target B cells in SLE aims at reducing the activity of these cells for the induction of remissions and/or amelioration of disease activity, reduction of organ involvement, and limitation of the complications and side effects caused by immunosuppressive therapies. Areas covered in this review This review describes the past and current clinical trials with B cell-targeted biologics in SLE, to provide a historical perspective and the state-of-the-art on the topic. What the reader will gain We will review how the disappointment in the field from promising agents has been instrumental in providing valuable lessons leading to an improved design of new trials that are now giving encouraging results Take home message In systemic lupus erythematosus (SLE), the use of B cell-based biologics in clinical trials has shown both disappointment and promise PMID:20919800

  7. 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

  8. 2B4-SAP signaling is required for the priming of naive CD8(+) T cells by antigen-expressing B cells and B lymphoma cells.

    PubMed

    Huang, Yu-Hsuan; Tsai, Kevin; Tan, Sara Y; Kang, Sohyeong; Ford, Mandy L; Harder, Kenneth W; Priatel, John J

    2017-01-01

    Mutations in SH2D1A gene that encodes SAP (SLAM-associated protein) result in X-linked lymphoproliferative disease (XLP), a rare primary immunodeficiency disease defined by exquisite sensitivity to the B-lymphotropic Epstein-Barr virus (EBV) and B cell lymphomas. However, the precise mechanism of how the loss of SAP function contributes to extreme vulnerability to EBV and the development of B cell lymphomas remains unclear. Here, we investigate the hypothesis that SAP is critical for CD8(+) T cell immune surveillance of antigen (Ag)-expressing B cells or B lymphoma cells under conditions of defined T cell receptor (TCR) signaling. Sh2d1a(-)(/)(-) CD8(+) T cells exhibited greatly diminished proliferation relative to wild type when Ag-presenting-B cells or -B lymphoma cells served as the primary Ag-presenting cell (APC). By contrast, Sh2d1a(-)(/)(-) CD8(+) T cells responded equivalently to wild-type CD8(+) T cells when B cell-depleted splenocytes, melanoma cells or breast carcinoma cells performed Ag presentation. Through application of signaling lymphocyte activation molecule (SLAM) family receptor blocking antibodies or SLAM family receptor-deficient CD8(+) T cells and APCs, we found that CD48 engagement on the B cell surface by 2B4 is crucial for initiating SAP-dependent signaling required for the Ag-driven CD8(+) T cell proliferation and differentiation. Altogether, a pivotal role for SAP in promoting the expansion and differentiation of B cell-primed viral-specific naive CD8(+) T cells may explain the selective immune deficiency of XLP patients to EBV and B cell lymphomas.

  9. Memory B cell subpopulations in the aged.

    PubMed

    Colonna-Romano, Giuseppina; Aquino, Alessandra; Bulati, Matteo; Di Lorenzo, Gabriele; Listì, Florinda; Vitello, Salvatore; Lio, Domenico; Candore, Giuseppina; Clesi, Gioacchino; Caruso, Calogero

    2006-01-01

    The literature on immunosenescence has focused mainly on T cell impairment. With the aim of gaining insight into B cell immunosenescence, the authors investigated the serum IgD levels in 24 young and 21 old people and analyzed their relationship with the number of CD19+CD27+ memory cells. Serum IgD were quantified by the use of radial immunodiffusion and the lymphocyte population CD19+CD27+ was identified by a FACScan flow cytometer. Serum IgD levels were significantly lower (p < 0.0001) in old subjects, and the percentage of CD19+CD27+ lymphocytes were significantly increased (p = 0.01) in old subjects. Finally, a significant negative correlation was found (p = 0.01) between serum concentrations of IgD and CD19+CD27+. The present results show that the levels of IgD are negatively age-related to the amount of B memory cells. This suggests that the B repertoire available to respond to new antigenic challenges is decreased in the elderly. In fact, many memory IgD- B cells fill immunologic space, and the number of naïve IgD+ B cells is dramatically decreased. Therefore, these preliminary results suggest that a decrease of naïve IgD+CD27- B cells and a concomitant increase of memory IgD-CD27+ B cells could represent hallmarks of B immunosenescence, might provide biomarkers related to the lifespan of humans, and could be useful for the evaluation of antiaging treatments.

  10. Comparative In Vitro Immune Stimulation Analysis of Primary Human B Cells and B Cell Lines

    PubMed Central

    Van Belle, Kristien; Herman, Jean; Boon, Louis; Waer, Mark

    2016-01-01

    B cell specific immunomodulatory drugs still remain an unmet medical need. Utilisation of validated simplified in vitro models would allow readily obtaining new insights in the complexity of B cell regulation. For this purpose we investigated which human B lymphocyte stimulation assays may be ideally suited to investigate new B lymphocyte immunosuppressants. Primary polyclonal human B cells underwent in vitro stimulation and their proliferation, production of immunoglobulins (Igs) and of cytokines, and expression of cell surface molecules were analysed using various stimuli. ODN2006, a toll-like receptor 9 (TLR9) agonist, was the most potent general B cell stimulus. Subsequently, we investigated on which human B cell lines ODN2006 evoked the broadest immunostimulatory effects. The Namalwa cell line proved to be the most responsive upon TLR9 stimulation and hence may serve as a relevant, homogeneous, and stable B cell model in an in vitro phenotypic assay for the discovery of new targets and inhibitors of the B cell activation processes. As for the read-out for such screening assay, it is proposed that the expression of activation and costimulatory surface markers reliably reflects B lymphocyte activation. PMID:28116319

  11. SAP expression in invariant NKT cells is required for cognate help to support B-cell responses.

    PubMed

    Detre, Cynthia; Keszei, Marton; Garrido-Mesa, Natividad; Kis-Toth, Katalin; Castro, Wilson; Agyemang, Amma F; Veerapen, Natacha; Besra, Gurdyal S; Carroll, Michael C; Tsokos, George C; Wang, Ninghai; Leadbetter, Elizabeth A; Terhorst, Cox

    2012-07-05

    One of the manifestations of X-linked lymphoproliferative disease (XLP) is progressive agammaglobulinemia, caused by the absence of a functional signaling lymphocyte activation molecule (SLAM)-associated protein (SAP) in T, invariant natural killer T (NKT) cells and NK cells. Here we report that α-galactosylceramide (αGalCer) activated NKT cells positively regulate antibody responses to haptenated protein antigens at multiple checkpoints, including germinal center formation and affinity maturation. Whereas NKT cell-dependent B cell responses were absent in SAP(-/-).B6 mice that completely lack NKT cells, the small number of SAP-deficient NKT cells in SAP(-/-).BALB/c mice adjuvated antibody production, but not the germinal center reaction. To test the hypothesis that SAP-deficient NKT cells can facilitate humoral immunity, SAP was deleted after development in SAP(fl/fl).tgCreERT2.B6 mice. We find that NKT cell intrinsic expression of SAP is dispensable for noncognate helper functions, but is critical for providing cognate help to antigen-specific B cells. These results demonstrate that SLAM-family receptor-regulated cell-cell interactions are not limited to T-B cell conjugates. We conclude that in the absence of SAP, several routes of NKT cell-mediated antibody production are still accessible. The latter suggests that residual NKT cells in XLP patients might contribute to variations in dysgammaglobulinemia.

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

    PubMed

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

    2015-05-19

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

  13. Autoimmune lymphoproliferative syndrome-like disease with somatic KRAS mutation.

    PubMed

    Takagi, Masatoshi; Shinoda, Kunihiro; Piao, Jinhua; Mitsuiki, Noriko; Takagi, Mari; Matsuda, Kazuyuki; Muramatsu, Hideki; Doisaki, Sayoko; Nagasawa, Masayuki; Morio, Tomohiro; Kasahara, Yoshihito; Koike, Kenichi; Kojima, Seiji; Takao, Akira; Mizutani, Shuki

    2011-03-10

    Autoimmune lymphoproliferative syndrome (ALPS) is classically defined as a disease with defective FAS-mediated apoptosis (type I-III). Germline NRAS mutation was recently identified in type IV ALPS. We report 2 cases with ALPS-like disease with somatic KRAS mutation. Both cases were characterized by prominent autoimmune cytopenia and lymphoadenopathy/splenomegaly. These patients did not satisfy the diagnostic criteria for ALPS or juvenile myelomonocytic leukemia and are probably defined as a new disease entity of RAS-associated ALPS-like disease (RALD).

  14. A monoclonal antibody that recognizes B cells and B cell precursors in mice

    PubMed Central

    1981-01-01

    The monoclonal antibody, RA3-2C2, appears to be specific for cells within the B cell lineage. This antibody does not recognize thymocytes, peripheral T cells, or nonlymphoid hematopoietic cells in the spleen or bone marrow. Nor does it recognize the pluripotent hematopoietic stem cells, the spleen colony-forming unit, All sIg+ B cells and most plasma cells are RA3-2C2+. In addition, approximately 20% of nucleated bone marrow cells are RA3-2C2+ but sIg-. This population contains B cell precursors that can give rise to sIg+ cells within 2 d in vitro. PMID:6787164

  15. Progenitors for Ly-1 B cells are distinct from progenitors for other B cells

    PubMed Central

    1985-01-01

    Data from previous multiparameter fluorescence-activated cell sorter (FACS) analysis and sorting studies define a subset of murine B cells that expresses the Ly-1 surface determinant in conjunction with IgM, IgD, Ia, and other typical B cell markers. These Ly-1 B cells are physically and functionally distinct. They express more IgM and less IgD than most other B cells; they are not normally found in lymph node or bone marrow; they are always present at low frequencies (1-5%) in normal spleens, and, as we show here, they comprise about half of the B cells (10-20% of total cells) recovered from the peritoneal cavity in normal mice. Furthermore, most of the commonly studied IgM autoantibodies in normal and autoimmune mice are produced by these Ly-1 B cells, even though they seldom produce antibodies to exogenous antigens such as trinitrophenyl-Ficoll or trinitrophenyl-keyhole limpet hemocyanin. Cell transfer studies presented here demonstrate that the progenitors of Ly-1 B cells are different from the progenitors of the predominant B cell populations in spleen and lymph node. In these studies, we used FACS analysis and functional assays to characterize donor-derived (allotype-marked) B cells present in lethally irradiated recipients 1-2 mo after transfer. Surprisingly, adult bone marrow cells typically used to reconstitute B cells in irradiated recipients selectively failed to reconstitute the Ly-1 B subset. Liver, spleen, and bone marrow cells from young mice, in contrast, reconstituted all B cells (including Ly-1 B), and peritoneal "washout" cells (PerC) from adult mice uniquely reconstituted Ly-1 B. Bone marrow did not block Ly- 1 B development, since PerC and newborn liver still gave rise to Ly-1 B when jointly transferred with marrow. These findings tentatively assign Ly-1 B to a distinct developmental lineage originating from progenitors that inhabit the same locations as other B cell progenitors in young animals, but move to unique location(s) in adults. PMID

  16. B Cell-Activating Factor Regulates Different Aspects of B Cell Functionality and Is Produced by a Subset of Splenic B Cells in Teleost Fish

    PubMed Central

    Tafalla, Carolina; González, Lucia; Castro, Rosario; Granja, Aitor G.

    2017-01-01

    In mammals, B cell functionality is greatly influenced by cytokines released by innate cells, such as macrophages or dendritic cells, upon the early recognition of common pathogen patterns through invariant receptors. B cell-activating factor (BAFF) is one of these innate B cell-helper signals and plays a key role in the survival and differentiation of B cells. Although, evolutionarily, teleost fish constitute the first animal group in which adaptive immunity based on Ig receptors is present, fish still rely greatly on innate responses. In this context, we hypothesized that BAFF would play a key role in the control of B cell responses in fish. Supporting this, our results show that teleost BAFF recapitulates mammalian BAFF stimulating actions on B cells, upregulating the expression of membrane MHC II, improving the survival of fish naïve B cells and antibody-secreting cells, and increasing the secretion of IgM. Surprisingly, we also demonstrate that BAFF is not only produced in fish by myeloid cells but is also produced by a subset of splenic B cells. Thus, if this B cell-produced BAFF proves to be actively regulating this same B cell subset, our findings point to an ancient mechanism to control B cell differentiation and survival in lower vertebrates, which has been silenced in mammals in physiological conditions, but reemerges under pathological conditions, such as B cell lymphomas and autoimmune diseases. PMID:28360916

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

    PubMed Central

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

    2015-01-01

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

  18. Unmasking Evans syndrome: T-cell phenotype and apoptotic response reveal autoimmune lymphoproliferative syndrome (ALPS).

    PubMed

    Teachey, David T; Manno, Catherine S; Axsom, Kelly M; Andrews, Timothy; Choi, John K; Greenbaum, Barbara H; McMann, Joseph M; Sullivan, Kathleen E; Travis, Susan F; Grupp, Stephan A

    2005-03-15

    Autoimmune lymphoproliferative syndrome (ALPS) is a rare disorder of disrupted lymphocyte homeostasis. Clinical manifestations of ALPS vary but typically include autoimmune cytopenias, organomegaly, lymphadenopathy, and increased risk of malignancies. A similar spectrum of symptoms may be seen in some patients with Evans syndrome (ES), a hematologic disorder defined by autoimmune destruction of at least 2 hematologic cell types. We hypothesized that a subset of patients diagnosed with ES may have ALPS. We screened 12 children with ES by flow cytometric analysis for CD4-/CD8- (double negative) T cells (DNTs) and with the definitive test for ALPS, defective in vitro Fas-mediated apoptosis. Six of the patients had elevated DNTs, suggestive of ALPS and also had defective Fas-mediated apoptosis. The other 6 patients displayed normal T-cell apoptosis; 5 of whom had normal DNTs, and 1 had a borderline result. Thus, 7 (58%) of 12 patients with ES had elevated DNTs suggestive of ALPS, with functional confirmation in 6 of 7. This suggests that analysis of DNTs may be a sensitive first-line screening test, serving as a marker of patients who should undergo definitive testing for ALPS. Our data further suggest that a number of patients with ES may have ALPS, a novel finding with important therapeutic implications.

  19. Memory B Cells of Mice and Humans.

    PubMed

    Weisel, Florian; Shlomchik, Mark

    2017-01-30

    Wecomprehensively review memory B cells (MBCs), covering the definition of MBC and their identities and subsets, how MBCs are generated, where they are localized, how they are maintained, and how they are reactivated. Whereas naive B cells adopt multiple fates upon stimulation, MBCs are more restricted in their responses. Evolving work reveals that the MBC compartment in mice and humans consists of distinct subpopulations with differing effector functions. We discuss the various approaches to define subsets and subset-specific roles. A major theme is the need to both deliver faster effector function upon reexposure and readapt to antigenically variant pathogens while avoiding burnout, which would be the result if all MBCs generated only terminal effector function. We discuss cell-intrinsic differences in gene expression and signaling that underlie differences in function between MBCs and naive B cells and among MBC subsets and how this leads to memory responses. Expected final online publication date for the Annual Review of Immunology Volume 35 is April 26, 2017. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

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

    PubMed

    Martínez-Feito, Ana; Melero, Josefa; Mora-Díaz, Sergio; Rodríguez-Vigil, Carmen; Elduayen, Ramón; González-Granado, Luis I; Pérez-Méndez, Dolores; Sánchez-Zapardiel, Elena; Ruiz-García, Raquel; Menchén, Miguela; Díaz-Madroñero, Josefa; Paz-Artal, Estela; Del Orbe-Barreto, Rafael; Riñón, Marta; Allende, Luis M

    2016-01-01

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

  1. Anti-CD20 monoclonal antibodies: beyond B-cells.

    PubMed

    Avivi, Irit; Stroopinsky, Dina; Katz, Tamar

    2013-09-01

    Anti-CD20 monoclonal antibodies (MoAbs), employed in treating CD20⁺ lymphomas and autoimmune diseases, appear to have broader functions than just eradicating malignant B-cells and decreasing autoantibody production. Rituximab-induced T-cell inactivation, reported both in-vitro and in-vivo, may contribute to the increased risk of T-cell-dependent infections, observed in patients receiving this therapy. T-cell polarization into a suppressive phenotype, often observed in patients receiving rituximab for autoimmune disorders, was reported to be associated with prolonged remissions. Elimination of B-cells serving as antigen-presenting cells, thereby causing impaired T-cell activation, could play a significant role in induction of these changes. Direct binding of rituximab to a CD20dim T-cell population, inducing its depletion, may contribute to the decreased T-cell activation following rituximab therapy. Further investigation of the complex network through which rituximab and new anti-CD20 MoAbs act, would advance the employment of these agents in different clinical settings.

  2. B-cell populations discriminate between pediatric- and adult-onset multiple sclerosis

    PubMed Central

    Schwarz, Alexander; Balint, Bettina; Korporal-Kuhnke, Mirjam; Jarius, Sven; von Engelhardt, Kathrin; Fürwentsches, Alexandra; Bussmann, Cornelia; Ebinger, Friedrich; Haas, Jürgen

    2016-01-01

    Objective: To comparatively assess the B-cell composition in blood and CSF of patients with pediatric-onset multiple sclerosis (pedMS) and adult-onset multiple sclerosis (adMS). Methods: In this cross-sectional study, we obtained blood and CSF samples from 25 patients with pedMS (8–18 years) and 40 patients with adMS (23–65 years) and blood specimens from 66 controls (1–55 years). By using multicolor flow cytometry, we identified naive, transitional, isotype class-switched memory, nonswitched memory, and double-negative memory B-cell subsets as well as plasmablasts (PB) and terminally differentiated plasma cells (PC). Flow cytometric data were compared to concentrations of B-cell-specific cytokines in serum and CSF as determined by ELISA. Results: Frequencies of circulating naive B-cells decreased with higher age in controls but not in patients with multiple sclerosis (MS). B-cell patterns in CSF differed between pedMS and adMS with an acute relapse: in pedMS-derived CSF samples, high frequencies of nonswitched memory B cells and PB were present, whereas class-switched memory B cells and PC dominated in the CSF of patients with adMS. In pedMS, PB were also elevated in the periphery. Accumulation of PB in the CSF correlated with high intrathecal CXCL-13 levels and augmented intrathecal synthesis of immunoglobulin G and immunoglobulin M. Conclusions: We demonstrate distinct changes in intrathecal B-cell homeostasis in patients with pedMS during active disease, which differ from those in adults by an expansion of plasmablasts in blood and CSF and similarly occur in prototypic autoantibody-driven autoimmune disorders. This emphasizes the particular importance of activated B-lymphocyte subsets for disease progression in the earliest clinical stages of MS. PMID:28053999

  3. Facial manifestations of Epstein-Barr virus-related lymphoproliferative disease in childhood acute lymphoblastic leukemia in remission: Two atypical presentations.

    PubMed

    Lu, Benjamin Y; Kojima, Lisa; Huang, Mary S; Friedmann, Alison M; Ferry, Judith A; Weinstein, Howard J

    2016-11-01

    Epstein-Barr virus-related lymphoproliferative disease (EBV-LPD) rarely occurs in patients with acute lymphoblastic leukemia (ALL), who have not received hematopoietic transplantation. We describe EBV-LPD manifesting as facial lesions in two children with ALL in remission. One patient was a 16-year-old male with T-cell ALL with an EBV-positive angiocentric polymorphous lip lesion presenting as right-sided facial swelling. The other patient was a 12-year-old male with B-cell ALL with an EBV-positive polymorphous lymphoplasmacytic infiltrate presenting as bilateral dacryoadenitis. Neither patient had known primary immunodeficiencies. Both cases improved with immunosuppressant de-escalation. These cases suggest that immunosuppression induced by maintenance chemotherapy is sufficient to promote EBV-LPD.

  4. Curative drug treatment of trypanosomosis leads to the restoration of B-cell lymphopoiesis and splenic B-cell compartments.

    PubMed

    Cnops, J; Bockstal, V; De Trez, C; Miquel, M C; Radwanska, M; Magez, S

    2015-09-01

    African trypanosomosis is a parasitic disease affecting both humans (sleeping sickness) and animals (nagana). In murine trypanosomosis, the B-cell compartment is rapidly destroyed after infection. In addition, B-cell lymphopoiesis in the bone marrow is abrogated, B-cell subsets in the spleen are irreversibly depleted, and B-cell memory is destroyed. Here, we investigated the effect of cure of infection on the B-cell compartment. Suramin and diminazene aceturate were used in this study as these drugs exhibit different modes of uptake and different mechanisms of trypanocidal action. Curative drug treatment of trypanosomosis infection led to the re-initiation of B-cell lymphopoiesis in the bone marrow, and to the repopulation of splenic B-cell subsets, independent of the drug used. Neither of these drugs by itself induced measurable effects on B-cell lymphopoiesis in the bone marrow or B-cell homoeostasis in the spleen in healthy, naïve animals.

  5. 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

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

    PubMed

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

    2015-12-01

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

  7. 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

  8. B Cell Receptor Affinity for Insulin Dictates Autoantigen Acquisition and B Cell Functionality in Autoimmune Diabetes

    PubMed Central

    Packard, Thomas A.; Smith, Mia J.; Conrad, Francis J.; Johnson, Sara A.; Getahun, Andrew; Lindsay, Robin S.; Hinman, Rochelle M.; Friedman, Rachel S.; Thomas, James W.; Cambier, John C.

    2016-01-01

    B cells have been strongly implicated in the development of human type 1 diabetes and are required for disease in the NOD mouse model. These functions are dependent on B cell antigen receptor (BCR) specificity and expression of MHC, implicating linked autoantigen recognition and presentation to effector T cells. BCR-antigen affinity requirements for participation in disease are unclear. We hypothesized that BCR affinity for the autoantigen insulin differentially affects lymphocyte functionality, including tolerance modality and the ability to acquire and become activated in the diabetogenic environment. Using combined transgenic and retrogenic heavy and light chain to create multiple insulin-binding BCRs, we demonstrate that affinity for insulin is a critical determinant of the function of these autoreactive cells. We show that both BCR affinity for insulin and genetic background affect tolerance induction in immature B cells. We also find new evidence that may explain the enigmatic ability of B cells expressing 125 anti-insulin BCR to support development of TID in NOD mice despite a reported affinity beneath requirements for binding insulin at in vivo concentrations. We report that when expressed as an antigen receptor the affinity of 125 is much higher than determined by measurements of the soluble form. Finally, we show that in vivo acquisition of insulin requires both sufficient BCR affinity and permissive host/tissue environment. We propose that a confluence of BCR affinity, pancreas environment, and B cell tolerance-regulating genes in the NOD animal allows acquisition of insulin and autoimmunity. PMID:27834793

  9. Regulation of B cell fate by chronic activity of the IgE B cell receptor

    PubMed Central

    Yang, Zhiyong; Robinson, Marcus J; Chen, Xiangjun; Smith, Geoffrey A; Taunton, Jack; Liu, Wanli; Allen, Christopher D C

    2016-01-01

    IgE can trigger potent allergic responses, yet the mechanisms regulating IgE production are poorly understood. Here we reveal that IgE+ B cells are constrained by chronic activity of the IgE B cell receptor (BCR). In the absence of cognate antigen, the IgE BCR promoted terminal differentiation of B cells into plasma cells (PCs) under cell culture conditions mimicking T cell help. This antigen-independent PC differentiation involved multiple IgE domains and Syk, CD19, BLNK, Btk, and IRF4. Disruption of BCR signaling in mice led to consistently exaggerated IgE+ germinal center (GC) B cell but variably increased PC responses. We were unable to confirm reports that the IgE BCR directly promoted intrinsic apoptosis. Instead, IgE+ GC B cells exhibited poor antigen presentation and prolonged cell cycles, suggesting reduced competition for T cell help. We propose that chronic BCR activity and access to T cell help play critical roles in regulating IgE responses. DOI: http://dx.doi.org/10.7554/eLife.21238.001 PMID:27935477

  10. Regulation of B cell fate by chronic activity of the IgE B cell receptor.

    PubMed

    Yang, Zhiyong; Robinson, Marcus J; Chen, Xiangjun; Smith, Geoffrey A; Taunton, Jack; Liu, Wanli; Allen, Christopher D C

    2016-12-09

    IgE can trigger potent allergic responses, yet the mechanisms regulating IgE production are poorly understood. Here we reveal that IgE(+) B cells are constrained by chronic activity of the IgE B cell receptor (BCR). In the absence of cognate antigen, the IgE BCR promoted terminal differentiation of B cells into plasma cells (PCs) under cell culture conditions mimicking T cell help. This antigen-independent PC differentiation involved multiple IgE domains and Syk, CD19, BLNK, Btk, and IRF4. Disruption of BCR signaling in mice led to consistently exaggerated IgE(+) germinal center (GC) B cell but variably increased PC responses. We were unable to confirm reports that the IgE BCR directly promoted intrinsic apoptosis. Instead, IgE(+) GC B cells exhibited poor antigen presentation and prolonged cell cycles, suggesting reduced competition for T cell help. We propose that chronic BCR activity and access to T cell help play critical roles in regulating IgE responses.

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

    MedlinePlus

    ... and Hairy Cell Leukemia: Introduction Request Permissions Leukemia - B-cell Prolymphocytic Leukemia and Hairy Cell Leukemia: Introduction ... t k e P Types of Cancer Leukemia - B-cell Prolymphocytic Leukemia and Hairy Cell Leukemia Guide ...

  12. NKT Cell Responses to B Cell Lymphoma

    PubMed Central

    Li, Junxin; Sun, Wenji; Subrahmanyam, Priyanka B.; Page, Carly; Younger, Kenisha M.; Tiper, Irina V.; Frieman, Matthew; Kimball, Amy S.; Webb, Tonya J.

    2014-01-01

    Natural killer T (NKT) cells are a unique subset of CD1d-restricted T lymphocytes that express characteristics of both T cells and natural killer cells. NKT cells mediate tumor immune-surveillance; however, NKT cells are numerically reduced and functionally impaired in lymphoma patients. Many hematologic malignancies express CD1d molecules and co-stimulatory proteins needed to induce anti-tumor immunity by NKT cells, yet most tumors are poorly immunogenic. In this study, we sought to investigate NKT cell responses to B cell lymphoma. In the presence of exogenous antigen, both mouse and human NKT cell lines produce cytokines following stimulation by B cell lymphoma lines. NKT cell populations were examined ex vivo in mouse models of spontaneous B cell lymphoma, and it was found that during early stages, NKT cell responses were enhanced in lymphoma-bearing animals compared to disease-free animals. In contrast, in lymphoma-bearing animals with splenomegaly and lymphadenopathy, NKT cells were functionally impaired. In a mouse model of blastoid variant mantle cell lymphoma, treatment of tumor-bearing mice with a potent NKT cell agonist, α-galactosylceramide (α-GalCer), resulted in a significant decrease in disease pathology. Ex vivo studies demonstrated that NKT cells from α-GalCer treated mice produced IFN-γ following α-GalCer restimulation, unlike NKT cells from vehicle-control treated mice. These data demonstrate an important role for NKT cells in the immune response to an aggressive hematologic malignancy like mantle cell lymphoma. PMID:24955247

  13. Complement activation by a B cell superantigen.

    PubMed

    Kozlowski, L M; Soulika, A M; Silverman, G J; Lambris, J D; Levinson, A I

    1996-08-01

    Staphylococcal protein A (SpA), acting as a B cell superantigen, binds to the Fab region of human VH3+ Igs. Using SpA abrogated of its IgG Fc binding activity (Mod SpA) as a model B cell superantigen, we determined whether such an interaction causes complement activation. Addition of Mod SpA to human serum led to complement consumption and the generation of C3a. To determine whether this complement activation 1) was due to an interaction between VH3+ Igs and the Fab binding site of SpA and 2) proceeded via the classical complement pathway, we tested a panel of monoclonal IgM proteins for the ability to hind C1q following interaction with SpA. C1q binding was restricted to SpA-reactive, VH3+ IgM proteins. To formally determine whether the binding of SpA to the reactive VH3+ IgM proteins led to complement activation, we reconstituted the serum from a hypogammaglobulinemic patient with monoclonal IgM proteins and measured complement consumption and C3a generation following the addition of Mod SpA. We observed complement consumption and C3a production only in Mod SpA-treated serum reconstituted with a VH3+, SpA-binding, IgM protein. Taken together, these results provide compelling evidence that the interaction of the Fab binding site of SpA and VH3+ Igs can lead to complement activation via the classical pathway. This novel interaction may have significant implications for the in vivo properties of a B cell superantigen.

  14. Emerging role of infectious etiologies in the pathogenesis of marginal zone B-cell lymphomas.

    PubMed

    Zucca, Emanuele; Bertoni, Francesco; Vannata, Barbara; Cavalli, Franco

    2014-10-15

    Extranodal marginal zone B-cell lymphomas of the mucosa-associated lymphoid tissue (MALT) arise from lymphoid populations that are induced by chronic inflammation in extranodal sites. The most frequently affected organ is the stomach, where MALT lymphoma is incontrovertibly associated with a chronic gastritis induced by a microbial pathogen, Helicobacter pylori. Gastric MALT lymphoma therefore represents a paradigm for evaluating inflammation-associated lymphomagenesis, which may lead to a deeper understanding of a possible etiologic association between other microorganisms and nongastric marginal zone lymphomas. Besides infectious etiology, chronic inflammation caused by autoimmune diseases, such as Sjögren syndrome or Hashimoto thyroiditis, can also carry a significant risk factor for the development of marginal zone lymphoma. In addition to the continuous antigenic drive, additional oncogenic events play a relevant role in lymphoma growth and progression to the point at which the lymphoproliferative process may eventually become independent of antigenic stimulation. Recent studies on MALT lymphomas have in fact demonstrated genetic alterations affecting the NF-κB) pathway, a major signaling pathway involved in many cancers. This review aims to present marginal zone lymphoma as an example of the close pathogenetic link between chronic inflammation and tumor development, with particular attention to the role of infectious agents and the integration of these observations into everyday clinical practice. See all articles in this CCR Focus section, "Paradigm Shifts in Lymphoma."

  15. Unexplained lymphadenopathies: autoimmune lymphoproliferative syndrome in an adult patient

    PubMed Central

    Leal-Seabra, Fatima; Costa, Gonçalo Sarmento; Coelho, Henrique Pereira; Oliveira, Agripino

    2016-01-01

    Autoimmune lymphoproliferative syndrome (ALPS) is characterised by massive enlargement of the lymphoid organs, autoimmune cytopenias and a predisposition to develop lymphoid malignancies. The basic defect is a disturbance of the lymphocyte apoptosis, and a high number of circulating TCRab CD3+CD4−CD8− T-cells (double-negative T cells (DNT cells)). We describe a case of a 41-year-old man with fever, hepatosplenomegaly, multiple lymphadenopathy, autoimmune haemolytic anaemia and severe thrombocytopenia. Peripheral blood immunophenotyping revealed elevation of the characteristic DNT cells in 8% and high levels of interleukin 10. Histopathological analysis of lymph nodes showed lymphadenitis with paracortical hyperplasia. It was assumed as a probable diagnosis of ALPS, and the procedure was to medicate the patient with steroids. As a result, a significant clinical improvement was achieved, and he has been in remission for 2 years. To our knowledge, this is the first case reported in a Portuguese adult patient. PMID:27979843

  16. Unexplained lymphadenopathies: autoimmune lymphoproliferative syndrome in an adult patient.

    PubMed

    Leal-Seabra, Fatima; Costa, Gonçalo Sarmento; Coelho, Henrique Pereira; Oliveira, Agripino

    2016-12-15

    Autoimmune lymphoproliferative syndrome (ALPS) is characterised by massive enlargement of the lymphoid organs, autoimmune cytopenias and a predisposition to develop lymphoid malignancies. The basic defect is a disturbance of the lymphocyte apoptosis, and a high number of circulating TCRab CD3(+)CD4(-)CD8(-) T-cells (double-negative T cells (DNT cells)). We describe a case of a 41-year-old man with fever, hepatosplenomegaly, multiple lymphadenopathy, autoimmune haemolytic anaemia and severe thrombocytopenia. Peripheral blood immunophenotyping revealed elevation of the characteristic DNT cells in 8% and high levels of interleukin 10. Histopathological analysis of lymph nodes showed lymphadenitis with paracortical hyperplasia. It was assumed as a probable diagnosis of ALPS, and the procedure was to medicate the patient with steroids. As a result, a significant clinical improvement was achieved, and he has been in remission for 2 years. To our knowledge, this is the first case reported in a Portuguese adult patient.

  17. Autoimmune lymphoproliferative syndrome: an update and review of the literature.

    PubMed

    Shah, Shaili; Wu, Eveline; Rao, V Koneti; Tarrant, Teresa K

    2014-09-01

    Autoimmune lymphoproliferative syndrome (ALPS) is characterized by immune dysregulation due to a defect in lymphocyte apoptosis. The clinical manifestations may be noted in multiple family members and include lymphadenopathy, splenomegaly, increased risk of lymphoma, and autoimmune disease, which typically involves hematopoietic cell lines manifesting as multilineage cytopenias. Since the disease was first characterized in the early 1990s, there have been many advances in the diagnosis and management of this syndrome. The inherited genetic defect of many ALPS patients has involved (FAS) pathway signaling proteins, but there remain those patients who carry undefined genetic defects. Despite ALPS having historically been considered a primary immune defect presenting in early childhood, adult onset presentation is increasingly becoming recognized and more so in genetically undefined patients and those with somatic FAS mutations. Thus, future research may identify novel pathways and/or regulatory proteins important in lymphocyte activation and apoptosis.

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

    PubMed

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

    2015-12-18

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

  19. 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.

  20. Diagnosis of autoimmune lymphoproliferative syndrome caused by FAS deficiency in adults.

    PubMed

    Lambotte, Olivier; Neven, Bénédicte; Galicier, Lionel; Magerus-Chatinet, Aude; Schleinitz, Nicolas; Hermine, Olivier; Meyts, Isabelle; Picard, Capucine; Godeau, Bertrand; Fischer, Alain; Rieux-Laucat, Frédéric

    2013-03-01

    A diagnosis of autoimmune lymphoproliferative syndrome caused by FAS deficiency during adulthood is unusual. We analyzed 17 cases of autoimmune lymphoproliferative syndrome caused by FAS deficiency diagnosed during adulthood in French reference centers for hereditary immunodeficiencies and for immune cytopenias. Twelve of the 17 patients had developed their first symptoms during childhood. The diagnosis of autoimmune lymphoproliferative syndrome had been delayed for a variety of reasons, including unusual clinical manifestations, late referral to a reference center, and the occurrence of somatic FAS mutations. The 5 other patients presented their first symptoms after the age of 16 years. In these patients, three germline heterozygous FAS mutations were predicted to be associated with haploinsufficiency and a somatic event on the second FAS allele was observed in 2 cases. Autoimmune lymphoproliferative syndrome may well be diagnosed in adulthood. The occurrence of additional genetic events may account for the delayed disease onset.

  1. Autoimmune lymphoproliferative syndrome (ALPS) in a patient with a new germline Fas gene mutation.

    PubMed

    Del-Rey, Manuel J; Manzanares, Javier; Bosque, Alberto; Aguiló, Juan I; Gómez-Rial, José; Roldan, Ernesto; Serrano, Antonio; Anel, Alberto; Paz-Artal, Estela; Allende, Luis M

    2007-01-01

    Autoimmune lymphoproliferative syndrome (ALPS) is a rare genetic disorder characterized by chronic lymphoproliferation, autoimmune manifestations and expansion of TCRalphabeta+CD4-CD8- lymphocytes. The main pathogenic factor is a defective Fas-mediated apoptosis generally caused by mutations in the Fas gene. This report describes a new heterozygous Fas gene mutation in a boy with clinical and immunological features of ALPS. In vitro, T-cell blasts from the patient are completely resistant to the effects on the anti-Fas cytotoxic mAb CH-11, they also have a higher proliferation rate than T cells from healthy donors, while PHA-induced AICD is normal. The location of the mutation (I246S) found in the intracytoplasmic death domain, and the conservation of that residue in four different species from human suggest that I246 is an essential amino acid for Fas function. The patient has inherited the mutation from his father who also shows defective Fas-mediated apoptosis but the clinical and immunological manifestations are much less severe. These results provide evidence that the penetrance of genetic defects in Fas is variable and that other factors may influence the phenotype of the disease.

  2. Hyperactive mTOR pathway promotes lymphoproliferation and abnormal differentiation in autoimmune lymphoproliferative syndrome.

    PubMed

    Völkl, Simon; Rensing-Ehl, Anne; Allgäuer, Andrea; Schreiner, Elisabeth; Lorenz, Myriam Ricarda; Rohr, Jan; Klemann, Christian; Fuchs, Ilka; Schuster, Volker; von Bueren, André O; Naumann-Bartsch, Nora; Gambineri, Eleonora; Siepermann, Kathrin; Kobbe, Robin; Nathrath, Michaela; Arkwright, Peter D; Miano, Maurizio; Stachel, Klaus-Daniel; Metzler, Markus; Schwarz, Klaus; Kremer, Anita N; Speckmann, Carsten; Ehl, Stephan; Mackensen, Andreas

    2016-07-14

    Autoimmune lymphoproliferative syndrome (ALPS) is a human disorder characterized by defective Fas signaling, resulting in chronic benign lymphoproliferation and accumulation of TCRαβ(+) CD4(-) CD8(-) double-negative T (DNT) cells. Although their phenotype resembles that of terminally differentiated or exhausted T cells, lack of KLRG1, high eomesodermin, and marginal T-bet expression point instead to a long-lived memory state with potent proliferative capacity. Here we show that despite their terminally differentiated phenotype, human ALPS DNT cells exhibit substantial mitotic activity in vivo. Notably, hyperproliferation of ALPS DNT cells is associated with increased basal and activation-induced phosphorylation of serine-threonine kinases Akt and mechanistic target of rapamycin (mTOR). The mTOR inhibitor rapamycin abrogated survival and proliferation of ALPS DNT cells, but not of CD4(+) or CD8(+) T cells in vitro. In vivo, mTOR inhibition reduced proliferation and abnormal differentiation by DNT cells. Importantly, increased mitotic activity and hyperactive mTOR signaling was also observed in recently defined CD4(+) or CD8(+) precursor DNT cells, and mTOR inhibition specifically reduced these cells in vivo, indicating abnormal programming of Fas-deficient T cells before the DNT stage. Thus, our results identify the mTOR pathway as a major regulator of lymphoproliferation and aberrant differentiation in ALPS.

  3. Autoimmune lymphoproliferative syndrome (ALPS) caused by Fas (CD95) mutation mimicking sarcoidosis.

    PubMed

    Müllauer, Leonhard; Emhofer, Josef; Wohlfart, Sabine; Pichlhöfer, Bettina; Stary, Susanne; Ebetsberger, Georg; Mannhalter, Christine; Chott, Andreas

    2008-02-01

    Autoimmune lymphoproliferative syndrome (ALPS) is an inherited disorder associated with defects in apoptosis, characterized by childhood onset of lymphadenopathy, splenomegaly, hyperimmunoglobulinemia, and autoimmune disease. ALPS is most frequently associated with a mutation in the cell death receptor Fas (CD95). Very rarely a mutation in caspase 10 is present. An increase of CD4/CD8 double negative T cells in the peripheral blood and lymph nodes is a feature characteristic of ALPS. Additionally, histiocytic proliferations resembling sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfman disease) were reported recently in patients with ALPS. In the rare cases with a caspase 10 mutation an accumulation of dendritic cells in lymphoid organs was noted. We describe a different, sarcoidosislike, histiocytic infiltration of lymph nodes that persisted for years in a girl, that was initially supposed to suffer from sarcoidosis, but was eventually diagnosed as ALPS, associated with a missense mutation in the intracellular death domain of Fas. This sarcoidosislike histologic picture extends the spectrum of histiocytic lymph node alterations observed in ALPS and alerts of a potential diagnostic pitfall.

  4. Investigation of common variable immunodeficiency patients and healthy individuals using autoimmune lymphoproliferative syndrome biomarkers.

    PubMed

    Roberts, C A; Ayers, L; Bateman, E A L; Sadler, R; Magerus-Chatinet, A; Rieux-Laucat, F; Misbah, S A; Ferry, B L

    2013-12-01

    Autoimmune lymphoproliferative syndrome (ALPS) is a disorder of dysregulated lymphocyte homeostasis. Biomarkers including elevated CD3+TCRαβ+CD4-CD8- double negative T cells (TCRαβ+ DNT), IL-10, sCD95L and vitamin B12 can be used to differentiate between ALPS and common variable immunodeficiency (CVID) patients with an overlapping clinical phenotype. We investigated the utility of ALPS biomarkers in 13 CVID patients with lymphoproliferation and/or autoimmune cytopaenia with comparison to 33 healthy controls. Vitamin B12 (P < 0.01) and IL-10 (P < 0.0001), but not sCD95L or TCRαβ+ DNT, were increased in CVID compared to controls. The 95th percentile for TCRαβ+ DNT in healthy controls was used to define a normal range up to 2.3% of total lymphocytes or 3.4% of T cells. These frequencies lie markedly beyond the cut offs used in current ALPS diagnostic criteria (≥ 1.5% of total lymphocytes or 2.5% of CD3+ lymphocytes), suggesting these limits may have poor specificity for ALPS.

  5. A survey of 90 patients with autoimmune lymphoproliferative syndrome related to TNFRSF6 mutation.

    PubMed

    Neven, Bénédicte; Magerus-Chatinet, Aude; Florkin, Benoit; Gobert, Delphine; Lambotte, Olivier; De Somer, Lien; Lanzarotti, Nina; Stolzenberg, Marie-Claude; Bader-Meunier, Brigitte; Aladjidi, Nathalie; Chantrain, Christophe; Bertrand, Yves; Jeziorski, Eric; Leverger, Guy; Michel, Gérard; Suarez, Felipe; Oksenhendler, Eric; Hermine, Olivier; Blanche, Stéphane; Picard, Capucine; Fischer, Alain; Rieux-Laucat, Frédéric

    2011-11-03

    Autoimmune lymphoproliferative syndrome (ALPS) is a genetic disorder characterized by early-onset, chronic, nonmalignant lymphoproliferation, autoimmune manifestations, and susceptibility to lymphoma. The majority of ALPS patients carry heterozygous germline (ALPS-FAS) or somatic mutations (ALPS-sFAS) of the TNFRSF6 gene coding for FAS. Although the clinical features of ALPS have been described previously, long-term follow-up data on morbidity and mortality are scarce. We performed a retrospective analysis of clinical and genetic features of 90 ALPS-FAS and ALPS-sFAS patients monitored over a median period of 20.5 years. Heterozygous germline mutations of TNFRSF6 were identified in 83% of probands. Somatic TNFRSF6 mutations were found in 17% of index cases (all located within the intracellular domain of FAS). Sixty percent of the ALPS-FAS patients with mutations in the extracellular domain had a somatic mutation affecting the second allele of TNFRSF6; age at onset was later in these patients. No other genotype-phenotype correlations could be found. Long-term analysis confirmed a trend toward spontaneous remission of lymphoproliferation in adulthood but mixed outcomes for autoimmune manifestations. We observed significant and potentially life-threatening disease and treatment-related morbidity, including a high risk of sepsis after splenectomy that calls for careful long-term monitoring of ALPS patients. We also noted a significantly greater occurrence of disease-related symptoms in male than in female patients.

  6. Autoimmune lymphoproliferative syndrome in pregnancy: a case of favorable mother-fetal outcome in a well-controlled disease.

    PubMed

    Patti, Simona; Perrone, Giuseppina; De Pratti, Valentina; Quinti, Isabella; Milito, Cinzia; Brunelli, Roberto

    2015-03-01

    The autoimmune lymphoproliferative syndrome (ALPS) is a disorder of abnormal lymphocyte survival caused by the dysregulation of the Fas apoptotic pathway. The Fas gene is expressed at the maternal-fetal interface and is involved in the regulation of immune response and implantation. Altered Fas expression may result in altered apoptosis and, ultimately, affect both the immune response and implantation; it is in fact associated with recurrent pregnancy loss, preterm premature rupture of membranes and pre-eclampsia. Currently, there are over 500 cases of ALPS reported worldwide from various racial and ethnic backgrounds. Up to date, the published work contains no specific reports on pregnancy outcome in women affected by ALPS. We present a case of full-term uneventful pregnancy in a patient affected by ALPS. A specific clinical follow-up in a pregnant woman with primary immunologic disease is suggested.

  7. Fludarabine, cyclophosphamide, doxorubicin (FCD), and rituximab: a remission induction therapy for aggressive pediatric post-transplant lymphoproliferative disease (PTLD).

    PubMed

    Giraldi, Eugenia; Provenzi, Massimo; Fiocchi, Roberto; Colledan, Michele; Cornelli, Pieremilio; Torre, Giuliano; Rambaldi, Alessandro; Conter, Valentino

    2011-08-01

    Management of aggressive, usually late-occurring, post-transplant lymphoproliferative disorders (PTLDs), a life-threatening complication after solid organ transplants, remains controversial. Four children affected by aggressive CD20+ PTLDs received a chemo-immunotherapy regimen for remission induction based on fludarabine, cyclophosphamide, doxorubicin, and rituximab, associated with a rapid discontinuation of immunosuppression (IS). Subsequent consolidation chemotherapy consisted of Berlin-Frankfurt-Münster-modified blocks. All patients achieved a complete remission, which persisted for 25, 68+, 80+, and 103+ months after diagnosis. Therapy was well tolerated. No patients developed allograft rejection during PTLD treatment. Our experience suggests that this chemo-immunotherapeutic approach may be an effective treatment strategy while allowing for a concomitant discontinuation of IS.

  8. Clinical immunotherapy of B-cell malignancy using CD19-targeted CAR T-cells.

    PubMed

    Maher, John

    2014-02-01

    The CD19 molecule is ubiquitously expressed throughout all stages of B-cell differentiation, but is not found on haemopoietic stem cells. Since most B-cell leukaemias and lymphomas retain CD19 expression, it represents an excellent target for immunotherapy of these malignant disorders. Over the past 10 years, compelling pre-clinical evidence has accrued to indicate that expression of a CD19-targeted chimeric antigen receptor (CAR) in peripheral blood T-cells exerts therapeutic efficacy in diverse models of B-cell malignancy. Building on this, clinical studies are ongoing in several centres in which autologous CD19-specific CAR T-cells are undergoing evaluation in patients with acute and chronic B-cell leukaemia and refractory lymphoma. Early data have generated considerable excitement, providing grounds to speculate that CAR-based immunotherapy will radically alter existing management paradigms in B-cell malignancy. The focus of this mini-review is to evaluate these emerging clinical data and to speculate on clinical prospects for this new therapeutic modality.

  9. B-cell deficiency and severe autoimmunity caused by deficiency of protein kinase C δ.

    PubMed

    Salzer, Elisabeth; Santos-Valente, Elisangela; Klaver, Stefanie; Ban, Sol A; Emminger, Wolfgang; Prengemann, Nina Kathrin; Garncarz, Wojciech; Müllauer, Leonhard; Kain, Renate; Boztug, Heidrun; Heitger, Andreas; Arbeiter, Klaus; Eitelberger, Franz; Seidel, Markus G; Holter, Wolfgang; Pollak, Arnold; Pickl, Winfried F; Förster-Waldl, Elisabeth; Boztug, Kaan

    2013-04-18

    Primary B-cell disorders comprise a heterogeneous group of inherited immunodeficiencies, often associated with autoimmunity causing significant morbidity. The underlying genetic etiology remains elusive in the majority of patients. In this study, we investigated a patient from a consanguineous family suffering from recurrent infections and severe lupuslike autoimmunity. Immunophenotyping revealed progressive decrease of CD19(+) B cells, a defective class switch indicated by low numbers of IgM- and IgG-memory B cells, as well as increased numbers of CD21(low) B cells. Combined homozygosity mapping and exome sequencing identified a biallelic splice-site mutation in protein C kinase δ (PRKCD), causing the absence of the corresponding protein product. Consequently, phosphorylation of myristoylated alanine-rich C kinase substrate was decreased, and mRNA levels of nuclear factor interleukin (IL)-6 and IL-6 were increased. Our study uncovers human PRKCD deficiency as a novel cause of common variable immunodeficiency-like B-cell deficiency with severe autoimmunity.

  10. A B cell explanation for autoimmune disease: the forbidden clone returns.

    PubMed

    McQueen, Fiona

    2012-04-01

    More than 60 years ago, Burnet first proposed the 'forbidden clone' hypothesis postulating that autoimmune disease arises as a result of persistence of self-reactive clones of lymphocytes that should have been deleted via immune tolerance. These autoreactive clones could effect immune-mediated end-organ damage via peripheral self-antigen recognition. Recent evidence that stretches across the boundaries of many medical specialties supports this proposal, implicating a B cell precursor as the culprit. The success of B cell depleting therapy in rheumatoid arthritis, anti-neutrophil cytoplasmic antibodies (ANCA) associated vasculitis, polymyositis, lupus and autoimmune diseases as diverse as multiple sclerosis and idiopathic thrombocytopenic purpura supports this proposal. Clonality of B cells and plasma cells has been described in a number of autoimmune disorders and the presence of autoantibodies, which may arise years before the onset of clinical disease, supports the notion of autoreactivity within the B cell lineage. T cell activation within the end-organ would be predicted by cognate B-T cell interactions and resultant tissue inflammation and destruction could produce diverse clinical manifestations dictated by the original specificity of the autoimmune B cell.

  11. Genomic abnormalities of Waldenström macroglobulinemia and related low-grade B-cell lymphomas.

    PubMed

    Braggio, Esteban; Fonseca, Rafael

    2013-04-01

    Waldenström macroglobulinemia (WM) is a lymphoproliferative disease characterized by a heterogeneous lymphoplasmacytic bone marrow infiltrate and monoclonal immunoglobulin M production. WM shows similarities in presentations with related B-cell malignancies, sometimes making it difficult to distinguish them. To better characterize the genetic basis of WM, we performed a comparative genomic analysis with the related entities, lymphoplasmacytic lymphomas without monoclonal immunoglobulin M protein, marginal zone lymphomas, chronic lymphocytic leukemia, and monoclonal gammopathy of undetermined significance. Overall, WM shows a very stable karyotype and shares most of the chromosomal abnormalities with most of the indolent B-cell malignancies. Trisomy 4 is unique to WM; however, no candidate genes have been identified in the chromosome. Abnormalities that affect myeloid differentiation primary response 88 (MYD88)--interleukin-1 receptor-associated kinase 4 (IRAK4) and nuclear factor kappa B (NF-κB) signaling pathways were found in a significant proportion of WM cases, which suggest their relevance in the pathogenesis of the disease and opening new avenues that may be a guide to design novel therapeutic approaches.

  12. Rationally designed BCL6 inhibitors target activated B cell diffuse large B cell lymphoma

    PubMed Central

    Cardenas, Mariano G.; Yu, Wenbo; Beguelin, Wendy; Teater, Matthew R.; Geng, Huimin; Goldstein, Rebecca L.; Oswald, Erin; Hatzi, Katerina; Yang, Shao-Ning; Cohen, Joanna; Shaknovich, Rita; Vanommeslaeghe, Kenno; Cheng, Huimin; Liang, Dongdong; Cho, Hyo Je; Tam, Wayne; Du, Wei; Leonard, John P.; Elemento, Olivier; Cierpicki, Tomasz; Xue, Fengtian; MacKerell, Alexander D.; Melnick, Ari M.

    2016-01-01

    Diffuse large B cell lymphomas (DLBCLs) arise from proliferating B cells transiting different stages of the germinal center reaction. In activated B cell DLBCLs (ABC-DLBCLs), a class of DLBCLs that respond poorly to current therapies, chromosomal translocations and amplification lead to constitutive expression of the B cell lymphoma 6 (BCL6) oncogene. The role of BCL6 in maintaining these lymphomas has not been investigated. Here, we designed small-molecule inhibitors that display higher affinity for BCL6 than its endogenous corepressor ligands to evaluate their therapeutic efficacy for targeting ABC-DLBCL. We used an in silico drug design functional-group mapping approach called SILCS to create a specific BCL6 inhibitor called FX1 that has 10-fold greater potency than endogenous corepressors and binds an essential region of the BCL6 lateral groove. FX1 disrupted formation of the BCL6 repression complex, reactivated BCL6 target genes, and mimicked the phenotype of mice engineered to express BCL6 with corepressor binding site mutations. Low doses of FX1 induced regression of established tumors in mice bearing DLBCL xenografts. Furthermore, FX1 suppressed ABC-DLBCL cells in vitro and in vivo, as well as primary human ABC-DLBCL specimens ex vivo. These findings indicate that ABC-DLBCL is a BCL6-dependent disease that can be targeted by rationally designed inhibitors that exceed the binding affinity of natural BCL6 ligands. PMID:27482887

  13. Rationally designed BCL6 inhibitors target activated B cell diffuse large B cell lymphoma.

    PubMed

    Cardenas, Mariano G; Yu, Wenbo; Beguelin, Wendy; Teater, Matthew R; Geng, Huimin; Goldstein, Rebecca L; Oswald, Erin; Hatzi, Katerina; Yang, Shao-Ning; Cohen, Joanna; Shaknovich, Rita; Vanommeslaeghe, Kenno; Cheng, Huimin; Liang, Dongdong; Cho, Hyo Je; Abbott, Joshua; Tam, Wayne; Du, Wei; Leonard, John P; Elemento, Olivier; Cerchietti, Leandro; Cierpicki, Tomasz; Xue, Fengtian; MacKerell, Alexander D; Melnick, Ari M

    2016-09-01

    Diffuse large B cell lymphomas (DLBCLs) arise from proliferating B cells transiting different stages of the germinal center reaction. In activated B cell DLBCLs (ABC-DLBCLs), a class of DLBCLs that respond poorly to current therapies, chromosomal translocations and amplification lead to constitutive expression of the B cell lymphoma 6 (BCL6) oncogene. The role of BCL6 in maintaining these lymphomas has not been investigated. Here, we designed small-molecule inhibitors that display higher affinity for BCL6 than its endogenous corepressor ligands to evaluate their therapeutic efficacy for targeting ABC-DLBCL. We used an in silico drug design functional-group mapping approach called SILCS to create a specific BCL6 inhibitor called FX1 that has 10-fold greater potency than endogenous corepressors and binds an essential region of the BCL6 lateral groove. FX1 disrupted formation of the BCL6 repression complex, reactivated BCL6 target genes, and mimicked the phenotype of mice engineered to express BCL6 with corepressor binding site mutations. Low doses of FX1 induced regression of established tumors in mice bearing DLBCL xenografts. Furthermore, FX1 suppressed ABC-DLBCL cells in vitro and in vivo, as well as primary human ABC-DLBCL specimens ex vivo. These findings indicate that ABC-DLBCL is a BCL6-dependent disease that can be targeted by rationally designed inhibitors that exceed the binding affinity of natural BCL6 ligands.

  14. Multiple layers of B cell memory with different effector functions.

    PubMed

    Dogan, Ismail; Bertocci, Barbara; Vilmont, Valérie; Delbos, Frédéric; Mégret, Jérome; Storck, Sébastien; Reynaud, Claude-Agnès; Weill, Jean-Claude

    2009-12-01

    Memory B cells are at the center of longstanding controversies regarding the presence of antigen for their survival and their re-engagement in germinal centers after secondary challenge. Using a new mouse model of memory B cell labeling dependent on the cytidine deaminase AID, we show that after immunization with a particulate antigen, B cell memory appeared in several subsets, comprising clusters of immunoglobulin M-positive (IgM(+)) and IgG1(+) B cells in germinal center-like structures that persisted up to 8 months after immunization, as well as IgM(+) and IgG1(+) B cells with a memory phenotype outside of B cell follicles. After challenge, the IgG subset differentiated into plasmocytes, whereas the IgM subset reinitiated a germinal center reaction. This model, in which B cell memory appears in several layers with different functions, reconciles previous conflicting propositions.

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

    PubMed Central

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

    2016-01-01

    Objective: To investigate the role of very late antigen-4 (VLA-4) on regulatory B cells (Breg) in CNS autoimmune disease. Methods: Experimental autoimmune encephalomyelitis (EAE) was induced in mice selectively deficient for VLA-4 on B cells (CD19cre/α4f/f) by immunization with myelin oligodendrocyte glycoprotein (MOG) peptide (p)35–55 or recombinant human (rh) MOG protein. B-cell and T-cell populations were examined by flow cytometry and immunohistochemistry. Breg were evaluated by intracellular IL-10 staining of B cells and, secondly, by coexpression of CD1d and CD5. Results: As previously reported, EAE was less severe in B-cell VLA-4-deficient vs control CD19cre mice when induced by rhMOG, a model that is B-cell-dependent and leads to efficient B-cell activation and antibody production. Paradoxically, B-cell VLA-4-deficient mice developed more severe clinical disease than control mice when EAE was induced with MOG p35-55, a B-cell-independent encephalitogen that does not efficiently activate B cells. Peripheral T-cell and humoral immune responses were not altered in B-cell VLA-4-deficient mice. In MOG p35-55-induced EAE, B-cell VLA-4 deficiency reduced CNS accumulation of B but not T cells. Breg were detected in the CNS of control mice with MOG p35-55-induced EAE. However, more severe EAE in B-cell VLA-4-deficient mice was associated with virtual absence of CNS Breg. Conclusions: Our results demonstrate that CNS accumulation of Breg is VLA-4-dependent and suggest that Breg may contribute to regulation of CNS autoimmunity in situ. These observations underscore the need to choose the appropriate encephalitogen when studying how B cells contribute to pathogenesis or regulation of CNS autoimmunity. PMID:27027096

  16. 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

  17. Inebilizumab, a B Cell-Depleting Anti-CD19 Antibody for the Treatment of Autoimmune Neurological Diseases: Insights from Preclinical Studies

    PubMed Central

    Chen, Ding; Gallagher, Sandra; Monson, Nancy L.; Herbst, Ronald; Wang, Yue

    2016-01-01

    Exaggerated or inappropriate responses by B cells are an important feature in many types of autoimmune neurological diseases. The recent success of B-cell depletion in the treatment of multiple sclerosis (MS) has stimulated the development of novel B-cell-targeting therapies with the potential for improved efficacy. CD19 has emerged as a promising target for the depletion of B cells as well as CD19-positive plasmablasts and plasma cells. Inebilizumab (MEDI-551), an anti-CD19 antibody with enhanced antibody-dependent cell-mediated cytotoxicity against B cells, is currently being evaluated in MS and neuromyelitis optica. This review discusses the role of B cells in autoimmune neurological disorders, summarizes the development of inebilizumab, and analyzes the recent results for inebilizumab treatment in an autoimmune encephalitis mouse model. The novel insights obtained from these preclinical studies can potentially guide future investigation of inebilizumab in patients. PMID:27886126

  18. The majority of human memory B cells recognizing RhD and tetanus resides in IgM+ B cells.

    PubMed

    Della Valle, Luciana; Dohmen, Serge E; Verhagen, Onno J H M; Berkowska, Magdalena A; Vidarsson, Gestur; Ellen van der Schoot, C

    2014-08-01

    B cell memory to T cell-dependent (TD) Ags are considered to largely reside in class-switched CD27(+) cells. However, we previously observed that anti-RhD (D) Igs cloned from two donors, hyperimmunized with D(+) erythrocytes, were predominantly of the IgM isotype. We therefore analyzed in this study the phenotype and frequency of D- and tetanus toxoid-specific B cells by culturing B cells in limiting dilution upon irradiated CD40L-expressing EL4.B5 cells and testing the culture supernatant. Most Ag-specific B cells for both TD Ags were found to reside in the IgM-expressing B cells, including CD27(-) B cells, in both hyperimmunized donors and nonhyperimmunized volunteers. Only shortly after immunization a sharp increase in Ag-specific CD27(+)IgG(+) B cells was observed. Next, B cells were enriched with D(+) erythrocyte ghosts and sorted as single cells. Sequencing of IGHV, IGLV, IGKV, and BCL6 genes from these D-specific B cell clones demonstrated that both CD27(-)IgM(+) and CD27(+)IgM(+) B cells harbored somatic mutations, documenting their Ag-selected nature. Furthermore, sequencing revealed a clonal relationship between the CD27(-)IgM(+), CD27(+)IgM(+), and CD27(+)IgG(+) B cell subsets. These data strongly support the recently described multiple layers of memory B cells to TD Ags in mice, where IgM(+) B cells represent a memory reservoir which can re-enter the germinal center and ensure replenishment of class-switched memory CD27(+) B cells from Ag-experienced precursors.

  19. 137 Hypogammaglobulinemia in a Boy: Consider Also X-linked Lymphoproliferative Disease

    PubMed Central

    Gamez, Luisa; Yamazaki, Marco Antonio; Espinosa, Sara; Lugo-Reyes, Saul; Hernandez, Victor

    2012-01-01

    Background X-linked lymphoproliferative disease (XLP) is a primary immunodeficiency presenting with a variety of clinical manifestations, the most common being dysgammaglobulinemia and B-cell lymphoma. The first gene causing XLP, when defective, was termed SH2D1A or SAP for signaling lymphocyte activation molecule (SLAM)-associated protein. The absence of SH2D1A leads to an overwhelming and uncontrolled TH1- shifted cytotoxic immune response, which might, at least in part, explain the severe clinical picture. A second gene, XIAP (X-linked inhibitor of apoptosis), was later identified. Methods An 8 year old Mexican boy was admitted in June 2008 for bronchopneumonia, with no previous history of recurrent or severe infections. He had a family history of a brother deceased at 7 years from fulminate hepatitis, who was diagnosed with agammaglobulinemia. A laboratory evaluation for primary immunodeficiency was made, including serum immunoglobulins: IgG 30 mg/dL, IgA <5 mg/dL IgM 8.6 mg/dL; and flow citometry for lymphocyte subpopulations: CD3+ 2590 mm3 (56%) CD4+ 1004 mm3 (42%), CD8+ 1267 mm3(53%) CD16/56 171mm3 (41%) CD19+ 1493 mm3 (35%). The patient was started on monthly intravenous gammaglobulin (IVIG) therapy. He was admitted in December 2008 with fever and severe abdominal pain; an exploratory laparotomy revealed a rectal-sigmoid tumor. The biopsy reported an atypical Burkitt lymphoma (Immunophenotype “B”: Bcl 2+, CD10+) with surgical margins negative for malignancy. Bone marrow aspirate and biopsy were negative for malignancy. In February 2009, management with chemotherapy was started with the diagnosis of Burkitt's lymphoma stage III. Patient received 6 courses of chemotherapy with complete response to induction; for consolidation, 4 doses of rituximab were given. PCR amplification and direct automated sequencing by the Sanger method was performed in both genes known to be responsible for XLP in chromosome X. Results A hemizygous splice-site deletion in SAP

  20. BIP induces mice CD19(hi) regulatory B cells producing IL-10 and highly expressing PD-L1, FasL.

    PubMed

    Tang, Youfa; Jiang, Qing; Ou, Yanghui; Zhang, Fan; Qing, Kai; Sun, Yuanli; Lu, Wenjie; Zhu, Huifen; Gong, Feili; Lei, Ping; Shen, Guanxin

    2016-01-01

    Many studies have shown that B cells possess a regulatory function in mouse models of autoimmune diseases. Regulatory B cells can modulate immune response through many types of molecular mechanisms, including the production of IL-10 and the expression of PD-1 Ligand and Fas Ligand, but the microenvironmental factors and mechanisms that induce regulatory B cells have not been fully identified. BIP (binding immunoglobulin protein), a member of the heat shock protein 70 family, is a type of evolutionarily highly conserved protein. In this article, we have found that IL-10(+), PD-L1(hi) and FasL(hi) B cells are discrete cell populations, but enriched in CD19(hi) cells. BIP can induce IL-10-producing splenic B cells, IL-10 secretion and B cells highly expressing PD-L1 and FasL. CD40 signaling acts in synergy with BIP to induce regulatory B cells. BIP increased surface CD19 molecule expression intensity and IL-10(+), PD-L1(hi) and FasL(hi) B cells induced by BIP share the CD19(hi) phenotype. Furthermore, B cells treated with BIP and anti-CD40 can lead to suppression of T cell proliferation and the effect is partially IL-10-dependent and mainly BIP-induced. Taken together, our findings identify a novel function of BIP in the induction of regulatory B cells and add a new reason for the therapy of autoimmune disorders or other inflammatory conditions.

  1. Impairment of B-cell functions during HIV-1 infection.

    PubMed

    Amu, Sylvie; Ruffin, Nicolas; Rethi, Bence; Chiodi, Francesca

    2013-09-24

    A variety of B-cell dysfunctions are manifested during HIV-1 infection, as reported early during the HIV-1 epidemic. It is not unusual that the pathogenic mechanisms presented to elucidate impairment of B-cell responses during HIV-1 infection focus on the impact of reduced T-cell numbers and functions, and lack of germinal center formation in lymphoid tissues. To our understanding, however, perturbation of B-cell phenotype and function during HIV-1 infection may begin at several different B-cell developmental stages. These impairments can be mediated by intrinsic B-cell defects as well as by the lack of proper T-cell help. In this review, we will highlight some of the pathways and molecular interactions leading to B-cell impairment prior to germinal center formation and B-cell activation mediated through the B-cell receptor in response to HIV-1 antigens. Recent studies indicate a regulatory role for B cells on T-cell biology and immune responses. We will discuss some of these novel findings and how these regulatory mechanisms could potentially be affected by the intrinsic defects of B cells taking place during HIV-1 infection.

  2. Age-related alterations of the CD19 complex and memory B cells in children with Down syndrome.

    PubMed

    Seckin, Ayse Nazli; Ozdemir, Hulya; Ceylan, Ayca; Artac, Hasibe

    2017-02-14

    Children with Down syndrome (DS) have a high incidence of recurrent respiratory tract infections, leukaemia and autoimmune disorders, suggesting immune dysfunction. The present study evaluated the role of the CD19 complex and memory B cells in the pathogenesis of immunodeficiency in children with DS. The expression levels (median fluorescein intensity-MFI) of CD19, CD21 and CD81 molecules on the surface of B cells and memory B cell subsets were studied in 37 patients and 39 healthy controls. Twenty-nine of the DS group had congenital cardiac disease. The B cell count was significantly low in children with DS compared with healthy age-matched controls for all three age groups (under 2 years; 2-6 years and older than 6 years). The MFI of CD19 was reduced in all the age groups, whereas that of CD21 was increased in those older than 2 years with DS. The expression level of CD81 was significantly increased in those older than 6 years. Age-related changes were also detected in memory B cell subsets. The frequency of CD27(+)IgD(+)IgM(+) natural effector B cells was reduced in children with DS who had needed hospitalisation admission due to infections. The observed intrinsic defects in B cells may be responsible for the increased susceptibility of children with DS to severe respiratory tract infections.

  3. FcR-Like 2 Inhibition of B Cell Receptor-Mediated Activation of B Cells

    PubMed Central

    Jackson, Tanisha A.; Haga, Christopher L.; Ehrhardt, Götz R. A.; Davis, Randall S.; Cooper, Max D.

    2017-01-01

    FcR-like (FCRL) 2 is a transmembrane protein with immunomodulatory potential that is preferentially expressed by memory B cells in humans. It has two consensus ITIMs in addition to a putative ITAM sequence in its cytoplasmic domain. We have confirmed the cellular distribution of FCRL2 and analyzed its functional potential to show that coligation with the BCR leads to tyrosine phosphorylation of its ITIM motifs and subsequent Src homology region 2 domain-containing phosphatase-1 recruitment to facilitate inhibition of BCR signaling. Mutational analysis indicates that the tyrosine residues in both inhibitory motifs of FCRL2 are required for complete inhibition of BCR signaling, whereas tyrosines in the putative activation motif are dispensable for signal modulation. These findings suggest a negative immunomodulatory function for FCRL2 in the regulation of memory B cells. PMID:21068405

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

    PubMed Central

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

    2015-01-01

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

  5. B cell depletion for autoimmune diseases in paediatric patients.

    PubMed

    Jansson, Annette F; Sengler, Claudia; Kuemmerle-Deschner, Jasmin; Gruhn, Bernd; Kranz, A Birgitta; Lehmann, Hartwig; Kleinert, Daniela; Pape, Lars; Girschick, Hermann J; Foeldvari, Ivan; Haffner, Dieter; Haas, Johannes P; Moebius, Dagmar; Foell, Dirk; Peitz, Joachim; Grote, Veit

    2011-01-01

    Data on B cell depletion therapy in severe autoimmune diseases in paediatric patients are very limited. We conducted a retrospective cohort study and recruited patients who were treated with rituximab (RTX) and followed up for at least 6 months through the German societies of paediatric rheumatology and nephrology. The aim was to describe the spectrum of autoimmune disorders for which RTX was used and to describe the applied therapeutic regimens, the observed efficacy, as well as potential immunological side effects. The need to develop standard treatment guidelines for future trials should be discussed. Sixty-five patients were included. Nineteen patients suffered from systemic lupus erythematosus, 13 from vasculitic disorders, 12 from hematological autoimmune diseases, 5 from mixed connective tissue disorders, 4 from juvenile idiopathic arthritis, and 9 had other autoimmune diseases. Adverse, infusion-related events were reported in 12/65 (18%) patients. Considering laboratory and clinical parameters, 13 patients (22%) were in complete remission, 31 (52%) were in partial remission, 6 (10%) were unchanged and 10 (17%) had progressed after 6 months. In 46% of the patients, the steroid dose could be more than halved. IgG, IgM and IgA decreased from normal levels prior to RTX therapy to below normal levels at 6 months in 2/22 (9%), 10/21 (48%), and 4/22 (18%) patients, respectively. Immunoglobulin deficiency or prolonged CD20 depletion was reported in eight patients after an observation period longer than 12 months. RTX therapy led to a perceivable reduction in disease activity. However, long-term immunological alterations may occur in more than 10% of the patients. Guidelines and protocols for off-label therapy are desirable to document reasonable follow-up data. Controlled prospective studies for RTX therapies in children with standardised therapeutic and diagnostic protocols are urgently needed.

  6. Chronic active B-cell-receptor signalling in diffuse large B-cell lymphoma.

    PubMed

    Davis, R Eric; Ngo, Vu N; Lenz, Georg; Tolar, Pavel; Young, Ryan M; Romesser, Paul B; Kohlhammer, Holger; Lamy, Laurence; Zhao, Hong; Yang, Yandan; Xu, Weihong; Shaffer, Arthur L; Wright, George; Xiao, Wenming; Powell, John; Jiang, Jian-Kang; Thomas, Craig J; Rosenwald, Andreas; Ott, German; Muller-Hermelink, Hans Konrad; Gascoyne, Randy D; Connors, Joseph M; Johnson, Nathalie A; Rimsza, Lisa M; Campo, Elias; Jaffe, Elaine S; Wilson, Wyndham H; Delabie, Jan; Smeland, Erlend B; Fisher, Richard I; Braziel, Rita M; Tubbs, Raymond R; Cook, J R; Weisenburger, Dennis D; Chan, Wing C; Pierce, Susan K; Staudt, Louis M

    2010-01-07

    A role for B-cell-receptor (BCR) signalling in lymphomagenesis has been inferred by studying immunoglobulin genes in human lymphomas and by engineering mouse models, but genetic and functional evidence for its oncogenic role in human lymphomas is needed. Here we describe a form of 'chronic active' BCR signalling that is required for cell survival in the activated B-cell-like (ABC) subtype of diffuse large B-cell lymphoma (DLBCL). The signalling adaptor CARD11 is required for constitutive NF-kappaB pathway activity and survival in ABC DLBCL. Roughly 10% of ABC DLBCLs have mutant CARD11 isoforms that activate NF-kappaB, but the mechanism that engages wild-type CARD11 in other ABC DLBCLs was unknown. An RNA interference genetic screen revealed that a BCR signalling component, Bruton's tyrosine kinase, is essential for the survival of ABC DLBCLs with wild-type CARD11. In addition, knockdown of proximal BCR subunits (IgM, Ig-kappa, CD79A and CD79B) killed ABC DLBCLs with wild-type CARD11 but not other lymphomas. The BCRs in these ABC DLBCLs formed prominent clusters in the plasma membrane with low diffusion, similarly to BCRs in antigen-stimulated normal B cells. Somatic mutations affecting the immunoreceptor tyrosine-based activation motif (ITAM) signalling modules of CD79B and CD79A were detected frequently in ABC DLBCL biopsy samples but rarely in other DLBCLs and never in Burkitt's lymphoma or mucosa-associated lymphoid tissue lymphoma. In 18% of ABC DLBCLs, one functionally critical residue of CD79B, the first ITAM tyrosine, was mutated. These mutations increased surface BCR expression and attenuated Lyn kinase, a feedback inhibitor of BCR signalling. These findings establish chronic active BCR signalling as a new pathogenetic mechanism in ABC DLBCL, suggesting several therapeutic strategies.

  7. DiGeorge syndrome who developed lymphoproliferative mediastinal mass.

    PubMed

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

    2015-03-01

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

  8. Transitional B cells: step by step towards immune competence.

    PubMed

    Chung, James B; Silverman, Michael; Monroe, John G

    2003-06-01

    Transitional B cells mark the crucial link between bone-marrow (BM) immature and peripheral mature B cells. Examination reveals unexpected heterogeneity, consisting of contiguous subsets with phenotypic and functional differences. Data point to the late transitional B-cell stage as a crucial juncture at which developing B cells gain access to splenic follicles, become responsive to T-cell help and lose sensitivity to negative selection, characterizing the immature B-cell response to B-cell antigen receptor (BCR) signaling in vitro and in vivo. The biological and molecular processes directing maturation through this stage are becoming clearer through biochemical studies and murine models deficient in various components of the BCR signaling pathway.

  9. RP105-Negative B Cells in Systemic Lupus Erythematosus

    PubMed Central

    Koarada, Syuichi; Tada, Yoshifumi

    2012-01-01

    Systemic lupus erythematosus (SLE) is a multisystem disease characterized by B cells producing autoantibodies against nuclear proteins and DNA, especially anti-double-strand DNA (dsDNA) antibodies. RP105 (CD180), the toll-like receptor- (TLR-) associated molecule, is expressed on normal B cells. However, RP105-negative B cells increase in peripheral blood from patients with active SLE. RP105 may regulate B-cell activation, and RP105-negative B cells produce autoantibodies and take part in pathophysiology of SLE. It is possible that targeting RP105-negative B cells is one of the treatments of SLE. In this paper, we discuss the RP105 biology and clinical significance in SLE. PMID:21941580

  10. The PI3K pathway in B cell metabolism.

    PubMed

    Jellusova, Julia; Rickert, Robert C

    2016-09-01

    B cell growth and proliferation is tightly regulated by signaling through the B cell receptor and by other membrane bound receptors responding to different cytokines. The PI3K signaling pathway has been shown to play a crucial role in B cell activation, differentiation and survival. Activated B cells undergo metabolic reprograming in response to changing energetic and biosynthetic demands. B cells also need to be able to coordinate metabolic activity and proliferation with nutrient availability. The PI3K signaling network has been implicated in regulating nutrient acquisition, utilization and biosynthesis, thus integrating receptor-mediated signaling with cell metabolism. In this review, we discuss the current knowledge about metabolic changes induced in activated B cells, strategies to adapt to metabolic stress and the role of PI3K signaling in these processes.

  11. Innate response activator B cells: origins and functions

    PubMed Central

    Swirski, Filip K.

    2015-01-01

    Innate response activator (IRA) B cells are a subset of B-1a derived B cells that produce the growth factors granulocyte macrophage colony stimulating factor and IL-3. In mouse models of sepsis and pneumonia, B-1a B cells residing in serosal sites recognize bacteria, migrate to the spleen or lung, and differentiate to IRA B cells that then contribute to the host response by amplifying inflammation and producing polyreactive IgM. In atherosclerosis, IRA B cells accumulate in the spleen, where they promote extramedullary hematopoiesis and activate classical dendritic cells. In this review, we focus on the ontogeny and function of IRA B cells in acute and chronic inflammation. PMID:25957266

  12. Distinct processing of the pre-B cell receptor and the B cell receptor.

    PubMed

    Cohen, Sharon; Haimovich, Joseph; Hollander, Nurit

    2013-06-01

    It has been recently demonstrated that while oligosaccharide moieties of μ heavy chains in the B-cell receptor (BCR) are of the complex type as expected, those of the pre-BCR on the surface of pre-B cells contain oligosaccharide moieties of the high-mannose type only. This is unique, because high-mannose glycans are generally restricted to the endoplasmic reticulum and not presented on the surface of mammalian cells. In the present study, we examined the processing of the unusually glycosylated μ heavy chains in pre-B cells. We demonstrate that the pre-BCR reaches the cell surface by a non-conventional brefeldin A-sensitive monensin-insensitive transport pathway. Although pre-BCR complexes consist of μ heavy chains with high-mannose oligosaccharide moieties, they are stably expressed in the plasma membrane and demonstrate turnover rates similar to those of the BCR. Thus, rapid internalization cannot account for their low surface expression, as previously postulated. Rather, we demonstrate that the low pre-BCR abundance in the plasma membrane results, at least in part, from insufficient production of surrogate light chains, which appears to be a limiting factor in pre-BCR expression.

  13. B-cell Non-Hodgkin Lymphomas with Plasmacytic Differentiation.

    PubMed

    Harmon, Charles M; Smith, Lauren B

    2016-03-01

    B-cell non-Hodgkin lymphomas with plasmacytic differentiation are a diverse group of entities with extremely variable morphologic features. Diagnostic challenges can arise in differentiating lymphoplasmacytic lymphoma from marginal zone lymphoma and other low-grade B-cell lymphomas. In addition, plasmablastic lymphomas can be difficult to distinguish from diffuse large B-cell lymphoma or other high-grade lymphomas. Judicious use of immunohistochemical studies and molecular testing can assist in appropriate classification.

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

    PubMed

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

    2016-02-02

    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.

  15. Relevant B Cell Epitopes in Allergic Disease

    PubMed Central

    Pomés, Anna

    2010-01-01

    The 3-dimensional structure of an allergen defines the accessible parts on the surface of the molecule or epitopes that interact with antibodies. Mapping the antigenic determinants for IgE antibody binding has been pursued through strategies based on the use of overlapping synthetic peptides, recombinant allergenic fragments or unfolded allergens. These approaches led to the identification of mostly linear epitopes and are useful for food allergens that undergo digestion or food processing. For inhaled allergens, conformational epitopes appear to be the primary targets of IgE responses. Knowledge of the molecular structure of allergens alone and in complex with antibodies that interfere with IgE antibody binding is important to understand the immune recognition of B cell-antigenic determinants on allergens and the design of recombinant allergens for immunotherapy. Starting with the molecular cloning and expression of allergens, and with the advent of X-ray crystallography and nuclear magnetic resonance techniques, we have been able to visualize conformational epitopes on allergens. PMID:19940500

  16. Auto-reactive B cells in transgenic mice.

    PubMed

    Pasquali, Jean-Louis; Soulas-Sprauel, Pauline; Korganow, Anne-Sophie; Martin, Thierry

    2007-12-01

    In order to understand how the natural occurrence of autoreactive B cells is controlled in normal individuals, and how self reactive B cells can escape this control during diverse clinical situations, many different transgenic mice have been generated expressing self reactive antibodies. In this review, we focus our attention on disease-associated self reactive transgenic models which show the variety of the tolerization mechanisms. The same transgenic lines are also used to analyse the effects of the autoimmune genetic background on the self reactive B cell fate, as well as to study the influence of infectious agents on the behaviour of the auto-reactive transgenic B cells.

  17. Transcriptional networks in developing and mature B cells.

    PubMed

    Matthias, Patrick; Rolink, Antonius G

    2005-06-01

    The development of B cells from haematopoietic stem cells proceeds along a highly ordered, yet flexible, pathway. At multiple steps along this pathway, cells are instructed by transcription factors on how to further differentiate, and several check-points have been identified. These check-points are initial commitment to lymphocytic progenitors, specification of pre-B cells, entry to the peripheral B-cell pool, maturation of B cells and differentiation into plasma cells. At each of these regulatory nodes, there are transcriptional networks that control the outcome, and much progress has recently been made in dissecting these networks. This article reviews our current understanding of this exciting field.

  18. CD23 can negatively regulate B-cell receptor signaling

    PubMed Central

    Liu, Chaohong; Richard, Katharina; Wiggins, Melvin; Zhu, Xiaoping; Conrad, Daniel H.; Song, Wenxia

    2016-01-01

    CD23 has been implicated as a negative regulator of IgE and IgG antibody responses. However, whether CD23 has any role in B-cell activation remains unclear. We examined the expression of CD23 in different subsets of peripheral B cells and the impact of CD23 expression on the early events of B-cell receptor (BCR) activation using CD23 knockout (KO) mice. We found that in addition to marginal zone B cells, mature follicular B cells significantly down regulate the surface expression level of CD23 after undergoing isotype switch and memory B-cell differentiation. Upon stimulation with membrane-associated antigen, CD23 KO causes significant increases in the area of B cells contacting the antigen-presenting membrane and the magnitude of BCR clustering. This enhanced cell spreading and BCR clustering is concurrent with increases in the levels of phosphorylation of tyrosine and Btk, as well as the levels of F-actin and phosphorylated Wiskott Aldrich syndrome protein, an actin nucleation promoting factor, in the contract zone of CD23 KO B cells. These results reveal a role of CD23 in the negative regulation of BCR signaling in the absence of IgE immune complex and suggest that CD23 down-regulates BCR signaling by influencing actin-mediated BCR clustering and B-cell morphological changes. PMID:27181049

  19. Age effects on B cells and humoral immunity in humans

    PubMed Central

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

    2010-01-01

    Both humoral and cellular immune responses are impaired in aged individuals, leading to decreased vaccine responses. Although T cell defects occur, defects in B cells play a significant role in age-related humoral immune changes. The ability to undergo class switch recombination (CSR), the enzyme for CSR, AID (activation-induced cytidine deaminase) and the transcription factor E47 are all decreased in aged stimulated B cells. We here present an overview of age-related changes in human B cell markers and functions, and also discuss some controversies in the field of B cell aging. PMID:20728581

  20. 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

  1. B cell receptor-mediated internalization of salmonella: a novel pathway for autonomous B cell activation and antibody production.

    PubMed

    Souwer, Yuri; Griekspoor, Alexander; Jorritsma, Tineke; de Wit, Jelle; Janssen, Hans; Neefjes, Jacques; van Ham, S Marieke

    2009-06-15

    The present paradigm is that primary B cells are nonphagocytosing cells. In this study, we demonstrate that human primary B cells are able to internalize bacteria when the bacteria are recognized by the BCR. BCR-mediated internalization of Salmonella typhimurium results in B cell differentiation and secretion of anti-Salmonella Ab by the Salmonella-specific B cells. In addition, BCR-mediated internalization leads to efficient Ag delivery to the MHC class II Ag-loading compartments, even though Salmonella remains vital intracellularly in primary B cells. Consequently, BCR-mediated bacterial uptake induces efficient CD4(+) T cell help, which boosts Salmonella-specific Ab production. BCR-mediated internalization of Salmonella by B cells is superior over extracellular Ag extraction to induce rapid and specific humoral immune responses and efficiently combat infection.

  2. Generation of high-titre virus stocks using BrK.219, a B-cell line infected stably with recombinant Kaposi's sarcoma-associated herpesvirus.

    PubMed

    Kati, Semra; Hage, Elias; Mynarek, Martin; Ganzenmueller, Tina; Indenbirken, Daniela; Grundhoff, Adam; Schulz, Thomas F

    2015-06-01

    Kaposi's sarcoma-associated herpesvirus (KSHV) is a gamma-2-lymphotropic human oncogenic herpesvirus associated with Kaposi's sarcoma (KS) and two B-cell lymphoproliferative diseases, primary effusion lymphoma (PEL) and multicentric Castleman's disease (MCD). KSHV establishes latency soon after infection in vivo and in vitro. Consequently, it is technically difficult to generate high-titre virus stocks required for infection experiments in tissue culture. Currently used methods of KSHV stock production involve induction of the lytic/productive cycle in PEL cell lines or in adherent cell lines harbouring recombinant KSHV genomes. In this study, the BJAB-derived B-cell line BrK.219, which is infected latently with a recombinant KSHV (rKSHV.219), is used to produce high-titre virus stocks. BrK.219 cells enter the lytic KSHV replication cycle upon cross-linking of B-cell receptors (BCRs) with anti-IgM antibodies without the need for additional, potentially toxic chemical inducers. High cell concentrations can be cultured and induced easily in spinner flasks, saving time and resources. The established protocol allows the generation of KSHV virus stocks with titres of up to 10(6) IU/ml in unconcentrated culture supernatants, representing a 10(3)-10(4)-fold improvement compared to conventional methods.

  3. Rainbow trout CK9, a CCL25-like ancient chemokine that attracts and regulates B cells and macrophages, the main antigen presenting cells in fish

    PubMed Central

    Aquilino, Carolina; Granja, Aitor G.; Castro, Rosario; Wang, Tiehui; Abos, Beatriz; Parra, David; Secombes, Christopher J.; Tafalla, Carolina

    2016-01-01

    CK9 is a rainbow trout (Oncorhynchus mykiss) CC chemokine phylogenetically related to mammalian CCL25. Although CK9 is known to be transcriptionally regulated in response to inflammation particularly in mucosal tissues, its functionality has never been revealed. In the current work, we have demonstrated that CK9 is chemoattractant for antigen presenting cells (APCs) expressing major histocompatibility complex class II (MHC II) on the cell surface. Among these APCs, CK9 has a strong chemotactic capacity for both B cells (IgM+ and IgT+) and macrophages. Along with its chemotactic capacities, CK9 modulated the MHC II turnover of B lymphocytes and up-regulated the phagocytic capacity of both IgM+ cells and macrophages. Although CK9 had no lymphoproliferative effects, it increased the survival of IgT+ lymphocytes. Furthermore, we have established that the chemoattractant capacity of CK9 is strongly increased after pre-incubation of leukocytes with a T-independent antigen, whereas B cell receptor (BCR) cross-linking strongly abrogated their capacity to migrate to CK9, indicating that CK9 preferentially attracts B cells at the steady state or under BCR-independent stimulation. These results point to CK9 being a key regulator of B lymphocyte trafficking in rainbow trout, able to modulate innate functions of teleost B lymphocytes and macrophages. PMID:27003360

  4. Gata3 restrains B cell proliferation and cooperates with p18INK4c to repress B cell lymphomagenesis

    PubMed Central

    Liu, Shiqin; Chan, Ho Lam; Bai, Feng; Ma, Jinshan; Scott, Alexandria; Robbins, David J.; Capobianco, Anthony J.; Zhu, Ping; Pei, Xin-Hai

    2016-01-01

    GATA3, a lineage specifier, controls lymphoid cell differentiation and its function in T cell commitment and development has been extensively studied. GATA3 promotes T cell specification by repressing B cell potential in pro T cells and decreased GATA3 expression is essential for early B cell commitment. Inherited genetic variation in GATA3 has been associated with lymphoma susceptibility. However, it remains elusive how the loss of function of GATA3 promotes B cell development and induces B cell lymphomas. In this study, we found that haploid loss of Gata3 by heterozygous germline deletion increased B cell populations in the bone marrow (BM) and spleen, and decreased CD4 T cell populations in the thymus, confirming that Gata3 promotes T and suppresses B cell development. We discovered that haploid loss of Gata3 reduced thymocyte proliferation with induction of p18Ink4c (p18), an inhibitor of CDK4 and CDK6, but enhanced B cell proliferation in the BM and spleen independent of p18. Loss of p18 partially restored Gata3 deficient thymocyte proliferation, but further stimulated Gata3 deficient B cell proliferation in the BM and spleen. Furthermore, we discovered that haploid loss of Gata3 in p18 deficient mice led to the development of B cell lymphomas that were capable of rapidly regenerating tumors when transplanted into immunocompromised mice. These results indicate that Gata3 deficiency promotes B cell differentiation and proliferation, and cooperates with p18 loss to induce B cell lymphomas. This study, for the first time, reveals that Gata3 is a tumor suppressor specifically in B cell lymphomagenesis. PMID:27588406

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

    PubMed Central

    Dalloul, Ali

    2013-01-01

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

  6. Krüppel-Like Factor 4 Regulates B Cell Number and Activation-Induced B Cell Proliferation1

    PubMed Central

    Klaewsongkram, Jettanong; Yang, Yinhua; Golech, Susanne; Katz, Jonathan; Kaestner, Klaus H.; Weng, Nan-ping

    2008-01-01

    Krüppel-like factor 4 (Klf4) is a transcription factor and functions in regulating cell differentiation, cell growth, and cell cycle. Although Klf4 is expressed in lymphocytes, its function in lymphocytes is unknown. In this study, we report that the levels of Klf4 expression were low in pro-B cells and continuously increased in pre-B and in mature B cells. Upon activation, Klf4 was rapidly decreased in mature B cells after 2 h of activation. A modest decrease in numbers of pre-B cells in bone marrow and mature B cells in spleen was observed in Klf4-deficient mice. In the absence of Klf4, fewer B cells entered the S phase of the cell cycle and completed cell division in response to the engagement of BCR and/or CD40 in vitro. Furthermore, the delay in entering the cell cycle is associated with decreased expression of cyclin D2 in B cells that lack Klf4 expression. We then demonstrated that Klf4 directly bound to the promoter of cyclin D2 and regulated its expression. These findings demonstrate that Klf4 regulates B cell number and activation-induced B cell proliferation through directly acting on the promoter of cyclin D2. PMID:17878366

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

    PubMed

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

    2015-10-01

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

  8. Evidence for B cell activation in patients with active rheumatoid arthritis.

    PubMed Central

    Youinou, P Y; Irving, W L; Shipley, M; Hayes, J; Lydyard, P M

    1984-01-01

    Peripheral blood lymphocytes and in some cases synovial eluate cells from 51 patients with rheumatoid arthritis (RA), were analysed for the percentages of cells bearing surface light chains (total B cells), IgM and IgD. In addition, their capacity to form rosettes with mouse erythrocytes (mRFC)--a property of a B cell subpopulation--was determined. Activity of the disease was assessed by clinical and laboratory criteria and classified as very active, moderately active and inactive. Normal, age and sex matched individuals and a group of patients with a variety of other rheumatological disorders, were used as control populations. Although there was no significant difference in percentages of total B cells in any of the groups compared with normal controls, there was a small but significant increase in the ratio of cells bearing IgM to those bearing IgD in patients with very active disease. This was paralleled by a significant decrease in the mRFC in this disease activity group. Patients with inactive disease showed no change in their proportions of IgM:IgD, but did show a significant increase in mRFC. These results are discussed in terms of the presence of activated B cells in patients with very active RA. PMID:6607144

  9. 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.

  10. 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.

  11. 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

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

    PubMed

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

    2015-09-01

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

  13. Essential role for B cells in transplantation tolerance

    PubMed Central

    Redfield, Robert R; Rodriguez, Eduardo; Parsons, Ronald; Vivek, Kumar; Mustafa, Moiz M; Noorchashm, Hooman; Naji, Ali

    2017-01-01

    T lymphocytes are the primary targets of immunotherapy in clinical transplantation. However, B lymphocytes are detrimental to graft survival by virtue of their capacity to present antigen to T cells via the indirect pathway of allorecognition and the generation of donor specific alloantibody. Furthermore, the long-term survival of organ allografts remains challenged by chronic rejection, a process in which activated B cells have been found to play a significant role. Therefore, the achievement of transplantation tolerance will likely require induction of both T and B cell tolerance to alloantigens. Moreover, human and animal investigations have shown that subsets of B cells, Transitional and Regulatory, are inherently tolerogenic. Developing therapeutic strategies that exploit these populations may be key to achieving transplantation tolerance. In this review we describe the current evidence for the essential role of B cells in transplant tolerance and discuss emerging B cell directed strategies to achieve allograft tolerance. PMID:21982511

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

    PubMed Central

    Ankeny, Daniel P.; Popovich, Phillip G.

    2010-01-01

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

  15. 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.

  16. 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

  17. The rap GTPases regulate B cell morphology, immune-synapse formation, and signaling by particulate B cell receptor ligands.

    PubMed

    Lin, Kevin B L; Freeman, Spencer A; Zabetian, Saba; Brugger, Hayley; Weber, Michele; Lei, Victor; Dang-Lawson, May; Tse, Kathy W K; Santamaria, Rene; Batista, Facundo D; Gold, Michael R

    2008-01-01

    B lymphocytes spread and extend membrane processes when searching for antigens and form immune synapses upon contacting cells that display antigens on their surface. Although these dynamic morphological changes facilitate B cell activation, the signaling pathways underlying these processes are not fully understood. We found that activation of the Rap GTPases was essential for these changes in B cell morphology. Rap activation was important for B cell receptor (BCR)- and lymphocyte-function-associated antigen-1 (LFA-1)-induced spreading, for BCR-induced immune-synapse formation, and for particulate BCR ligands to induce localized F-actin assembly and membrane-process extension. Rap activation and F-actin assembly were also required for optimal BCR signaling in response to particulate antigens but not soluble antigens. Thus by controlling B cell morphology and cytoskeletal organization, Rap might play a key role in the activation of B cells by particulate and cell-associated antigens.

  18. The growth of B cell receptor microcluster is a universal response of B cells encountering antigens with different motion features.

    PubMed

    Wan, Zhengpeng; Liu, Wanli

    2012-07-01

    B lymphocyte cell senses and acquires foreign antigens through clonal distributed B cell receptors (BCRs) expressed on the surface of plasma membrane. The presentation formats of antigens are quite diverse. Based on their Brownian diffusion mobility, there are three forms: free mobile soluble antigens, lateral mobile membrane bound antigens, and fixed immobile antigens. Here, using high resolution high speed live cell imaging approaches, we provide evidence that BCR microclusters are formed on the surface of B cells shortly after B cell's encountering of antigens with each format of motion features. Through high speed live cell imaging, we determine that these BCR microclusters show dynamic growth feature and by doing so function as the basic platforms for B cells to acquire the antigens. We propose that the formation and dynamic growth of BCR microcluster is a universal mechanism for B cell to response to antigens with diverse motion features.

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

    PubMed Central

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

    2014-01-01

    Integrin-ligand interactions between germinal center (GC) B cells and antigen-presenting follicular dendritic cells (FDCs) have been suggested to play central roles during GC responses but their in vivo requirement has not been directly tested. Here we show that while integrins αLβ2 and α4β1 are highly expressed and functional on mouse GC B cells, removal of single integrins or their ligands had little effect on B cell participation in the GC response. Combined β2-integrin deficiency and α4-integrin blockade also did not affect the GC response against a particulate antigen. However, the combined integrin deficiency did cause B cells to be outcompeted in splenic GC responses against a soluble protein antigen and in mesenteric lymph node GC responses against gut-derived antigens. Similar findings were made for β2-deficient B cells in mice lacking VCAM1 on FDCs. The reduced fitness of the GC B cells did not appear to be due to decreased antigen acquisition, proliferation rates or pAKT levels. In summary, our findings provide evidence that αLβ2 and α4β1 play overlapping and context-dependent roles in supporting interactions with FDCs that can augment the fitness of responding GC B cells. We also find that mouse GC B cells upregulate αvβ3 and adhere to vitronectin and milk fat globule EGF-factor-8 protein. Integrin β3-deficient B cells contributed in a slightly exaggerated manner to GC responses suggesting this integrin has a regulatory function in GC B cells. PMID:24740506

  20. 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.

  1. 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

  2. Circulating clonotypic B cells in classic Hodgkin lymphoma.

    PubMed

    Jones, Richard J; Gocke, Christopher D; Kasamon, Yvette L; Miller, Carole B; Perkins, Brandy; Barber, James P; Vala, Milada S; Gerber, Jonathan M; Gellert, Lan L; Siedner, Mark; Lemas, M Victor; Brennan, Sarah; Ambinder, Richard F; Matsui, William

    2009-06-04

    Although Hodgkin and Reed-Sternberg (HRS) cells are B lymphoid cells, they are unlike any normal cells of that lineage. Moreover, the limited proliferative potential of HRS cells belies the clinical aggressiveness of Hodgkin lymphoma (HL). More than 20 years ago, the L428 HL cell line was reported to contain a small population of phenotypic B cells that appeared responsible for the continued generation of HRS cells. This observation, however, has never been corroborated, and such clonotypic B cells have never been documented in HL patients. We found that both the L428 and KM-H2 HL cell lines contained rare B-cell subpopulations responsible for the generation and maintenance of the predominant HRS cell population. The B cells within the HL cell lines expressed immunoglobulin light chain, the memory B-cell antigen CD27, and the stem cell marker aldehyde dehydrogenase (ALDH). Clonal CD27(+)ALDH(high) B cells, sharing immunoglobulin gene rearrangements with lymph node HRS cells, were also detected in the blood of most newly diagnosed HL patients regardless of stage. Although the clinical significance of circulating clonotypic B cells in HL remains unclear, these data suggest they may be the initiating cells for HL.

  3. YY1 Is Required for Germinal Center B Cell Development.

    PubMed

    Banerjee, Anupam; Sindhava, Vishal; 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.

  4. 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.

  5. Phenotypic Approaches to Identify Inhibitors of B Cell Activation

    PubMed Central

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

    2015-01-01

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

  6. 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.

  7. The emerging role of estrogen in B cell malignancies.

    PubMed

    Ladikou, Eleni-Eirini; Kassi, Eva

    2017-03-01

    Increasing evidence implicates a role of estrogens in hematological malignancies. We reviewed current knowledge on the emerging role of estrogens and estrogen receptors in normal B-cell function, chronic lymphocytic leukemia, and B-cell lymphoma. Data support that (1) normal human peripheral blood cells (mononuclear cells, total lymphocytes, T as well as B lymphocytes, and NK cells) express both estrogen receptor subtypes (ERα and ERβ), (2) B-cell malignancies express mainly ERβ while selective ERβ agonists inhibit cell growth and induce apoptosis, (3) estrogens regulate, via an ER-mediated pathway, gene expression of cyclins, kinases, bcl-2 proto-oncogene, activation-induced deaminase (AID), and transcription factors, associated with changes in BCR signaling and B cell tumorigenesis. In conclusion, estrogen receptors play an important role in normal B-cell function and B-cell tumorigenesis; however, further investigations are required to delineate the role of estrogens and estrogen receptors in the etiopathogenesis and therapy of B-cell malignancies.

  8. [The role of IRA B cells in selected inflammatory processes].

    PubMed

    Zasada, Magdalena; Rutkowska-Zapała, Magdalena; Lenart, Marzena; Kwinta, Przemko

    2016-03-16

    The first report about the discovery of new, previously unknown immune cells named IRA B cells (innate response activator B cells) appeared in 2012. So far, their presence has been verified in both mice and humans. However, IRA B cells belong to the family of B lymphocytes and have a number of characteristics unique to this group of cells. IRA B cells are formed from activated B1a lymphocytes after their contact with a pathogen. B1a lymphocytes mainly reside within body cavities. Activated by the pathogen, they move on into secondary lymphoid organs (spleen, lymph nodes) where they differentiate into IRA B cells. IRA B cells are a rich source of granulocyte-macrophage colony stimulating factor (GM-CSF). GM-CSF can stimulate IRA B cells in an autocrine manner for the secretion of intracellular stocks of immunoglobulin M (IgM), which can facilitate pathogens' phagocytosis by neutrophils. GM-CSF also stimulates neutrophils into active phagocytosis. Rapid eradication of the pathogen can prevent the development of an excessive inflammatory response, which can be dangerous for the organism. Until now the involvement of IRA B lymphocytes in the pathogenesis of sepsis and pneumonia has been proven, as well as their role in the progression of atherosclerotic lesions in mice. There is research in progress on the possibility of increasing the number of IRA B cells, for example by intravenous supply of modified immunoglobulins. It is necessary to characterize human IRA B cells and to determine their role in the functioning of the immune system.

  9. 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,