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1

Incidence and clinicobiologic characteristics of leukemic B-cell chronic lymphoproliferative disorders with more than one B-cell clone  

Microsoft Academic Search

Leukemic B-chronic lymphoproliferative disorders (B-CLPDs) are generally be- lieved to derive from a monoclonal B cell; biclonality has only occasionally been reported. In this study, we have explored the incidence of B-CLPD cases with 2 or more B-cell clones and established both the phenotypic differences between the coexisting clones and the clinicobiologic features of these patients. In total, 53 B-CLPD

Maria-Luz Sanchez; Julia Almeida; David Gonzalez; Marcos Gonzalez; Maria-Antonia Garcia-Marcos; Ana Balanzategui; Maria-Consuelo Lopez-Berges; Josep Nomdedeu; Teresa Vallespi; Marcos Barbon; Alejandro Martin; Pilar de la Fuente; Guillermo Martin-Nunez; Javier Fernandez-Calvo; Jesus-Maria Hernandez; Jesus F. San Miguel; Alberto Orfao

2003-01-01

2

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

PubMed

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

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

2014-08-01

3

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

PubMed Central

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

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

4

Molecular lesions in B-cell lymphoproliferative disorders: recent contributions from studies utilizing high-throughput sequencing techniques.  

PubMed

Next-generation sequencing techniques are powerful high-throughput methods that have enabled the comprehensive documentation of genetic lesions in numerous hematological malignancies. In recent times, the genomes of multiple different B-cell lymphoproliferative disorders including chronic lymphocytic leukemia, diffuse large B-cell lymphoma, Burkitt lymphoma, splenic marginal zone lymphoma, mantle cell lymphoma, hairy cell leukemia and Waldenström macroglobulinemia have been documented. Between them, these studies have reinforced and provided insight into the mechanisms for the dysregulation of known pathways (e.g. nuclear factor-?B [NF-?B]), uncovered the importance of new pathways for oncogenesis (e.g. mRNA processing), identified disease-defining mutations and provided meaningful new targets which are already being translated into therapeutic interventions. This review summarizes the molecular lesions that have been discovered in B-cell lymphoproliferative disorders thus far by studies utilizing high-throughput sequencing techniques and the aberrations in the numerous intracellular pathways that have been shown to be involved. PMID:23550993

Blombery, Piers A; Dickinson, Michael; Westerman, David A

2014-01-01

5

Gene expression profiling of Epstein-Barr virus-positive and -negative monomorphic B-cell posttransplant lymphoproliferative disorders.  

PubMed

Although most posttransplant lymphoproliferative disorders (PTLD) are related to Epstein-Barr virus (EBV) infection, approximately 20% lack detectable EBV (EBV-). It is uncertain whether the latter cases are truly distinct from EBV+ PTLD or possibly relate to another infectious agent. This study used gene expression profiling to further investigate the relationship between EBV+ and EBV- monomorphic B-cell PTLD, and to search for clues to their pathogenesis. Affymetrix HU133A GeneChips were used to compare 4 EBV+ and 4 EBV- cases of monomorphic B-cell PTLD. Hierarchical clustering successfully distinguished the EBV+ and EBV- groups. Relative to EBV- PTLD, 54 transcripts were over-expressed in EBV+ PTLD. The transcripts identified included IRF7 (a known regulator of EBV LMP1 expression), EBI2 (EBV-induced gene 2), and 3 that are interferon induced (MX1, IFITM1, and IFITM3). In addition, the EBV+ group contained 232 transcripts decreased relative to the EBV- group, including changes concordant with those previously reported after EBV infection of cultured B-cell lines. In summary, in a small group of monomorphic B-cell PTLD, EBV+ cases demonstrated a subset of gene expression changes associated with EBV infection of B cells. By contrast, EBV- PTLD lacked viral-associated changes suggesting that they are biologically distinct. PMID:17721324

Craig, Fiona E; Johnson, Lawrence R; Harvey, Stephen A K; Nalesnik, Michael A; Luo, Jianhua H; Bhattacharya, Soumyaroop D; Swerdlow, Steven H

2007-09-01

6

Cutaneous B-cell lymphoproliferative disorders: report of the 2011 Society for Hematopathology/European Association for Haematopathology workshop.  

PubMed

The diagnosis and classification of the cutaneous B-cell lymphomas can be quite a challenge, with a definitive diagnosis sometimes being elusive, even when an extensive workup has been performed. Distinction of benign from neoplastic disorders can be difficult, with some hyperplasias mimicking lymphomas and vice versa. There are only a limited number of skin-specific B-cell lymphomas, including primary cutaneous follicle center lymphoma and primary cutaneous diffuse large B-cell lymphoma, leg type. Cutaneous marginal zone lymphomas have distinctive features but are classified with the other mucosa-associated lymphoid tissue lymphomas. It is important, however, to also remember that many other B-cell lymphomas/ plasma cell neoplasms can primarily, or more often secondarily, involve the skin. Some may mimic one of the skin-specific lymphomas but have very different clinical implications. Iatrogenic and senescent immunodeficiency-associated lymphoproliferative disorders that are often Epstein-Barr virus (EBV) positive can also primarily involve the skin, including cases also known as EBV-positive mucocutaneous ulcer. PMID:23525619

Swerdlow, Steven H; Quintanilla-Martinez, Leticia; Willemze, Rein; Kinney, Marsha C

2013-04-01

7

Methotrexate-associated B-cell lymphoproliferative disorders presenting in the skin: A clinicopathologic and immunophenotypical study of 10 cases.  

PubMed

Methotrexate (MTX)-associated B-cell lymphoproliferative disorders (B-LPD) may first present in the skin, but their clinicopathologic features are still ill defined. Differentiation from primary cutaneous follicle center lymphoma and primary cutaneous diffuse large B-cell lymphoma, leg type (PCLBCL-LT) is important, as MTX-associated B-LPD may show spontaneous regression after withdrawal of MTX therapy. In the present study, the clinicopathologic and phenotypical features of 10 patients with MTX-associated B-LPD first presenting in the skin, including 5 EBV(+) and 5 EBV(-) cases, were investigated. Six patients had skin-limited disease. Clinically, abrogation of MTX therapy resulted in a complete response in 4 cases and a partial response in another 2. The 5-year disease-specific survival was 90%. MTX-associated B-LPD differed from primary cutaneous follicle center lymphoma by the presence of ulcerating and/or generalized skin lesions, an infiltrate composed of centroblasts/immunoblasts rather than large centrocytes, reduced staining for CD79a, and expression of BCL2, IRF4, and FOXP1 in most cases. EBV(+) MTX-associated B-LPD differed from PCLBCL-LT by the presence ulcerative skin lesions, marked tumor cell polymorphism, reduced staining for CD79a, and expression of CD30 and EBV. EBV(-) cases showed morphologic and immunophenotypical similarities to PCLBCL-LT but differed by presentation with generalized skin lesions in 4 of 5 cases. The results of this study, showing a relatively good clinical outcome and spontaneous disease regression after only withdrawal of MTX in a considerable proportion of patients, underscores the importance of a careful wait-and-see policy before considering more aggressive therapies in patients with MTX-associated B-LPD of the skin. PMID:24805861

Koens, Lianne; Senff, Nancy J; Vermeer, Maarten H; Willemze, Rein; Jansen, Patty M

2014-07-01

8

Multiple monoclonal B cell expansions and c-myc oncogene rearrangements in acquired immune deficiency syndrome-related lymphoproliferative disorders. Implications for lymphomagenesis  

PubMed Central

AIDS (acquired immune deficiency syndrome) and ARC (AIDS-related complex) are associated with a spectrum of lymphoproliferative disorders ranging from lymphadenopathy syndrome (LAS), an apparently benign polyclonal lymphoid hyperplasia, to B cell non-Hodgkin's lymphoma (B-NHL), i.e., malignant, presumably monoclonal B cell proliferations. To gain insight into the process of lymphomagenesis in AIDS and to investigate a possible pathogenetic relationship between LAS and NHL, we investigated the clonality of the B or T lymphoid populations by Ig or T beta gene rearrangement analysis, the presence of rearrangements involving the c-myc oncogene locus, and the presence of human immunodeficiency virus (HIV) sequences in both LAS and B-NHL biopsies. Our data indicate that multiple clonal B cell expansions are present in a significant percentage of LAS (approximately 20%) and B- NHL (60%) biopsies. c-myc rearrangements/translocations are detectable in 9 of our 10 NHLs, but not in any of the LAS cases. However, only one of the B cell clones, identified by Ig gene rearrangements carries a c- myc gene rearrangement, suggesting that only one clone carries the genetic abnormality associated with malignant B cell lymphoma. Furthermore, the frequency of detection of c-myc rearrangements in AIDS- associated NHLs of both Burkitt and non-Burkitt type suggest that the biological alterations present in AIDS favor the development of lymphomas carrying activated c-myc oncogenes. Finally, our data show that HIV DNA sequences are not detectable in LAS nor in NHL B cell clones, suggesting that HIV does not play a direct role in NHL development. Taken together, these observations suggest a model of multistep lymphomagenesis in AIDS in which LAS would represent a predisposing condition to NHL. Immunosuppression and EBV infection present in LAS can favor the expansion of B cell clones, which in turn may increase the probability of occurrence of c-myc rearrangements leading to malignant transformation. PMID:3491176

1986-01-01

9

Aberrant expression of tetraspanin molecules in B-cell chronic lymphoproliferative disorders and its correlation with normal B-cell maturation  

Microsoft Academic Search

Tetraspanin proteins form signaling complexes between them and with other membrane proteins and modulate cell adhesion and migration properties. The surface expression of several tetraspanin antigens (CD9, CD37, CD53, CD63, and CD81), and their interacting proteins (CD19, CD21, and HLA-DR) were analyzed during normal B-cell maturation and compared to a group of 67 B-cell neoplasias. Three patterns of tetraspanin expression

S Barrena; J Almeida; M Yunta; A López; N Fernández-Mosteirín; M Giralt; M Romero; L Perdiguer; M Delgado; A Orfao; P A Lazo; PA Lazo

2005-01-01

10

Composite B-cell and T-cell lineage post-transplant lymphoproliferative disorder of the lung with unusual cutaneous manifestations of mycosis fungoides.  

PubMed

We present the case of a 17-year-old male kidney transplant recipient who presented initially with dermatologic symptoms and was found to have histologic changes in the skin that were consistent with mycosis fungoides. Shortly after this diagnosis was made, imaging studies demonstrated multifocal interstitial and airspace consolidation in both lungs. Physical examination revealed no lymphadenopathy or hepatosplenomegaly, but an open lung biopsy revealed an Epstein-Barr virus (EBV)-negative monomorphic T-cell posttransplant lymphoproliferative disorder (PTLD) with a concomitant EBV-positive B-cell PTLD involving the same lesion of the lung. Polymerase chain reaction analysis demonstrated clonal T-cell receptor gene rearrangements in both the skin and the lung biopsies. Interestingly, 1 clone was shared between the skin and lung while a second clone was present only in the lung. To our knowledge, this is the first reported case of a PTLD presenting in the skin in which there was a subsequent discovery of composite, bilineal B- and T-cell PTLD of the lung. PMID:22214855

Mills, Kyle C; Sangüeza, Omar P; Beaty, Michael W; Raffeld, Mark; Pang, Changlee S

2012-04-01

11

Oral Lesions and Lymphoproliferative Disorders  

PubMed Central

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

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

2010-01-01

12

Post-transplant lymphoproliferative disorder presenting as epistaxis.  

PubMed

An unusual case of epistaxis resulting from post-transplant lymphoproliferative disorder is described. A 30-year-old woman who had undergone renal transplantation 12 years previously presented with profuse, posterior, unilateral epistaxis. The initial findings, workup and treatment are presented. A post-nasal space (PNS) mass was detected and biopsy showed this to be an Epstein-Barr virus-positive polymorphous B-cell post-transplant lymphoproliferative disorder. Computed tomography findings showed a polypoid lesion protruding from the sphenoethmoidal recess and filling the left PNS. Post-transplant lymphoproliferative disorder is well known to involve tonsil tissue. Commonly, this is the first presentation of the disease in children. However, until now post-transplant lymphoproliferative disorder has not been described in the PNS or nasal cavity presenting as epistaxis. We conclude that all transplant patients presenting with epistaxis should be followed up for an accurate examination of the PNS and nasal cavity after the acute episode. PMID:15638984

Clarke, Jonathan D; Stock, David; Singh, Vijay

2004-11-01

13

Immunoglobulin and T cell receptor gene rearrangements and in situ immunophenotyping in lymphoproliferative disorders  

Microsoft Academic Search

We investigated for rearrangements of the immunoglobulin (Ig) heavy and light chain genes and of the T cell receptor? (TCRT?) andß (TCrß) genes 45 biopsy samples from a variety of lymphoproliferative disorders. They were diagnosed histopathologically and immunophenotypically as non-Hodgkin's lymphomas (NHLs) of the B cell type (19 cases), NHLs of the T cell type (3 cases), NHLs of “undetermined“

Antonino Carbone; Valli De Re; Annunziata Gloghini; Rachele Volpe; Manuela Tavian; Umberto Tirelli; Silvio Monfardini; Mauro Boiocchi

1989-01-01

14

Familial Aggregation of Lymphoproliferative Disorders from the Scandinavian Family Cancer Database  

Cancer.gov

Familial aggregation of lymphoproliferative disorders from the Scandinavian family cancer database Print This Page Familial Aggregation of Lymphoproliferative Disorders from the Scandinavian Family Cancer Database Our Research

15

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

PubMed Central

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

Randen, Ulla; Tr?en, Gunhild; Tierens, Anne; Steen, Chloe; Warsame, Abdirashid; Beiske, Klaus; Tj?nnfjord, Geir E.; Berentsen, Sigbj?rn; Delabie, Jan

2014-01-01

16

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

PubMed

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

Randen, Ulla; Trøen, Gunhild; Tierens, Anne; Steen, Chloé; Warsame, Abdirashid; Beiske, Klaus; Tjønnfjord, Geir E; Berentsen, Sigbjørn; Delabie, Jan

2014-03-01

17

Therapeutic options in post-transplant lymphoproliferative disorders.  

PubMed

Post-transplantation lymphoproliferative disorders (PTLD) are the second most frequent malignancies after solid organ transplantation and cover a wide spectrum ranging from polyclonal early lesions to monomorphic lymphoma. Available treatment modalities include immunosuppression reduction, immunotherapy with anti-B-cell monoclonal antibodies, chemotherapy, antiviral therapy, cytotoxic T-cell therapy as well as surgery and irradiation. Owing to the small number of cases and the heterogeneity of PTLD, current treatment strategies are mostly based on case reports and small, often retrospective studies. Moreover, many studies on the treatment of PTLD have involved a combination of different treatment options, complicating the evaluation of individual treatment components. However, there has been significant progress over the last few years. Three prospective phase II trials on the efficacy of rituximab monotherapy have shown significant complete remission rates without any relevant toxicity. A prospective, multicenter, international phase II trial evaluating sequential treatment with rituximab and CHOP-based chemotherapy (cyclophosphamide, doxorubicin, vincristine, prednisone) is ongoing and preliminary results have been promising. Cytotoxic T-cell therapy targeting Epstein-Barr virus (EBV)-infected B cells has shown low toxicity and high efficacy in a phase II trial and will be a future therapeutic option at specialized centers. Here, we review the currently available data on the different treatment modalities with a focus on PTLD following solid organ transplantation in adult patients. PMID:23556105

Zimmermann, Heiner; Trappe, Ralf Ulrich

2011-12-01

18

Therapeutic options in post-transplant lymphoproliferative disorders  

PubMed Central

Post-transplantation lymphoproliferative disorders (PTLD) are the second most frequent malignancies after solid organ transplantation and cover a wide spectrum ranging from polyclonal early lesions to monomorphic lymphoma. Available treatment modalities include immunosuppression reduction, immunotherapy with anti-B-cell monoclonal antibodies, chemotherapy, antiviral therapy, cytotoxic T-cell therapy as well as surgery and irradiation. Owing to the small number of cases and the heterogeneity of PTLD, current treatment strategies are mostly based on case reports and small, often retrospective studies. Moreover, many studies on the treatment of PTLD have involved a combination of different treatment options, complicating the evaluation of individual treatment components. However, there has been significant progress over the last few years. Three prospective phase II trials on the efficacy of rituximab monotherapy have shown significant complete remission rates without any relevant toxicity. A prospective, multicenter, international phase II trial evaluating sequential treatment with rituximab and CHOP-based chemotherapy (cyclophosphamide, doxorubicin, vincristine, prednisone) is ongoing and preliminary results have been promising. Cytotoxic T-cell therapy targeting Epstein–Barr virus (EBV)-infected B cells has shown low toxicity and high efficacy in a phase II trial and will be a future therapeutic option at specialized centers. Here, we review the currently available data on the different treatment modalities with a focus on PTLD following solid organ transplantation in adult patients. PMID:23556105

Zimmermann, Heiner

2011-01-01

19

Angioimmunoblastic T cell lymphoma: an unusual presentation of posttransplant lymphoproliferative disorder in a pediatric patient.  

PubMed

Posttransplant lymphoproliferative disorders (PTLD) are a potentially life-threatening complication of immunosuppression in transplant recipients. The majority of cases are Epstein-Barr virus-associated lesions of B cell origin. T cell PTLD is rare, particularly in pediatric patients. We present an unusual case of monomorphic T cell PTLD with features of angioimmunoblastic T cell lymphoma in an 8-year-old heart transplant patient, presenting with cranial nerve palsy. PMID:24157860

Kraus, Teresa S; Twist, Clare J; Tan, Brent T

2014-01-01

20

Cutaneous presentation of plasmablastic post-transplant lymphoproliferative disorder in a 14-month-old.  

PubMed

We present a 14-month-old female child who developed multiple erythematous nodules on her abdomen 5 months after liver and small bowel transplantation. Skin biopsy revealed a dense infiltrate of large cells in the dermal and subcutaneous layers with frequent mitotic figures. The cells were noted to have abundant cytoplasm, prominent nucleoli, and open chromatin. Immunohistochemical stains were positive for CD138, CD56, Ki67 (>90%), and lambda chain restriction. Rare mature B cells (CD20) and rare T cells (CD3) were noted. She was diagnosed with high-grade post-transplant lymphoproliferative disorder most consistent with plasmablastic lymphoma. PMID:20199447

Hernandez, Claudia; Cetner, Aaron S; Wiley, Elizabeth L

2009-01-01

21

Incidence of lymphoproliferative disorders in patients with celiac disease.  

PubMed

Prior studies describe an increased incidence of lymphoma in celiac disease. However, few studies differentiate among lymphoproliferative disorders (LPDs). Our aim was to determine incidences of LPD subtypes in celiac disease patients, describe patterns of celiac disease presentation in patients who develop LPD, and compare survival in patients with various LPD subtypes. We conducted a retrospective cohort study of adults with biopsy-proven celiac disease seen at a US referral center from 1981 to 2010, identified patients with comorbid LPD, and calculated standardized incidence ratios (SIR) for each LPD subtype. In our cohort of 1,285 patients with celiac disease, there were 40 patients with LPD [SIR = 6.48, 95% confidence interval (CI) = 4.62-8.64] including 33 with non-Hodgkin lymphoma (NHL, SIR = 6.91, 95% CI = 4.26-8.28). The incidences of NHL subtypes including enteropathy-associated T-cell (EATL, n = 12), non-EATL T-cell (SIR = 22.43, 95% CI = 7.08-46.41), diffuse large B-cell (SIR = 5.37, 95% CI = 1.93-10.52), mantle cell (SIR = 32.21, 95% CI = 6.07-78.97), and marginal zone (SIR = 37.17, 11.73-76.89) lymphoma remained significantly elevated when only those diagnosed with celiac before LPD were considered (n = 24, NHL SIR = 4.47, 95% CI = 2.86-6.44). Patients who developed LPD were older at time of celiac disease diagnosis (57.9 ± 15.5 versus 42.5 ± 17.4 years, P < 0.0001) and more likely to present with diarrhea (60.0% versus 39.8% P = 0.016), abdominal pain (17.5% versus 5.5% P = 0.0046), and/or weight loss (12.5% versus 4.0%, P = 0.028). EATL patients had a shorter average survival than non-EATL NHL patients (3.2 versus 15.0 years, P = 0.016). The incidence of LPD is increased in celiac disease patients. Those diagnosed later in life who present with symptoms of malabsorption are more likely to be diagnosed with LPD. PMID:22641457

Leslie, Lori A; Lebwohl, Benjamin; Neugut, Alfred I; Gregory Mears, John; Bhagat, Govind; Green, Peter H R

2012-08-01

22

The Seville expert workshop for progress in posttransplant lymphoproliferative disorders.  

PubMed

: Posttransplant lymphoproliferative disorders (PTLDs) are associated with significant morbidity and mortality among solid-organ transplant patients, but approaches to diagnosis and management vary considerably. An international multidisciplinary panel evaluated current understanding of risk factors and classification systems and developed recommendations to aid in PTLD prevention. We considered evidence on PTLD risk factors including Epstein-Barr virus serostatus and immunosuppression and identified knowledge gaps for future research. Recommendations address prophylactic and preemptive strategies to minimize PTLD development, including modulation of immunosuppression and antiviral drug regimens. Finally, new classification criteria were outlined that may help facilitate standardized reporting and improve our understanding of PTLD. PMID:22992767

Glotz, Denis; Chapman, Jeremy R; Dharnidharka, Vikas R; Hanto, Douglas W; Castro, Maria C R; Hirsch, Hans H; Leblond, Véronique; Mehta, Aneesh K; Moulin, Bruno; Pagliuca, Antonio; Pascual, Julio; Rickinson, Alan B; Russo, Francesco P; Trappe, Ralf U; Webster, Angela C; Zuckermann, Andreas O; Gross, Thomas G

2012-10-27

23

Hematopoietic Neoplasias in Horses: Myeloproliferative and Lymphoproliferative Disorders  

PubMed Central

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

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

2010-01-01

24

Incidence of phenotypic aberrations in a series of 467 patients with B chronic lymphoproliferative disorders: basis for the design of specific four-color stainings to be used for minimal residual disease investigation  

Microsoft Academic Search

Multiparameter immunophenotypic analysis of neoplastic cells has proven to be of great help for the investigation of minimal residual disease in acute leukemias; however, its utility has not been systematically explored in B cell chronic lymphoproliferative disorders. The aim of the present study was to investigate the incidence of phenotypic aberrations in a series of 467 consecutive leukemic B cell

ML Sánchez; J Almeida; B Vidriales; MC López-Berges; MA García-Marcos; MJ Moro; A Corrales; MJ Calmuntia; JF San Miguel; A Orfao

2002-01-01

25

Invasive fungal infections in lymphoproliferative disorders: a monocentric retrospective experience.  

PubMed

Invasive fungal infections (IFIs) seem to be a relevant cause of morbidity and mortality in patients with chronic lymphoproliferative disorders. We studied retrospectively the epidemiology, clinical manifestations and outcome of invasive fungal infections in 42 patients with lymphoproliferative diseases, treated between January 2004 and February 2012 for probable or proven IFI. In our entire population (1355 patients) of chronic lymphoproliferative malignancies, the incidence of probable/proven IFI was 3% (molds 2.3%, yeasts 0.5%, mixed infections 0.2%). Eight patients developed a yeast infection documented by blood cultures in seven cases and by the microscopic observation of Candida spp. in the vitreum after vitrectomy in one case. Among molds we diagnosed three proven infections by histologic evidence of Aspergillus spp. (n = 2) and Mucor (n = 1) in the lung and 28 probable mycoses. Three mixed infections from both molds and yeasts were also observed. Twenty-two cases showed positivity of galactomannan antigen in the serum (n = 16), in bronchoalveolar lavage (BAL) fluid (n = 4) or in both (n = 2). Cultures were positive in 11 cases. The overall rate of response to therapy was 64%. Fungal-attributable mortality rate was 17%, with a significant difference between molds and yeasts (16% vs. 25%, p = 0.03). At univariate analysis, the only risk factors related to mortality were severe and prolonged neutropenia (p = 0.003) and age (p = 0.03). Among molds, the rapid start of antifungals was probably partially responsible, together with new drugs, for the reduction of mortality, despite the severe immunosuppression of these patients. PMID:24138328

Nosari, Anna Maria; Pioltelli, Maria Luisa; Riva, Marta; Marbello, Laura; Nichelatti, Michele; Greco, Antonino; Molteni, Alfredo; Vismara, Eleonora; Gabutti, Cristina; Volonterio, Alberto; Lombardi, Pierluigi; Morra, Enrica

2014-08-01

26

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

PubMed

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

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

2011-11-01

27

EBV-positive Mucocutaneous Ulcer in Organ Transplant Recipients: A Localized Indolent Posttransplant Lymphoproliferative Disorder.  

PubMed

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. PMID:25007145

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

2014-11-01

28

Post-transplant lymphoproliferative disorders of oral cavity.  

PubMed

Post-transplant lymphoproliferative disorders (PTLD) are long-term complications of immunosuppression after solid organ/bone marrow transplantation. In most cases, PTLD arises as a result of primary or reactivated Epstein-Barr virus infection in a host with impaired cellular immunity. PTLD is most often seen in the gastrointestinal tract, although it has also been reported in other organ systems, including the central nervous system and, rarely, in the head and neck. It is characterized histologically by abnormal lymphoid cell proliferation. Although many forms of PTLD do not meet all of the histologic criteria of lymphoma, they often behave clinically in a malignant fashion if left untreated. We present 3 rare cases of PTLD manifesting in the oral cavity as mucosal masses after solid organ transplantation. There are only 8 published reports of PTLD in the literature presenting as oral lesions. The clinical, pathologic, and therapeutic spectra of PTLD are discussed. PMID:18442744

Ojha, Junu; Islam, Nadim; Cohen, Donald M; Marshal, David; Reavis, Michael R; Bhattacharyya, Indraneel

2008-05-01

29

Relative adrenal insufficiency in post-transplant lymphoproliferative disorder.  

PubMed

Post-transplant lymphoproliferative disorder is treated with rapid decrement of immunosuppressive therapy. This cannot be achieved with ease in patients on long-term glucocorticoid therapy, as chronically suppressed adrenal glands may not be capable of mounting adequate response to stress. A 52-year-old Caucasian male presented with fever, orthostatic hypotension, lymphadenopathy and hyponatraemia. Serum cortisol levels were within normal levels with a sub optimal response to stimulation by ACTH. Hyponatraemia and orthostasis responded poorly to fluid restriction, saline and salt repletion but corrected after increasing the steroid dose. The normal baseline cortisol levels represented a stimulated adrenal gland, however, the ACTH stimulation had inadequate response. This sub optimal stimulation and a good response to increased steroids suggest the presence of relative or occult adrenal insufficiency. Relative adrenal insufficiency must be considered in patients who have received prolonged glucocorticoid therapy and have symptoms such as hypotension and/or hyponatraemia. PMID:12865574

Cinclair, R D; Rice, J C; Agraharkar, M

2003-01-01

30

EBV-associated lymphoproliferative disorders misdiagnosed as Crohn's disease.  

PubMed

Epstein-Barr virus (EBV) plays an etiological role in various diseases. EBV-associated lymphoproliferative disorder (LPD) is usually observed in individuals with congenital or acquired immune deficiencies but was also recently reported in non-immunocompromised individuals. Two cases of immunocompetent patients with EBV-associated T-cell LPD of the small bowel and colon who were initially misdiagnosed as Crohn's disease (CD) are reported here. EBV-associated T-cell LPD with primary gastrointestinal tract involvement can manifest as multiple discrete ulcers of the small and/or large bowel that are similar to the lesions found in CD or intestinal tuberculosis. However, when patients have multiple intestinal ulcers that are not typical of CD or intestinal tuberculosis and the clinical course is unusual, clinicians should consider the possibility of EBV-associated LPD that involves the gastrointestinal tract because the treatment strategy and prognosis are completely different. PMID:23078910

Na, Hee Kyong; Ye, Byong Duk; Yang, Suk-Kyun; Yang, Dong-Hoon; Jung, Kee Wook; Kim, Kyung Jo; Byeon, Jeong-Sik; Myung, Seung-Jae; Huh, Jooryung; Kim, Jin-Ho

2013-09-01

31

Cladribine and Fludarabine Nucleoside Change the Levels of CD Antigens on B-Lymphoproliferative Disorders  

PubMed Central

The purine analogs, fludarabine nucleoside (FdA), and cladribine (CdA) (1??M, 24 hours), significantly changed the levels of some surface antigens on the human B-cell lines MEC2 and Raji. Changes in the surface proteins were identified using a Cluster of Differentiation (CD) antibody microarray that captures live cells and confirmed by flow cytometry. For Raji cells, CdA up-regulated CD10, CD54, CD80, and CD86, with repression of CD22, while FdA up-regulated CD20, CD54, CD80, CD86 and CD95. For MEC2 cells, CdA up-regulated CD11a, CD20, CD43, CD45, CD52, CD54, CD62L, CD80, CD86, and CD95, but FdA had no effect. Up-regulation of particular CD antigens induced on a B-cell lymphoproliferative disorder by a purine analog could provide targets for therapeutic antibodies with synergistic cell killing. PMID:22084681

Cassano, Carlos; Mactier, Swetlana; Mulligan, Stephen P.; Belov, Larissa; Huang, Pauline; Christopherson, Richard I.

2010-01-01

32

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

Microsoft Academic Search

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

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

2002-01-01

33

Rare presentation of post-transplant lymphoproliferative disorder isolated to gastroesophageal junction  

PubMed Central

Post transplant lymphoproliferative disorder (PTLD) represents a life threatening disorder occurring after transplantation, ranging from a polyclonal mononucleosis like illness to a monomorphic high grade neoplasm with cytologic and histopathologic evidence indicative of transformation to lymphoma. PTLD of diffuse large B-cell lymphoma (DLBCL) subtype, isolated to the esophagus is a rare diagnosis. We describe the first case of an immunocompromised adult patient diagnosed with DLBCL-PTLD limited to his esophagus without an associated mass or locoregional lymphadenopathy on imaging since the institution of the revised Cheson criteria, which includes positron emission tomography-computed tomography as the standard staging modality. Even more unique to our case was the suggestion of underlying cytomegalovirus (CMV) gastritis leading to a hypothesis about a less well understood relationship between CMV and Epstein Barr virus (EBV). In the post transplant setting, immunocompromised state, or EBV positive state, upper gastrointestinal symptoms should prompt investigation with an upper endoscopy (EGD). Additionally, specific to our case, the fact that the patients’ presentation was suspicious for CMV gastritis raises the possibility that the CMV infection predated his PTLD increasing his risk of acquiring PTLD. This reemphasizes the importance and diagnostic utility of early screening with EGD in patients after transplantation. PMID:24363831

Haverkos, Brad M; Oza, Veeral M; Johnson, Andrea; Walker, Jon; Shana'ah, Arwa

2013-01-01

34

Gamma heavy-chain disease: defining the spectrum of associated lymphoproliferative disorders through analysis of 13 cases.  

PubMed

Gamma heavy-chain disease (gHCD) is defined as a lymphoplasmacytic neoplasm that produces an abnormally truncated immunoglobulin gamma heavy-chain protein that lacks associated light chains. There is scant information in the literature regarding the morphologic findings in this rare disorder, but cases have often been reported to resemble lymphoplasmacytic lymphoma (LPL). To clarify the spectrum of lymphoproliferative disorders that may be associated with gHCD, this study reports the clinical, morphologic, and phenotypic findings in 13 cases of gHCD involving lymph nodes (n=7), spleen (n=2), bone marrow (n=8), or other extranodal tissue biopsies (n=3). Clinically, patients showed a female predominance (85%) with frequent occurrence of autoimmune disease (69%). Histologically, 8 cases (61%) contained a morphologically similar neoplasm of small lymphocytes, plasmacytoid lymphocytes, and plasma cells that was difficult to classify with certainty, whereas the remaining 5 cases (39%) showed the typical features of one of several other well-defined entities in the 2008 WHO classification. This report demonstrates that gHCD is associated with a variety of underlying lymphoproliferative disorders but most often shows features that overlap with cases previously reported as "vaguely nodular, polymorphous" LPL. These findings also provide practical guidance for the routine evaluation of small B-cell neoplasms with plasmacytic differentiation that could represent a heavy-chain disease and give suggestions for an improved approach to the WHO classification of gHCD. PMID:22301495

Bieliauskas, Shannon; Tubbs, Raymond R; Bacon, Chris M; Eshoa, Camellia; Foucar, Kathryn; Gibson, Sarah E; Kroft, Steven H; Sohani, Aliyah R; Swerdlow, Steven H; Cook, James R

2012-04-01

35

Gamma Heavy-chain Disease: Defining the Spectrum of Associated Lymphoproliferative Disorders Through Analysis of 13 Cases  

PubMed Central

Gamma heavy-chain disease (gHCD) is defined as a lymphoplasmacytic neoplasm that produces an abnormally truncated immunoglobulin gamma heavy-chain protein that lacks associated light chains. There is scant information in the literature regarding the morphologic findings in this rare disorder, but cases have often been reported to resemble lymphoplasmacytic lymphoma (LPL). To clarify the spectrum of lymphoproliferative disorders that may be associated with gHCD, this study reports the clinical, morphologic, and phenotypic findings in 13 cases of gHCD involving lymph nodes (n = 7), spleen (n = 2), bone marrow (n = 8), or other extranodal tissue biopsies (n = 3). Clinically, patients showed a female predominance (85%) with frequent occurrence of autoimmune disease (69%). Histologically, 8 cases (61%) contained a morphologically similar neoplasm of small lymphocytes, plasmacytoid lymphocytes, and plasma cells that was difficult to classify with certainty, whereas the remaining 5 cases (39%) showed the typical features of one of several other well-defined entities in the 2008 WHO classification. This report demonstrates that gHCD is associated with a variety of underlying lymphoproliferative disorders but most often shows features that overlap with cases previously reported as “vaguely nodular, polymorphous” LPL. These findings also provide practical guidance for the routine evaluation of small B-cell neoplasms with plasmacytic differentiation that could represent a heavy-chain disease and give suggestions for an improved approach to the WHO classification of gHCD. PMID:22301495

Bieliauskas, Shannon; Tubbs, Raymond R.; Bacon, Chris M.; Eshoa, Camellia; Foucar, Kathryn; Gibson, Sarah E.; Kroft, Steven H.; Sohani, Aliyah R.; Swerdlow, Steven H.; Cook, James R.

2013-01-01

36

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

PubMed

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. PMID:25307322

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

2014-12-01

37

Precursors to Lymphoproliferative Malignancies  

PubMed Central

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

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

2013-01-01

38

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

PubMed

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

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

2014-01-01

39

Proto-oncogene expression in T-cell chronic lymphoproliferative disorders  

SciTech Connect

Experiments were performed to examine expression of proto-oncogenes and other related genes in ten cases of chronic T-cell lymphoproliferative disorders. The helper vs. suppressor nature of the T-cells was determined using monoclonal antibodies. RNA was isolated from peripheral blood mononuclear cells and/or lymph node sections and 5'-end labelled with ..gamma..-/sub 32/P-ATP. RNA preparations were hybridized under stringent conditions to an excess of nitrocellulose-bound specific cloned DNA; autoradiographs were analyzed by microdensitometry. Hybridizations of PHA-activated T-cells to various probes as well as hybridizations of RNA samples to parent plasmid were negative in all experiments. Results revealed increased expression of K-ras, B-lym, transferrin receptor, ..cap alpha..-tubulin and ..cap alpha..-interferon in 5/5 helper T-cell lymphoproliferative disorders, while 5/5 suppressor T-cell disorders demonstrated levels of hybridization to these clones no higher than background. However, studies of T-suppressor disorders demonstrated enhanced levels of ..beta..-interferon-specific RNA in 5/5 patients, an increase not apparent in T-helper chronic lymphoproliferative disorders. There was no correlation of this pattern of gene expression with the aggressive nature of the disease since T-cells from 2/5 suppressor disorders were actively proliferating.

Doerge, M.J.; Hooper, W.C.; Phyliky, R.L.; Witzig, T.E.; Banks, P.M.; Li, C.Y.; Woloschak, G.E.

1986-03-05

40

Primary Involvement of Allografted liver in Post-Transplant Lymphoproliferative Disorders, Report of Two Pediatric Cases and Review of the Literature  

PubMed Central

Post-transplant lymphoproliferative disorder is a lymphocyte proliferating disease, usually of B cell origin, and rarely of T cell. Involvement of liver itself in liver transplant recipients as the primary organ is not common. Herein we report our experience in two patients who primarily presented in the allografted liver, both of whom were promptly diagnosed after liver biopsy and treated successfully .Now after a few months; both of the patients are alive with normal liver function tests and negative imaging studies. PMID:23396650

Geramizadeh, Bita; Nikeghbalian, Sama; Dehghani, Seyed Mohsen; Bahador, Ali; Salahi, Heshmatollah; Malekhosseini, Seyedali

2012-01-01

41

Class III beta-tubulin shows unique expression patterns in a variety of neoplastic and non-neoplastic lymphoproliferative disorders.  

PubMed

Class III beta-tubulin (TUBB3) expression in carcinoma is associated with resistance to tubulin-binding chemotherapeutic agents. Recently, follicular dendritic cells (FDCs) were reported to express TUBB3 under physiologic conditions. We investigated TUBB3 expression in a wide range of lymphoproliferative disorders using immunohistochemistry. Dual immunostaining for Bcl-6 and TUBB3 revealed that some germinal center B cells also express TUBB3 in addition to FDCs. In Hodgkin lymphomas (HLs), 47.1% (40/85) expressed TUBB3 in the tumor cells with an all-or-none pattern. TUBB3 expression in HL was more common in mixed cellularity type than nodular sclerosis type (P=0.032). Among non-HLs, 79.3% (23/29) of anaplastic large cell lymphoma (ALCL), 8% (2/25) of extranodal natural killer/T-cell lymphoma, and 75% (21/28) of Burkitt lymphoma showed TUBB3 expression with an all-or-none pattern. Of diffuse large B-cell lymphoma, 15.2% (32/210) expressed TUBB3 in a heterogeneous pattern. In ALCL, TUBB3 expression was more common in systemic ALCL than in primary cutaneous ALCL (P=0.046). Diffuse large B-cell lymphomas with a germinal center B-like subgroup exhibited TUBB3 expression more frequently than non-GCB-like subgroup (P=0.01). Otherwise, none of the 18 angioimmunoblastic T-cell lymphomas; 18 peripheral T-cell lymphomas, not otherwise specified; 12 follicular lymphomas; 62 marginal zone lymphomas; 7 mantle cell lymphomas; 8 small lymphocytic lymphomas; or 2 FDC sarcomas expressed TUBB3. In angioimmunoblastic T-cell lymphoma and Castleman disease, TUBB3 was positive in immunoblasts corresponding to Epstein-Barr virus-infected or Kaposi sarcoma herpes virus-infected cells. A variety of neoplastic and non-neoplastic lymphoproliferative disorders exhibited characteristic TUBB3 expression patterns; these results suggest potential for diagnostic utility, some insight into the pathobiology of TUBB3 expression, and potential therapeutic implications. PMID:20220512

Yoon, Sun Och; Kim, Wook Youn; Go, Heounjeong; Paik, Jin Ho; Kim, Ji Eun; Kim, Young A; Huh, Joo R; Jeon, Yoon Kyung; Kim, Chul-Woo

2010-05-01

42

Utility and Diagnostic Pitfalls of SOX11 Monoclonal Antibodies in Mantle Cell Lymphoma and Other Lymphoproliferative Disorders.  

PubMed

Mantle cell lymphoma (MCL) is classically characterized by t(11;14) leading to cyclin D1 overexpression. Recently the transcription factor SOX11 has been discovered to be expressed in most MCL, including cyclin D1-negative cases. In this study we assess the performance of 2 commercially available monoclonal antibodies, Atlas Antibodies (Stockholm, Sweden) clone CLO142 and Cell Marque (Rocklin, CA) clone MRQ-58, for SOX11 immunohistochemistry in MCL, both cyclin D1 positive and cyclin D1 negative, as well as in cases of other small B-cell lymphoproliferative disorders, diffuse large B-cell lymphomas (DLBCLs), Burkitt lymphomas, and lymphoblastic leukemia/lymphomas. We also performed Western blots to further characterize the antibody specificity. Both antibodies show reliable, clear nuclear staining in MCL with variable specificity. However, the MRQ-58 antibody was more specific for MCL than CLO142, which showed considerably more nonspecific staining, especially in DLBCLs (59% positive vs. 4% positive with MRQ-58). In addition we reconfirmed the utility of SOX11 IHC for identifying cases of cyclin D1-negative blastoid MCL. However, we also identified cases of SOX11-positive DLBCL and splenic marginal zone lymphoma. Although SOX11 IHC is a powerful, and relatively accessible, tool to identify MCLs with variant immunophenotypes and/or morphology, these latter 2 cases highlight the need for strict criteria for interpreting SOX11 staining. PMID:25229384

Nakashima, Megan O; Durkin, Lisa; Bodo, Juraj; Lin, Jeffrey; Quintanilla-Martinez, Leticia; Fu, Kai; Hsi, Eric D

2014-01-01

43

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

PubMed Central

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

Paydas, Saime; Paydas, Semra; Balal, Mustafa; Ac?kal?n, Arbil; Ergin, Melek; Gurkan, Emel; Baslam?sl?, Fikri

2013-01-01

44

The recognition and classification of lymphoproliferative disorders of the gut.  

PubMed

Gastrointestinal lymphomas can be difficult to diagnose, particularly in small samples, when early in development, or when of unusual types. In this review, we describe lymphoid proliferations in the gastrointestinal tract in a location-based manner, including, mouth, esophagus, stomach, small intestine, and large bowel. For the purpose of differential diagnosis, benign mimics of lymphoma are also described. Lymphoma types that are specifically addressed include plasmablastic, extranodal natural killer/T-cell-nasal type, extranodal marginal zone lymphoma (eg, mucosa-associated lymphoid tissue lymphoma), diffuse large B cell, primary follicular of small intestine, enteropathy-associated T cell, and Burkitt and mantle cell. Immunohistochemical markers useful in the diagnostic approach are elaborated in detail. PMID:24613566

O'Malley, Dennis P; Goldstein, Neal S; Banks, Peter M

2014-05-01

45

Pityriasis lichenoides: A clonal T-cell lymphoproliferative disorder  

Microsoft Academic Search

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

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

2002-01-01

46

Successful treatment of intraocular post-transplant lymphoproliferative disorder with intravenous rituximab.  

PubMed

We reported a rare case of intraocular post-transplant lymphoproliferative disorder (PTLD) arising in a 3-year-old liver transplant recipient who had a prior history of systemic PTLD. The first PTLD entered remission after treatment with intravenous rituximab and withdrawal of immunosuppressants. One year after remission, she presented with granulomatous uveitis and iris nodules in the right eye. Iris biopsy confirmed recurrence of intraocular PTLD, which resolved completely after a second course of intravenous rituximab. Pediatr Blood Cancer 2015;62:169-172. © 2014 Wiley Periodicals, Inc. PMID:25174958

Iu, Lawrence P; Yeung, Jane C; Loong, Florence; Chiang, Alan K

2015-01-01

47

Intralymphatic cutaneous anaplastic large cell lymphoma/lymphomatoid papulosis: expanding the spectrum of CD30-positive lymphoproliferative disorders.  

PubMed

Intravascular large B-cell lymphomas and EBV NK/T-cell lymphomas commonly follow an aggressive clinical course. We recently reported an entirely intravascular anaplastic large cell lymphoma (ALCL) in the skin with a surprisingly indolent clinical course; interestingly, this lymphoma involved the lymphatic rather than the blood vasculature. We hypothesized that intravascular skin-limited ALCL is distinct from aggressive systemic intravascular lymphomas in its intralymphatic localization and clinical course. We now describe 18 cases of cutaneous intravascular large cell lymphoproliferations from 4 institutions. All 12 intravascular large T-cell lesions were intralymphatic; the majority (9) were CD30 T-cell lymphoproliferative disorders (TLPDs), 5 further classified as intravascular ALK ALCL. One ALK ALCL and 2 benign microscopic intravascular T-cell proliferations were also intralymphatic. A single case of otherwise typical cutaneous follicle center lymphoma contained intralymphatic centroblasts. The clinical and pathologic characteristics of the CD30 TLPDs were similar to those of their extravascular counterparts, including extralymphatic dermal involvement in a subset, DUSP22-IRF4 translocations in half of tested ALK ALCLs, and associated mycosis fungoides in 1; most were skin-limited at baseline and remained so at relapse. All 5 cases of intravascular large B-cell lymphoma involved the blood vasculature and behaved in a clinically aggressive manner; the ALK ALCL, although intralymphatic, was systemic and clinically aggressive. We propose that cutaneous ALK ALCL and related CD30 ALK TLPDs involving the lymphatics are part of an expanding spectrum of CD30 TLPDs. The identification of intralymphatic as distinct from blood vascular localization may provide critical prognostic and therapeutic information. PMID:24805854

Samols, Mark A; Su, Albert; Ra, Seong; Cappel, Mark A; Louissant, Abner; Knudson, Ryan A; Ketterling, Rhett P; Said, Jonathan; Binder, Scott; Harris, Nancy Lee; Feldman, Andrew L; Kim, Jinah; Kim, Youn H; Gratzinger, Dita

2014-09-01

48

Targeted Activation of Human V?9V?2-T Cells Controls Epstein-Barr Virus-Induced B Cell Lymphoproliferative Disease.  

PubMed

Epstein-Barr virus-induced lymphoproliferative disease (EBV-LPD) after transplantation remains a serious and life-threatening complication. Herein we showed that the aminobisphosphonate pamidronate-expanded human V?9V?2-T cells efficiently killed EBV-transformed autologous lymphoblastoid B cell lines (EBV-LCL) through ?/?-TCR and NKG2D receptor triggering and Fas and TRAIL engagement. By inoculation of EBV-LCL in Rag2(-/-)?c(-/-) mice and humanized mice, we established lethal EBV-LPD with characteristics close to those of the human disease. Adoptive transfer of pamidronate-expanded V?9V?2-T cells alone effectively prevented EBV-LPD in Rag2(-/-)?c(-/-) mice and induced EBV-LPD regression in EBV(+) tumor-bearing Rag2(-/-)?c(-/-) mice. Pamidronate treatment inhibited EBV-LPD development in humanized mice through selective activation and expansion of V?9V?2-T cells. This study provides proof-of-principle for a therapeutic approach using pamidronate to control EBV-LPD through V?9V?2-T cell targeting. PMID:25220446

Xiang, Zheng; Liu, Yinping; Zheng, Jian; Liu, Ming; Lv, Aizhen; Gao, Yulong; Hu, Huaidong; Lam, Kowk-Tai; Chan, Godfrey Chi-Fung; Yang, Yuanzhong; Chen, Honglin; Tsao, George Sai-Wah; Bonneville, Marc; Lau, Yu-Lung; Tu, Wenwei

2014-10-13

49

Auto-immune lymphoproliferative disorder and other secondary immune thrombocytopenias in childhood.  

PubMed

Primary immune thrombocytopenia (ITP) in childhood, typically presents as an acute self-limiting illness. However, secondary ITP is often a chronic disorder due to an underlying disease. Combined cytopenias in childhood, that is, secondary ITP occurring with auto-immune hemolytic anemia and/or auto-immune neutropenia, are often associated with disorders characterized by immune dysregulation. Such disorders include systemic lupus erythematosus, auto-immune lymphoproliferative syndrome, and common variable immune deficiency. Evans syndrome describes the combination of ITP, autoimmune hemolytic anemia, and/or autoimmune neutropenia. However, it is now clear that some patients with Evans syndrome have an underlying immunodeficiency. This report focuses on combined auto-immune cytopenias and highlights the challenges in their diagnosis and management. PMID:23109501

Price, Victoria

2013-01-01

50

Rituximab is Indispensable for Pediatric Heart Transplant Recipients Developing Post Transplant Lymphoproliferative Disorders  

PubMed Central

Rituximab, an anti-CD20 agent, has been suggested as an effective strategy to deal with post transplant lymphoproliferative disorders (PTLD). In the current study, we aim to evaluate the efficacy of rituximab therapy in heart transplant population developing PTLD. A comprehensive search of the literature was performed to gather the available data on lymphoproliferative disorders occurring in heart transplant patients. Finally, data of 125 patients from 26 previously published studies were included into the study. Patients who underwent rituximab therapy had significantly worse tumoral histopathology features (P-value= 0.003). Survival analyses showed no significant difference regarding receiving rituximab therapy for heart recipients; however, when the analysis was repeated only including data of pediatric patients, significant beneficial effects for pediatric were found for rituximab therapy. In fact, no children undergoing rituximab therapy died during the follow up. In conclusion, this study showed that rituximab therapy in pediatric heart transplant recipients with PTLD represents surprisingly excellent results, making rituximab an indispensable agent in the management of the disease. To define feasibility of rituximab therapy in adult recipients of heart graft with PTLD, randomized controlled trials are needed. PMID:24575284

Karbasi-Afshar, R; Taheri, S

2013-01-01

51

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

PubMed

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

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

52

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

Microsoft Academic Search

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

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

2007-01-01

53

[Identification of splenic marginal zone lymphoma from B lymphoproliferative disorders by flow cytometry].  

PubMed

The splenic marginal zone lymphoma (SMZL) is a relatively rare chronic B lymphoproliferative disease, which primarily manifest increase of peripheral blood lymphocyte count and/or scale, and splenomegaly, while the peripheral superficial lymph nodes are often not swollen. Therefore, the splenectomy are usually needed to confirm the diagnosis, but the majority of patients could not accept such management, resulting in early difficult diagnosis. This study was purposed to explore the more prior way for diagnosis based flow cytometry (FCM). Six patients with suspected diagnosis of SMZL were used as research objects, 10 healthy bone marrow donors and 10 cases of chronic lymphocytic leukemia (CLL), 3 cases of hairy cell leukemia (HCL), 3 cases of lymphatic plasma cell lymphoma/Waldenströ's macroglobulinemia (LPL/WM) were selected as control. The immunophenotype of bone marrow cells were analyzed and compared by FCM using a panel of antibodies including CD45, CD5, CD10, CD19, CD20, CD22, CD23, CD25, CD103, CD11c, CD123, ?,?, Cyclin D1, and combined with bone marrow cell morphology. The results indicated that 6 cases of suspected SMZL showed a large increase of lymphocytes and splenomegaly. Because absence of peripheral lymphadenopathy, 6 patients did not suffer from lymph node biopsy, only 1 patient underwent diagnostic splenectomy. The immunophenotypes of bone marrow in patients and controls were analyzed by FCM, as a result, except for the healthy donors, varying degrees of abnormal mature B cell clones were found in bone marrow of all patients, and the further differentiation from other B-cell tumors was performed through CD5, CD10 expression and combination with other B-cell phenotype. All 6 cases of SMZL patients expressed CD19(+) and CD20(+), but CD10 expression was negative, 4 patients expressed CD5(-), 2 patients expressed CD5(+). The expressions of CD23, CD38, ZAP-70, CD11c, CD103, CD123, Cyclin D1 were negative. The morphological examination of bone marrow cells showed velutinous abnormal lymphocytes. Combined with clinical characteristics, 6 patients were diagnosed as SMZL, 1 patient suffered from splenectomy because of concurrent hypersplenism, and this postoperative pathologic examination confirmed the patient with SMZL. Ten cases of CLL mainly expressed CD5, CD23; 3 cases of HCL had more typical morphology of "hair like" in addition to CD11c, CD103 and CD123 positive; 3 cases of LPL/WM had significantly increased light chain restriction expression, IgM, plasmacytoid lymphocytes. It is concluded that the FCM immunophenotype analysis can be used as a powerful tools for clinical diagnosis of SMZL. PMID:24763004

Hu, Yang; Chen, Yan; Wang, Li-Hua; Chen, Xue; Fang, Fang; Liu, Shi-Qin; Wu, Xue-Qiang; Zhu, Ping

2014-04-01

54

Correlations of hematological parameters with bone marrow findings in chronic lymphoproliferative disorders associated with hepatitis viruses  

PubMed Central

Abstract Background. Hepatitis B and C viruses’ infections are often associated with hematological disorders in evolution, suggesting that these viruses have a tropism for peripheral blood and/or bone marrow cells. Aim. To analyze the hematological parameters and bone marrow findings in a group of patients diagnosed with chronic lymphoproliferative disorders (CLD) and hepatitis viruses B, C, D infections, which were included in the research grant (acronym LIMFO-VIR) between December 2007 and May 2010 in the Hematology Department of the Emergency University Hospital of Bucharest. Methods and results. Patients were diagnosed by using immunopathology according to the WHO criteria. The analyzed group included 42 patients (both sexes), with the mean age of 60,35 years. The most frequent hematologic disease was non-Hodgkin’s lymphoma 30/42 (71,42%), followed by chronic lymphocytic leukemia (16,66%) and Hodgkin’s lymphoma (7,14%). Hepatitis viruses were distributed: 17/42 (40,47%) patients with HBV, 22/42 (52,38%) with HCV and 3/42 (7,14%) had a double/triple association of viruses. Most of the patients had an indolent type of disease - 27/42 (64,28%), whereas 15/42 (35,71%) had an aggressive one, pattern found both in the HBV and HCV infected groups. An abnormal bone marrow result was revealed in 32/42 (76,19%) patients, 19 (59,37%) of them being HCV infected. Myelodysplasia was found in 6/42(14,28%) patients, the majority being HCV infected, all having an indolent form of CLD. The antiviral therapy did not influence the hematological parameters (no significant differences were found between the groups with/without an antiviral therapy). Discussions. Patients with hepatitis virus infections may associate neutropenia and thrombocytopenia; the mechanisms are thought to involve hypersplenism, autoimmune processes and antiviral therapy. We excluded the influence of chemotherapy, as the study was performed before the treatment. In our group, patients whether HBV or HCV infected, presented an isolated cytopenia. The abnormal bone marrow cellularity (increased or decreased) and dysplasia were found especially in the HCV group. There are studies showing no association between myelodysplasia and hepatitis viruses; others found a strong relation of these. One of the mechanisms of myelodysplasia could be a dysregulation of the immune system. Conclusions. Bone marrow/peripheral blood features correlate with the type of viral infection and HCV is more prone to develop additional hematological changes than HBV. The degree of bone marrow involvement by CLDs influences these features. We considered mandatory to perform a bone marrow analysis at the diagnosis of CLDs to stage and to establish if other bone marrow changes were present, a crucial aspect for therapy and outcome of the disease. The association between the hepatitis viruses – myelodysplasia- autoimmunity seems to have a role in the lymphoproliferative disorders etiology. Abbreviations: CLD – chronic lymphoproliferative disorders; NHL- non-Hodgkin’s lymphoma, CLL- chronic lymphocytic leukemia, HL- Hodgkin’s lymphoma, MDS – myelodysplastic syndrome, AML – acute myeloid leukemia PMID:24868264

Ciufu, C; Arama, V; Bumbea, H; Dobrea, C; Ion, I; Vladareanu, AM

2013-01-01

55

[Nodular lymphoid hyperplasia - a rare case of lymphoproliferative disorder of the lungs].  

PubMed

Nodular lymphoid hyperplasia (NLH) belongs to a very rare, mild, lymphoproliferative disease of unestablished aetiology historically included in the group of pseudolymphomas. Its existence was controversial for many years, until modern techniques of pathomorphological diagnosis approved it as a separate entity of lung disease. It manifests in the form of well limited nodules localized in the lungs, which are mostly identified accidentally. Clinical symptoms are rare and nonspecific; the disease usually occupies only one lung. Pathomorphological diagnosis requires immunohistochemical designation of expressions of numerous antigens in order to exclude malignant lymphoma of the lungs. Surgical resection is used in cases of larger nodules; the smaller ones require periodic observation, and the prognosis is good. The authors describe the case of 65-year-old woman with pulmonary nodules which were detected accidentally in the right lung. The patient was qualified for right-sided videothoracoscopy and removal of the lung nodule. In classic HE staining of the histological material, the presence of lymphoid infiltration of the lungs was revealed, which formed lymph follicles with reactive germinal centres. In order to differentiate from the malignant lymphatic expansion, immunohistochemical designations were made, which showed positive expression of CD20 antigen in the B cell zone, positive expression of the CD3 antigen in the T cells zone, positive expression of CD23 antigen in the lymph follicles, negative expression of bcl-2 in the lymph follicles, and positive expression of MIB-1 in the germinal centres of lymph follicles. Such a histopathological and immunohistochemical picture provided the basis for diagnosis of nodular lymphoid hyperplasia of the lung. PMID:23258474

Rogozi?ski, Pawe?; Bruli?ski, Krzysztof; Malinowski, Eugeniusz; Wandzel, Piotr; Kucharzewski, Marek

2013-01-01

56

Comparative analysis of post-transplant lymphoproliferative disorder after kidney transplantation versus hematopoietic stem cell transplantation.  

PubMed

Post-transplant lymphoproliferative disorder (PTLD) is a major complication caused by immune-suppression after transplantation. Survival outcome is known to be poor and the characteristics are not fully understood because of its rare incidence. This single center retrospective study enrolled 41 adult PTLD patients after kidney-transplantation (KT, n = 28) and hematopoietic stem cell transplantation (HSCT, n = 13) from 1992 to 2012. We compared the characteristics and estimated the survival outcomes according to several factors [age-adjusted-IPI (aaIPI), pathologic subtype, viral status, extranodal manifestation] and added some significant parameters to aaIPI scoring system. Post-HSCT-PTLD patients were younger and showed earlier onset, and viral status was more frequently identified. Ten-year OS of the entire group was 44% but the 10-year OS was not significantly different between post-KT-PTLD and post-HSCT-PTLD (39% vs. 56%, P = 0.860). The time onset of PTLD and viral statuses were not meaningful, however, aaIPI, age > 50, extranodal manifestation and monomorphic subtype were predictive for OS. We used those factors for PTLD-specific scoring which showed intermediate-risk (HR = 7.1, P = 0.019) and high-risk (HR = 16.5, P = 0.001) presented worse OS compared to low-risk subgroup. Although the treatment strategies were heterogenous, this study showed comprehensive PTLD data between KT versus HSCT, and our PTLD-specific scoring might be validated by another larger studies. PMID:24684689

Yoon, Jae-Ho; Lee, Seok; Kim, Hee-Je; Lee, Jong-Wook; Min, Woo-Sung; Chung, Byung Ha; Yang, Chul Woo; Kim, Yong-Soo; Kim, Ji-Il; Moon, In Sung; Oh, Eun Ji; Park, Gyeong-Sin; Cho, Seok-Goo

2014-07-01

57

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 Central

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. PMID:24817974

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

58

Renal involvement in myeloproliferative and lymphoproliferative disorders. A study of autopsy cases.  

PubMed

A considerable proportion of cases of myeloproliferative and lymphoproliferative disorders exhibit renal involvement. However, it is unclear whether the cytologic features, immunophenotype or grade of malignancy of the cells infiltrating the kidney differ from those of the primary tumor. This study was performed on 120 autopsy cases with the following diagnoses: acute myelogenous leukemia (AML, n = 22; subtypes M1 + M2, n = 12, subtype M4, n = 10), chronic myelogenous leukemia (CML, n = 7), agnogenic myeloid metaplasia/myelofibrosis (AMM/MF, n = 6), acute lymphocytic leukemia (ALL, n = 6), chronic lymphocytic leukemia (CLL, n = 9), other low-grade non-Hodgkin's lymphomas (low-grade NHL, n = 24), high-grade NHL (n = 21) and multiple myeloma (MM, n = 25). Renal involvement was investigated by light microscopy and immunohistochemistry. It was found in 34% of the cases, and was most common in ALL (83%) and low-grade NHL (50%) and least common in high-grade NHL (10%) and MM (12%). Dense infiltration of almost the entire kidney was most commonly seen in AML, low-grade NHL and ALL. Infiltration was bilateral and involved both the cortex and medulla in the majority of cases. When involvement of other organs was compared with that of the kidney, the lung was found to be involved in approximately the same number of cases, but liver involvement was more common and heart involvement less common. Reactive lymphocytic infiltration of the kidney was found in 18 of the 120 cases (15%), and was distinguished from scanty tumorous infiltration by immunohistochemical staining. No major phenotypical differences were found between the tumor cells infiltrating the kidney and those of the primary tumors in the bone marrow or lymph nodes. However, in one case of CML, the cells infiltrating the kidney were negative for KP1 and chloroacetate esterase, but could be identified by reactivity for CD34. The grade of malignancy in NHL was similar in both the nodal and renal manifestations. PMID:9065578

Xiao, J C; Walz-Mattmüller, R; Ruck, P; Horny, H P; Kaiserling, E

1997-02-01

59

The pathology of posttransplant lymphoproliferative disorders occurring in the setting of cyclosporine A-prednisone immunosuppression.  

PubMed Central

Posttransplant lymphoproliferative disorders (PTLDs) were diagnosed in 43 patients from the Pittsburgh-Denver series between June 1980 and March 1987. This constitutes a detection rate of 1.7%. Major categories of clinical presentation included a mononucleosislike syndrome, gastrointestinal/abdominal disease, and solid organ disease. The median time of onset in patients initially immunosuppressed with cyclosporine-A (CsA)-containing regimens was 4.4 months after transplant, regardless of tumor clonality. A strong association of PTLD with Epstein-Barr virus (EBV) was observed. A histologic spectrum of lesions from polymorphic to monomorphic was observed. Whereas polymorphic lesions could be either clonal or nonclonal, monomorphic lesions appeared to be clonal in composition. The presence of large atypical cells (atypical immunoblasts) or necrosis did not appreciably worsen the prognosis. Twelve patients had clonal, 13 had nonclonal, and five had both clonal and nonclonal tumors. Clonality was indeterminate in 13 cases. Most patients were treated with a regimen based on reduced immunosuppression and supportive surgery. Almost all nonclonal and about half of the clonal lesions respond to this conservative therapy, indicating that it is an appropriate first line of treatment. This behavior suggests that a spectrum of lesions ranging from infectious mononucleosis to malignant lymphoma constitutes the entity known as PTLD. Some monoclonal tumors can undergo regression, however, apparently in response to host immune control mechanisms. Because of its short latency and strong association with EBV, PTLD is an important model for the study of virus-associated tumor progression in humans. Images Figure 1 Figure 2A Figure 2B Figure 3 Figure 4 Figure 5 Figure 6 PMID:2845789

Nalesnik, M. A.; Jaffe, R.; Starzl, T. E.; Demetris, A. J.; Porter, K.; Burnham, J. A.; Makowka, L.; Ho, M.; Locker, J.

1988-01-01

60

Expression of p16/INK4a in Posttransplantation Lymphoproliferative Disorders  

PubMed Central

It was recently demonstrated that classification of posttransplantation lymphoproliferative disorders (PT-LPDs) into morphological and molecular categories is clinically relevant. It was also reported that PT-LPD not associated with Epstein-Barr virus (EBV) had a more aggressive course than most lesions associated with EBV. Because the cyclin-dependent kinase inhibitor p16/INK4a has been reported to be frequently inactivated in high-grade lymphomas, we evaluated 17 PT-LPD to determine whether p16/INK4a expression could be correlated to morphology, EBV detection, and a Ki-67 labeling index. We demonstrated that tumors with no p16/INK4a expression (n = 8) had a predominantly monomorphic appearance, and most were EBV negative (respectively, 7/8 and 5/8), whereas lesions with p16/INK4a expression (n = 9) were mostly polymorphic PT-LPD (6/9) (P = 0.049) and associated with EBV (9/9) (P = 0.015). In particular, strong p16/INK4a expression was observed in atypical immunoblasts and Reed-Sternberg-like cells. Furthermore, the proliferation index was significantly higher in tumors lacking p16/INK4a expression than in other lesions (P = 0.0008). In conclusion, down-regulation of p16/INK4a was mostly observed in PT-LPD lesions known to follow more aggressive courses: monomorphic tumors and EBV-negative PT-neoplasms. Conversely, overexpression of p16/INK4a was associated with EBV-positive PT-LPD. While p16/INK4a might play a role in the proliferative rate of LP-LPD, further investigations are needed to assess the clinical relevance of p16/INK4a expression in predicting the evolution of tumors and to explain how EBV could favor p16/INK4a protein accumulation in lesions. PMID:10793069

Martin, Antoine; Baran-Marzak, Fanny; El Mansouri, Said; Legendre, Christophe; Leblond, Veronique; Charlotte, Frederic; Davi, Frederic; Canioni, Danielle; Raphael, Martine

2000-01-01

61

Diffuse large B-cell lymphoma: A metabolic disorder?  

PubMed Central

Patient Male, 81 Final Diagnosis: Non-Hodgkin lymphoma Symptoms: General weakness • hypoglycemia • metabolic acidosis Medication: — Clinical Procedure: — Specialty: Hematology Objective: Challenging differential diagnosis Background: B cell lymphoma constitutes 80–85% of cases of Non Hodgkin’s lymphoma in the Untied States. Metabolic complications may arise from the disease itself or through its end organ involvement. Case Report: We describe a case of a diffuse large B cell lymphoma diagnosed by abdominal computed tomography after it initially presented as hypoglycemia not correctable by dextrose infusion that instead resulted in increased anion gap metabolic acidosis with elevated lactate levels. Conclusions: The case illustrates how lymphomas can present unusually with hypoglycemia and lactic acidosis, the latter being an ominous sign that can occur without liver involvement. In this regard, the case demonstrates the metabolic sequelae of lymphoma that should raise suspicion for an underlying process. This has implications for diagnosis, treatment, and patient survival. Attention should be paid especially in the primary care setting in order to minimize delays in diagnosis. PMID:24349605

Tanios, Georges; Aranguren, Ines M.; Goldstein, Jack S.; Patel, Chirag B.

2013-01-01

62

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

PubMed

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

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

2014-12-01

63

A possible familial lymphoproliferative disorder in two male siblings of children with recurrent wheezing and lung infections since infancy.  

PubMed

Malignancies that result in wheezing in infants are very uncommon. Given its rarity in children, the diagnosis is challenging, and in the absence of a high index of suspicion, delayed diagnosis is not uncommon. Here we report two male siblings of children who presented with recurrent wheezing and recurrent lung infections since infancy. Both children showed no laboratory evidence of immunodeficiency. Lymphocytic interstitial pneumonia or hypersensitivity pneumonitis was histologically suspected in lung biopsy specimens from the older brother. He subsequently developed Epstein-Barr virus (EBV)-associated hemophagocytic lymphohistiocytosis and died. Based on the family history, we screened mutations among PRF1, Munc13-4, STX11, SH2D1A, and XIAP genes for the younger brother, but did not identify any mutations. He also underwent lung biopsy, which showed interstitial infiltration of lymphoid cells. In situ hybridization for EBV-encoded RNA showed a positive nuclear signal in the lymphoid cells. The presence of clonal B-cell proliferations was detected by clonally rearranged immunoglobulin studies. Lymphomatoid granulomatosis grade 3 was finally diagnosed. The progression of disease was rapid, and the patient died, despite rituximab therapy. The similar clinical manifestations in two male siblings suggest the possibility that a previously undescribed genetic defect contributed to these familial lymphoproliferative malignancies. PMID:24934116

Chen, Shih-Hsiang; Hsia, Shao-Hsuan; Lin, Jainn-Jim; Wong, Kin-Sun; Wang, Chih-Wei; Shih, Lee-Yung; Lee, Wen-I

2014-10-01

64

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

PubMed

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. PMID:24811204

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

2014-10-01

65

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

PubMed Central

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

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

2014-01-01

66

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

ClinicalTrials.gov

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

2013-06-03

67

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

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

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

68

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

Microsoft Academic Search

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

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

1996-01-01

69

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

PubMed Central

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

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

2014-01-01

70

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

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, the time course and similarity of the 2 cases of EBV-PTLD and the effect on day 28 T-cell counts support a relationship between the development of EBV-PTLD and the administration of rabbit ATG. The differences between equine and rabbit ATG are not yet clearly defined, and they should not be considered interchangeable in this regimen without further study. PMID:14506660

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

71

Absence of the V617F JAK2 Mutation in the Lymphoid Compartment in a Patient with Essential Thrombo- cythemia and B-Chronic Lymphocytic Leukemia and in Two Relatives with Lymphoproliferative Disorders  

Microsoft Academic Search

Background: Myeloproliferative neoplasms likely involve both myeloid and lymphoid lineages. Nevertheless, the coincidence of chronic myeloproliferative and lymphoproliferative diseases in the same patient is a rare phenomenon. Methods: We report a case of a patient having essential thrombocythemia (ET) and B-chronic lymphocytic leukemia (B-CLL). In this patient and in 2 relatives with lymphoproliferative disorders, we searched for JAK2V617F mutation in

Caterina Musolino; Alessandro Allegra; Giuseppa Penna; Raffaella Centorrino; Maria Cuzzola; Arianna D’Angelo; Pasquale Iacopino; Andrea Alonci

2009-01-01

72

Immune-mediated disorders causing bleeding or thrombosis in lymphoproliferative diseases.  

PubMed

Bleeding and thrombosis are important complications in patients with malignant lymphomas. They may be due to direct actions of the lymphoma, such as venous compression or bone marrow infiltration, but they may also be caused by paraneoplastic phenomena, which are immune-mediated in most of the cases. The most important paraneoplastic immune-mediated disorders in lymphomas causing bleeding are autoimmune thrombocytopenia, acquired hemophilia A and acquired von Willebrand syndrome. In addition, there are a variety of other less common immune-mediated bleeding conditions, such as acquired thrombasthenia, acquired factor X-, V-, XI-, XII-, or prothrombin deficiency. The presence of antiphospholipid antibodies is a rare condition predisposing to venous and arterial thrombosis and there are other very uncommon conditions, which predispose exclusively to arterial thrombosis such as hyperlipidemic xanthomatosis. Interestingly, there is hardly any correlation between the histological type and the aggressiveness of lymphoma and the type and prevalence of the immune-mediated conditions. Successful treatment of the underlying lymphoma is often associated with definite and sustained resolution of the immune-mediated disorder. PMID:24615692

Lechner, Klaus; Pabinger, Ingrid; Obermeier, Hanna Lena; Knoebl, Paul

2014-04-01

73

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

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

2014-10-20

74

Mapping the x-linked lymphoproliferative syndrome  

SciTech Connect

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.

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

1987-04-01

75

Distinct clonal origins of systemic mastocytosis and associated B-cell lymphoma  

Microsoft Academic Search

Systemic mastocytosis (SM) may rarely be associated with lymphoproliferative disorders. In such cases, the relationship between the neoplastic mast cells and the malignant lymphocytes remains unclear. We describe a patient with indolent SM whose bone marrow showed evidence of low-grade B-cell lymphoma. By detecting the activating KIT mutation D816V in the microdissected bone marrow mast cells, but not in the

Young Kim; Lawrence M. Weiss; Yuan-Yuan Chen; Vinod Pullarkat

2007-01-01

76

Cutaneous B-cell lymphoma: important diagnostic tools.  

PubMed

Primary cutaneous B-cell lymphomas (PCBCL) represent a heterogeneous group of lymphoproliferative disorders characterized by clonal proliferation of neoplastic B-cells in the skin. The recent joint World Health Organization (WHO) and European Organization for the Research and Treatment of Cancer (EORTC) classification recognizes three major subgroups of PCBCL: primary cutaneous follicle center lymphoma (PCFCL), primary cutaneous marginal zone B-cell lymphoma (PCMZL) and primary cutaneous large B-cell lymphoma, leg type (PCLBCL-LT). Recent advances in the field and the availability of new methodological tools have greatly enhanced our insights into the biology of cutaneous B-cell lymphomas and allow a more precise definition of these entities. Considerable progress over the past decade has led to significantly improved diagnostic accuracy allowing earlier diagnosis, targeted strategies and improved therapeutic results in the management of primary cutaneous B-cell lymphomas. This review presents an overview of primary cutaneous B-cell lymphomas with an emphasis on the proper incorporation of current and emerging diagnostic tools into the work-up and classification of this group of unique malignancies. PMID:20461044

Ferenczi, K

2010-06-01

77

Successful treatment of systemic and central nervous system post-transplant lymphoproliferative disorder without the use of high-dose methotrexate or radiation.  

PubMed

Post-transplant lymphoproliferative disorder (PTLD) describes a spectrum of conditions with highest incidence in the first year post-solid organ transplant in pediatric patients. Central nervous system (CNS) involvement with PTLD carries high mortality risk with no consensus on optimal therapeutic regimen. We present the case of a 7-year old heart transplant patient diagnosed with widespread monomorphic, CD20+, Epstein-Barr virus-positive PTLD, including CNS involvement. In addition to immunosuppression reduction and rituximab, she was treated with multiagent systemic and intrathecal chemotherapy. She achieved a prompt and complete clinical and radiologic remission, which has been sustained for over 46 months since diagnosis. Pediatr Blood Cancer 2014;61:2107-2109. © 2014 Wiley Periodicals, Inc. PMID:25066638

Mahapatra, Sidharth; Chin, Clifford C; Iagaru, Andrei; Heerema-McKenney, Amy; Twist, Clare J

2014-11-01

78

Chronic hepatitis C virus infection breaks tolerance and drives polyclonal expansion of autoreactive B cells.  

PubMed

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

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

2012-07-01

79

Constitutive AP-1 Activity and EBV Infection Induce PD-L1 in Hodgkin Lymphomas and Post-transplant Lymphoproliferative Disorders: Implications for Targeted Therapy  

PubMed Central

Purpose Programmed cell death ligand 1 (PD-L1) is a molecule expressed on antigen-presenting cells that engages the PD-1 receptor on T cells and inhibits T-cell receptor signaling. The PD-1 axis can be exploited by tumor cells to dampen host anti-tumor immune responses and foster tumor cell survival. PD-1 blockade has shown promise in multiple malignancies but should be directed towards patients in whom it will be most effective. In recent studies, we found that the chromosome 9p24.1 amplification increased the gene dosage of PD-L1 and its induction by JAK2 in a subset of patients with classical Hodgkin lymphoma (cHL). However, cHLs with normal 9p24.1 copy numbers also expressed detectable PD-L1, prompting analyses of additional PD-L1 regulatory mechanisms. Experimental Design Herein, we utilized immunohistochemical, genomic and functional analyses to define alternative mechanisms of PD-L1 activation in cHL and additional EBV+ lymphoproliferative disorders. Results We identified an AP-1-responsive enhancer in the PD-L1 gene. In cHL Reed Sternberg cells, which exhibit constitutive AP-1 activation, the PD-L1 enhancer binds AP-1 components and increases PD-L1 promoter activity. In addition, we defined EBV infection as an alternative mechanism for PD-L1 induction in cHLs with diploid 9p24.1. PD-L1 was also expressed by EBV-transformed lymphoblastoid cell lines as a result of latent membrane protein 1-mediated, JAK/STAT-dependent promoter and AP-1-associated enhancer activity. In addition, over 70% of EBV+ post-transplant lymphoproliferative disorders expressed detectable PD-L1. Conclusions AP-1 signaling and EBV infection represent alternative mechanisms of PD-L1 induction and extend the spectrum of tumors in which to consider PD-1 blockade. PMID:22271878

Green, Michael R.; Rodig, Scott; Juszczynski, Przemyslaw; Ouyang, Jing; Sinha, Papiya; O'Donnell, Evan; Neuberg, Donna; Shipp, Margaret A.

2012-01-01

80

Antibodies Elicited by Naked DNA Vaccination against the Complementary determining Region 3 Hypervariable Region of Immunoglobulin Heavy Chain Idiotypic Determinants of B-lymphoproliferative Disorders Specifically React with Patients' Tumor Cells 1  

Microsoft Academic Search

Several reports have suggested that the mechanism of protection in- duced by antiidiotypic vaccination against low-grade lymphoproliferative disorders is likely to be antibody mediated. Here we test the hypothesis that DNA vaccination with the short peptide encompassing the comple- mentary-determining region 3 hypervariable region of immunoglobulin heavy chain (VH-CDR3) may elicit a specific antibody immune response able to recognize the

Monica Rinaldi; Francesco Ria; Paola Parrella; Emanuela Signori; Anna Serra; Silvia A. Ciafre; Isabella Vespignani; Marzia Lazzari; Maria Giulia Farace; Giuseppe Saglio; Vito M. Fazio

81

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

ClinicalTrials.gov

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

2014-05-07

82

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

PubMed Central

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

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

2011-01-01

83

Lymphoproliferative lesions of the skin  

PubMed Central

Diagnosis and differential diagnosis of cutaneous lymphoproliferative disorders is one of the most difficult areas in dermatopathology, and biopsies are often taken to rule out a cutaneous lymphoma in patients with “unclear” or “therapy?resistant” skin lesions. Histopathological features alone often enable a given case to be classified to a diagnostic group (eg, epidermotropic lymphomas), but seldom allow a definitive diagnosis to be made. Performing several biopsies from morphologically different lesions is suggested, especially in patients with suspicion of mycosis fungoides. Immunohistochemistry is often crucial for proper classification of the cases, but in some instances is not helpful (eg, early lesions of mycosis fungoides). Although molecular techniques provide new, powerful tools for diagnosing cutaneous lymphoproliferative disorders, results of molecular methods should always be interpreted with the clinicopathological features, keeping in mind the possibility of false positivity and false negativity. In many cases, a definitive diagnosis can be made only on careful correlation of the clinical with the histopathological, immunophenotypical and molecular features. PMID:16873563

Cerroni, L

2006-01-01

84

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

PubMed Central

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

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

2010-01-01

85

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

PubMed

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

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

2014-07-31

86

Quantitative polymerase chain reaction for human herpesvirus diagnosis and measurement of Epstein-Barr virus burden in posttransplant lymphoproliferative disorder  

Microsoft Academic Search

Human herpesviruses can cause acute diseases such as chicken pox or mononucleosis, but also may reactivate during immunosuppression and result in severe or life-threatening illnesses such as shingles or lympho- proliferative disorders. We report the development and validation of a quantitative PCR method to measure viral burden for all eight human herpesviruses (HSV1, HSV2, VZV, EBV, CMV, HHV6, HHV7, and

Xin Bai; Gregory Hosler; Beverly Barton Rogers; D. Brian Dawson; Richard H. Scheuermann

87

Epstein-Barr virus-related reactive lymphoproliferative disorders in middle-aged or elderly patients presenting with atypical features. A clinicopathological study of six cases.  

PubMed

We report six cases of Epstein-Barr virus (EBV)-associated lymphoproliferative disorders (LPDs) in middle-aged and elderly patients exhibiting atypical clinical findings. The patients, two males and four females, ranged in age from 52 to 74 years, with a median age of 64 years. Clinically, they were characterized by tonsillar tumor, cervical lymphadenopathy, and absence of atypical lymphocytosis of the peripheral blood. "B"symptoms were recorded in only two cases. Pancytopenia was recorded in one case during the disease course. The clinical course was self-limited. Histologically, all lesions were characterized by effacement of the follicles and expansion of the interfollicular area with proliferation of small vessels, indicating atypical lymphoid proliferation. In the interfollicular area, there was a mixed infiltrate, including small-to-medium-sized lymphocytes, plasma cells, and T-and B-immunoblasts. Immunoblasts resembling Reed-Sternberg cells were observed in four lesions. Three lesions contained numerous mature plasma cells, plasmacytoid cells, and immature plasma cells in some areas. In situ hybridization demonstrated a varying number of EBV-infected lymphocytes in the interfollicular area. The overall histomorphologic findings of the present six cases were similar to those of infectious mononucleosis (IM) in younger patients. However, the clinical findings were quite different from those of IM in the younger age population. To avoid overdiagnosis and overtreatment, we emphasize the need to be aware of the atypical clinical presentation of EBV-related LPDs in middle-aged or elderly patients, and to turn careful attention to these clinical and laboratory findings as well as to the morphologic features. PMID:17662540

Kojima, Masaru; Kashimura, Makoto; Itoh, Hideaki; Noro, Akihiro; Akikusa, Bunshiro; Iijima, Misa; Shimizu, Kazuhiko; Masawa, Nobuhide; Nakamura, Shigeo

2007-01-01

88

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

PubMed Central

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. PMID:24427369

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

89

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

PubMed

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

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

2013-11-01

90

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

PubMed

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

Pavlovi?, Mirjana D; Jandrli?, Davorka R; Miti?, Nenad S

2014-05-01

91

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

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

2014-01-01

92

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

ClinicalTrials.gov

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 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 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; Splenic Marginal Zone Lymphoma; Waldenström Macroglobulinemia

2014-02-18

93

Monoclonal B cell lymphocytosis and "in situ" lymphoma.  

PubMed

The finding of monoclonal B-cell populations not fulfilling criteria for a lymphoid malignancy has given great impulse to study mechanisms involved in lymphomagenesis and factors responsible for the transition from B-cell precursor states to overt lymphoproliferative disorders. Monoclonal B cell expansions were initially recognized in peripheral blood of otherwise healthy subjects (thus defined monoclonal B-cell lymphocytosis, MBL) and in most cases share the immunophenotypic profile of chronic lymphocytic leukemia (CLL). The clinical relevance of this phenomenon is different according to B-cell count: high-count MBL is considered a preneoplastic condition and progresses to CLL requiring treatment at a rate of 1-2% per year, while low-count MBL, though persisting over time, has not shown a clinical correlation with frank leukemia so far. MBL other than CLL-like represent a minority of cases and are ill-defined entities for which clinical and biological information is still scanty. In situ follicular lymphoma (FL) and mantle cell lymphoma (MCL) are characterized by the localization of atypical lymphoid cells, carrying t(14;18)(q32;q21) or t(11;14)(q13;q32), only in the germinal centers and mantle zones respectively, where their normal counterparts are localized. The localization of these cells indicates that germinal centers or mantle zones provide appropriate microenvironments for cells carrying these oncogenic alterations to survive or proliferate. The progression of these lesions to overt lymphomas occurs rarely and may require the accumulation of additional genetic events. Individuals with these lymphoid proliferations should be managed with caution. PMID:23999128

Karube, Kennosuke; Scarfò, Lydia; Campo, Elias; Ghia, Paolo

2014-02-01

94

Autoimmune Lymphoproliferative Syndrome Misdiagnosed as Hemophagocytic Lymphohistiocytosis  

PubMed Central

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

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

2013-01-01

95

Mycobacterium haemophilum as the Initial Presentation of a B-Cell Lymphoma in a Liver Transplant Patient  

PubMed Central

A 66-year-old woman presented with pustular lesions of her face, trunk, and limbs and an acute arthritis of the knees and elbows. She had a complex medical background and had been on immunosuppressants for three years after a liver transplant. Tissue samples from her skin lesions and synovial fluid showed acid-fast bacilli. Mycobacterium haemophilum, an atypical mycobacteria, was later grown on culture. During her treatment with combination antibiotic therapy, she developed a pronounced generalised lymphadenopathy. Histology showed features of a diffuse B-cell lymphoma, a posttransplant lymphoproliferative disorder (PTLD). PMID:24523979

Doherty, T.; Lynn, M.; Cavazza, A.; Sames, E.; Hughes, R.

2014-01-01

96

Acute Progression of BCR-FGFR1 Induced Murine B-Lympho/Myeloproliferative Disorder Suggests Involvement of Lineages at the Pro-B Cell Stage  

PubMed Central

Constitutive activation of FGFR1, through rearrangement with various dimerization domains, leads to atypical myeloproliferative disorders where, although T cell lymphoma are common, the BCR-FGFR1 chimeric kinase results in CML-like leukemia. As with the human disease, mouse bone marrow transduction/transplantation with BCR-FGFR1 leads to CML-like myeloproliferation as well as B-cell leukemia/lymphoma. The murine disease described in this report is virtually identical to the human disease in that both showed bi-lineage involvement of myeloid and B-cells, splenomegaly, leukocytosis and bone marrow hypercellularity. A CD19+ IgM? CD43+ immunophenotype was seen both in primary tumors and two cell lines derived from these tumors. In all primary tumors, subpopulations of these CD19+ IgM? CD43+ were also either B220+ or B220?, suggesting a block in differentiation at the pro-B cell stage. The B220? phenotype was retained in one of the cell lines while the other was B220+. When the two cell lines were transplanted into syngeneic mice, all animals developed the same B-lymphoblastic leukemia within 2-weeks. Thus, the murine model described here closely mimics the human disease with bilineage myeloid and B-cell leukemia/lymphoma which provides a representative model to investigate therapeutic intervention and a better understanding of the etiology of the disease. PMID:22701616

Sharma, Suash; Cowell, John K.

2012-01-01

97

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

PubMed Central

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

2013-01-01

98

Epstein-Barr Virus-Positive Diffuse Large B-Cell Lymphoma of the Elderly: What We Know So Far  

PubMed Central

Epstein-Barr virus–positive (EBV-positive) diffuse large B-cell lymphoma (DLBCL) of the elderly is a newly described lymphoproliferative disorder recently included as a “provisional” entity in the most current WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. The objective of this review is to provide a thorough and current summary of the existing knowledge of this subtype of DLBCL. We will review and discuss the incidence of EBV expression in DLBCL, the pathogenesis behind EBV-driven malignant transformation of B cells, the different EBV latency patterns associated with DLBCL, the distinct pathologic characteristics of EBV-positive DLBCL, the potential predictive and prognostic value of EBV tumoral status in patients with DLBCL, and potential strategies for the treatment of this rare entity, which is characterized by a suboptimal response to therapy and poor survival rate. PMID:21212426

Beltran, Brady E.; Miranda, Roberto N.; Paydas, Semra; Winer, Eric S.; Butera, James N.

2011-01-01

99

Allogeneic haematopoietic stem-cell transplantation with reduced intensity conditioning for advanced stage Hodgkin's lymphoma in Sweden: high incidence of post transplant lymphoproliferative disorder.  

PubMed

Allogeneic transplantation after reduced intensity conditioning (allo-RIC) is a treatment option for patients with Hodgkin's lymphoma (HL) relapsing after autologous transplantation. In all, 23 adult patients with HL underwent allo-RIC in Sweden between 2000 and 2007. The median number of previous treatment lines was five and 20 patients (87%) were previously autografted. TRM at 100 days and at 1 year was 13 and 22% respectively. Acute GVHD grades II-IV developed in 7 out of 23 patients (30%) and chronic GVHD in 10 out of 20 patients at risk (50%). The OS and EFS at three years was 59 and 27%, respectively. Four patients (17%) developed post transplant lymphoproliferative disease (PTLD) after a median time of 55 days (range 38-95); two of these patients later died. The study confirmed that allo-RIC is feasible, but associated with a substantial relapse rate: only 20% of the patients were still alive 7 years after the transplant. A finding of high incidence of PTLD needs to be confirmed in a larger trial that includes patients with non-HL and CLL. PMID:20956959

Johansson, J E; Remberger, M; Lazarevic, V Lj; Hallböök, H; Wahlin, A; Kimby, E; Juliusson, G; Omar, H; Hägglund, H

2011-06-01

100

Isolated post-transplantation lymphoproliferative disease involving the breast and axilla as peripheral T-cell lymphoma.  

PubMed

Post-transplantation lymphoproliferative disorders (PTLDs) are a heterogeneous group of diseases that represent serious complications following immunosuppressive therapy for solid organ or hematopoietic-cell recipients. In contrast to B-cell PTLD, T-cell PTLD is less frequent and is not usually associated with Epstein Barr Virus infection. Moreover, to our knowledge, isolated T-cell PTLD involving the breast is extremely rare and this condition has never been reported previously in the literature. Herein, we report a rare case of isolated T-cell PTLD of the breast that occurred after a patient had been treated for allogeneic peripheral blood stem cell transplantation due to acute myeloblastic leukemia. PMID:24043963

Hwang, Ji-Young; Cha, Eun Suk; Lee, Jee Eun; Sung, Sun Hee

2013-01-01

101

Primary cutaneous diffuse large B-cell lymphoma (PCDLBCL), leg-type and other: an update on morphology and treatment.  

PubMed

Primary cutaneous B-cell lymphoma (PCBCL) is an heterogeneous group of lymphoproliferative disorders, which account for 25-30% of all primary cutaneous lymphoma and include three main histotypes: 1) primary cutaneous marginal zone B-cell lymphoma (PCMZL); 2) primary cutaneous follicular center cell lymphoma (PCFCL); 3) primary cutaneous diffuse large B-cell lymphoma (DLBCL), leg type (PCDLBCL-LT). PCMZL and PCFCL are indolent lymphomas, with an excellent prognosis despite an high rate of cutaneous recurrences; in contrast, PCDLBCL-LT is clinically more aggressive and usually requires to be treated with multi-agent chemotherapy and anti-CD20 monoclonal antibodies. PCDLBCL-LT histologically consists of large round cells (centroblasts and immunoblasts), is characterized by strong bcl-2 expression, in the absence of t(14;18) translocation, and resembles the activated B-cell type of nodal DLBCL. Recently, the term primary cutaneous DLBCL-other (PCDLBCL-O) has been proposed to include diffuse lymphomas composed of large transformed B-cells that lack the typical features of PCDLBCL-LT and do not conform to the definition of PCFCL. Some clinical studies suggested that such cases have an indolent clinical course and may be treated in a conservative manner; however, data regarding the actual prognosis and clinical behaviour of these peculiar cases are still too limited. The spectrum of primary cutaneous DLBCL also encompasses some rare morphological variants, such as anaplastic or plasmablastic subtypes and T-cell rich B-cell lymphoma, and some recently described, exceedingly rare DLBCL subtypes, such as intravascular large B-cell lymphoma and EBV-associated large B-cell lymphoma of the elderly, which often present in the skin. PMID:23149705

Paulli, M; Lucioni, M; Maffi, A; Croci, G A; Nicola, M; Berti, E

2012-12-01

102

Fc?-receptor IIIA polymorphism p.158F has no negative predictive impact on rituximab therapy with and without sequential chemotherapy in CD20-positive posttransplant lymphoproliferative disorder.  

PubMed

We retrospectively analyzed the p.V158F polymorphism of Fc?-receptor IIIA (FCGR3A, CD16) in patients with PTLD treated with rituximab monotherapy. Previous reports had indicated that the lower affinity F allele affects rituximab-mediated antibody-dependent cellular cytotoxicity (ADCC) and is linked to inferior outcome of rituximab monotherapy in B cell malignancies. 25 patients with PTLD after solid organ transplantation were included in this analysis. They had received 4 weekly doses of rituximab as part of two clinical trials, which had a rituximab monotherapy induction regimen in common. 16/25 patients received further treatment with CHOP-21 after rituximab monotherapy (PTLD-1, NCT01458548). The FCGR3A status was correlated to the response after 4 cycles of rituximab monotherapy. Response to rituximab monotherapy was not affected by F carrier status. This is in contrast to previous findings in B cell malignancies where investigators found a predictive impact of FCGR3A status on outcome to rituximab monotherapy. One explanation for this finding could be that ADCC is impaired in transplant recipients receiving immunosuppression. These results suggest that carrying a FCRG3A F allele does not negatively affect rituximab therapy in immunosuppressed patients. PMID:24741582

Zimmermann, Heiner; Weiland, Theresa; Nourse, Jamie P; Gandhi, Maher K; Reinke, Petra; Neuhaus, Ruth; Karbasiyan, Mohsen; Gärtner, Barbara; Anagnostopoulos, Ioannis; Riess, Hanno; Trappe, Ralf U; Oertel, Stephan

2014-01-01

103

Disorders of B cells and helper T cells in the pathogenesis of the immunoglobulin deficiency of patients with ataxia telangiectasia.  

PubMed Central

The pathogenesis of the immunoglobulin deficiency of 20 patients with ataxia telangiectasia was studied using an in vitro immunoglobulin biosynthesis system. 10 patients had no detectable IgA in their serum as assessed by radial diffusion in agar and 3 had a reduced serum IgA concentration. The peripheral blood mononuclear cells of 17 of the patients and 17 normal controls were cultured with pokeweed mitogen for 12 d and the immunoglobulin in the supernatants measured. The immunoglobulin synthesis was below the lower limit of the normal 95% confidence interval for IgM in 5 patients, for IgG in 8, and for IgA in 14. The mononuclear cells from 9 of the 10 patients with a serum IgA concentration less than 0.1 mg/ml failed to synthesize IgA in vitro. None of the patients manifested excessive suppressor cell activity. All patients had reduced but measurable helper T cell activity for immunoglobulin synthesis by co-cultured normal pokeweed mitogen-stimulated B cells (geometric mean 22% of normal). Furthermore, the addition of normal irradiated T cells to patient peripheral blood mononuclear cells led to an augmentation of IgM synthesis in 15 of 17 and to increased IgG synthesis in 9 of the 17 patients studied, including 9 of the 12 patients who had synthesized IgG before the addition of the irradiated T cells. In addition, IgA synthesis was increased in all eight patients examined that had serum IgA concentrations greater than 0.1 mg/ml. These studies suggest that a helper T cell defect contributes to the diminished immunoglobulin synthesis. However, a helper T cell defect does not appear to be the sole cause since there was no IgA synthesis by the peripheral blood mononuclear cells of 9 of the 10 patients with a profoundly reduced serum IgA even when co-cultured with normal T cells. Furthermore, the cells of the nine patients with profoundly reduced IgA levels examined also failed to produce IgA when stimulated with the relatively helper T cell-independent polyclonal activators, Nocardia water soluble mitogen or Epstein-Barr virus. Taken together these data support the view that the reduced immunoglobulin synthesis of these patients is due to defects of both B cells and helper T cells. Such a broad defect in lymphocyte maturation taken in conjunction with our demonstration of persistent alpha fetoprotein production by ataxia telangiectasia patients provides support for the proposal that these patients exhibit a generalized defect in tissue differentiation. PMID:6822665

Waldmann, T A; Broder, S; Goldman, C K; Frost, K; Korsmeyer, S J; Medici, M A

1983-01-01

104

Hairy cell leukemia: A B-lymphocytic disorder derived from splenic marginal zone lymphocytes?  

Microsoft Academic Search

Although there is increasing evidence that the majority of cases of hairy cell leukemia represent B-lymphoproliferative disorders, the exact subset of B-cells from which hairy cells are derived, is still unclear. On the basis of results obtained in previous studies, and data collected from the literature, it is suggested that B-lymphocytes normally residing in the marginal zone of the splenic

J. J. van den Oord; C. de Wolf-Peeters; V. J. Desmet

1985-01-01

105

B-cell lymphoma in a patient with complete interferon gamma receptor 1 deficiency  

PubMed Central

Immunosuppression-associated lymphoproliferative disorders can be related to primary as well as acquired immune disorders. Interferon gamma receptor (IFN-?R) deficiency is a rare primary immune disorder, characterized by increased susceptibility to mycobacterial infections. Here we report the first case of an Epstein Barr Virus (EBV) related B-cell lymphoma in a patient with complete IFN-?R1 deficiency. The patient was a 20-year-old man with homozygous 22Cdel in IFNGR1 resulting in complete absence of IFN-?R1 surface expression and complete lack of responsiveness to IFN-? in vitro. He had disseminated refractory Mycobacterium avium complex and Mycobacterium abscessus infections. At age 18 he presented with new spiking fever and weight loss that was due to an EBV-positive B-cell non-Hodgkin lymphoma. Two years later he died of progressive lymphoma. IFN-? plays an important role in tumor protection and rejection. Patients with IFN-?R deficiencies and other immune deficits predisposing to mycobacterial disease seem to have an increased risk of malignancies, especially those related to viral infections. As more of these patients survive their early infections, cancer awareness and tumor surveillance may need to become a more routine part of management. PMID:23800860

Bax, Hannelore I.; Freeman, Alexandra F.; Anderson, Victoria L.; Vesterhus, Per; Laerum, Dan; Pittaluga, Stefania; Wilson, Wyndham H.; Holland, Steven M.

2013-01-01

106

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

PubMed Central

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

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

2014-01-01

107

Immunodeficiency syndromes. X-linked agammaglobulinemia, common variable immunodeficiency, Chédiak-Higashi syndrome, Wiskott-Aldrich syndrome, and X-linked lymphoproliferative disorder.  

PubMed

The incidence and mortality of neoplasia in patients with primary immunodeficiencies exceed the anticipated rates in the normal population by approximately 100 to 300 times. Lymphoreticular malignancies account for the majority of tumors, although solid tumors, especially gastric carcinoma, occur with increased frequency as well. More than half of these neoplasms are diagnosed by ten years of age, except in patients with a later age of onset of immunodeficiency. Five primary immunodeficiency disorders with an increased risk of neoplasia are reviewed. PMID:7712652

Paller, A S

1995-01-01

108

Necrotic, ulcerative bronchitis, the presenting feature of lymphoproliferative disease following heart-lung transplantation.  

PubMed Central

Following heart-lung transplantation two of 21 patients who survived more than 100 days developed post-transplant lymphoproliferative disease. Both presented with localised ulcerative bronchitis documented at flexible bronchoscopy four months after transplantation. Histological examination showed necrosis with acute inflammation and ulceration. Case 2 demonstrated lymphoproliferative disease from biopsies subsequently taken at rigid bronchoscopy. Case 1 later developed lung nodules and a monoclonal high grade B cell non-Hodgkin's lymphoma was confirmed by an open lung biopsy. The bronchoscopic features described should alert clinicians to post-transplant lymphoproliferative disease as an underlying diagnosis and suggest that bronchus associated lymphoid tissue is the initial site for clonal proliferation in the disease. Images PMID:7701465

Egan, J. J.; Hasleton, P. S.; Yonan, N.; Rahman, A. N.; Deiraniya, A. K.; Carroll, K. B.; Woodcock, A. A.

1995-01-01

109

HHV8-positive, EBV-positive Hodgkin lymphoma-like large B-cell lymphoma and HHV8-positive intravascular large B-cell lymphoma.  

PubMed

Human herpesvirus type 8 (HHV8), also known as Kaposi's sarcoma-associated herpesvirus, is a human gamma herpesvirus that underlies the pathogenesis of Kaposi's sarcoma, primary effusion lymphoma and multicentric Castleman's disease. We recently encountered two cases of HHV8-positive large B-cell lymphoma with features not previously described. The first patient was a 61-year-old immunocompetent man with an enlarged cervical lymph node containing scattered large, bizarre cells in a reactive background of lymphocytes, plasma cells and scattered regressed follicles resembling those of hyaline-vascular Castleman's disease. The appearance suggested classical Hodgkin's lymphoma, but the large cells were negative for CD15, CD30, CD20 and CD3, and positive for MUM1/IRF4, EMA, HHV8, EBER and dim IgM lambda. The second patient was a 59-year-old HIV-positive man who died after several weeks of fever, night sweats, anemia, thrombocytopenia, hepatosplenomegaly and multiorgan failure. At autopsy an intravascular large B-cell lymphoma that was positive for MUM1/IRF4, HHV8 and IgM lambda, and negative for CD20 and EBER involved multiple organs, including lung, heart, kidney, liver and spleen. On the basis of the histologic features in these two cases, the presence of HHV8 was unexpected. These cases expand the spectrum of lymphoproliferative disorders that can be associated with HHV8. PMID:19287457

Ferry, Judith A; Sohani, Aliyah R; Longtine, Janina A; Schwartz, Robert A; Harris, Nancy L

2009-05-01

110

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

PubMed Central

By whole-genome and/or Sanger sequencing, we recently identified a somatic mutation (MYD88 L265P) that stimulates nuclear factor ?B 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 ?CT 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

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

111

B cells in autoimmunity  

PubMed Central

B-cell development is tightly regulated, including the induction of B-cell memory and antibody-secreting plasmablasts and plasma cells. In the last decade, we have expanded our understanding of effector functions of B cells as well as their roles in human autoimmune diseases. The current review addresses the role of certain stages of B-cell development as well as plasmablasts/plasma cells in immune regulation under normal and autoimmune conditions with particular emphasis on systemic lupus erythematosus. Based on preclinical and clinical data, B cells have emerged increasingly as both effector cells as well as cells with immunoregulatory potential. PMID:19849820

2009-01-01

112

Frequency of 5'IGH deletions in B-cell chronic lymphocytic leukemia.  

PubMed

In a retrospective analysis of a large group of cases (n=291) with B-cell CLL diagnosis, the various characteristics of IGH aberrations as identified by fluorescence in situ hybridization (FISH) probes were studied. Conventional cytogenetic and FISH studies with the standard panel (13q14, 11q13, 17p13, 12 centromere), and with IGH break-apart probes were done for each case. Abnormal karyotypes were detected with conventional cytogenetics in 29% of cases, and FISH detected abnormalities in 70%. Deletion of 13q14 was the most frequent anomaly, followed by trisomy 12, deletion of 11q, and deletion of 17p. Among the IGH abnormalities detected, translocations with unknown partners (split signals) occurred in only a small group of patients (15%). Instead, deletion of 5'IGH, corresponding to the variable IGH segment (IGH(V)) was the most recurrent aberration, observed in 82% (the second most common finding among our patients). This deletion was associated with good prognostic markers: 13q14 deletion, normal karyotype, and CD38 and ZAP-70 negative expression. Although not exclusive to CLL, the deletion occurred in a high frequency, in contrast to its rarity in other B-cell lymphoproliferative disorders. Longitudinal studies are warranted, to determine when in the disease progression this abnormality is acquired, as a potential early marker, and its impact on the natural history of CLL. PMID:19264231

Quintero-Rivera, Fabiola; Nooraie, Farzad; Rao, P Nagesh

2009-04-01

113

Type II mixed cryoglobulinaemia as an oligo rather than a mono B-cell disorder: evidence from GeneScan and MALDI-TOF analyses  

Microsoft Academic Search

Objective. To identify and characterize rheumatoid factor (RF)-producing B-cells and cryoprecipitate immunoglobulin (Ig) M in hepatitis C virus (HCV)-positive patients. Methods. We purified and characterized, by peptide mass fingerprinting integrated with an NCBI IgBlast data bank search, the IgM component of cryoprecipitate and analysed the VDJ pattern of bone marrow B-cells by gene scan analysis of 17 HCV-positive patients with

V. De Re; S. De Vita; D. Sansonno; D. Gasparotto; M. P. Simula; F. A. Tucci; A. Marzotto; M. Fabris; A. Gloghini; A. Carbone; F. Dammacco; M. Boiocchi

2006-01-01

114

Immune Disorder HSCT Protocol  

ClinicalTrials.gov

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

2014-04-16

115

Expression of Active Protein Kinase B in T Cells Perturbs Both T and B Cell Homeostasis and Promotes Inflammation1  

E-print Network

develop lymphoproliferative disorders with lethal autoimmune disease. This lymphoproliferative/autoimmune. Ohashi,2 * and James R. Woodgett* The molecular mechanisms that contribute to autoimmunity remain poorly defined. While inflammation is considered to be one of the major checkpoints in autoimmune disease

Woodgett, Jim

116

B-cell Lymphoma  

Cancer.gov

B-cell Lymphoma Lymphomas are cancers that arise from lymphoid cells, which are part of the immune system. The World Health Organization currently recognizes about 70 different types of lymphoma and divides them into four major groups: mature B-cell neoplasms,

117

New Potential Therapeutic Approach for the Treatment of B-Cell Malignancies Using Chlorambucil/Hydroxychloroquine-Loaded Anti-CD20 Nanoparticles  

PubMed Central

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

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; Lucafo, Marianna; Mansilla, Eduardo; Garrovo, Chiara; Marin, Gustavo H.; Baj, Gabriele; Gattei, Valter; Pozzato, Gabriele; Nunez, Luis; Macor, Paolo

2013-01-01

118

Cutaneous Manifestations as Presenting Sign of Autoimmune Lymphoproliferative Syndrome in Childhood  

Microsoft Academic Search

Autoimmune lymphoproliferative syndrome is a disorder due to a defect of lymphocyte apoptosis, whose clinical manifestations consist of hyperplasia of lymphoid tissues and autoimmune diseases. We report on a 26-month-old child who presented with frequent eruptions of weals and angioedema without any apparent triggering factor, who subsequently developed an erythematopapular rash with a histological pattern of a lymphoplasmacellular infiltrate. Familial

Luigi Auricchio; Laura Vitiello; Marsilio Adriani; Pasqualina Ferri; Annalisa Chiocchetti; Guido Pettinato; Luigi Racioppi; Luigi Maiuri; Umberto Dianzani; Claudio Pignata

2005-01-01

119

B Cell Maturation  

NSDL National Science Digital Library

This Flash animation shows intracellular and extracellular interactions that illustrate the maturation stages of B cells in the bone marrow. It uses sound and mouse-over identification to help students learn more and retain the information.

American Society For Microbiology;

2003-05-12

120

NK cell-mediated lysis is essential to kill Epstein-Barr virus transformed lymphoblastoid B cells when using rituximab.  

PubMed

Rituximab is a humanized chimeric monoclonal antibody, targeted against the pan B cell marker CD20. It is frequently used to treat a variety of B cell lymphomas and immunosuppression associated lymphoproliferations such as posttransplant lymphoproliferative disorder (PTLD). The response rate of rituximab treatment is 65%, but the exact in vivo mechanism of action is not yet fully understood, although antibody-dependent cell-mediated cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), and direct induction of apoptosis have been suggested as effector mechanism. Rituximab may affect different types of lymphomas through different mechanisms. As lymphoblastoid cell lines (LCLs) are well-established in vitro models of PTLD, we investigated the effect of rituximab on these cells using a custom built automated laser confocal fluorescent microscope. We found that rituximab alone was not effective at inducing cell death of EBV-transformed B cells. The antibody was effective in the complement-mediated CDC. Rituximab could induce NK cell-mediated ADCC but it was more effective in the presence of untreated fresh human plasma compared to heat-inactivated human plasma. Our data suggest that complement-enhanced NK-mediated ADCC is required for effective rituximab mediated killing of EBV-transformed B cells. Determining and monitoring of serum complement levels and in vitro killing efficacy of NK cells of PTLD patients might help to predict resistant cases to rituximab therapy. On the other hand our results suggest a possibility that rituximab should be combined only with cytotoxic drugs that spare NK function when treating PTLD patients. PMID:18834693

Markasz, Laszlo; Vanherberghen, Bruno; Flaberg, Emilie; Otvös, Rita; Stuber, Gyorgy; Gustafsson Jernberg, Asa; Olah, Eva; Skribek, Henriette; Szekely, Laszlo

2009-07-01

121

Epstein-Barr virus-positive diffuse large B-cell lymphoma of the elderly complicated by the onset of acute myeloid leukemia.  

PubMed

We herein describe the case of a 62-year-old woman who presented with anemia and an 8-month history of weight loss. Bone marrow aspiration showed increased myeloblasts. The histopathology findings of biopsy specimens of the right cervical lymph node and intestinal mass indicated B-lymphoproliferative disorder (B-LPD) with Hodgkin lymphoma-like morphologic features and polymorphous diffuse large B-cell lymphoma (DLBCL), respectively. In addition, both types of lymphoma cells were positive for Epstein-Barr virus (EBV)-encoded small RNA-1. The patient was diagnosed with EBV-associated B-LPD and simultaneous acute myeloid leukemia (AML). This is the first case of a patient diagnosed with simultaneous EBV-positive DLBCL of the elderly and AML. PMID:24390529

Kunitomi, Akane; Kotani, Shinichi; Ukyo, Naoya; Ono, Kazuo; Nakamine, Hirokazu; Nohgawa, Masaharu

2014-01-01

122

Lymphadenitis and lymphoproliferative lesions associated with the human herpes virus-6 (HHV-6)  

Microsoft Academic Search

Summary  A newly described herpes virus, human herpes virus 6, (HHV-6), has been linked to exanthema subitum but beyond this its pathogenetic\\u000a impact remains to be determined. A large body of evidence links it to various lymphoproliferative disorders and this study\\u000a was conducted to identify forms of lymphoproliferation linked to HHV-6. We studied biopsy samples from 32 patients with disorders\\u000a of

Bettina Borisch; Klaus Ellinger; Frank Neipel; Bernhard Fleckenstein; Thomas Kirchner; Maria Michaela Ott; Hans Konrad Miiller-Hermelink

1992-01-01

123

Syk Activation of Phosphatidylinositol 3-Kinase/Akt Prevents HtrA2-dependent Loss of X-linked Inhibitor of Apoptosis Protein (XIAP) to Promote Survival of Epstein-Barr Virus+ (EBV+) B Cell Lymphomas*  

PubMed Central

B cell lymphoma survival requires tonic or ligand-independent signals through activation of Syk by the B cell receptor. The Epstein-Barr virus (EBV) protein latent membrane 2a (LMP2a), a mimic of the B cell receptor, provides constitutive survival signals for latently infected cells through Syk activation; however, the precise downstream mechanisms coordinating this survival response in EBV+ B cell lymphomas remain to be elucidated. Herein, we assess the mechanism of Syk survival signaling in EBV+ B cell lymphomas from post-transplant lymphoproliferative disorder (PTLD) to discover virally controlled therapeutic targets involved in lymphomagenesis and tumor progression. Using small molecule inhibition and siRNA strategies, we show that Syk inhibition reduces proliferation and induces apoptosis of PTLD-derived EBV+ B cell lines. Syk inhibition also reduces autocrine IL-10 production. Although Syk inhibition attenuates signaling through both the PI3K/Akt and Erk pathways, only PI3K/Akt inhibition causes apoptosis of PTLD-derived cell lines. Loss of the endogenous caspase inhibitor XIAP is observed after Syk or PI3K/Akt inhibition. The loss of XIAP and apoptosis that results from Syk or PI3K/Akt inhibition is reversed by inhibition of the mitochondrial protease HtrA2. Thus, Syk drives EBV+ B cell lymphoma survival through PI3K/Akt activation, which prevents the HtrA2-dependent loss of XIAP. Syk, Akt, and XIAP antagonists may present potential new therapeutic strategies for PTLD through targeting of EBV-driven survival signals. PMID:21908615

Hatton, Olivia; Phillips, Lori K.; Vaysberg, Maria; Hurwich, Jordan; Krams, Sheri M.; Martinez, Olivia M.

2011-01-01

124

Reversing B cell aging  

PubMed Central

Age-related alterations in the cellular composition of the B lineage are a major cause of the poor antibody response to vaccination and to infectious agents among the elderly population. The mechanisms leading to these changes are poorly understood. Recently, we have shown that these changes reflect, at least in part, homeostatic pressures imposed by long-lived B cells that accumulate with aging, and that aging in the B lineage can be reversed upon alteration of B cell homeostasis by depletion. Here we discuss homeostatic causes for B lineage immunosenescence, and the potential for its rejuvenation. PMID:21483035

Mehr, Ramit; Melamed, Doron

2011-01-01

125

Regulatory T Cells in B Cell Follicles  

PubMed Central

Understanding germinal center reactions is crucial not only for the design of effective vaccines against infectious agents and malignant cells but also for the development of therapeutic intervention for the treatment of antibody-mediated immune disorders. Recent advances in this field have revealed specialized subsets of T cells necessary for the control of B cell responses in the follicle. These cells include follicular regulatory T cells and Qa-1-restricted cluster of differentiation (CD)8+ regulatory T cells. In this review, we discuss the current knowledge related to the role of regulatory T cells in the B cell follicle.

Chang, Jae-Hoon

2014-01-01

126

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

Microsoft Academic Search

BACKGROUND: Autoimmune lymphoproliferative syndrome (ALPS) is a rare inherited disorder characterized by defective function of Fas, autoimmune manifestations that predominantly involve blood cells, polyclonal accumulation of lymphocytes in the spleen and lymph nodes with lymphoadenomegaly and\\/or splenomegaly, and expansion of TCR??+ CD4\\/CD8 double-negative (DN) T cells in the peripheral blood. Most frequently, it is due to Fas gene mutations, causing

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

2007-01-01

127

Burkitt’s lymphoma variant of post-transplant lymphoproliferative disease (PTLD)  

Microsoft Academic Search

The occurrence of posttransplant lymphoproliferative disorder (PTLD) in solid organ allograft recipients can be quite varied\\u000a in clinical presentation, histopathological characteristics and frequency. A variety of lymphomas can develop as a PTLD although\\u000a some types appear infrequently and remain poorly understood in this clinical setting. In this report, we describe two cases\\u000a of Burkitt’s lymphoma presenting as a PTLD following

Melissa A. Pasquale; Debbie Weppler; Jon Smith; Michael Icardi; Alexandra Amador; Monica Gonzalez; Tomoaki Kato; Andreas Tzakis; Phillip Ruiz

2002-01-01

128

Ibrutinib for B cell malignancies  

PubMed Central

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

2014-01-01

129

Analysis of the cells involved in the lymphoproliferative response to Coxiella burnetii antigens.  

PubMed Central

Vaccination with an inactivated, whole cell, Q fever vaccine (Q-vax) induces lasting antibody conversion and a positive delayed-type hypersensitivity (DTH) skin reaction in about 60% of recipients but a long-lasting positive lymphoproliferative or mitogenic response to C. burnetii antigens with peripheral blood mononuclear cells (PBMC) in 85-95% of subjects. Analysis of the lymphoproliferative response to C. burnetii antigens has now been made by fractionation-reconstitution experiments with PBMC from vaccines, from past infections, and from healthy controls. The major contributor to the response in immune subjects proved to be the T lymphocyte. T cells were stimulated by both the phase I and phase II antigens of two prototype strains of C. burnetii and responses were greatly amplified by addition of IL-2. Similar T lymphocyte stimulation profiles were obtained with the 'Priscilla' strain of C. burnetii which represents a different biotype of Coxiella isolated from Q fever endocarditis; Q-vax is therefore likely to protect against endocarditis strains. Fractionation-reconstitution experiments with T and B cells from vaccines and subjects infected in the past, using various antigenic or haptenic fractions from C. burnetii indicate that protein, non-lipopolysaccharide components of the organism are responsible for the mitogenic response of immune T cells. However, the role of the lipopolysaccharide in the protective immunogen has still to be defined. PMID:2070564

Izzo, A A; Marmion, B P; Hackstadt, T

1991-01-01

130

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

PubMed

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 (??=?0.92; P?B-cells (??=?-0.02; P?=?0.89), whole blood and plasma (??=?0.24; P?=?0.24), or enriched B-cells and plasma (??=?0.08; P?=?0.77). Testing of enriched B-cells appeared to be the most sensitive method for detection of EBV DNA as well as for exploration of the cellular reservoir. Quantitation of EBV DNA in plasma and B-cell culture supernatant may be of interest to assess EBV reactivation dynamics and response to treatment as well as to decipher EBV host-pathogen interactions in various clinical scenarios. PMID:24265067

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

131

Evidence for immunoglobulin heavy chain variable region gene replacement in a patient with B cell chronic lymphocytic leukemia.  

PubMed

Immunoglobulin heavy chain variable (V) gene replacement is an unusual recombinatorial event characterized by rearrangement of a germline V gene to a preformed VDJ gene complex. This phenomenon has occasionally been implicated in the emergence of clonal subpopulations during the course of acute lymphoblastic leukemia; it has also been found in murine precursor B cell lines. V gene replacement has never been described in lymphoproliferative disorders corresponding to more differentiated stages of B cell ontogeny. The present communication provides evidence for the operation of the same mechanism in B cell chronic lymphocytic leukemia (B-CLL). Genomic DNA and total cellular RNA extracted from peripheral blood mononuclear cells of a 48-year-old female patient diagnosed as having typical B-CLL were subjected to polymerase chain reaction (PCR) amplification aiming to detect rearranged clonal heavy and light chain variable genes (VH and VL, respectively). PCR consistently gave two VH amplification products, both at the DNA and the RNA level; similar analysis for the VL region revealed the presence of a single rearranged VK gene. Direct sequence analysis of the PCR products revealed that, except for a number of silent mutations, the single rearranged VK gene was identical to the germline A1-A17 VK gene. The two rearranged VH gene segments belong to the VHl and VHIII gene families and are closely homologous, respectively, to the germline gene segments V1-18 and V3-30, which have been shown to be used by autoantibodies. Both rearranged VH genes showed identical in-frame D-N-JH junctions and JH gene usage (JH5b), whereas the VH-N-D junctions were different. The above findings indicate that, during the course of the disease of our patient, VH gene replacement took place giving rise to two different clonally related subpopulations. This raises the intriguing possibility that the recombinase machinery, which governs Ig recombinatorial processes, might be operative even at more advanced stages in B cell ontogeny. PMID:8751479

Stamatopoulos, K; Kosmas, C; Stavroyianni, N; Loukopoulos, D

1996-09-01

132

EBV and posttransplantation lymphoproliferative disease: what to do?  

PubMed

This review summarizes the available evidence and outlines our approach to the prophylaxis and management of posttransplantation lymphoproliferative disorder (PTLD) in adult solid organ transplantation recipients. We attempt to reduce immunosuppression as tolerated in every patient with suspected PTLD in close cooperation with their transplantation physician. There is no evidence to guide the decision when to initiate further treatment; we usually wait no longer than 4 weeks and always initiate further therapy unless there is a complete or at least good partial remission. If clinical and histological findings indicate rapidly progressive disease, we initiate additional therapy significantly earlier. CD20-positive PTLD accounts for approximately 75% of PTLD cases. Outside of clinical trials, we currently regard sequential therapy with rituximab and CHOP (cyclophosphamide, hydroxydaunorubicin, vincristine, prednisone/prednisolone) chemotherapy as standard evidence-based treatment for CD20-positive PTLD unresponsive to immunosuppression. We also discuss our approach to the rare instance of adults with PTLD associated with primary EBV infection, localized (stage I) disease, rare PTLD subtypes, and refractory/relapsed disease based on the available retrospective data and our own experience. In addition to immunotherapy and chemotherapy, this includes local therapy approaches such as surgery and radiotherapy in stage I disease, plasmacytoma-like PTLD, and primary CNS PTLD. We also provide our view on the current indications for the use of allogeneic cytotoxic T cells, even though this treatment modality is so far unavailable in our clinical practice. PMID:24319169

Zimmermann, Heiner; Trappe, Ralf U

2013-01-01

133

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

PubMed Central

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

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

2011-01-01

134

Evolution of B Cell Immunity  

PubMed Central

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

Sunyer, J. Oriol

2013-01-01

135

B Cell Superantigens Subvert Innate Functions of B Cells  

Microsoft Academic Search

Some infectious agents produce molecules capable of interacting specifically with the immunoglobulin variable regions, independently of the conventional binding site. They are referred to as B cell superantigens, and include protein A of Staphylococcus aureus, protein L of Peptostreptococcus magnus, and gp120 of HIV-1. To test their effects in vivo, we used transgenic mice whose immunoglobulin loci were inactivated and

M. Zouali

2007-01-01

136

B cell targets in rheumatoid arthritis  

Microsoft Academic Search

B cells are critical to the pathogenesis of rheumatoid arthritis (RA). There is substantial evidence of the efficacy of depletion\\u000a of B cells in many patients with RA using the first licensed agent, rituximab. Recent research has focused on enhancing efficacy\\u000a using other targets to inhibit B cell function, including other B cell-depleting antibodies and cytokines critical to B cell

Edward M. Vital; Shouvik Dass; Paul Emery

137

CD20+ B cell depletion alters T cell homing.  

PubMed

Depleting mAbs against the pan B cell marker CD20 are remarkably effective in the treatment of autoimmune-mediated inflammatory disorders, but the underlying mechanisms are poorly defined. The primary objective of this study was to find a mechanistic explanation for the remarkable clinical effect of the anti-CD20 mAbs in a representative nonhuman primate autoimmune-mediated inflammatory disorder model, experimental autoimmune encephalomyelitis (EAE) in common marmosets, allowing detailed analysis of secondary lymphoid organs (SLO). We observed that the depletion of CD20(+) B cells creates a less immunostimulatory environment in the SLO reflected by reduced expression of MHC class II, CD40, CD83, and CD80/CD86. APCs isolated from SLO of B cell-depleted EAE monkeys were also less responsive to mitogenic stimulation. The depleted B cell areas were replenished by T cells, of which the majority expressed CD127 (IL-7R) and CCR7. Such effects were not detected in EAE marmosets treated with mAb against BLyS or APRIL, where B cell depletion via withdrawal of essential survival cytokines was not associated with a marked clinical effect. We propose that at least part of the efficacy of anti-CD20 mAb therapy is attributable to the sustained CCR7 expression on T cells within SLO, limiting their release into the circulation. PMID:24696233

Kap, Yolanda S; van Driel, Nikki; Laman, Jon D; Tak, Paul P; 't Hart, Bert A

2014-05-01

138

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

Microsoft Academic Search

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

Arne Hansen; Peter E Lipsky; Thomas Dörner

2007-01-01

139

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

PubMed

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

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

2012-12-01

140

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

PubMed

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

Shain, K H; Tao, J

2014-08-01

141

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

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

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

2014-01-01

142

Common variable immune deficiency (CVID) presenting as an autoimmune disease: role of memory B cells  

Microsoft Academic Search

Common variable immunodeficiency (CVID) is a clinically heterogeneous disorder. Most often patients present with recurrent sinopulmonary infections, although it may present with autoimmune manifestations. Immune cytopenias, particularly thrombocytopenia and hemolytic anemia, are the most commonly observed. While the pathophysiology of CVID remains elusive, in many patients it may be due to an intrinsic B cell defect. Memory B cells (CD27+)

Bret R. Haymore; Cecilia P. Mikita; George C. Tsokos

2008-01-01

143

Tyrosine Residues in Phospholipase C 2 Essential for the Enzyme Function in B-cell Signaling*  

E-print Network

(such as B- and T-cell antigen receptors) that are linked to the activation of nonreceptor tyrosine and signaling disorders in a subset of cell types including B-cells, platelets, and mast cells (7Tyrosine Residues in Phospholipase C 2 Essential for the Enzyme Function in B-cell Signaling

Williams, Roger L.

144

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

PubMed Central

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

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

2010-01-01

145

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

PubMed Central

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

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

2012-01-01

146

Lipid rafts and B-cell activation  

Microsoft Academic Search

The B-cell antigen receptor acts during B-cell activation both to initiate signalling cascades and to transport antigen into the cell for subsequent processing and presentation. Recent evidence indicates that membrane microdomains, termed lipid rafts, have a role in B-cell activation as platforms for B-cell receptor (BCR) signalling and might also act in antigen trafficking. Lipid rafts might facilitate the regulation

Susan K. Pierce

2002-01-01

147

[Single B cell monoclonal antibody technologies and applications].  

PubMed

Monoclonal antibodies (mAbs) contribute a lot to the development of numerous fields in life science as a pivotal tool in modern biological research. Development of the PCR methods and maturation of antibody production have made it possible to generate mAbs from single human B cells by single cell RT-PCR with successional cloning and expression in vitro. Compared to traditional monoclonal antibody technologies, single B cell technologies require relatively fewer cells, which are highly efficient in obtaining specific mAbs in a rapid way with preservation of the natural heavy and light chain pairing. With so many advantages, single B cell technologies have been proved to be an attractive approach for retrieval of naive and antigen-experienced antibody repertoires generated in vivo, design of rationale structure-based vaccine, evaluation and development of basic B cell biology concepts in health and autoimmunity, and prevention of infectious diseases by passive immunization and therapy for disorders. Accordingly, this review introduced recent progresses in the single B cell technologies for generating monoclonal antibodies and applications. PMID:23016302

Chi, Xiangyang; Yu, Changming; Chen, Wei

2012-06-01

148

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

PubMed

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

Collins, Christopher M; Speck, Samuel H

2014-05-01

149

Contributions of B cells to lupus pathogenesis.  

PubMed

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the production of autoantibodies. This review summarizes first the results obtained in the mouse that have revealed how B cell tolerance is breached in SLE. We then review the B cell subsets, in addition to the autoAb producing cells, which contribute to SLE pathogenesis, focusing on marginal zone B cells, B-1 cells and regulatory B cells. Finally, we review the interactions between B cells and other immune cells that have been implicated in SLE, such as dendritic cells, macrophages, neutrophils and T cells. PMID:24332482

Sang, Allison; Zheng, Ying-Yi; Morel, Laurence

2014-12-01

150

Molecular programming of B cell memory  

PubMed Central

The development of high-affinity B cell memory is regulated through three separable phases, each involving antigen recognition by specific B cells and cognate T helper cells. Initially, antigen-primed B cells require cognate T cell help to gain entry into the germinal centre pathway to memory. Once in the germinal centre, B cells with variant B cell receptors must access antigens and present them to germinal centre T helper cells to enter long-lived memory B cell compartments. Following antigen recall, memory B cells require T cell help to proliferate and differentiate into plasma cells. A recent surge of information — resulting from dynamic B cell imaging in vivo and the elucidation of T follicular helper cell programmes — has reshaped the conceptual landscape surrounding the generation of memory B cells. In this Review, we integrate this new information about each phase of antigen-specific B cell development to describe the newly unravelled molecular dynamics of memory B cell programming. PMID:22158414

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

2014-01-01

151

B-cell biology and development.  

PubMed

B cells develop from hematopoietic precursor cells in an ordered maturation and selection process. Extensive studies with many different mouse mutants provided fundamental insights into this process. However, the characterization of genetic defects causing primary immunodeficiencies was essential in understanding human B-cell biology. Defects in pre-B-cell receptor components or in downstream signaling proteins, such as Bruton tyrosine kinase and B-cell linker protein, arrest development at the pre-B-cell stage. Defects in survival-regulating proteins, such as B-cell activator of the TNF-? family receptor (BAFF-R) or caspase recruitment domain-containing protein 11 (CARD11), interrupt maturation and prevent differentiation of transitional B cells into marginal zone and follicular B cells. Mature B-cell subsets, immune responses, and memory B-cell and plasma cell development are disturbed by mutations affecting Toll-like receptor signaling, B-cell antigen receptor coreceptors (eg, CD19), or enzymes responsible for immunoglobulin class-switch recombination. Transgenic mouse models helped to identify key regulatory mechanisms, such as receptor editing and clonal anergy, preventing the activation of B cells expressing antibodies recognizing autoantigens. Nevertheless, the combination of susceptible genetic backgrounds with the rescue of self-reactive B cells by T cells allows the generation of autoreactive clones found in patients with many autoimmune diseases and even in those with primary immunodeficiencies. The rapid progress of functional genomic research is expected to foster the development of new tools that specifically target dysfunctional B lymphocytes to treat autoimmunity, B-cell malignancies, and immunodeficiency. PMID:23465663

Pieper, Kathrin; Grimbacher, Bodo; Eibel, Hermann

2013-04-01

152

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

PubMed Central

Summary 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. PMID:19930184

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

2010-01-01

153

Novel molecular and cellular therapeutic targets in acute lymphoblastic leukemia and lymphoproliferative disease  

PubMed Central

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

Seif, Alix E.; Reid, Gregor S. D.; Teachey, David T.; Grupp, Stephan A.

2010-01-01

154

Accumulation of peripheral autoreactive B cells in the absence of functional human regulatory T cells  

PubMed Central

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

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

155

Accumulation of peripheral autoreactive B cells in the absence of functional human regulatory T cells.  

PubMed

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

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; Meffre, Eric

2013-02-28

156

Expression of Essential B Cell Development Genes in Horses with Common Variable Immunodeficiency  

PubMed Central

Common variable immunodeficiency (CVID) is a heterogeneous disorder of B cell differentiation or function with inadequate antibody production. Our laboratory studies a natural form of CVID in horses characterized by late-onset B cell lymphopenia due to impaired B cell production in the bone marrow. This study was undertaken to assess the status of B cell differentiation in the bone marrow of CVID-affected horses by measuring the expression of genes essential for early B cell commitment and development. Standard RT-PCR revealed that most of the transcription factors and key signaling molecules that directly regulate B cell differentiation in the bone marrow and precede PAX5 are expressed in the affected horses. Yet, the expression of PAX5 and relevant target genes was variable. Quantitative RT-PCR analysis confirmed that the mRNA expression of E2A, PAX5, CD19, and IGHD was significantly reduced in equine CVID patients when compared to healthy horses (p < 0.05). In addition, the PAX5/EBF1 and PAX5/B220 ratios were significantly reduced in CVID patients (p < 0.01). Immunohistochemical analysis confirmed the absence of PAX5-BSAP expression in the bone marrow of affected horses. Our data suggest that B cell development seems to be impaired at the transition between pre-pro-B cells and pro-B cells in equine CVID patients. PMID:22464097

Tallmadge, R.L.; Such, K.A.; Miller, K.C.; Matychak, M.B.; Felippe, M.J.B.

2012-01-01

157

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

PubMed

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

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

2014-07-01

158

Dominant inhibition of Fas ligand-mediated apoptosis due to a heterozygous mutation associated with autoimmune lymphoproliferative syndrome (ALPS) Type Ib  

Microsoft Academic Search

BACKGROUND:: Autoimmune lymphoproliferative syndrome (ALPS) is a disorder of lymphocyte homeostasis and immunological tolerance due primarily to genetic defects in Fas (CD95\\/APO-1; TNFRSF6), a cell surface receptor that regulates apoptosis and its signaling apparatus. METHODS:: Fas ligand gene mutations from ALPS patients were identified through cDNA and genomic DNA sequencing. Molecular and biochemical assessment of these mutant Fas ligand proteins

Lilia L Bi; George Pan; T Prescott Atkinson; Lixin Zheng; Janet K Dale; Christopher Makris; Vishnu Reddy; Jay M McDonald; Richard M Siegel; Jennifer M Puck; Michael J Lenardo; Stephen E Straus

2007-01-01

159

Lack of expression of inhibitory KIR3DL1 receptor in patients with natural killer cell-type lymphoproliferative disease of granular lymphocytes  

PubMed Central

Background Natural killer cell-type lymphoproliferative disease of granular lymphocytes is a disorder characterized by chronic proliferation of CD3?CD16+ granular lymphocytes. By flow cytometry analysis, we previously demonstrated a dysregulation in killer immunoglobulin-like receptor (KIR) expression in natural killer cells from patients with this lymphoproliferative disease, the activating KIR receptors being mostly expressed. We also found that patients with natural killer cell-type lymphoproliferative disease of granular lymphocytes usually had KIR genotypes characterized by multiple activating KIR genes. Design and Methods We investigated the mRNA levels of the KIR3DL1 inhibitory and the related KIR3DS1 activating receptors in 15 patients with natural killer cell-type lymphoproliferative disease of granular lymphocytes and in ten controls. These genes are usually expressed when present in the genome of the Caucasian population. Results We demonstrated the complete lack of KIR3DL1 expression in most of the patients analyzed, with the receptor being expressed in 13% of patients compared to in 90% of controls (P<0.01). Interestingly, studies of the methylation patterns of KIR3DL1 promoter showed a significantly higher methylation status (0.76 ± 0.12 SD) in patients than in healthy subjects (0.49±0.10 SD, P<0.01). The levels of expression of DNA methyl transferases, which are the enzymes responsible for DNA methylation, did not differ between patients and controls. Conclusions In this study we showed, for the first time, a consistent down-regulation of the inhibitory KIR3DL1 signal due to marked methylation of its promoter, thus suggesting that together with the increased expression of activating receptors, the lack of the inhibitory signal could also play a role in the pathogenesis of natural killer cell-type lymphoproliferative disease of granular lymphocytes. PMID:20410181

Gattazzo, Cristina; Teramo, Antonella; Miorin, Marta; Scquizzato, Elisa; Cabrelle, Anna; Balsamo, Mirna; Agostini, Carlo; Vendrame, Elena; Facco, Monica; Albergoni, Maria Paola; Trentin, Livio; Vitale, Massimo; Semenzato, Gianpietro; Zambello, Renato

2010-01-01

160

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

ClinicalTrials.gov

Post-transplant Lymphoproliferative Disorder; Prolymphocytic Leukemia; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Small Lymphocytic Lymphoma; Refractory Chronic Lymphocytic Leukemia; Refractory Hairy Cell Leukemia; Waldenström Macroglobulinemia

2014-10-15

161

KLF2- A Negative Regulator of Pre-B Cell Clonal Expansion and B Cell Activation  

PubMed Central

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

Winkelmann, Rebecca; Sandrock, Lena; Kirberg, Jorg; Jack, Hans-Martin; Schuh, Wolfgang

2014-01-01

162

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

PubMed

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

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

2014-01-01

163

[Synchronous Hepatocellular Carcinoma and B-Cell Non-Hodgkin's Lymphoma in Chronic Hepatitis C Patient].  

PubMed

Hepatitis C virus (HCV) is one of the main viral causes of hepatocellular carcinoma (HCC) and is associated with lymphoproliferative disorder such as non-Hodgkin's lymphoma (NHL). However, there are only few case reports on concomitantly induced NHL and HCC by HCV. Herein, we report a case of synchronous NHL and HCC in a patient with chronic hepatitis C which was unexpectedly diagnosed during liver transplantation surgery. This case suggests that although intrahepatic lymph node enlargements are often considered as reactive or metastatic lymphadenopathy in chronic hepatitis C patients with HCC, NHL should also be considered as a differential diagnosis. PMID:25252867

Lee, Soon Il; Heo, Nae-Yun; Park, Seung Ha; Joo, Young-Don; Kim, Il Hwan; Park, Jeong-Ik; Kim, Ji Yeon; Kim, Seung Ho; Shim, Hye Kyung

2014-09-25

164

Immortalization of antigen selected B cells.  

PubMed

This paper reports the generation of monoclonal antibody producing hybridomas from a small number of antigen-specific B cells selected by panning on antigen-coated dishes and rosetting with antigen-coupled paramagnetic beads. Anti-HIV positive B cells from spleen could be recovered by panning with an efficiency of 5% and a purity of 24%. Immunobead selection of anti-HIV positive B cells from the same mice yielded a recovery of 17% and a purity of 7%. Various experimental conditions with respect to the selection of specific B cells were investigated, leading to an optimized protocol for the isolation of a limited subset of B cells. The selected cells retained their property to produce immunoglobulins and could be clonally expanded in the presence of human T cell supernatant and irradiated murine thymoma helper cells to generate sufficient cells for a mini-electrofusion with NS-1 myeloma cells. Up to 78 specific hybridomas could be generated from one anti-HIV positive B cell. An overall efficiency of specific B cell immortalization of up to 10% was obtained. PMID:7687638

Steenbakkers, P G; van Wezenbeek, P M; Olijve, W

1993-07-01

165

Innate B cells: oxymoron or validated concept?  

PubMed Central

B lymphocytes promote the initial innate interferon response to viral pathogens without the need for antigen receptor activation. B cell dependent IFN production requires the cytokine, lymphotoxin-?. The LT? pathway is well known to regulate lymphoid organogenesis and homeostasis by differentiating stromal cells and macrophages. However, in response to viral pathogens these same B cell-regulated populations rapidly produce type 1 interferons. Thus, B cells act as innate effector cells via LT? homeostatic pathways, which serve as innate host barriers to viral pathogens. PMID:24358807

2012-01-01

166

MIF promotes B cell chemotaxis through the receptors CXCR4 and CD74 and ZAP-70 signaling.  

PubMed

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). PMID:24760155

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

167

The B cell helper side of neutrophils  

PubMed Central

Neutrophils use opsonizing antibodies to enhance the clearance of intruding microbes. Recent studies indicate that splenic neutrophils also induce antibody production by providing helper signals to B cells lodged in the MZ of the spleen. Here, we discuss the B cell helper function of neutrophils in the context of growing evidence indicating that neutrophils function as sophisticated regulators of innate and adaptive immune responses. PMID:23630389

Cerutti, Andrea; Puga, Irene; Magri, Giuliana

2013-01-01

168

B cell memory and idiotype network regulation  

Microsoft Academic Search

This investigation examined the clonal dynamics of B-cell expression and evaluated the role of idiotype network interactions in shaping the expressed secondary B-cell repertoire. Three interrelated experimental approaches were applied. The first approach was designed to distinguish between regulatory influences controlled by the major histocompatibility complex (MHC) and regulatory influences controlled by non-MHC factors including the idiotype network. This approach

Peter George Seferian

1991-01-01

169

[Morphologic features of the binucleated lymphocytes for the assesment of persistent B-cell polyclonal lymphocytosis].  

PubMed

Observation of binucleated lymphocytes on a blood film is a cornerstone event to assess persistent polyclonal B-cell lymphocytosis diagnosis (PPBL). But seldom case reports mentioned their finding in other contexts, mainly B-cell lymphoproliferative neoplasms such chronic lymphocytic leukemia or in reactive circumstances as multiple sclerosis undergoing natalizumab treatment. We aimed to check if some particular morphologic features were more specificaly linked to PPBL, reviewing blood films of series of patients affected by PPBL or harbouring binucleated lymphocytes whatever the diagnosis was. We found that binucleated cells in PPBL were heterogeneous but mostly midde-sized cells, asymetricaly bilobed with nucleoli, and with a moderately basophilic cytoplasm. Though mainly observed in PPBL patients, all that criteria remained unspecific. Conversely, the morphologic features of the other lymphoid cells were of good clinical value to affirm PPBL, either monocytoid or hyperbasophilic cells being systematically found. We think that a substantial percentage of binucleated lymphocytes, harbouring morphologic features such as described, and in a context of monocytoid and/or hyperbasophilic lymphocytes is predictive of PPBL diagnosis. PMID:24342786

Lesesve, Jean-François; Gressot, Anne-Lise; Cornet, Edouard; Mossafa, Hossein; Troussard, Xavier

2013-01-01

170

Decreased Levels of Total Immunoglobulin in Children with Autism is not a Result of B Cell Dysfunction  

PubMed Central

Autism spectrum disorders are a heterogeneous group of behaviorally defined disorders having complex etiologies. We previously reported a direct correlation between lower plasma levels of the immunoglobulins (Ig) IgG and IgM and increased severity of behavioral symptoms in children with autism. Our current objective was to determine if these reduced plasma levels of IgG and IgM are the result of defective B cell development, activation, or function. Results suggest no differences in the B cell parameters measured, indicating that decreased Ig in autism is not a result of B cell dysfunction and other immune cells might be involved. PMID:22854260

Heuer, Luke S.; Rose, Melissa; Ashwood, Paul; Van de Water, Judy

2012-01-01

171

Adenosine production by human B cells and B cell-mediated suppression of activated T cells  

PubMed Central

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

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

2013-01-01

172

Nonrandon X chromosome inactivation in B cells from carriers of X chromosome-linked severe combined immunodeficiency  

SciTech Connect

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.

Conley, M.E.; Lavoie, A.; Briggs, C.; Brown, P.; Guerra, C.; Puck, J.M.

1988-05-01

173

Abnormal B cell response to T cell-independent polyclonal B cell activators in haemophilia A.  

PubMed Central

In addition to T cell abnormalities, patients with haemophilia A show a separate B cell dysfunction. Characteristic are elevated spontaneous IgG (not IgM) levels in the patient's sera and in the culture supernatants of peripheral blood mononuclear cells. It is also observed that these cells fail to show a differentiation response to T cell-independent B cell activators. The B cell dysfunction correlates with the amount of factor VIII concentrates given prophylactically to patients with severe haemophilia. In contrast to the acquired immune deficiency syndrome (AIDS), the proliferation response to B cell mitogens is not affected. PMID:3017621

Kekow, J; Plendl, H; Gross, W L

1986-01-01

174

Posttransplant Lymphoproliferative Disease after Pediatric Solid Organ Transplantation  

PubMed Central

Patients after solid organ transplantation (SOT) carry a substantially increased risk to develop malignant lymphomas. This is in part due to the immunosuppression required to maintain the function of the organ graft. Depending on the transplanted organ, up to 15% of pediatric transplant recipients acquire posttransplant lymphoproliferative disease (PTLD), and eventually 20% of those succumb to the disease. Early diagnosis of PTLD is often hampered by the unspecific symptoms and the difficult differential diagnosis, which includes atypical infections as well as graft rejection. Treatment of PTLD is limited by the high vulnerability towards antineoplastic chemotherapy in transplanted children. However, new treatment strategies and especially the introduction of the monoclonal anti-CD20 antibody rituximab have dramatically improved outcomes of PTLD. This review discusses risk factors for the development of PTLD in children, summarizes current approaches to therapy, and gives an outlook on developing new treatment modalities like targeted therapy with virus-specific T cells. Finally, monitoring strategies are evaluated. PMID:24174972

Behrends, Uta

2013-01-01

175

Interleukin-21 Overexpression Dominates T Cell Response to Epstein-Barr Virus in a Fatal Case of X-Linked Lymphoproliferative Syndrome Type 1  

PubMed Central

Interleukin-21 (IL-21) is a cytokine whose actions are closely related to B cell differentiation into plasma cells as well as to CD8+ cytolytic T cell effector and memory generation, influencing the T lymphocyte response to different viruses. X-linked lymphoproliferative syndrome type 1 (XLP-1) is a primary immunodeficiency syndrome that is characterized by a high susceptibility to Epstein-Barr virus. We observed in a pediatric patient with XLP-1 that IL-21 was expressed in nearly all peripheral blood CD4+ and CD8+ T cells. However, IL-21 could not be found in the lymph nodes, suggesting massive mobilization of activated cells toward the infection's target organs, where IL-21-producing cells were detected, resulting in large areas of tissue damage. PMID:23467775

Ortega, Consuelo; Estevez, Orlando A.; Fernandez, Silvia; Aguado, Rocio; Rumbao, Jose M.; Gonzalez, Teresa; Perez-Navero, Juan L.

2013-01-01

176

Transitional B cells are the target of negative selection in the B cell compartment  

PubMed Central

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 three compartments not only allows to define the target population of physiological processes like negative selection, but will also be a helpful tool for an accurate description of possible developmental blocks in mutant mice. PMID:7760002

1995-01-01

177

Visualization of splenic marginal zone B cell shuttling and follicular B cell egress  

PubMed Central

The splenic marginal zone (MZ) is a unique microenvironment where resident immune cells are exposed to the open blood circulation1,2. Despite its importance in responses against blood-borne antigens, lymphocyte migration in the MZ has not been intravitally visualized due to challenges associated with achieving adequate imaging depth in this abdominal organ. Here we develop a 2-photon microscopy procedure to study MZ and follicular (FO) B cell movement in the live spleen. We show that MZ B cells are highly motile and exhibit long membrane extensions. MZ B cells shuttle between MZ and follicles with at least one fifth of the cells exchanging between compartments per hour, a behavior that explains their ability to rapidly deliver antigens from the open blood circulation to the secluded follicles. FO B cells also transit from follicles to MZ but unlike MZ B cells, they fail to undergo integrin-mediated adhesion, become caught in fluid flow and are carried into the red pulp. FO B cell egress via the MZ is sphingosine-1-phosphate receptor-1 (S1PR1)-dependent. This study shows that MZ B cells migrate continually between MZ and follicles and establishes the MZ as a site of S1PR1-dependent B cell exit from follicles. The work also shows how adhesive differences of closely related cells critically influences their behavior in the same microenvironment. PMID:23263181

Arnon, Tal I.; Horton, Robert M.; Grigorova, Irina L.; Cyster, Jason G.

2012-01-01

178

Ibrutinib and indolent B-cell lymphomas.  

PubMed

Most patients with indolent B-cell lymphomas fail to achieve complete remission with current treatment approaches and invariably relapse. During the past decade, innovative immunochemotherapy strategies have substantially improved disease control rates but not survival, thus providing the rationale for development of novel agents targeting dysregulated pathways that are operable in these hematological malignancies. Ibrutinib, a novel first-in-human Bruton's tyrosine kinase (BTK) inhibitor, has progressed into phase III trials after early-phase clinical studies demonstrated effective target inhibition, increased tumor response rates, and significant improvement in survival, particularly in patients with indolent B-cell lymphomas. Recently, the compound was designated a "breakthrough therapy" by the United States Food and Drug Administration for the treatment of patients with relapsed or refractory mantle cell lymphoma and Waldenström macroglobulinemia. This review summarizes recent achievements of ibrutinib, with a focus on its emerging role in the treatment of patients with indolent B-cell lymphoid malignancies. PMID:24445187

Akinleye, Akintunde; Furqan, Muhammad; Adekunle, Oluwaseyi

2014-08-01

179

The complement system in B cell regulation.  

PubMed

Early studies of animals bearing natural deficiencies in complement C3 and C4 and mice transiently deficient in C3 suggested that the complement system played a role in humoral immunity. Identification and characterization of the complement receptors CD21 and CD35 and their expression on B lymphocytes provided evidence for a direct role for complement in "linkage of innate and adaptive immunity". More recent studies of mice bearing targeted deficiencies in complement proteins C3, C4 or the receptors CD21/CD35 has confirmed the importance of complement in B cell responses in vivo and extended our understanding to distinct stages in B cell differentiation in which complement participates in humoral immunity. In this review, a role for complement is described in five distinct stages of B cell differentiation. PMID:15159059

Carroll, Michael C

2004-06-01

180

Autoimmune lymphoproliferative syndrome (ALPS) caused by Fas (CD95) mutation mimicking sarcoidosis.  

PubMed

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. PMID:18223337

Müllauer, Leonhard; Emhofer, Josef; Wohlfart, Sabine; Pichlhöfer, Bettina; Stary, Susanne; Ebetsberger, Georg; Mannhalter, Christine; Chott, Andreas

2008-02-01

181

Burkitt s lymphoma variant of post-transplant lymphoproliferative disease (PTLD).  

PubMed

The occurrence of posttransplant lymphoproliferative disorder (PTLD) in solid organ allograft recipients can be quite varied in clinical presentation, histopathological characteristics and frequency. A variety of lymphomas can develop as a PTLD although some types appear infrequently and remain poorly understood in this clinical setting. In this report, we describe two cases of Burkitt s lymphoma presenting as a PTLD following liver transplantation. The recipients were 12 and 44 years of age and displayed gastrointestinal involvement by the tumors several years following transplant. The tumors displayed the typical histological features of Burkitt s lymphoma and were markedly positive for EBV. The tumors displayed similar immunophenotypic characteristics by flow cytometry and had rearrangements of the immunoglobulin J-H heavy chain. The tumors required aggressive chemotherapy and a cessation of immunosuppressive therapy. This report demonstrates that Burkitt s type lymphomas can develop in the posttransplant setting and that these tumors contain morphologic, cytofluorographic and molecular features identical to Burkitt s lymphomas that occur in non-transplant patients. Our experience is that these PTLD- Burkitt s lymphomas behave aggressively and require intensive chemotherapeutic intervention. PMID:12172573

Pasquale, Melissa A; Weppler, Debbie; Smith, Jon; Icardi, Michael; Amador, Alexandra; Gonzalez, Monica; Kato, Tomoaki; Tzakis, Andreas; Ruiz, Phillip

2002-01-01

182

BAFF and selection of autoreactive B cells  

PubMed Central

BAFF is a critical survival factor for transitional and mature B cells and is a promising therapeutic target for SLE. A BAFF inhibitor, belimumab, is the first new drug in 50 years to be approved for the treatment of SLE. However, the mechanism of action of this drug is not entirely clear. In this review we will focus on the role of the BAFF–APRIL signaling pathway in the selection of autoreactive B cells and discuss whether altered selection is the mechanism for the therapeutic efficacy of BAFF inhibition in SLE. PMID:21752714

Liu, Zheng; Davidson, Anne

2011-01-01

183

B-cell cutaneous lymphoid hyperplasia representing progressive transformation of germinal center: a report of 2 cases.  

PubMed

Cutaneous lymphoid hyperplasia (CLH) is a reactive polyclonal benign lymphoproliferative process predominantly composed of B cells or T cells, either localized or disseminated. The authors report histomorphologic, immunophenotypic, and genotypic findings of 2 cases of B-cell CLH demonstrating progressive transformation of germinal center (PTGC). Histologically, most of the lymphoid follicles were PTGCs with a few hyperplastic germinal centers. PTGC was characterized by enlarged but well-circumscribed follicles without clear demarcation of the germinal center and mantle zone, which contained a predominance of small lymphocytes and variable numbers of centrocytes, centroblasts, and immunoblasts. However, there were no centroblasts and immunoblasts resembling lymphocytic and/or histiocytic Reed-Sternberg cell variants in nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) in either lesion. These unusual CLHs should be differentiated from the primary cutaneous marginal zone B-cell lymphoma, primary cutaneous follicular lymphoma, particularly "floral variant," or NLPHL. To avoid overdiagnosis and overtreatment, immunophenotypic and genotypic studies are required along with careful morphologic examination. PMID:18815203

Kojima, Masaru; Sakurai, Shinji; Shimizu, Ken; Itoh, Hideaki

2010-10-01

184

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

Microsoft Academic Search

We report three patients who developed severe supraglottic airway obstruction due to Epstein-Barr virus lymphoproliferative\\u000a disease following allogeneic bone marrow transplantation. In addition to enlarged pharyngeal lymphoid tissue seen in all three\\u000a patients, two had supraglottic airway narrowing and two developed pulmonary lymphoproliferative disease. They were treated\\u000a with unmanipulated T cells or EBV-specific cytotoxic T lymphocytes. Life-threatening upper airway obstruction

Barry D. Fletcher; Helen E. Heslop; Sue C. Kaste; Sara Bodner

1998-01-01

185

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

PubMed Central

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

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

2014-01-01

186

Aberrant B cell selection and activation in systemic lupus erythematosus.  

PubMed

The detrimental role of B lymphocytes in systemic lupus erythematosus (SLE) is evident from the high levels of pathogenic antinuclear autoantibodies (ANAs) found in SLE patients. Affirming this causative role, additional antibody-independent roles of B cells in SLE were appreciated. In recent years, many defects in B cell selection and activation have been identified in murine lupus models and SLE patients that explain the increased emergence and persistence of autoreactive B cells and their lowered activation threshold. Therefore, clinical trials with B cell depletion regimens in SLE patients were initiated but disappointingly the efficacy of B cell depleting agents proved to be limited. Remarkably however, a major breakthrough in SLE therapy was accomplished by blocking B cell survival factors rather then eliminating B cells. This surprising finding indicates that although SLE is a B cell-driven disease, the amplifying crosstalk between B cells and other cells of the immune system likely evokes the observed tolerance breakdown in B cells. Moreover, this implies that intelligent interception of pro-inflammatory loops rather then selectively silencing B cells will be key to the development of new SLE therapies. In this review, we will not only highlight the intrinsic B cell defects that facilitate the persistence of autoreactive B cells and their activation, but in addition we will focus on B cell extrinsic signals derived from T cells and innate immune cells that lower the activation threshold for B cells. PMID:23768157

Kil, Laurens P; Hendriks, Rudi W

2013-08-01

187

[B cell targeting therapy using the anti-CD20 antibody in autoimmune diseases].  

PubMed

Systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) are representative autoimmune diseases thought to involve disturbances in T and B cell functions. Immune complexes consisting of antigens and autoantibodies secreted from activated B cells cause severe inflammation in various organs. Since often patients with RA and SLE are refractory to these conventional treatments such as immunosuppressants and corticosteroids, innovative approaches need to be developed. CD20 is a surface molecule specific for B cells and rituximab is a chimeric antibody specific for human CD20 and is known to deplete B cells. Recently, the potential efficacy of B-cell depletion therapy with rituximab has been reported in several autoimmune diseases. Rituximab is now approved for use in combination with methotrexate in refractory RA patients in the United States and EU. We reported that SLE patients with organ-threatening disorders that are resistant to intensive conventional therapies, were treated by once a week administration of anti-CD20 antibody rituximab, and that sufficient evidence concerning the excellent tolerability and high efficacy of rituximab therapy was obtained in both a pilot study and a nation-wide phase I/II clinical examination Moreover, a rapid and marked reduction in the expression of the co-stimulatory molecules CD40 and CD80 on B-cells was found in SLE patients, implying that reduction of both the quantity and the quality of B-cells by rituximab could improve the disease course in refractory SLE. Therefore, targeting B-cells may have potential interests by bringing about a breakthrough in the treatment of RA, SLE and other autoimmune diseases. PMID:19483410

Tanaka, Yoshiya

2009-06-01

188

Function of marginal zone B cells in antiviral B-cell responses.  

PubMed

B cells of the marginal zone (MZ) compartment are poised to combat infectious threats reaching the bloodstream. They owe this ability to their unique location at the ports of entry of blood-borne pathogens as well as to their distinct functional properties. MZ B cells respond to antigen encounters with rapid activation, local antibody secretion, and isotype switching. In addition, they are involved in antigen trapping, transport, and presentation. Herein, we review the current data on the functional characteristics that enable the MZ B-cell population to act as an efficient first line of defense against systemic infections. PMID:16167884

Gatto, Dominique; Bachmann, Martin F

2005-01-01

189

New insights in the regulation of human B cell differentiation  

PubMed Central

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

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

2009-01-01

190

In vivo control of B-cell survival and antigen-specific B-cell responses.  

PubMed

Targeted modification of the mouse genome provides the capability to manipulate complex physiological processes in a precise and controlled manner. Investigation of B-lymphocyte biology has benefited not only from the targeted modification of genes controlling B-cell survival and responsiveness, but also from the manipulation of antigen specificity made possible by targeting endogenous immunoglobulin loci. In this review, we discuss recent results obtained from our laboratory using gene-targeted mouse models to investigate the in vivo regulation of B-cell survival and responsiveness. The control of BAFF-dependent survival signals by the TRAF2- and TRAF3-signaling proteins is discussed as is the potential involvement of these molecules in B-lineage malignancies. We also outline the development and use of the SW(HEL) model for analyzing antigen-specific B-cell responses in vivo. This includes insights into the control of early decision-making during T-dependent B-cell differentiation, the affinity maturation and plasma cell differentiation of germinal center B cells, and the identification of EBI2 as a key regulator of B-cell migration and differentiation. PMID:20727031

Chan, Tyani D; Gardam, Sandra; Gatto, Dominique; Turner, Vivian M; Silke, John; Brink, Robert

2010-09-01

191

Molecular surveillance for lymphoproliferative disease virus in hunter-killed wild turkeys (Meleagris gallopavo) from the eastern United States.  

E-print Network

??Three avian retroviruses can cause lymphoid tumors in galliforms, including avian leukosis virus, reticuloendotheliosis virus, and lymphoproliferative disease virus (LPDV). Historically, LPDV was considered a… (more)

Thomas, Jesse Michael

2013-01-01

192

B Cell Repopulation After Alemtuzumab Induction--Transient Increase in Transitional B Cells and Long-Term Dominance of Na?ve B Cells  

PubMed Central

In organ transplantation, the composition of the B-cell compartment is increasingly identified as an important determinant for graft outcome. Whereas naïve and transitional B cells have been associated with long-term allograft survival and operational tolerance, memory B cells have been linked to decreased allograft survival. Alemtuzumab induction therapy effectively depletes B cells, but is followed by rapid repopulation up to levels exceeding base line. The characteristics of the repopulating B cells are currently unknown. We studied the phenotypic and functional characteristics of B cells longitudinally in 19 kidney transplant recipients, before and at 6, 9 and 12 months after alemtuzumab induction therapy. A transient increase in transitional B cells and cells with phenotypic characteristics of regulatory B cells, as well as a long-term dominance in naïve B cells was found in alemtuzumab-treated kidney transplant recipients, which was not influenced by conversion from tacrolimus to sirolimus. At all time-points after treatment, B cells showed unaltered proliferative and IgM-producing capacity as compared to pretransplant samples, whereas the ability to produce IgG was inhibited long-term. In conclusion, induction therapy with alemtuzumab results in a long-term shift toward naïve B cells with altered phenotypic and functional characteristics. PMID:22420490

Heidt, S; Hester, J; Shankar, S; Friend, P J; Wood, K J

2012-01-01

193

DEVELOPMENT OF CD27+ MARGINAL ZONE B CELLS REQUIRES GALT  

PubMed Central

Summary In species other than mouse, little is known about the origin and development of marginal zone (MZ) B cells. Using cross-reactive antibodies, we identified and characterized splenic MZ B cells in rabbits as CD27+CD23?. In rabbits in which organized GALT was surgically removed at birth, we found only CD23+ follicular (FO) B cells and almost no CD27+ MZ B cells in the spleen, indicating that GALT is required for the development of splenic MZ B cells. These findings lead us to suggest that commensal microbiota contribute to development of MZ B cells. PMID:23468368

Yeramilli, Venkata A.; Knight, Katherine L.

2013-01-01

194

Epstein-Barr Virus LMP2A Drives B Cell Development and Survival in the Absence of Normal B Cell Receptor Signals  

Microsoft Academic Search

Epstein-Barr virus (EBV) establishes a persistent latent infection in peripheral B lymphocytes in humans and is associated with a variety of malignancies and proliferative disorders. Latent membrane protein 2A (LMP2A) is one of only two viral proteins expressed in latently infected B lymphocytes in vivo. LMP2A blocks B cell receptor (BCR) signal transduction in vitro by binding the Syk and

Robert G Caldwell; Joanna B Wilson; Steven J Anderson; Richard Longnecker

1998-01-01

195

Ibrutinib in B-cell Lymphomas.  

PubMed

The standard frontline therapy for diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), and mantle cell lymphoma (MCL) includes the use of chemoimmunotherapy and/or radiation therapy. When patients with these diseases relapse or are refractory to therapy, their diseases are considered incurable outside of the setting of an autologous or allogeneic stem cell transplant, which many patients are not candidates for due to age or comorbidities. The oral Bruton's tyrosine kinase (BTK) inhibitor, ibrutinib, targets the B-cell receptor (BCR) signaling pathway that is critical in the survival of these malignancies. It has shown promising activity in certain subtypes of DLBCL, in relapsed or refractory FL, and in relapsed or refractory MCL for which it has recently received FDA approval and should be considered for use in patients in first relapse. Ibrutinib is an oral therapy taken daily that has been well tolerated by patients. Given the high response rates, tolerability, and acceptable toxicities of ibrutinib therapy, it is now being evaluated in combination therapy both in relapsed B-cell malignancies and frontline studies in DLBCL and MCL. Several other promising agents targeting different kinases in the BCR signaling pathway also are currently under investigation. PMID:24481980

Maddocks, Kami; Blum, Kristie A

2014-06-01

196

Human B cell defects in perspective.  

PubMed

While primary immune defects are generally considered to lead to severe and easily recognized disease in infants and children, a number of genetic defects impairing B cell function may not be clinically apparent or diagnosed until adult life. The commonest of these is common variable immune deficiency, the genetic origins of which are beginning to be at least partially understood. CVID affects ? 1/25,000 Caucasians and is characterized by a marked reduction in serum IgG, almost always in serum IgA, and reduced serum IgM in about half of all cases; these defects continue to provide an opportunity to investigate the genes necessary for B cell function in humans. Recently, a small number of genes necessary for normal B cell function have been identified in consanguineous families leading to varying degrees of hypogammaglobulinemia and loss of antibody production. In other studies, whole-exome sequencing and copy number variation, applied to large cohorts, have extended research into understanding both the genetic basis of this syndrome and the clinical phenotypes of CVID. PMID:22477523

Cunningham-Rundles, Charlotte

2012-12-01

197

Primary B cell lymphoma of the mediastinum.  

PubMed

Primary B cell mediastinal lymphoma has been recognized as a distinct entity recently. This is a retrospective study to define the clinical features and treatment outcome over a 10-year period. Twenty-four consecutive patients (male/female: 11/13) with B cell lymphoma primarily involving the mediastinum were studied. The median age was 34 years. Symptoms were mainly referrable to the chest, with superior vena cava syndrome (SVCO) present in one-third of the patients. Bulky disease was present in over half (58 per cent) and B symptoms were present in 38 per cent of patients. The overall CR rate was 70 per cent and the 5-year OS rates were 56 per cent and 72 per cent for all and CR patients respectively. Five (71 per cent) primary refractory patients and four (66 per cent) relapsed patients died despite salvage therapy. Six relapses occurred at a median of 6 months from treatment. This study showed that primary large B cell lymphoma of the mediastinum is a clinically distinct entity affecting young patients. A significant proportion attained CR and overall, more than half achieved prolonged remission, and most of the relapses occurred early. However, those who failed to attain CR or relapsed still had a poor outcome. An intensive therapy such as autologous bone marrow transplant has to be considered in this subgroup of patients. PMID:9267463

Chim, C S; Liang, R; Chan, A C; Kwong, Y L; Ho, F C; Todd, D

1996-12-01

198

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

PubMed

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

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

2013-01-01

199

Pathology of indolent B-cell neoplasms other than follicular lymphoma.  

PubMed

Indolent B-cell lymphomas include follicular lymphoma (FL), chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and marginal zone lymphomas (MZLs). They are a diverse group of disorders with different clinical, morphological, immunophenotypic and genetic features. However, because of several histological similarities, such as in cell size and nodular structure, it may sometimes be difficult to differentiate them and to make a definitive diagnosis. In this review article, we summarize the histopathology of indolent B-cell neoplasms excluding FL and including hairy cell leukemia, and briefly mention recent genetic findings useful for their differential diagnosis. In addition, a provisional subtype of low-grade B-cell lymphoma, "prolymphocytic/paraimmunoblastic lymphoma", is described. PMID:24942942

Sakata, Seiji; Tsuyama, Naoko; Takeuchi, Kengo

2014-01-01

200

Spin90 deficiency increases CXCL13-mediated B cell migration.  

PubMed

SPIN90 regulates actin dynamics, which is important for cell migration control. CXCL13-mediated B cell migration is essential for B cell immune responses. In this study, we investigated the role of SPIN90 in CXCL13-mediated B cell migration using Spin90 gene-deficient mice. Our chemokinesis analysis and transwell cell migration assay showed that SPIN90 is involved in CXCL13-mediated B cell migration. Moreover, the level of CXCR5, which is CXCL13 receptor, was increased in SPIN90-deficient B cells compared with wild-type B cells. Overall, our data suggest that SPIN90 plays an important role in B cell immune responses through the regulation of CXCL13-mediated B cell migration. PMID:24965518

Park, S-H; Kim, H-R; Jun, C-D; Song, W K; Park, S-G

2014-09-01

201

Cyclin D2 controls B cell progenitor numbers  

Microsoft Academic Search

Cyclin D2 affects B cell proliferation and differentiation in vivo. It is rate-limiting for B cell receptor (BCR)-dependent proliferation of B cells, and cyclin D2\\/ mice lack CD5(B1) B lymphocytes. We show here that the bone marrow (BM) of cyclin D2\\/ mice contains half the num- bers of Sca1B220 B cell progenitors but nor- mal levels of Sca1 progenitor cells

Azim Mohamedali; Ines Soeiro; Nicholas C. Lea; Janet Glassford; Lolita Banerji; Ghulam J. Mufti; Eric W.-F. Lam; N. Shaun; B. Thomas

2003-01-01

202

A bird's eye view on human B cells  

Microsoft Academic Search

We show in this review that there is a continuum between the chicken B-cell system classified as the first GALT model described and the human B-cell system. We propose that humans have conserved for one B-cell subpopulation, the marginal zone B-cell subset in charge of T-independent responses, the strategies of diversification used by GALT species to generate their pre-immune repertoire.

Jean-Claude Weill; Sandra Weller; Claude-Agnès Reynaud

2004-01-01

203

Emerging Role of Infectious Etiologies in the Pathogenesis of Marginal Zone B-cell Lymphomas.  

PubMed

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-?B) 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." Clin Cancer Res; 20(20); 5207-16. ©2014 AACR. PMID:25320370

Zucca, Emanuele; Bertoni, Francesco; Vannata, Barbara; Cavalli, Franco

2014-10-15

204

Congenital B cell lymphocytosis explained by novel germline CARD11 mutations  

PubMed Central

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

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

2012-01-01

205

Two loci affecting B cell responses to B cell maturation factors  

PubMed Central

B lymphocytes from DBA/2Ha mice have a genetic defect characterized by a failure to differentiate into antibody-secreting cells in response to a family of lymphokines termed B cell maturation factors (BMFs). By contrast, B cells from DBA/2Ha mice respond normally in PFC assays to the B cell mitogen LPS, and macrophages from these mice are activated by one of the three BMFs. Two loci are responsible for the B cell defect in DBA/2Ha mice. One locus (Bmfr-1) is constitutively expressed throughout life, and maps approximately 13 cM distal to the brown locus on chromosome 4. A second locus (Bmfr-2) becomes active only after sexual maturity and is closely linked to the dilute locus on chromosome 9. At both loci, alleles determining responsiveness to BMFs are dominant over nonresponder alleles. The effect of Bmfr-2 on B cell responsiveness may be related to levels of the steroid sex hormones. DBA/2Ha mice offer a tool for studying the genetic and hormonal regulation of the immune system. PMID:3079812

1986-01-01

206

B-Cell-Intrinsic Hepatitis C Virus Expression Leads to B-Cell-Lymphomagenesis and Induction of NF-?B Signalling  

PubMed Central

Hepatitis C virus (HCV) infection leads to the development of hepatic diseases, as well as extrahepatic disorders such as B-cell non-Hodgkin's lymphoma (B-NHL). To reveal the molecular signalling pathways responsible for HCV-associated B-NHL development, we utilised transgenic (Tg) mice that express the full-length HCV genome specifically in B cells and develop non-Hodgkin type B-cell lymphomas (BCLs). The gene expression profiles in B cells from BCL-developing HCV-Tg mice, from BCL-non-developing HCV-Tg mice, and from BCL-non-developing HCV-negative mice were analysed by genome-wide microarray. In BCLs from HCV-Tg mice, the expression of various genes was modified, and for some genes, expression was influenced by the gender of the animals. Markedly modified genes such as Fos, C3, LT?R, A20, NF-?B and miR-26b in BCLs were further characterised using specific assays. We propose that activation of both canonical and alternative NF-?B signalling pathways and down-regulation of miR-26b contribute to the development of HCV-associated B-NHL. PMID:24651473

Kasama, Yuri; Mizukami, Takuo; Kusunoki, Hideki; Peveling-Oberhag, Jan; Nishito, Yasumasa; Ozawa, Makoto; Kohara, Michinori; Mizuochi, Toshiaki; Tsukiyama-Kohara, Kyoko

2014-01-01

207

B cells flying solo Joanna Groom and Fabienne Mackay  

E-print Network

lupus erythematosus (SLE) is associated with the loss of B-cell tolerance, B-cell dysregulation studies have shown that dysregulation of T-cell function is another critical aspect driving disease that cooperation between T and B cells probably underlies disease progression in many patients. A similar

Cai, Long

208

Regulation of B cell receptor signaling : B cell activation through complement and the role of protein tyrosine phosphatase Shp2  

E-print Network

published that B cells lacking CD81, a tetraspanin receptortetraspanin CD81 is necessary for partitioning of coligated CD19/CD21-B celltetraspanin CD81 is necessary for partitioning of coligated CD19/CD21-B cell

Kolla, Ravi V.

2006-01-01

209

Altered Pattern of Naïve and Memory B cells and B1 Cells in Patients with Chronic Granulomatous Disease.  

PubMed

Chronic granulomatous disease (CGD) is a rare primary immunodeficiency disorder characterized by a greatly increased susceptibility to severe fungal and bacterial infections caused by defects in NADPH oxidase of phagocytic cells. We aimed to investigate immunophenotype alterations of naïve and memory B cells and B1a cells in peripheral whole blood from Iranian patients with CGD. Flow cytometric analysis was performed on peripheral blood samples from 31 CGD patients and 23 healthy controls (HC) to study naïve (IgD+/CD27-), memory (CD27+) B and B1a (CD5+) cells. Soluble CD27 (sCD27) and immunoglobulins were also measured by ELISA and the nephelometric method, respectively. We found significantly higher levels of naïve B cells and B1a cells but lower levels of memory B cells in CGD patients compared to HC.. There was no significant difference in soluble CD27 (sCD27) alteration between CGD patients and HC. Our findings suggested a role for NADPH oxidase in process of B cell differentiation and impairing conversion of naïve B cells to memory B cells and altered B1a cells in CGD patients. Increased susceptibility of CGD patients to opportunistic infections and autoimmune disorders could be partly explained by the altered phenotype of B lymphocytes in these patients. PMID:24659119

Mohsenzadegan, Monireh; Fattahi, Fahimeh; Fattahi, Fatemeh; Mirshafiey, Abbas; Fazlollahi, Mohammad Reza; Naderi Beni, Fariba; Movahedi, Masoud; Pourpak, Zahra

2014-06-01

210

Variability of memory B cell markers in a cohort of common variable immune deficiency patients over 6 months.  

PubMed

Common Variable Immunodeficiency Disorder (CVID) is a complex disorder that predisposes patients to recurrent and severe infections. Immunophenotypic classification schemes were developed to categorize patients with CVID into phenotypic and prognostic groups based on different memory B cell subsets. Whether the B cell subset analysis is stable over time has not been investigated. B cell phenotyping in patients with CVID (n = 15) and sex- and age-matched controls (n = 26) were carried out according to the three B cell classifications. Patients with CVID were evaluated monthly over 6 months. Controls were assessed once during the study. We scored how often each patient was assigned to the same group within each classification. The Freiburg classification assigned patients to the same group at a rate of 73% and the Paris classification at 88%. The EUROclass classification of smB- versus smB+ was at 90%. The two subclassifications [(smB-21low or smB-21norm) and transitional B] were at 87% and 97%, respectively. The level of naïve B cells measured in all patients with CVID during the 6-month evaluation was the most stable B cell subset. We conclude that all classifications systems show considerable variability, but the EUROclass classification was the most reliable scheme for our 15 CVID and 26 healthy cohorts. Our results indicate that phenotypic classifications within CVID will be difficult while there is variability of commonly used assays. PMID:23360162

Koopmans, W; Woon, S-T; Zeng, I S L; Jordan, A; Brothers, S; Browett, P; Ameratunga, R

2013-06-01

211

Identification and characterization of circulating human transitional B cells  

PubMed Central

Murine B-cell development begins in bone marrow and results in the generation of immature transitional B cells that transit to the spleen to complete their maturation. It remains unclear whether the same developmental pathway takes place in humans. Using markers characteristic of human bone marrow immature B cells, we have identified a population of circulating human B cells with a phenotype most similar to mouse transitional type I (T1) B cells, although these human counterparts express CD5. These cells die rapidly in culture, and B-cell activation factor member of the tumor necrosis factor (TNF) family (BAFF) does not effect their survival regardless of B-cell receptor (BCR) stimulation. In contrast, bone marrow stromal cells or interleukin-4 (IL-4) significantly enhanced their survival. In the presence of T-cell signals provided by IL-4 or CD40 ligation, BCR stimulation can induce progression into cell cycle. Interestingly, circulating B cells that phenotypically and functionally resemble murine T2 B cells are found in cord blood and adult peripheral blood, suggesting that B-cell maturation may not be restricted to the spleen. Notably, increased proportions of T1 B cells were found in blood of patients with systemic lupus erythematosus (SLE), although bone marrow production and selection appeared to be normal. PMID:15701725

Sims, Gary P.; Ettinger, Rachel; Shirota, Yuko; Yarboro, Cheryl H.; Illei, Gabor G.; Lipsky, Peter E.

2005-01-01

212

Systemic EBV T-cell lymphoproliferative disease of young adults.  

PubMed

T/NK cell proliferative EBV associated disease is a rare one which is more common in eastern Asian countries. EBV is originally associated with B cells, and EBV associated T cell lymphoma is so rare. Hence we decided to describe a patient treated with misleading diagnoses such as TB and sarcoidosis for almost two years. The liver was biopsied after admission in this center, and gastric and colonic biopsy was also performed due to gastrointestinal bleeding. Diffuse infiltration of chronic inflammatory cells was seen, especially lymphocytes some of which were atypical. T lymphocyte markers were seen in these cells by immunohistochemical staining. Further studies demonstrated T lymphocytes associated with EBV to be positive which is very rare event. Although going under chemotherapy, there were no response and the patient died. PMID:24901859

Kheyri, Zahedin; Mojtahedzadeh, Aydin; Zamani, Farhad; Zaremehrjerdi, Ali; Babaheidarian, Pegah

2014-01-01

213

CX3CR1(+) B cells show immune suppressor properties.  

PubMed

The immune regulatory functions of B cells are not fully understood yet. The present study aims to characterize a subtype of B cells that expresses CX3CR1. In this study, peripheral blood samples were collected from patients with food allergies and healthy subjects. Peripheral B cells were analyzed by flow cytometry. T cell proliferation was assessed by carboxyfluorescein succinimidyl ester dilution assay. The results showed that the CX3CR1(+) B cells were detected in the peripheral blood samples of healthy subjects and were significantly less in patients with food allergies. CX3CR1(+) B cells expressed high levels of TGF-? and integrin ?v?6. CX3CR1(+) B cells could efficiently suppress other effector CD4(+) T cell activation. We conclude that human peripheral CX3CR1(+) B cells have immune suppressor properties. PMID:24970890

Wu, Zhiqiang

2014-08-15

214

B Cell Aortic Homing and Atheroprotection Depend on Id3  

PubMed Central

Rationale B cells are abundant in the adventitia of normal and diseased vessels. Yet, the molecular and cellular mechanisms mediating homing of B cells to the vessel wall and B cell effects on atherosclerosis are poorly understood. Inhibitor of Differentiation-3 (Id3), is important for atheroprotection in mice and polymorphism in the human ID3 gene has been implicated as a potential risk marker of atherosclerosis in humans. Yet the role of Id3 in B cell regulation of atherosclerosis is unknown. Objective To determine if Id3 regulates B cell homing to the aorta and atheroprotection, and identify molecular and cellular mechanisms mediating this effect. Methods and Results Loss of Id3 in Apoe?/? mice resulted in early and increased atherosclerosis. Flow cytometry revealed a defect in Id3?/? Apoe?/? mice in the number of B cells in the aorta, but not the spleen, lymph nodes and circulation. Similarly, B cells transferred from Id3?/? Apoe?/? mice into B cell deficient micereconstituted spleen, lymph node and blood similarly to B cells from Id3+/+ Apoe?/? mice, but aortic reconstitution and B cell-mediated inhibition of diet-induced atherosclerosis was significantly impaired. In addition to retarding initiation of atherosclerosis, B cells homed to regions of existing atherosclerosis, reduced macrophage content in plaque and attenuated progression of disease. The chemokine receptor, CCR6, was identified as an important Id3 target mediating aortic homing and atheroprotection. Conclusions Together, these results are the first to identify the Id3-CCR6 pathway in B cells and demonstrate its role in aortic B cell homing and B cell mediated protection from early atherosclerosis. PMID:22034493

Doran, Amanda C.; Lipinski, Michael J.; Oldham, Stephanie N.; Garmey, James C.; Campbell, Kirsti A.; Skaflen, Marcus D.; Cutchins, Alexis; Lee, Daniel J.; Glover, David K.; Kelly, Kimberly A.; Galkina, Elena V.; Ley, Klaus; Witztum, Joseph L.; Tsimikas, Sotirios; Bender, Timothy P.; McNamara, Coleen A.

2011-01-01

215

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

PubMed Central

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

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

2009-01-01

216

The Majority of Human Memory B Cells Recognizing RhD and Tetanus Resides in IgM+ B Cells  

PubMed Central

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. PMID:24965774

Della Valle, Luciana; Dohmen, Serge E.; Verhagen, Onno J. H. M.; Berkowska, Magdalena A.; Vidarsson, Gestur

2014-01-01

217

The majority of human memory B cells recognizing RhD and tetanus resides in IgM+ B cells.  

PubMed

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. PMID:24965774

Della Valle, Luciana; Dohmen, Serge E; Verhagen, Onno J H M; Berkowska, Magdalena A; Vidarsson, Gestur; Ellen van der Schoot, C

2014-08-01

218

B Cells in Multiple Sclerosis: Connecting the Dots  

PubMed Central

Over the last two decades B cells have increasingly moved into the spotlight in multiple sclerosis (MS) research. This interest was fuelled by growing understanding and acceptance of pathological involvement of B cells and antibodies in MS. Data derived from animal models of MS, human histopathological studies, and analyses of B cells in the peripheral blood and cerebrospinal fluid (CSF) have permitted the integration of B cells in our overall picture of MS immunopathogenesis. The as yet strongest direct evidence for a central role of B cells in MS autoimmunity was the demonstration that peripheral B cell depletion leads to a rapid decline of disease-activity in MS. While lending formidable impact to peripheral blood B cells as mediators of disease activity, the effects of anti-CD20 treatment also seemingly challenged the paradigm of a role of antibodies in targeted central nervous system (CNS) myelin destruction. This review shall attempt to provide an overview of our current understanding of B cell and antibody mediated mechanisms relevant to MS. We will include findings from, both, human studies, and animal models to highlight the complexity of B cell function as it pertains to MS. B cells appear to be effective drivers of inflammatory activity in MS by way of a diverse toolset of cellular functions. These functions appear to be closely linked to B cells that can be found in the periphery. However, by serving as the source of antibodies, B cells offer a direct humoral response that may target the CNS and lead to tissue specific destruction. Therefore, B cells participate in MS pathogenesis on both sides of the blood-brain barrier. PMID:21983151

von Budingen, H.-Christian; Bar-Or, Amit; Zamvil, Scott S.

2014-01-01

219

[Primary mediastinal B-cell lymphoma].  

PubMed

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

Coso, D; Rey, J; Bouabdallah, R

2010-02-01

220

Treatment of Diffuse Large B Cell Lymphoma  

PubMed Central

Diffuse large B cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma in all countries and all age groups. DLBCL is potentially curable, and the outcome of patients with DLBCL has completely changed with the introduction of therapy involving the monoclonal antibody rituximab in combination with chemotherapy. Nonetheless, relapse is detected after treatment with rituximab, cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisolone in approximately 30% of patients. It has recently become clear that DLBCL represents a heterogeneous admixture of quite different entities. Gene expression profiling has uncovered DLBCL subtypes that have distinct clinical behaviors and prognoses; however, incorporation of this information into treatment algorithms awaits further investigation. Future approaches to DLBCL treatment will use this new genetic information to identify potential biomarkers for prognosis and targets for treatment. PMID:23269875

2012-01-01

221

Gene Rearrangement in B and T-Lymphoproliferative Disease Detected by the Polymerase Chain Reaction  

Microsoft Academic Search

Gene rearrangement and monoclonality have been detected in normal cells and in lymphoproliferative disease by using the polymerase chain reaction and primers for the V and J regions of the lg heavy chain gene or T-cell receptor ychain gene. Using the lg primers monoclonality was detected in 20 of 20 normal B-lymphocyte clones and in 39 of 52 cases of

K. J. Trainor; M. J. Brisco; J. H. Wan; S. Neoh; S. Grist; A. A. Morley

222

Simultaneous and sequential concurrent myeloproliferative and lymphoproliferative neoplasms.  

PubMed

Concurrent manifestation of two chronic-stage myeloid and lymphoid/plasmacytoid neoplasms in one patient is rare and occurs in ?1% of patients. There has been no systematic analysis of which combinations are frequent/infrequent and whether two concurrent diseases in one patient are clonally related or represent independent diseases. We therefore characterised a series of cases from our own archive (n = 65) and collected a large number of previously reported cases of patients in whom myeloid and lymphoid/plasmacytoid neoplasms co-occurred (n = 185). The most frequent combination was Philadelphia chromosome-negative myeloproliferative neoplasm with concurrent B cell chronic lymphocytic leukaemia, accounting for approximately 50% of double-disease patients. We compared the quantity of unsorted bone marrow cell-derived JAK2(V617F) and KIT(D816V) alleles with the quantity of the lymphoid/plasmacytoid compartment and analysed a subfraction of cases with fluorescence in situ hybridisation. Although a common aberrant progenitor has been reported in some cases in the literature, we found evidence of two independent chronic-stage myeloid and lymphoid/plasmacytoid neoplasms. PMID:23257916

Hauck, Gesa; Jonigk, Danny; Kreipe, Hans; Hussein, Kais

2013-01-01

223

Differential Programming of B Cells in AID Deficient Mice  

PubMed Central

The Aicda locus encodes the activation induced cytidine deaminase (AID) and is highly expressed in germinal center (GC) B cells to initiate somatic hypermutation (SHM) and class switch recombination (CSR) of immunoglobulin (Ig) genes. Besides these Ig specific activities in B cells, AID has been implicated in active DNA demethylation in non-B cell systems. We here determined a potential role of AID as an epigenetic eraser and transcriptional regulator in B cells. RNA-Seq on different B cell subsets revealed that Aicda?/? B cells are developmentally affected. However as shown by RNA-Seq, MethylCap-Seq, and SNP analysis these transcriptome alterations may not relate to AID, but alternatively to a CBA mouse strain derived region around the targeted Aicda locus. These unexpected confounding parameters provide alternative, AID-independent interpretations on genotype-phenotype correlations previously reported in numerous studies on AID using the Aicda?/? mouse strain. PMID:23922811

Hogenbirk, Marc A.; Heideman, Marinus R.; Velds, Arno; van den Berk, Paul CM.; Kerkhoven, Ron M.; van Steensel, Bas; Jacobs, Heinz

2013-01-01

224

Dissecting teleost B cell differentiation using transcription factors.  

PubMed

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

Zwollo, Patty

2011-09-01

225

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

PubMed Central

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

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

2014-01-01

226

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

PubMed

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

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

2014-01-01

227

Transcriptional networks in developing and mature B cells  

Microsoft Academic Search

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

Antonius G. Rolink; Patrick Matthias

2005-01-01

228

Transcriptional and epigenetic regulation of B cell development  

Microsoft Academic Search

B cell development starts in the bone marrow where hematopoietic stem cells (HSCs) progress through sequential developmental\\u000a stages, as it differentiates into a naïve B cell expressing surface immunoglobulin. In the periphery, B cells that encounter\\u000a antigen can further differentiate into antibody-secreting plasma cells. In this review, we focus on two factors, E47 and ELL2,\\u000a which play important roles in

Patricia SantosFortuna; Fortuna Arumemi; Kyung Soo Park; Lisa Borghesi; Christine Milcarek

2011-01-01

229

Autoimmune lymphoproliferative syndrome and non-Hodgkin lymphoma: what 18F-fluorodeoxyglucose positron emission tomography/computed tomography can do in the management of these patients? Suggestions from a case report.  

PubMed

A young patient with undefined autoimmune lymphoproliferative syndrome (ALPS-U) and low back pain underwent a CT and MRI study that showed enhancing vertebral lesions, some pulmonary nodules and diffuse latero-cervical lymphadenopathy. A (18)F-FDG-PET/CT scan showed many areas of intense (18)F-FDG uptake in multiple vertebrae, in some ribs, in the sacrum, in the liver, in both lungs, in multiple lymph nodes spread in the cervical, thoracic and abdominal chains. A bone marrow biopsy showed a "lymphomatoid granulomatosis", a rare variant of B-cell non-Hodgkin lymphoma (NHL). After the treatment, the (18)F-FDG-PET/CT scan showed a complete metabolic response. PMID:23845452

Cistaro, A; Pazè, F; Durando, S; Cogoni, M; Faletti, R; Vesco, S; Vallero, S; Quartuccio, N; Treglia, G; Ramenghi, U

2014-01-01

230

Aberrant antibody affinity selection in SHIP-deficient B cells  

PubMed Central

The strength of the Ag receptor signal influences development and negative selection of B cells, and it might also affect B-cell survival and selection in the GC. Here, we have used mice with B-cell-specific deletion of the 5?-inositol phosphatase SHIP as a model to study affinity selection in cells that are hyperresponsive to Ag and cytokine receptor stimulation. In the absence of SHIP, B cells have lower thresholds for Ag- and interferon (IFN)-induced activation, resulting in augmented negative selection in the BM and enhanced B-cell maturation in the periphery. Despite a tendency to spontaneously downregulate surface IgM expression, SHIP deficiency does not alter anergy induction in response to soluble hen-egg lysozyme Ag in the MDA4 transgenic model. SHIP-deficient B cells spontaneously produce isotype-switched antibodies; however, they are poor responders in immunization and infection models. While SHIP-deficient B cells form GCs and undergo mutation, they are not properly selected for high-affinity antibodies. These results illustrate the importance of negative regulation of B-cell responses, as lower thresholds for B-cell activation promote survival of low affinity and deleterious receptors to the detriment of optimal Ab affinity maturation. PMID:23135975

Leung, Wai-Hang; Tarasenko, Tatiana; Biesova, Zuzana; Kole, Hemanta; Walsh, Elizabeth R.; Bolland, Silvia

2013-01-01

231

Age effects on B cells and humoral immunity in humans  

PubMed Central

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

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

2010-01-01

232

Aberrant antibody affinity selection in SHIP-deficient B cells.  

PubMed

The strength of the Ag receptor signal influences development and negative selection of B cells, and it might also affect B-cell survival and selection in the GC. Here, we have used mice with B-cell-specific deletion of the 5'-inositol phosphatase SHIP as a model to study affinity selection in cells that are hyperresponsive to Ag and cytokine receptor stimulation. In the absence of SHIP, B cells have lower thresholds for Ag- and interferon (IFN)-induced activation, resulting in augmented negative selection in the BM and enhanced B-cell maturation in the periphery. Despite a tendency to spontaneously downregulate surface IgM expression, SHIP deficiency does not alter anergy induction in response to soluble hen-egg lysozyme Ag in the MDA4 transgenic model. SHIP-deficient B cells spontaneously produce isotype-switched antibodies; however, they are poor responders in immunization and infection models. While SHIP-deficient B cells form GCs and undergo mutation, they are not properly selected for high-affinity antibodies. These results illustrate the importance of negative regulation of B-cell responses, as lower thresholds for B-cell activation promote survival of low affinity and deleterious receptors to the detriment of optimal Ab affinity maturation. PMID:23135975

Leung, Wai-Hang; Tarasenko, Tatiana; Biesova, Zuzana; Kole, Hemanta; Walsh, Elizabeth R; Bolland, Silvia

2013-02-01

233

B-cell targeted therapeutics in clinical development  

PubMed Central

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

2013-01-01

234

Age effects on B cells and humoral immunity in humans.  

PubMed

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

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

2011-07-01

235

AID expression during B-cell development: searching for answers.  

PubMed

Expression of activation-induced cytidine deaminase (AID) by germinal center (GC) B cells drives the processes of immunoglobulin (Ig) somatic hypermutation (SHM) and class switch recombination (CSR) necessary for the generation of high affinity IgG serum antibody and the memory B-cell compartment. Increasing evidence indicates that AID is also expressed at low levels in developing B cells but to date, this early, developmentally regulated AID expression has no known function. Does the timing and extent of AID expression in developmentally immature, non-GC B cells provide clues to reveal its physiologic role? PMID:21136202

Kuraoka, Masayuki; McWilliams, Laurie; Kelsoe, Garnett

2011-04-01

236

Regulatory T cells and B cells: implication on autoimmune diseases  

PubMed Central

The regulatory T (Treg) cells play an important role in the maintenance of homeostasis and the prevention of autoimmune diseases. Although most studies are focusing on the role of Treg cells in T cells and T cells-mediated diseases, these cells also directly affect B cells and other non-T cells. This manuscript updates the role of Treg cells on the B cells and B cell-mediated diseases. In addition, the mechanisms whereby Treg cells suppress B cell responses have been discussed. PMID:24294353

Wang, Ping; Zheng, Song Guo

2013-01-01

237

Invasin of Yersinia pseudotuberculosis activates human peripheral B cells.  

PubMed Central

The Yersinia pseudotuberculosis cell surface-located protein invasin was found to promote binding between the pathogen and resting peripheral B cells via beta 1 integrin receptors (CD29). B cells responded by expressing several activation markers and by growing, In contrast, T cells did not react, although these cells express CD29. An isogenic invA mutant failed to activate B cells. The mutation could be complemented by providing the invA+ gene in trans. Purified invasin alone did not activate B cells, although it was able to block the binding of bacteria to the cells. PMID:8641788

Lundgren, E; Carballeira, N; Vazquez, R; Dubinina, E; Branden, H; Persson, H; Wolf-Watz, H

1996-01-01

238

BAFF ENHANCES CHEMOTAXIS OF PRIMARY HUMAN B CELLS. A PARTICULAR SYNERGY BETWEEN BAFF AND CXCL13 ON MEMORY B CELLS  

Microsoft Academic Search

B-cell-activating factor of the TNF family, (BAFF), and a proliferation-inducing li- gand (APRIL) regulate B-lymphocyte sur- vival and activation. We report that BAFF, but not APRIL, increased the chemotactic response of primary human B cells to CCL21, CXCL12, and CXCL13. The BAFF- induced increase in B-cell chemotaxis was totally abolished by blockade of BAFF-R and was strongly dependent on the

Gamal BADR; Gwenoline BORHIS; Eric A. LEFEVRE; Nada CHAOUL; Frederique DESHAYES; Valérie DESSIRIER; Genevieve LAPREE; Andreas TSAPIS; Yolande RICHARD

2008-01-01

239

B-Cell Restricted Saporin Immunotoxins: Activity Against B-Cell Lines and Chronic Lymphocytic Leukemia Cells  

Microsoft Academic Search

B cell-restricted immunotoxins were constructed by con- jugating anti-B monoclonal antibodies to saporin, the major ribosome inactivating protein from the seeds of the plant Saponaria officinalis. HD37-SAP is directed against CD1 9, the broadest B cell-specific determinant. HD39-SAP and HD6-SAP recognize two different epitopes on the CD22 molecule, an antigen present on the cell surface of B cells at late

Marco Bregni; Salvatore Siena; Anna Formosa; Douglas A. Lappi; Darlene Martineau; Fabio Malavasi; Bernd Dorken; Gianni Bonadonna; Alessandro M. Gianni

1989-01-01

240

Exacerbation of interstitial granulomatous dermatitis with arthritis by anakinra in a patient with diffuse large B-cell lymphoma.  

PubMed

Interstitial granulomatous dermatitis with arthritis (IGDA) is a rare idiopathic skin disorder with variable cutaneous expression, typically associated with a seronegative arthritis. Histopathology of this disorder reveals a granulomatous infiltrate with foci of collagen degeneration in the deep reticular dermis. We present a case of IGDA in a 56-year-old man with diffuse large B-cell lymphoma, exacerbated by the administration of anakinra. PMID:24480300

Michailidou, D; Voulgarelis, M; Pikazis, D

2014-01-01

241

Characterization of Two Distinct Lymphoproliferative Diseases Caused by Ectopic Expression of the Notch Ligand DLL4 on T Cells  

PubMed Central

Notch signaling is essential for the development of T cell progenitors through the interaction of NOTCH1 receptor on their surface with the ligand, Delta-like 4 (DLL4), which is expressed by the thymic epithelial cells. Notch signaling is quickly shut down once the cells pass ?-selection, and CD4/CD8 double positive (DP) cells are unresponsive to Notch. Over the past two decades a number of papers reported that over-activation of Notch signaling causes T cell acute lymphoblastic leukemia (T-ALL), a cancer that prominently features circulating monoclonal CD4/CD8 double positive T cells in different mouse models. However, the possible outcomes of Notch over-activation at different stages of T cell development are unknown, and the fine timing of Notch signaling that results in T-ALL is poorly understood. Here we report, by using a murine model that ectopically expresses DLL4 on developing T cells, that the T-ALL onset is highly dependent on a sustained Notch activity throughout the DP stage, which induces additional mutations to further boost the signaling. In contrast, a shorter period of Notch activation that terminates at the DP stage causes a polyclonal, non-transmissible lymphoproliferative disorder that is also lethal. These observations resolved the discrepancy of previous papers on DLL4 driven hematological diseases in mice, and show the critical importance of the timing and duration of Notch activity. PMID:24386421

Latkowski, Jo-Ann; Henderson, Tanya; Schlessinger, Karni; Ding, Yi; Shen, Jie; Tadokoro, Carlos E.; Lafaille, Juan J.

2013-01-01

242

Marginal Zone B-Cells, a Gatekeeper of Innate Immunity  

PubMed Central

To maintain the integrity of an organism constantly challenged by pathogens, the immune system is endowed with a variety of cell types. B lymphocytes were initially thought to only play a role in the adaptive branch of immunity. However, a number of converging observations revealed that two B-cell subsets, marginal zone (MZ) and B1 cells, exhibit unique developmental and functional characteristics, and can contribute to innate immune responses. In addition to their capacity to mount a local antibody response against type-2 T-cell-independent (TI-2) antigens, MZ B-cells can participate to T-cell-dependent (TD) immune responses through the capture and import of blood-borne antigens to follicular areas of the spleen. Here, we discuss the multiple roles of MZ B-cells in humans, non-human primates, and rodents. We also summarize studies – performed in transgenic mice expressing fully human antibodies on their B-cells and in macaques whose infection with Simian immunodeficiency virus (SIV) represents a suitable model for HIV-1 infection in humans – showing that infectious agents have developed strategies to subvert MZ B-cell functions. In these two experimental models, we observed that two microbial superantigens for B-cells (protein A from Staphylococcus aureus and protein L from Peptostreptococcus magnus) as well as inactivated AT-2 virions of HIV-1 and infectious SIV preferentially deplete innate-like B-cells – MZ B-cells and/or B1 B-cells – with different consequences on TI and TD antibody responses. These data revealed that viruses and bacteria have developed strategies to deplete innate-like B-cells during the acute phase of infection and to impair the antibody response. Unraveling the intimate mechanisms responsible for targeting MZ B-cells in humans will be important for understanding disease pathogenesis and for designing novel vaccine strategies. PMID:22566852

Zouali, Moncef; Richard, Yolande

2011-01-01

243

How B Cells Influence Bone Biology in Health and Disease  

PubMed Central

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

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

2010-01-01

244

B-cell selection and the development of autoantibodies  

PubMed Central

The clearest evidence that B cells play an important role in human autoimmunity is that immunotherapies that deplete B cells are very effective treatments for many autoimmune diseases. All people, healthy or ill, have autoreactive B cells, but not at the same frequency. A number of genes influence the level of these autoreactive B cells and whether they are eliminated or not during development at a central checkpoint in the bone marrow (BM) or at a later checkpoint in peripheral lymphoid tissues. These genes include those encoding proteins that regulate signaling through the B-cell receptor complex such as Btk and PTPN22, proteins that regulate innate signaling via Toll-like receptors (TLRs) such as MyD88 and interleukin-1 receptor-associated kinase 4, as well as the gene encoding the activation-induced deaminase (AID) essential for B cells to undergo class switch recombination and somatic hypermutation. Recent studies have revealed that TLR signaling elements and AID function not only in peripheral B cells to help mediate effective antibody responses to foreign antigens, but also in the BM to help remove autoreactive B-lineage cells at a very early point in B-cell development. Newly arising B cells that leave the BM and enter the blood and splenic red pulp can express both AID and TLR signaling elements like TLR7, and thus are fully equipped to respond rapidly to antigens (including autoantigens), to isotype class switch, and to undergo somatic hypermutation. These red pulp B cells may thus be an important source of autoantibody-producing cells arising particularly in extrafollicular sites, and indeed may be as significant a source of autoantibody-producing cells as B cells arising from germinal centers. PMID:23281837

2012-01-01

245

Signaling circuits in early B-cell development.  

PubMed

Early B-cell development is an ordered and highly regulated process with alternating phases of cell proliferation and differentiation leading to B cells with the ability to recognize an extraordinarily large repertoire of different antigens. Here, we discuss what is currently known about the receptors in B-cell progenitors and how their signaling pathways influence immunoglobulin (Ig) gene rearrangement and the transcriptional program of early B cells. In particular, we address the interplay of the interleukin-7 receptor and the pre-B-cell receptor (preBCR) in shaping the survival, proliferation, and differentiation of early B cells. Each receptor addresses a unique set of signaling components but they also share signaling pathways, most prominently the MAPK/Erk and phosphoinositide-3 kinase pathways. The latter pathway regulates transcription factors of the FoxO family that play a central role in the proliferation to differentiation switch of pre-B cells. Interestingly, these two alternative cellular programs (proliferation and differentiation) are both controlled by the preBCR. Finally, we discuss how mutations or alterations of these pathways result in deregulated pre-B-cell expansion and leukemia. PMID:24507157

Reth, Michael; Nielsen, Peter

2014-01-01

246

Streptozotocin is not toxic to the human fetal B cell  

Microsoft Academic Search

Summary  It has been generally assumed that because streptozotocin is toxic to the adult B cell of most species, it should also damage B cells obtained at earlier stages of development. This paper examines whether this is true for human fetal pancreata obtained from the therapeutic termination of pregnancies during the first half of the second trimester. Experiments were carried out

B. E. Tuch; J. R. Turtle; C. J. Simeonovic

1989-01-01

247

Cells of the synovium in rheumatoid arthritis. B cells  

Microsoft Academic Search

There is significant evidence arising from experimental models that autoantibodies play a key role in the pathogenesis of inflammatory arthritis. In addition to autoantibody production, B cells efficiently present antigen to T cells, produce soluble factors, including cytokines and chemokines, and form B cell aggregates in the target organ of rheumatoid arthritis. In this review we analyze the multifaceted role

Claudia Mauri; Michael R Ehrenstein

2007-01-01

248

B cells: the old new players in reproductive immunology.  

PubMed

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

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

2014-01-01

249

What are regulatory B cells? David Gray1  

E-print Network

Research, School of Biological Sciences, University of Edinburgh, Ashworth Labs, Edinburgh, UK 2 Centre for B cells had been suspected for many years and in 1996 Janeway's group [2] showed that in the mouse model of multiple sclerosis, EAE, a genetic lack of B cells led to exacerbated disease. Subsequent

MacDonald, Andrew

250

B cells do not present antigen covalently linked to microspheres.  

PubMed Central

B cells have been shown to present antigen to T cells very efficiently through their capacity to capture antigens by their membrane immunoglobulin. This direct cognate interaction of T and B cells results in the proliferation and differentiation of B cells. This concept has been established using soluble proteins. However, most of the antigens to which the immune system is exposed are included in complex particulate structures such as bacteria or parasites. The capacity of B cells to present these large and complex antigens is still unclear. To address this question we have studied the presentation by trinitrophenyl (TNP)-specific B cells of the same antigen TNP-KLH (keyhole limpet haemocyanin), either in a soluble form or covalently linked to poly(acrolein) microspheres, from 0.25 to 1.5 microns in diameter. In the presence of irradiated splenocytes or purified macrophages as a source of antigen-presenting cells (APC), KLH-specific T cells proliferated in response to soluble TNP-KLH or to TNP-KLH coupled to beads. In contrast, TNP-specific memory B cells were totally ineffective in presenting the TNP-KLH beads to KLH-specific T cells whereas they presented very efficiently soluble TNP-KLH. Similar results were obtained with the A20 B lymphoma or with lipopolysaccharide (LPS)-activated TNP-specific B cells. These results therefore indicate that B cells are unable to present large size particulate antigens such as bacteria or parasites. PMID:8509143

Galelli, A; Charlot, B; Deriaud, E; Leclerc, C

1993-01-01

251

B cell function in the immune response to helminths  

PubMed Central

Similar T helper (Th)2-type immune responses are generated against different helminths parasites, but the mechanisms that initiate Th2 immunity, and the specific immune components that mediate protection against these parasites, can vary greatly. B cells are increasingly recognized as important during the Th2-type immune response to helminths, and B cell activation might be a target for effective vaccine development. Antibody production is a function of B cells during helminth infection and understanding how polyclonal and antigen-specific antibodies contribute should provide important insights into how protective immunity develops. In addition, B cells might also contribute to the host response against helminths through antibody-independent functions including, antigen-presentation, as well as regulatory and effector activity. In this review, we examine the role of B cells during Th2-type immune response to these multicellular parasites. PMID:21159556

Harris, Nicola

2010-01-01

252

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

PubMed

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

Furtado, João; Isenberg, David A

2013-09-01

253

Therapeutic down-regulation of central and peripheral B-cell-activating factor (BAFF) production in pediatric opsoclonus–myoclonus syndrome  

Microsoft Academic Search

Opsoclonus–myoclonus syndrome (OMS) is an autoimmune, paraneoplastic, central nervous system disorder, characterized by cerebrospinal fluid (CSF) B-cell expansion and various putative autoantibodies. To investigate the role of B-cell activating factor (BAFF) in OMS and the effect of disease-modifying immunotherapies used to treat it, BAFF was measured by enzyme-linked immunoadsorbent assay in the CSF and serum of 161 children with OMS

Michael R. Pranzatelli; Elizabeth D. Tate; Erik R. Hoefgen; Jennifer A. Swan; Jerry A. Colliver

2008-01-01

254

Post-transplantation B cell activating factor and B cell recovery before onset of chronic graft-versus-host disease.  

PubMed

Excessive levels of B cell activating factor (BAFF) are found in patients with active chronic graft-versus-host disease (cGVHD). In mice, BAFF has been shown to be essential for B cell recovery after myeloablation. To assess how BAFF levels relate to transplantation factors and subsequent development of cGVHD, we prospectively monitored 412 patients in the first year after allogeneic peripheral blood or bone marrow hematopoietic stem cell transplantation (HSCT) and censored data at time of cGVHD onset. In patients who did not develop cGVHD, we affirmed a temporal pattern of gradually decreasing BAFF levels as B cell numbers increase after myeloablative conditioning. In contrast, after reduced-intensity conditioning, BAFF levels remained high throughout the first post-HSCT year, suggesting that the degree of myeloablation resulted in delayed B cell recovery associated with persistence of higher BAFF levels. Given that high BAFF/B cell ratios have been associated with active cGVHD, we examined differences in early BAFF/B cell ratios and found significantly different BAFF/B cell ratios at 3 months post-HSCT only after myeloablative conditioning in patients who subsequently developed cGVHD. In addition to HSCT conditioning type, the use of sirolimus was significantly associated with higher BAFF levels after HSCT, and this also was potentially related to lower B cell numbers. Taken together, our results are important for interpreting BAFF measurements in cGVHD biomarker studies. PMID:24462743

Jacobson, Caron A; Sun, Lixian; Kim, Haesook T; McDonough, Sean M; Reynolds, Carol G; Schowalter, Michael; Koreth, John; Cutler, Corey S; Ho, Vincent T; Alyea, Edwin P; Armand, Philippe; Blazar, Bruce R; Soiffer, Robert J; Antin, Joseph H; Ritz, Jerome; Sarantopoulos, Stefanie

2014-05-01

255

Genomic Uracil Homeostasis during Normal B Cell Maturation and Loss of This Balance during B Cell Cancer Development.  

PubMed

Activation-induced deaminase (AID) converts DNA cytosines to uracils in immunoglobulin genes, creating antibody diversification. It also causes mutations and translocations that promote cancer. We examined the interplay between uracil creation by AID and its removal by UNG2 glycosylase in splenocytes undergoing maturation and in B cell cancers. The genomic uracil levels remain unchanged in normal stimulated B cells, demonstrating a balance between uracil generation and removal. In stimulated UNG(-/-) cells, uracil levels increase by 11- to 60-fold during the first 3 days. In wild-type B cells, UNG2 gene expression and enzymatic activity rise and fall with AID levels, suggesting that UNG2 expression is coordinated with uracil creation by AID. Remarkably, a murine lymphoma cell line, several human B cell cancer lines, and human B cell tumors expressing AID at high levels have genomic uracils comparable to those seen with stimulated UNG(-/-)splenocytes. However, cancer cells express UNG2 gene at levels similar to or higher than those seen with peripheral B cells and have nuclear uracil excision activity comparable to that seen with stimulated wild-type B cells. We propose that more uracils are created during B cell cancer development than are removed from the genome but that the uracil creation/excision balance is restored during establishment of cell lines, fixing the genomic uracil load at high levels. PMID:25154417

Shalhout, Sophia; Haddad, Dania; Sosin, Angela; Holland, Thomas C; Al-Katib, Ayad; Martin, Alberto; Bhagwat, Ashok S

2014-11-01

256

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

Microsoft Academic Search

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

Michael J. Eck; Cox Terhorst; Pablo Engel

2003-01-01

257

Lymphoproliferative response and its relationship with histological lesions in experimental ovine paratuberculosis and its diagnostic implications  

Microsoft Academic Search

Lymphoproliferative response (LPR) was studied in 19 lambs orally infected (Group I) with Mycobacterium avium subsp. paratuberculosis (MAP) with in vitro lymphocyte stimulation test using MTT dye reduction assay. The non-specific LPR against Con A and specific LPR against sonicated\\u000a antigen and johnin PPD (purified protein derivatives) were estimated on preinfection (0 day) and various days postinfection\\u000a period (15 to

N. P. Kurade; B. N. Tripathi

2008-01-01

258

B cells regulate CD4+ T cell responses to papain following B cell receptor-independent papain uptake.  

PubMed

Papain, a cysteine protease allergen with inherent adjuvant activity, induces potent IL-4 expression by T cells in the popliteal lymph nodes of mice following footpad immunization. In this study, we identify a novel, non-BCR-mediated capacity for B cells to rapidly bind and internalize papain. B cells subsequently regulate the adaptive immune response by enhancing ICOS expression on CD4(+) T cells and amplifying Th2 and follicular helper T cell induction. Ab blockade of ICOS ligand, expressed by popliteal lymph node B cells, but not dendritic cells, at the peak of the response inhibits IL-4 responses in wild-type mice but not B cell-deficient mice. Thus, B cells play a critical role in amplifying adjuvant-dependent Th2 polarization following noncanonical acquisition and internalization of the cysteine protease papain. PMID:24928991

Dwyer, Daniel F; Woodruff, Matthew C; Carroll, Michael C; Austen, K Frank; Gurish, Michael F

2014-07-15

259

B Cell Signal Transduction in Germinal Center B Cells is Short-Circuited by Increased Phosphatase Activity  

PubMed Central

Germinal centers (GCs) generate memory B and plasma cells, essential for long-lived humoral immunity. GC B cells with high affinity B cell receptors (BCRs) are selectively expanded. To enable this selection, BCRs of such cells are thought to signal differently from those with lower affinity. We show that, surprisingly, most proliferating GC B cells did not demonstrate active BCR signaling. Rather, spontaneous and induced signaling was limited by increased phosphatase activity. Accordingly, both SHP-1 and SHIP-1 were hyperphosphorylated in GC cells and remained colocalized with BCRs after ligation. Furthermore, SHP-1 was required for GC maintenance. Intriguingly, GC B cells in the cell cycle G2 period regained responsiveness to BCR stimulation. These data have implications for how higher affinity B cells are selected in the GC. PMID:22555432

Khalil, Ashraf M.; Cambier, John C.; Shlomchik, Mark J.

2013-01-01

260

Epstein-Barr Virus Infection of Na?ve B Cells In Vitro Frequently Selects Clones with Mutated Immunoglobulin Genotypes: Implications for Virus Biology  

PubMed Central

Epstein-Barr virus (EBV), a lymphomagenic human herpesvirus, colonises the host through polyclonal B cell-growth-transforming infections yet establishes persistence only in IgD+ CD27+ non-switched memory (NSM) and IgD? CD27+ switched memory (SM) B cells, not in IgD+ CD27? naïve (N) cells. How this selectivity is achieved remains poorly understood. Here we show that purified N, NSM and SM cell preparations are equally transformable in vitro to lymphoblastoid cells lines (LCLs) that, despite upregulating the activation-induced cytidine deaminase (AID) enzyme necessary for Ig isotype switching and Ig gene hypermutation, still retain the surface Ig phenotype of their parental cells. However, both N- and NSM-derived lines remain inducible to Ig isotype switching by surrogate T cell signals. More importantly, IgH gene analysis of N cell infections revealed two features quite distinct from parallel mitogen-activated cultures. Firstly, following 4 weeks of EBV-driven polyclonal proliferation, individual clonotypes then become increasingly dominant; secondly, in around 35% cases these clonotypes carry Ig gene mutations which both resemble AID products and, when analysed in prospectively-harvested cultures, appear to have arisen by sequence diversification in vitro. Thus EBV infection per se can drive at least some naïve B cells to acquire Ig memory genotypes; furthermore, such cells are often favoured during an LCL's evolution to monoclonality. Extrapolating to viral infections in vivo, these findings could help to explain how EBV-infected cells become restricted to memory B cell subsets and why EBV-driven lymphoproliferative lesions, in primary infection and/or immunocompromised settings, so frequently involve clones with memory genotypes. PMID:22589726

Croom-Carter, Debbie; Shannon-Lowe, Claire; Kube, Dieter; Feederle, Regina; Delecluse, Henri-Jacques; Rickinson, Alan B.; Bell, Andrew I.

2012-01-01

261

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

PubMed Central

Combined clinicopathologic and immunomorphologic evidence is presented that would indicate that a murine leukemia virus (MuLV) with the dualtropic host range is capable of producing a clinically malignant lesion composed of immunoblasts and associated plasma cells in C57BL/6 mice. This process, morphologically diagnosed as an immunoblastic lymphoma of B cells using standard histopathologic criteria, was found to be distinctly polyclonal with regard to immunoglobulin (Ig) isotype when analyzed for both surface and cytoplasmic Ig. Further studies demonstrated that this clinicopathologically malignant, dualtropic MuLV-induced, polyclonal immunoblastic lymphoma of B cells in C57BL/6 mice was normal diploid and unable to be successfully transplanted to nonimmunosuppressed syngeneic recipients. Although all serum heavy and light chain components were found to be progressively elevated as the tumor load increased, the polyclonal increase in serum immunoglobulins was most pronounced for mu heavy and kappa light chains (ie, mu greater than gamma 2A greater than alpha greater than gamma 2B greater than gamma 1; kappa greater than lamba). The dissociation of clinicopathologic and biologic criteria for malignancy in the presently described dualtropic (RadLV) MuLV-induced B-cell lesion is sharply contrasted with the thymotropic (RadLV), MuLV-induced T-cell lymphoblastic lymphoma in C57BL/6 mice. This process is also a clinicopathologically malignant lesion but, when one uses biologic criteria, is found to be distinctly monoclonal, aneuploid, and easily transplanted to nonimmunosuppressed syngeneic recipients. The close clinicopathologic and biologic similarities of the dualtropic MuLV-induced animal model to corresponding human B-cell lymphoproliferative diseases are stressed. Images Figure 2 Figure 3 Figure 4 Figure 5 Figure 7 PMID:6282131

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

1982-01-01

262

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

PubMed Central

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

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

2014-01-01

263

Ligand mobility regulates B cell receptor clustering and signaling activation.  

PubMed

Antigen binding to the B cell receptor (BCR) induces receptor clustering, cell spreading, and the formation of signaling microclusters, triggering B cell activation. Although the biochemical pathways governing early B cell signaling have been well studied, the role of the physical properties of antigens, such as antigen mobility, has not been fully examined. We study the interaction of B cells with BCR ligands coated on glass or tethered to planar lipid bilayer surfaces to investigate the differences in B cell response to immobile and mobile ligands. Using high-resolution total internal reflection fluorescence (TIRF) microscopy of live cells, we followed the movement and spatial organization of BCR clusters and the associated signaling. Although ligands on either surface were able to cross-link BCRs and induce clustering, B cells interacting with mobile ligands displayed greater signaling than those interacting with immobile ligands. Quantitative analysis revealed that mobile ligands enabled BCR clusters to move farther and merge more efficiently than immobile ligands. These differences in physical reorganization of receptor clusters were associated with differences in actin remodeling. Perturbation experiments revealed that a dynamic actin cytoskeleton actively reorganized receptor clusters. These results suggest that ligand mobility is an important parameter for regulating B cell signaling. PMID:24411234

Ketchum, Christina; Miller, Heather; Song, Wenxia; Upadhyaya, Arpita

2014-01-01

264

Exploiting Human Memory B Cell Heterogeneity for Improved Vaccine Efficacy  

PubMed Central

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

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

2011-01-01

265

B Cell Receptor Signaling: Picky About PI3Ks  

NSDL National Science Digital Library

The B cell receptor (BCR) and the pre-BCR control cell fate at many stages of B cell development, survival, and antigen response. Most of these processes require the activation of phosphatidylinositol 3-kinase (PI3K). Previous work has pointed to p110δ as the key catalytic isoform of PI3K for many B cell responses. A study of mice with different combinations of PI3K mutations confirms the central role of p110δ in agonist-mediated signaling, while identifying an unexpected function for the p110α isoform in tonic signaling by the pre-BCR and mature BCR.

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

2010-08-10

266

Subcutaneous versus Intravenous Administration of Rituximab: Pharmacokinetics, CD20 Target Coverage and B-Cell Depletion in Cynomolgus Monkeys  

PubMed Central

The CD20-specific monoclonal antibody rituximab (MabThera®, Rituxan®) is widely used as the backbone of treatment for patients with hematologic disorders. Intravenous administration of rituximab is associated with infusion times of 4–6 hours, and can be associated with infusion-related reactions. Subcutaneous administration of rituximab may reduce this and facilitate administration without infusion-related reactions. We sought to determine the feasibility of achieving equivalent efficacy (measured by endogenous B-cell depletion) and long-term durability of CD20 target coverage for subcutaneously administered rituximab compared with intravenous dosing. In these preclinical studies, male cynomolgus monkeys were treated with either intravenous rituximab or novel subcutaneous formulation of rituximab containing human recombinant DNA-derived hyaluronidase enzyme. Peripheral blood samples were analyzed for serum rituximab concentrations, peripheral B-cell depletion, and CD20 target coverage, including subset analysis according to CD21+ status. Distal lymph node B-cell depletion and CD20 target coverage were also measured. Initial peak serum concentrations of rituximab were significantly higher following intravenous administration than subcutaneous. However, the mean serum rituximab trough concentrations were comparable at 2 and 7 days post-first dose and 9 and 14 days post-second dose. Efficacy of B-cell depletion in both peripheral blood and distal lymph nodes was comparable for both methods. In lymph nodes, 9 days after the second dose with subcutaneous and intravenous rituximab, B-cell levels were decreased by 57% and 42% respectively. Similarly, levels of peripheral blood B cells were depleted by >94% for both subcutaneous and intravenous dosing at all time points. Long-term recovery of free unbound surface CD20 levels was similar, and the duration of B-cell depletion was equally sustained over 2 months for both methods. These results demonstrate that, despite initial peak serum drug level differences, subcutaneous rituximab has similar durability, pharmacodynamics, and efficacy compared with intravenous rituximab. PMID:24265828

Mao, Cheng-Ping; Brovarney, Martin R.; Dabbagh, Karim; Birnbock, Herbert F.; Richter, Wolfgang F.; Del Nagro, Christopher J.

2013-01-01

267

B-cell restricted saporin immunotoxins: activity against B-cell lines and chronic lymphocytic leukemia cells.  

PubMed

B cell-restricted immunotoxins were constructed by conjugating anti-B monoclonal antibodies to saporin, the major ribosome inactivating protein from the seeds of the plant Saponaria officinalis. HD37-SAP is directed against CD19, the broadest B cell-specific determinant. HD39-SAP and HD6-SAP recognize two different epitopes on the CD22 molecule, an antigen present on the cell surface of B cells at late stages of differentiation. All three immunotoxins inhibited DNA synthesis and protein synthesis in target B lymphoma cells with a dose-related effect, in short incubation times and in the absence of potentiators. A clonogenic assay demonstrated that all immunotoxins could eliminate more than two logs of clonogenic malignant B cells with a two-hour incubation at concentrations not toxic to cells not bearing target antigens. The immunotoxin activity was evaluated by DNA synthesis inhibition in fresh B-chronic lymphocytic leukemia cells (B-CLL) stimulated to proliferate by incubation with an antibody specific for the receptor of C3b complement component (CR1) plus B cell growth factor. B-CLL cell DNA synthesis was actively inhibited by treatment at low immunotoxin concentration without need of potentiators. Immunotoxins exerted their effect also in whole blood of CLL patients under conditions achievable in vivo. We conclude that B cell-restricted immunotoxins HD37-SAP, HD39-SAP, and HD6-SAP are good candidates for in vivo therapy of B-cell malignancies. PMID:2465042

Bregni, M; Siena, S; Formosa, A; Lappi, D A; Martineau, D; Malavasi, F; Dorken, B; Bonadonna, G; Gianni, A M

1989-02-15

268

Gene therapy delivery of myelin oligodendrocyte glycoprotein (MOG) via hematopoietic stem cell transfer induces MOG-specific B cell deletion.  

PubMed

The various mechanisms that have been described for immune tolerance govern our ability to control self-reactivity and minimize autoimmunity. However, the capacity to genetically manipulate the immune system provides a powerful avenue to supplement this natural tolerance in an Ag-specific manner. We have previously shown in the mouse model of experimental autoimmune encephalomyelitis that transfer of bone marrow (BM) transduced with retrovirus encoding myelin oligodendrocyte glycoprotein (MOG) promotes disease resistance and CD4(+) T cell deletion within the thymus. However, the consequence of this strategy on B cell tolerance is not known. Using BM from IgH(MOG) mice that develop MOG-specific B cell receptors, we generated mixed chimeras together with BM-encoding MOG. In these animals, the development of MOG-specific B cells was abrogated, resulting in a lack of MOG-specific B cells in all B cell compartments examined. This finding adds a further dimension to our understanding of the mechanisms of tolerance that are associated with this gene therapy approach to treating autoimmunity and may have important implications for Ab-mediated autoimmune disorders. PMID:24532581

Chung, Jie-Yu; Figgett, William; Fairfax, Kirsten; Bernard, Claude; Chan, James; Toh, Ban-Hock; Mackay, Fabienne; Alderuccio, Frank

2014-03-15

269

The pre-B-cell receptor: selector of fitting immunoglobulin heavy chains for the B-cell repertoire  

Microsoft Academic Search

In this Opinion article, I address the role of the pre-B-cell receptor (pre-BCR) in the development of antigen-specific B cells in terms of immunoglobulin heavy chain (IgH) variable-region repertoire selection, precursor B-cell differentiation and proliferation, and IgH allelic exclusion. Comparisons with the role of the pre-T-cell receptor (pre-TCR) in T-cell development raise provocative questions. Why do B- and T-cell lineages

Fritz Melchers

2005-01-01

270

New targets for antibody therapy of pediatric B cell lymphomas.  

PubMed

Antibody therapy has become standard of care for adult B cell lymphoma patients. It is a potentially less toxic and more targeted approach for lymphoma therapy and should therefore be applied to treat pediatric B cell lymphoma patients as well. In pediatric lymphoma patients, however, clinical experience with monoclonal antibodies is very limited. This is in part due to smaller patient numbers and very good outcome with conventional chemotherapy. In addition, pediatric patient and lymphoma biology differ significantly from that found in adults often precluding extrapolation of the adult experience to children. This review focuses on targeting pediatric B cell lymphoma with monoclonal antibody therapy. The special characteristics of B cell lymphomas found in children are reviewed and six potential new lymphoma target antigens are discussed. Pediatr Blood Cancer 2014;61:2158-2163. © 2014 Wiley Periodicals, Inc. PMID:25154500

van Vuren, Annelies; Meyer-Wentrup, Friederike

2014-12-01

271

Recent advances in B-cell epitope prediction methods  

PubMed Central

Identification of epitopes that invoke strong responses from B-cells is one of the key steps in designing effective vaccines against pathogens. Because experimental determination of epitopes is expensive in terms of cost, time, and effort involved, there is an urgent need for computational methods for reliable identification of B-cell epitopes. Although several computational tools for predicting B-cell epitopes have become available in recent years, the predictive performance of existing tools remains far from ideal. We review recent advances in computational methods for B-cell epitope prediction, identify some gaps in the current state of the art, and outline some promising directions for improving the reliability of such methods. PMID:21067544

2010-01-01

272

Treating Relapsed or Refractory B-cell Lymphomas  

Cancer.gov

Scientists are studying the drug flavopiridol in this early phase clinical trial to see if it can be effective in treating diffuse large B-cell lymphoma and mantle cell lymphoma that has relapsed or been resistant to treatment.

273

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

PubMed

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

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

2014-08-19

274

B cell depletion in immune thrombocytopenia reveals splenic long-lived plasma cells  

PubMed Central

Primary immune thrombocytopenia (ITP) is a disorder caused by autoantibody-mediated platelet destruction and decreased platelet production. Rituximab, a B cell–depleting agent, has become the first-line treatment for ITP; however, patients with refractory disease usually require splenectomy. We identified antibody-secreting cells as the major splenic B cell population that is resistant to rituximab. The phenotype, antibody specificity, and gene expression profile of these cells were characterized and compared to those of antibody-secreting cells from untreated ITP spleens and from healthy tissues. Antiplatelet-specific plasma cells (PC) were detected in the spleens of patients with ITP up to 6 months after rituximab treatment, and the PC population displayed a long-lived program similar to the one of bone marrow PC, thus explaining for most of these patients the absence of response to rituximab and the response to splenectomy. When analyzed by multiplex PCR at the single-cell level, normal splenic PC showed a markedly different gene expression profile, with an intermediate signature, including genes characteristic of both long-lived PC and proliferating plasmablasts. Surprisingly, long-lived PC were not detected in untreated ITP spleens. These results suggest that the milieu generated by B cell depletion promotes the differentiation and settlement of long-lived PC in the spleen. PMID:23241960

Mahevas, Matthieu; Patin, Pauline; Huetz, Francois; Descatoire, Marc; Cagnard, Nicolas; Bole-Feysot, Christine; Le Gallou, Simon; Khellaf, Mehdi; Fain, Olivier; Boutboul, David; Galicier, Lionel; Ebbo, Mikael; Lambotte, Olivier; Hamidou, Mohamed; Bierling, Philippe; Godeau, Bertrand; Michel, Marc; Weill, Jean-Claude; Reynaud, Claude-Agnes

2012-01-01

275

Regulatory B cells suppress imiquimod-induced, psoriasis-like skin inflammation.  

PubMed

Psoriasis is an inflammatory cutaneous disorder characterized by marked epidermal thickening and Th1 and Th17 cell infiltration. At present, the contribution of B cells to the pathogenesis of psoriasis is unclear. In mice, topical application of imiquimod induces inflamed skin lesions and serves as an experimental animal model for human psoriasis. In this study, we showed that imiquimod-induced skin inflammation was more severe in CD19(-/-) than WT mice. These inflammatory responses were negatively regulated by a unique IL-10-producing CD1d(hi)CD5(+) regulatory B cell subset (B10 cells) that was absent in CD19(-/-) mice and represented only 1-2% of splenic B220(+) cells in WT mice. Splenic B10 cells entered the circulation and migrated to draining LNs during imiquimod-induced skin inflammation, thereby suppressing IFN-? and IL-17 production. Furthermore, adoptive transfer of these B10 cells from WT mice reduced inflammation in CD19(-/-) mice. The present findings provide direct evidence that B10 cells regulate imiquimod-induced skin inflammation and offer insights into regulatory B cell-based therapies for the treatment of psoriasis. PMID:23630391

Yanaba, Koichi; Kamata, Masahiro; Ishiura, Nobuko; Shibata, Sayaka; Asano, Yoshihide; Tada, Yayoi; Sugaya, Makoto; Kadono, Takafumi; Tedder, Thomas F; Sato, Shinichi

2013-10-01

276

Interaction of Btk and Akt in B cell signalingq  

Microsoft Academic Search

Reactive oxygen species (ROS) or reactive oxygen intermediates (ROIs) mediate complex signaling involving multiple pathways. In this report, we demonstrate for the first time that endogenous Bruton's tyrosine kinase (Btk) and Akt can interact with each other in DT40 chicken B cells and human Nalm6 B cells and that this interaction is inducible following H2O2 stimulation. This interaction is supported

Jessica Lindvall; Tahmina C. Islam

2002-01-01

277

Childhood sarcoidosis: A rare but fascinating disorder.  

PubMed

Childhood sarcoidosis is a rare multisystemic granulomatous disorder of unknown etiology. In the pediatric series reported from the southeastern United States, sarcoidosis had a higher incidence among African Americans. Most reported childhood cases have occurred in patients aged 13-15 years. Macrophages bearing an increased expression of major histocompatibility class (MHC) II molecules most likely initiate the inflammatory response of sarcoidosis by presenting an unidentified antigen to CD4+ Th (helper-inducer) lymphocytes. A persistent, poorly degradable antigen driven cell-mediated immune response leads to a cytokine cascade, to granuloma formation, and eventually to fibrosis. Frequently observed immunologic features include depression of cutaneous delayed-type hypersensitivity and a heightened helper T cell type 1 (Th1) immune response at sites of disease. Circulating immune complexes, along with signs of B cell hyperactivity, may also be found. The clinical presentation can vary greatly depending upon the organs involved and age of the patient. Two distinct forms of sarcoidosis exist in children. Older children usually present with a multisystem disease similar to the adult manifestations, with frequent hilar lymphadenopathy and pulmonary infiltrations. Early-onset sarcoidosis is a unique form of the disease characterized by the triad of rash, uveitis, and arthritis in children presenting before four years of age. The diagnosis of sarcoidosis is confirmed by demonstrating a typical noncaseating granuloma on a biopsy specimen. Other granulmatous diseases should be reasonably excluded. The current therapy of choice for sarcoidosis in children with multisystem involvement is oral corticosteroids. Methotrexate given orally in low doses has been effective, safe and steroid sparing in some patients. Alternative immunosuppressive agents, such as azathioprine, cyclophosphamide, chlorambucil, and cyclosporine, have been tried in adult cases of sarcoidosis with questionable efficacy. The high toxicity profile of these agents, including an increased risk of lymphoproliferative disorders and carcinomas, has limited their use to patients with severe disease refractory to other agents. Successful steroid sparing treatment with mycophenolate mofetil was described in an adolescent with renal-limited sarcoidosis complicated by renal failure. Novel treatment strategies for sarcoidosis have been developed including the use of TNF-alpha inhibitors, such as infliximab. The long-term course and prognosis is not well established in childhood sarcoidosis, but it appears to be poorer in early-onset disease. PMID:18811966

Shetty, Avinash K; Gedalia, Abraham

2008-01-01

278

Regulatory functions of B cells in allergic diseases.  

PubMed

B cells are essentially described for their capacity to produce antibodies ensuring anti-infectious immunity or deleterious responses in the case of autoimmunity or allergy. However, abundant data described their ability to restrain inflammation by diverse mechanisms. In allergy, some regulatory B-cell subsets producing IL-10 have been recently described as potent suppressive cells able to restrain inflammatory responses both in vitro and in vivo by regulatory T-cell differentiation or directly inhibiting T-cell-mediated inflammation. A specific deficit in regulatory B cells participates to more severe allergic inflammation. Induction of allergen tolerance through specific immunotherapy induces a specific expansion of these cells supporting their role in establishment of allergen tolerance. However, the regulatory functions carried out by B cells are not exclusively IL-10 dependent. Indeed, other regulatory mechanisms mediated by B cells are (i) the production of TGF-?, (ii) the promotion of T-cell apoptosis by Fas-Fas ligand or granzyme-B pathways, and (iii) their capacity to produce inhibitory IgG4 and sialylated IgG able to mediate anti-inflammatory mechanisms. This points to Bregs as interesting targets for the development of new therapies to induce allergen tolerance. In this review, we highlight advances in the study of regulatory mechanisms mediated by B cells and outline what is known about their phenotype as well as their suppressive role in allergy from studies in both mice and humans. PMID:25060230

Braza, F; Chesne, J; Castagnet, S; Magnan, A; Brouard, S

2014-11-01

279

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

E-print Network

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

Avalos, Ana M.

280

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

PubMed Central

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

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

2013-01-01

281

In-utero infection with HIV-1 associated with suppressed lymphoproliferative responses at birth.  

PubMed

In-utero exposure to HIV-1 may affect the immune system of the developing child and may induce HIV-1-specific immune responses, even in the absence of HIV-1 infection. We evaluated lymphoproliferative capacity at birth among 40 HIV-1-uninfected infants born to HIV-1-infected mothers and 10 infants who had acquired HIV-1 in utero. Cord blood mononuclear cells were assayed using [(3) H]-thymidine incorporation for proliferation in response to HIV-1 p55-gag and the control stimuli phytohaemagglutinin (PHA), Staphylococcus enterotoxin B (SEB) and allogeneic cells. In response to HIV-1 p55-gag, eight (20%) HIV-1-exposed, uninfected (EU) infants had a stimulation index (SI) ??2 and three (30%) in-utero?HIV-1 infected infants had SI ?2. The frequency and magnitude of responses to HIV-1 p55-gag were low overall, and did not differ statistically between groups. However, proliferative responses to control stimuli were significantly higher in EU infants than in infants infected in utero, with a median SI in response to PHA of 123 [interquartile range (IQR) 77-231] versus 18 (IQR 4-86) between EU and infected infants, respectively (P?lymphoproliferative responses at similar rates (20-30%), and although global immune function was preserved among EU infants, neonatal immune responses were significantly compromised by HIV-1 infection. Such early lymphoproliferative compromise may, in part, explain rapid progression to AIDS and death among HIV-1-infected infants. PMID:24853045

Lohman-Payne, B; Sandifer, T; OhAinle, M; Crudder, C; Lynch, J; Omenda, M M; Maroa, J; Fowke, K; John-Stewart, G C; Farquhar, C

2014-10-01

282

TIM-1 signaling in B cells regulates antibody production  

SciTech Connect

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

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

2011-03-11

283

Perinatal immunotoxicity of benzene toward mouse B cell development  

SciTech Connect

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

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

1989-01-01

284

Purification and immunophenotypic characterization of murine B10 B cells.  

PubMed

Regulatory B10 cells represent a rare CD1d(hi)CD5(+) IL-10-secreting B cell subset in mice which is induced to produce IL-10 after 5 h of in vitro stimulation with a combination of B cell mitogen and chemical stimulants. Although B10 cells only constitute 1-2 % of splenic CD19(+) B cells, they play important roles in controlling T cell-mediated immune responses in an antigen-specific and IL-10-dependent manner. The regulatory effects of B10 cells have been demonstrated in multiple mouse models of inflammatory and autoimmune diseases. Herein, we described current methods for identification and purification of CD1d(hi)CD5(+) B10 cells. PMID:25015271

Hong, Chao; Gao, Xiao-Ming

2014-01-01

285

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

SciTech Connect

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

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

1994-09-01

286

Radiotherapy of lymphoproliferative diseases of the orbit. Surveillance of 65 cases.  

PubMed

Sixty-five patients with lymphoproliferative disease of the orbit were treated at the Joint Radiation Oncology Center of the University of Pittsburgh. An analysis of these patients was stratified by their initial tumor histopathology: benign lymphoid hyperplasia (BLH) in 28, malignant lymphoma (ML) in 20, and lymphoid infiltrate of indeterminate histology (IH) in 17. The median follow-up was 42 months. Radiation treatment was efficacious in all three groups of patients. The actuarial local recurrence-free survival rate is 84%. Treatment programs usually consisted of 20 to 30 Gy delivered in 10 to 15 fractions. ML patients had significantly lower overall and disease-specific survival rates than IH and BLH patient (p less than or equal to 0.02). BLH patients had a significantly lower local recurrence-free survival than patients with IH and BLH (p = 0.03). There was no significant difference between the three groups of patients with regard to the subsequent development of systemic lymphoma. There were no significant differences in local (16%) or systemic (36%) relapse between patients irradiated with less than 30 Gy or greater than or equal to 30 Gy. Cataracts were detected in 46% of the patients treated with anterior-posterior fields, but none were detected in those treated with other techniques. The results of this study emphasize the importance of long-term follow-up and careful treatment planning for patients with lymphoproliferative diseases of the orbit. PMID:1524043

Keleti, D; Flickinger, J C; Hobson, S R; Mittal, B B

1992-10-01

287

Oxysterols direct B-cell migration through EBI2.  

PubMed

EBI2 (also called GPR183) is an orphan G-protein-coupled receptor that is highly expressed in spleen and upregulated upon Epstein-Barr-virus infection. Recent studies indicated that this receptor controls follicular B-cell migration and T-cell-dependent antibody production. Oxysterols elicit profound effects on immune and inflammatory responses as well as on cholesterol metabolism. The biological effects of oxysterols have largely been credited to the activation of nuclear hormone receptors. Here we isolate oxysterols from porcine spleen extracts and show that they are endogenous ligands for EBI2. The most potent ligand and activator is 7?,25-dihydroxycholesterol (OHC), with a dissociation constant of 450?pM for EBI2. In vitro, 7?,25-OHC stimulated the migration of EBI2-expressing mouse B and T cells with half-maximum effective concentration values around 500 pM, but had no effect on EBI2-deficient cells. In vivo, EBI2-deficient B cells or normal B cells desensitized by 7?,25-OHC pre-treatment showed reduced homing to follicular areas of the spleen. Blocking the synthesis of 7?,25-OHC in vivo with clotrimazole, a CYP7B1 inhibitor, reduced the content of 7?,25-OHC in the mouse spleen and promoted the migration of adoptively transferred pre-activated B cells to the T/B boundary (the boundary between the T-zone and B-zone in the spleen follicle), mimicking the phenotype of pre-activated B cells from EBI2-deficient mice. Our results show an unexpected causal link between EBI2, an orphan G-protein-coupled receptor controlling B-cell migration, and the known immunological effects of certain oxysterols, thus uncovering a previously unknown role for this class of molecules. PMID:21796211

Liu, Changlu; Yang, Xia V; Wu, Jiejun; Kuei, Chester; Mani, Neelakandha S; Zhang, Li; Yu, Jingxue; Sutton, Steven W; Qin, Ning; Banie, Homayon; Karlsson, Lars; Sun, Siquan; Lovenberg, Timothy W

2011-07-28

288

Evolution of B-cell malignancy; Pre-B-cell leukemia resulting from MYC activation in a B-cell neoplasm with a rearranged BCL2 gene  

SciTech Connect

The authors have analyzed the molecular genetics of the breakpoints involved in the t(8;14) and t(14;18) translocations of an acute pre-B-cell leukemia from a patient with a history of follicular lymphoma. In this patient's leukemic cells, the breakpoint of the t(14;18) translocation occurred in the major breakpoint-cluster region of the BCL2 gene and became linked to the J{sub H}4 joining-region gene segment of the immunoglobulin heavy-chain locus on the 14q+ chromosome as previously observed in follicular lymphoma. An N region and heptamer and nonamer signal sequences indicated that this translocation occurred as a mistake in V{sub H}-D{sub H}-J{sub H} joining (where V{sub H} and D{sub H} are the variable and diversity segments). In the t(8;14) translocation, the breakpoint was located immediately 5' of the first exon of the MYC protooncogene, which was juxtaposed with the C{gamma}2 constant gene segment of the second 14q+ chromosome. The finding of repeated sequences typical of switch regions suggested that this translocation occurred during heavy-chain isotype switching, resulting in progression to pre-B-cell leukemia with both the 5(8;14) and the t(14;18) translocations. The terminal deoxynucleotidyltransferase-positive phenotype of the patient's leukemic cells further suggests that the pre-B-cell leukemia was derived from a pre-B cell carrying a t(14;18) translocation in the original follicular lymphoma. The polymerase chain reaction method was then used to identify cancer cells in the bone marrow of the patient.

Gauwerky, C.E.; Haluska, F.G.; Tsujimoto, Y.; Nowell, P.C.; Croce, C.M. (Wistar Institute of Anatomy and Biology, Philadelphia, PA (USA))

1988-11-01

289

Regulation of AID, the B-cell genome mutator  

PubMed Central

The mechanisms by which B cells somatically engineer their genomes to generate the vast diversity of antibodies required to challenge the nearly infinite number of antigens that immune systems encounter are of tremendous clinical and academic interest. The DNA cytidine deaminase activation-induced deaminase (AID) catalyzes two of these mechanisms: class switch recombination (CSR) and somatic hypermutation (SHM). Recent discoveries indicate a significant promiscuous targeting of this B-cell mutator enzyme genome-wide. Here we discuss the various regulatory elements that control AID activity and prevent AID from inducing genomic instability and thereby initiating oncogenesis. PMID:23307864

Keim, Celia; Kazadi, David; Rothschild, Gerson; Basu, Uttiya

2013-01-01

290

Activation of B cells by non-canonical helper signals  

PubMed Central

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

Cerutti, Andrea; Cols, Montserrat; Puga, Irene

2012-01-01

291

Lnk Adaptor: Novel Negative Regulator of B Cell Lymphopoiesis  

NSDL National Science Digital Library

Originally thought to have the functions now ascribed to the linker for activation of T cells protein (LAT), Lnk is coming into its own as an adaptor protein that mediates signaling through several receptor pathways. An essential role for Lnk in B cell development and maturation was recently uncovered by Perlmutter and colleagues. Rudd discusses the role of Lnk in B cells and hypothesizes a mechanism whereby Lnk, and its closely related protein family members, the adaptor molecules containing pleckstrin homology (PH) and Src-homology 2 (SH2) domains (APS), and Src-homology 2-B protein (SH2-B), may mediate signal promotion or attenuation.

Christopher E. Rudd (Harvard Medical School;Department of Pathology REV)

2001-06-05

292

Serum Levels of the Homeostatic B Cell Chemokine, CXCL13, Are Elevated During HIV Infection  

Microsoft Academic Search

HIV infection is associated with B cell dysfunction, which includes B cell hyperactivation, hypergammaglob- ulinemia, impaired production of antibodies against specific antigens, and a loss of B cell memory. Because lymph node architecture is progressively destroyed during HIV infection, it is possible that normal B cell traf- ficking is impaired as well, which could be a cause or a result

Daniel P. Widney; Elizabeth C. Breen; W. John Boscardin; Scott G. Kitchen; Juan M. Alcantar; Jeffrey B. Smith; Jerome A. Zack; Roger Detels; Otoniel Martinez-Maza

2005-01-01

293

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

Microsoft Academic Search

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

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

2007-01-01

294

Regulation of VH Replacement by B Cell Receptor (BCR)-mediated Signaling in Human Immature B Cells  

PubMed Central

VH replacement provides a unique RAG-mediated recombination mechanism to edit non-functional IgH genes or IgH genes encoding self reactive B cell receptors (BCRs) and contributes to the diversification of antibody repertoire in mouse and human. Currently, it is not clear how VH replacement is regulated during early B lineage cell development. Here we show that crosslinking BCRs induces VH replacement in human EU12 ?HC+ cells and in the newly emigrated immature B cells purified from peripheral blood of healthy donors or tonsillar samples. BCR signaling-induced VH replacement is dependent on the activation of Syk and Src kinases; but is inhibited by CD19 co-stimulation, presumably through activation of the PI3 kinase pathway. These results show for the first time that VH replacement is regulated by BCR-mediated signaling in human immature B cells, which can be modulated by physiological and pharmacological treatments. PMID:23630348

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

2013-01-01

295

Translocation of the B cell receptor to lipid rafts is inhibited in B cells from BLV-infected, persistent lymphocytosis cattle  

Microsoft Academic Search

Bovine leukemia virus (BLV) infection causes a significant polyclonal expansion of CD5+, IgM+ B lymphocytes known as persistent lymphocytosis (PL) in approximately 30% of infected cattle. There is evidence that this expanded B cell population has altered signaling, and resistance to apoptosis has been proposed as one mechanism of B cell expansion. In human and murine B cells, antigen binding

Valerie T Hamilton; Diana M Stone; Glenn H Cantor

2003-01-01

296

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

PubMed

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

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

2014-11-01

297

Do follicular dendritic cells regulate lupus-specific B cells?  

PubMed

The factors that allow self-reactive B cells to escape negative selection and become activated remain poorly defined. In this review we describe recently published results in which a B cell receptor-knock-in mouse strain specific for nucleolar self-antigens was bred with mice deficient in complement C4 and discuss the implications for the lupus field. Absence of C4 leads to a breakdown in the elimination of autoreactive B cell clones at the transitional stage. This is characterized by a relative increase in their response to a range of stimuli, entrance into follicles and a greater propensity to form self-reactive germinal centers. In this review, a model is proposed in which, in the absence of complement C4, inappropriate clearance of apoptotic debris promotes chronic activation of myeloid cells and follicular dendritic cells, resulting in secretion of Type I interferon. This allows for the maturation and activation of self-reactive B cell clones leading to increased spontaneous formation of germinal centers and subsequent generation of autoantibodies. PMID:24636642

Heesters, Balthasar A; Das, Abhishek; Chatterjee, Priyadarshini; Carroll, Michael C

2014-12-01

298

Leukemia - B-Cell Prolymphocytic Leukemia and Hairy Cell Leukemia  

MedlinePLUS

... Net Patient Education Video : View a short video led by an ASCO expert in leukemia that provides basic information and areas of research. To continue reading this guide, use the menu on the side of your screen to select another section. ‹ Leukemia - B-cell Prolymphocytic ...

299

Phase II Cancer Vaccine Trial for B-Cell Lymphoma  

Cancer.gov

Since launching the nation's first phase II cancer vaccine trial for B-cell lymphoma in 1994, researchers at the National Cancer Institute (NCI) have vaccinated 21 patients with this common blood-cell tumor that strikes an estimated 41,000 Americans each year

300

An eruption of European B-cell biology.  

PubMed

Volcanic ash clouds disrupted the 2010 ESF/EMBO meeting on B cells and protection. Nevertheless, the delegates who did make it to Catalonia put together their own programme of talks covering a range of themes from mutualism to epigenetics. PMID:20725089

Cancro, Michael P

2010-09-01

301

B cell follicles and antigen encounters of the third kind  

Microsoft Academic Search

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

Jason G Cyster

2010-01-01

302

Bad-deficient mice develop diffuse large B cell lymphoma  

E-print Network

Bad-deficient mice develop diffuse large B cell lymphoma Ann M. Ranger*, Jiping Zha* , Hisashi. Korsmeyer, June 5, 2003 The proapoptotic activity of the ``BH3-only'' molecule BAD can be differentially regulated by survival factor signaling. Bad-deficient mice lacking both BAD long and BAD short proteins

Datta, Sandeep Robert

303

New Insights into Monoclonal B-Cell Lymphocytosis  

PubMed Central

Monoclonal B-cell lymphocytosis (MBL) is a premalignant condition characterized by the presence of less than 5000/?L circulating clonal B cells in otherwise healthy individuals. Three subcategories have been identified according to the immunophenotypic features: CLL-like, CD5(+) atypical, and CD5(?) MBL. CLL-like MBL is by far the most frequent and best studied category and further divided in low-count [LC] and high-count [HC] MBL, based on a cutoff value of 500/?L clonal B cells. LC-MBL typically remains stable and probably does not represent a truly premalignant condition, but rather an age-related immune senescence. On the other hand, HC-MBL is closely related to CLL-Rai0, bearing similar immunogenetic profile, and is associated with an annual risk of progression to CLL requiring therapy at a rate of 1.1%. Currently there are no reproducible factors for evaluating the risk of progression to CLL. CD5(?) MBL is characterized by an immunophenotype consistent with marginal zone origin and displays many similarities with marginal zone lymphomas (MZL), mainly the splenic MZL. The cutoff value of 5000/?L clonal B cells cannot probably be applied in CD5(?) MBL, requiring a new definition to describe those cases. PMID:25295254

Kalpadakis, Christina; Pangalis, Gerassimos A.; Sachanas, Sotirios; Vassilakopoulos, Theodoros P.; Kyriakaki, Stavroula; Korkolopoulou, Penelope; Koulieris, Efstathios; Moschogiannis, Maria; Yiakoumis, Xanthi; Tsirkinidis, Pantelis; Kyrtsonis, Marie-Christine; Levidou, Georgia; Papadaki, Helen A.; Panayiotidis, Panayiotis; Angelopoulou, Maria K.

2014-01-01

304

Post-transplantation lymphoproliferative disease in heart and heart–lung transplant recipients: 30-year experience at Stanford University  

Microsoft Academic Search

Background:Post-transplantation lymphoproliferative disease (PTLD) is an important source of morbidity and mortality in transplant recipients, with a reported incidence of 0.8% to 20%. Risk factors are thought to include immunosuppressive agents and viral infection. This study attempts to evaluate the impact of different immunosuppressive regimens, ganciclovir prophylaxis and other potential risk factors in the development of PTLD.

Shao-Zhou Gao; Sandra V Chaparro; Mark Perlroth; Jose G Montoya; Joan L Miller; Sue DiMiceli; Trevor Hastie; Phillip E Oyer; John Schroeder

2003-01-01

305

A feeder-free differentiation system identifies autonomously proliferating B cell precursors in human bone marrow.  

PubMed

The peripheral B cell compartment is maintained by homeostatic proliferation and through replenishment by bone marrow precursors. Because hematopoietic stem cells cycle at a slow rate, replenishment must involve replication of precursor B cells. To study proliferation of early human B cell progenitors, we established a feeder cell-free in vitro system allowing the development of B cells from CD34(+) hematopoietic stem cells up to the stage of immature IgM(+) B cells. We found that pro-B and pre-B cells generated in vitro can proliferate autonomously and persist up to 7 wk in culture in the absence of signals induced by exogenously added cytokines. Nevertheless, addition of IL-7 enhanced pre-B cell expansion and inhibited maturation into IgM(+) B cells. The B cell precursor subsets replicating in vitro were highly similar to the bone marrow B cell precursors cycling in vivo. The autonomous proliferation of B cell precursor subsets in vitro and their long-term persistence implies that proliferation during pro-B and pre-B cell stages plays an important role in the homeostasis of the peripheral B cell compartment. Our in vitro culture can be used to study defects in B cell development or in reconstitution of the B cell pool after depletion and chemotherapy. PMID:24379121

Kraus, Helene; Kaiser, Sandra; Aumann, Konrad; Bönelt, Peter; Salzer, Ulrich; Vestweber, Dietmar; Erlacher, Miriam; Kunze, Mirjam; Burger, Meike; Pieper, Kathrin; Sic, Heiko; Rolink, Antonius; Eibel, Hermann; Rizzi, Marta

2014-02-01

306

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

PubMed Central

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

Caoili, Salvador Eugenio C.

2012-01-01

307

Splenic B cell lymphoma with circulating villous lymphocytes: differential diagnosis of B cell leukaemias with large spleens  

Microsoft Academic Search

The clinical, haematological, morphological and histological features of a series of 22 patients presenting with splenic lymphoma with circulating villous lymphocytes were assessed and compared with those of patients with other forms of chronic B cell leukaemia in an attempt to differentiate this condition from hairy cell leukaemia, prolymphocytic leukaemia, and chronic lymphocytic leukaemia, with which this condition has many

J V Melo; U Hegde; A Parreira; I Thompson; I A Lampert; D Catovsky

1987-01-01

308

Aberrant immunoglobulin class switch recombination and switch translocations in activated B cell-like diffuse large B cell lymphoma.  

PubMed

To elucidate the mechanisms underlying chromosomal translocations in diffuse large B cell lymphoma (DLBCL), we investigated the nature and extent of immunoglobulin class switch recombination (CSR) in these tumors. We used Southern blotting to detect legitimate and illegitimate CSR events in tumor samples of the activated B cell-like (ABC), germinal center B cell-like (GCB), and primary mediastinal B cell lymphoma (PMBL) subgroups of DLBCL. The frequency of legitimate CSR was lower in ABC DLBCL than in GCB DLBCL and PMBL. In contrast, ABC DLBCL had a higher frequency of internal deletions within the switch mu (Smu) region compared with GCB DLBCL and PMBL. ABC DLBCLs also had frequent deletions within Sgamma and other illegitimate switch recombinations. Sequence analysis revealed ongoing Smu deletions within ABC DLBCL tumor clones, which were accompanied by ongoing duplications and activation-induced cytidine deaminase-dependent somatic mutations. Unexpectedly, short fragments derived from multiple chromosomes were interspersed within Smu in one case. These findings suggest that ABC DLBCLs have abnormalities in the regulation of CSR that could predispose to chromosomal translocations. Accordingly, aberrant switch recombination was responsible for translocations in ABC DLBCLs involving BCL6, MYC, and a novel translocation partner, SPIB. PMID:17353367

Lenz, Georg; Nagel, Inga; Siebert, Reiner; Roschke, Anna V; Sanger, Warren; Wright, George W; Dave, Sandeep S; Tan, Bruce; Zhao, Hong; Rosenwald, Andreas; Muller-Hermelink, Hans Konrad; Gascoyne, Randy D; Campo, Elias; Jaffe, Elaine S; Smeland, Erlend B; Fisher, Richard I; Kuehl, W Michael; Chan, Wing C; Staudt, Louis M

2007-03-19

309

The oncoprotein LMO2 is expressed in normal germinal-center B cells and in human B-cell lymphomas  

PubMed Central

We previously developed a multivariate model based on the RNA expression of 6 genes (LMO2, BCL6, FN1, CCND2, SCYA3, and BCL2) that predicts survival in diffuse large B-cell lymphoma (DLBCL) patients. Since LMO2 emerged as the strongest predictor of superior outcome, we generated a monoclonal anti-LMO2 antibody in order to study its tissue expression pattern. Immunohistologic analysis of over 1200 normal and neoplastic tissue and cell lines showed that LMO2 protein is expressed as a nuclear marker in normal germinal-center (GC) B cells and GC-derived B-cell lines and in a subset of GC-derived B-cell lymphomas. LMO2 was also expressed in erythroid and myeloid precursors and in megakaryocytes and also in lymphoblastic and acute myeloid leukemias. It was rarely expressed in mature T, natural killer (NK), and plasma cell neoplasms and was absent from nonhematolymphoid tissues except for endothelial cells. Hierarchical cluster analysis of immunohistologic data in DLBCL demonstrated that the expression profile of the LMO2 protein was similar to that of other GC-associated proteins (HGAL, BCL6, and CD10) but different from that of non-GC proteins (MUM1/IRF4 and BCL2). Our results warrant inclusion of LMO2 in multivariate analyses to construct a clinically applicable immunohistologic algorithm for predicting survival in patients with DLBCL. PMID:17038524

Natkunam, Yasodha; Zhao, Shuchun; Mason, David Y.; Chen, Jun; Taidi, Behnaz; Jones, Margaret; Hammer, Anne S.; Hamilton Dutoit, Stephen; Lossos, Izidore S.; Levy, Ronald

2007-01-01

310

CD5 Is Dissociated from the B-Cell Receptor in B Cells from Bovine Leukemia Virus-Infected, Persistently Lymphocytotic Cattle: Consequences to B-Cell Receptor-Mediated Apoptosis  

PubMed Central

Bovine leukemia virus (BLV), a retrovirus related to human T-cell leukemia virus types 1 and 2, can induce persistent nonneoplastic expansion of the CD5+ B-cell population, termed persistent lymphocytosis (PL). As in human CD5+ B cells, we report here that CD5 was physically associated with the B-cell receptor (BCR) in normal bovine CD5+ B cells. In contrast, in CD5+ B cells from BLV-infected PL cattle, CD5 was dissociated from the BCR. In B cells from PL cattle, apoptosis decreased when cells were stimulated with antibody to surface immunoglobulin M (sIgM), while in B cells from uninfected cattle, apoptosis increased after sIgM stimulation. The functional significance of the CD5-BCR association was suggested by experimental dissociation of the CD5-BCR interaction by cross-linking of CD5. This caused CD5+ B cells from uninfected animals to decrease apoptosis when stimulated with anti-sIgM. In contrast, in CD5+ B cells from PL animals, in which CD5 was already dissociated from the BCR, there was no statistically significant change in apoptosis when CD5 was cross-linked and the cells were stimulated with anti-sIgM. Disruption of CD5-BCR interactions and subsequent decreased apoptosis and increased survival in antigenically stimulated B cells may be a mechanism of BLV-induced PL. PMID:11160667

Cantor, Glenn H.; Pritchard, Suzanne M.; Dequiedt, Franck; Willems, Luc; Kettmann, Richard; Davis, William C.

2001-01-01

311

DNA microarray gene expression profile of marginal zone versus follicular B cells and idiotype positive marginal zone B cells before and after immunization with Streptococcus pneumoniae.  

PubMed

Marginal zone (MZ) B cells play an important role in the clearance of blood-borne bacterial infections via rapid T-independent IgM responses. We have previously demonstrated that MZ B cells respond rapidly and robustly to bacterial particulates. To determine the MZ-specific genes that are expressed to allow for this response, MZ and follicular (FO) B cells were sort purified and analyzed via DNA microarray analysis. We identified 181 genes that were significantly different between the two B cell populations. Ninety-nine genes were more highly expressed in MZ B cells while 82 genes were more highly expressed in FO B cells. To further understand the molecular mechanisms by which MZ B cells respond so rapidly to bacterial challenge, Id-positive and -negative MZ B cells were sort purified before (0 h) or after (1 h) i.v. immunization with heat-killed Streptococcus pneumoniae, R36A, and analyzed via DNA microarray analysis. We identified genes specifically up-regulated or down-regulated at 1 h following immunization in the Id-positive MZ B cells. These results give insight into the gene expression pattern in resting MZ vs FO B cells and the specific regulation of gene expression in Ag-specific MZ B cells following interaction with Ag. PMID:18453586

Kin, Nicholas W; Crawford, Dianna M; Liu, Jiabin; Behrens, Timothy W; Kearney, John F

2008-05-15

312

Akt and mTOR in B Cell Activation and Differentiation  

PubMed Central

Activation of phosphoinositide 3-kinase (PI3K) is required for B cell proliferation and survival. PI3K signaling also controls key aspects of B cell differentiation. Upon engagement of the B cell receptor (BCR), PI3K activation promotes Ca2+ mobilization and activation of NF?B-dependent transcription, events which are essential for B cell proliferation. PI3K also initiates a distinct signaling pathway involving the Akt and mTOR serine/threonine kinases. It has been generally assumed that activation of Akt and mTOR downstream of PI3K is essential for B cell function. However, Akt and mTOR have complex roles in B cell fate decisions and suppression of this pathway can enhance certain B cell responses while repressing others. In this review we will discuss genetic and pharmacological studies of Akt and mTOR function in normal B cells, and in malignancies of B cell origin. PMID:22888331

Limon, Jose J.; Fruman, David A.

2012-01-01

313

TGF-? detection and measurement in murine B cells: pros and cons of the different techniques.  

PubMed

Recent studies have demonstrated the importance of regulatory B cells in autoimmune, allergic, and inflammatory diseases. These B cells have an ability to suppress excessive immune reactions by multiple mechanisms. Most studies have focused on IL-10-producing B cells, but we have previously reported that transforming growth factor (TGF)-?1 secretion by B cells also plays an important role in intestinal homeostasis and mucosal inflammation. B cell-secreted TGF-? may be involved in the regulation of T cell immunity (differentiation, proliferation, and apoptosis) that is relevant to the pathogenesis of autoimmune or inflammatory disease. Here, we provide detailed instruction for detecting and measuring TGF-? produced by B cells. PMID:25015274

Mishima, Yoshiyuki; Ishihara, Shunji; Hansen, Jonathan J; Kinoshita, Yoshikazu

2014-01-01

314

Bisphosphonates target B cells to enhance humoral immune responses  

PubMed Central

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

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

2013-01-01

315

Mast cells, basophils and B cell connection network.  

PubMed

It has been proven that both resting and activated mast cells (MCs) and basophils are able to induce a significant increase in proliferation and survival of naïve and activated B cells, and their differentiation into antibody-producing cells. The immunological context in which this regulation occurs is of particular interest and the idea that these innate cells induce antibody class switching and production is increasingly gaining ground. This direct role of MCs and basophils in acquired immunity requires cell to cell contact as well as soluble factors and exosomes. Here, we review our current understanding of the interaction between B cells and MCs or basophils as well as the evidence supporting B lymphocyte-MC/basophil crosstalk in pathological settings. Furthermore, we underline the obscure aspects of this interaction that could serve as important starting points for future research in the field of MC and basophil biology in the peculiar context of the connection between innate and adaptive immunity. PMID:24671125

Merluzzi, Sonia; Betto, Elena; Ceccaroni, Alice Amaranta; Magris, Raffaella; Giunta, Marina; Mion, Francesca

2015-01-01

316

Unclassifiable B-cell lymphoma occurring after necrotizing pneumonia.  

PubMed

We report a case of CD20+ grey zone lymphoma (GZL) with Reed Sternberg cells as an unexpected pathological diagnosis of a destroyed right lower lobe after necrotizing pneumonia. These GZLs show overlapping features of classical Hodgkin's lymphoma and diffuse large B-cell lymphoma. GZLs are a rare specific entity of lymphomas, and the aetiology is unknown. The diagnosis is confirmed by pathological, immunohistochemical and molecular analyses. The optimal treatment is unknown. The prognosis of these patients is poor. PMID:23220936

Cogen, Anouschka; Bries, Greet; Verbeke, Sofie; Van Schil, Paul

2013-03-01

317

The ageing B cell population: Composition and function  

Microsoft Academic Search

Age related changes in the structure and function of the immune system, collectively termed immunosenescence, result in poor\\u000a responses to infections, increased susceptibility to cancers and increased incidence of autoimmune diseases. The humoral immune\\u000a response, maintained by the B cell compartment, has a key role in an effective immune system—not only in producing high affinity\\u000a antibodies that are crucial for

Alexander Ademokun; Yu-Chang Wu; Deborah Dunn-Walters

2010-01-01

318

CD3-Positive B Cells: A Storage-Dependent Phenomenon  

PubMed Central

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

Nagel, Angela; Mobs, Christian; Raifer, Hartmann; Wiendl, Heinz; Hertl, Michael; Eming, Rudiger

2014-01-01

319

Refining the Neuberger model: Uracil processing by activated B cells.  

PubMed

During the immune response, B cells undergo a programed mutagenic cascade to promote increased affinity and expanded antibody function. The two processes, somatic hypermutation (SHM) and class switch recombination (CSR), are initiated by the protein activation-induced deaminase (AID), which converts cytosine to uracil in the immunoglobulin loci. The presence of uracil in DNA promotes DNA mutagenesis though a subset of DNA repair proteins. Two distinct mechanisms have been proposed to control uracil processing. The first is through base removal by uracil DNA glycosylase (UNG), and the second is through detection by the mismatch repair (MMR) complex MSH2/6. In a study published in this issue of European Journal of Immunology, Dingler et al. [Eur. J. Immunol. 2014. 44: 1925-1935] examine uracil processing in B cells in the absence of UNG and SMUG1 glycosylases. Similar to UNG, SMUG1 is an uracil glycosylase which can remove the uracil base. While Smug1(-/-) mice show no clear deficiency in SHM or CSR, Ung(-/-) Smug1(-/-) mice display exacerbated phenotypes, suggesting a back-up role for SMUG1 in antibody diversity. This new information expands the model of uracil processing in B cells and raises several interesting questions about the dynamic relationship between base excision repair and MMR. PMID:24920531

Maul, Robert W; Gearhart, Patricia J

2014-07-01

320

Artesunate abolishes germinal center B cells and inhibits autoimmune arthritis.  

PubMed

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

Hou, Lifei; Block, Katharine E; Huang, Haochu

2014-01-01

321

Artesunate Abolishes Germinal Center B Cells and Inhibits Autoimmune Arthritis  

PubMed Central

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

Huang, Haochu

2014-01-01

322

Cyclin D1 inhibits mitochondrial activity in B cells.  

PubMed

Cyclin D1 is a cell cycle regulatory protein that acts at the G1-S transition, following its binding to and activation by the cyclin-dependent kinases 4 or 6. Cyclin D1 is absent from the entire B-cell lineage but is present in a large percentage of 2 types of malignant B-cell hemopathy--mantle cell lymphoma and multiple myeloma--suggesting a major role of this protein in the malignancy process. We show here, in an experimental model of cyclin D1 fusion protein transduction in mature B cells, that, cyclin D1 inhibits total mitochondrial activity. Cyclin D1 is localized at the outer mitochondrial membrane, bound to a voltage-dependent anion channel through its central domain, and it competes with hexokinase 2 for binding to this channel. The bound cyclin D1 decreases the supply of ADP, ATP, and metabolites, thereby reducing energy production. This function of cyclin D1 was also reported by others in normal and transformed mammary epithelial cells, suggesting that it may be ubiquitous. PMID:21343394

Tchakarska, Guergana; Roussel, Mikel; Troussard, Xavier; Sola, Brigitte

2011-03-01

323

A Soluble BAFF Antagonist, BR3-Fc, Decreases Peripheral Blood B Cells and Lymphoid Tissue Marginal Zone and Follicular B Cells in Cynomolgus Monkeys  

PubMed Central

BAFF (also known as BLyS), a member of the tumor necrosis factor superfamily, plays a critical role in the maturation and development of B cells. BAFF has three receptors on B cells, the most crucial of which is BR3. In this study, we demonstrate the biological outcome of BAFF blockade in cynomolgus monkeys using a soluble fusion protein consisting of human BR3 and human IgG1 Fc. In vitro, BR3-Fc blocked BAFF-mediated survival and proliferation of cynomolgus monkey B cells. Weekly treatment of cynomolgus monkeys with BR3-Fc for 13 to 18 weeks resulted in significant B-cell reduction in the peripheral blood and in lymphoid organs. CD21high B cells in lymphoid tissues, a subset analogous to human marginal zone B cells, expressed nearly twofold higher BR3 levels than did CD21med B cells. Lymphoid tissue flow cytometric analysis showed that BR3-Fc reduced this CD21high B-cell subset to a greater extent than it reduced CD21med B cells. Dual-label immunohistochemistry and morphometric image analysis supported these results by demonstrating that BR3-Fc reduced a significant proportion of the B cells within the splenic inner and outer marginal zones. These findings should prove very useful in guiding the desired therapeutic use of BR3-Fc for autoimmune diseases in the clinic. PMID:16436662

Vugmeyster, Yulia; Seshasayee, Dhaya; Chang, Wesley; Storn, Anahid; Howell, Kathy; Sa, Susan; Nelson, Tenea; Martin, Flavius; Grewal, Iqbal; Gilkerson, Ellen; Wu, Ben; Thompson, Jeff; Ehrenfels, Barbara N.; Ren, Song; Song, An; Gelzleichter, Thomas R.; Danilenko, Dimitry M.

2006-01-01

324

Revisiting the B-cell compartment in mouse and humans: more than one B-cell subset exists in the marginal zone and beyond  

PubMed Central

The immunological roles of B-cells are being revealed as increasingly complex by functions that are largely beyond their commitment to differentiate into plasma cells and produce antibodies, the key molecular protagonists of innate immunity, and also by their compartmentalisation, a more recently acknowledged property of this immune cell category. For decades, B-cells have been recognised by their expression of an immunoglobulin that serves the function of an antigen receptor, which mediates intracellular signalling assisted by companion molecules. As such, B-cells were considered simple in their functioning compared to the other major type of immune cell, the T-lymphocytes, which comprise conventional T-lymphocyte subsets with seminal roles in homeostasis and pathology, and non-conventional T-lymphocyte subsets for which increasing knowledge is accumulating. Since the discovery that the B-cell family included two distinct categories — the non-conventional, or extrafollicular, B1 cells, that have mainly been characterised in the mouse; and the conventional, or lymph node type, B2 cells — plus the detailed description of the main B-cell regulator, Fc?RIIb, and the function of CD40+ antigen presenting cells as committed/memory B-cells, progress in B-cell physiology has been slower than in other areas of immunology. Cellular and molecular tools have enabled the revival of innate immunity by allowing almost all aspects of cellular immunology to be re-visited. As such, B-cells were found to express “Pathogen Recognition Receptors” such as TLRs, and use them in concert with B-cell signalling during innate and adaptive immunity. An era of B-cell phenotypic and functional analysis thus began that encompassed the study of B-cell microanatomy principally in the lymph nodes, spleen and mucosae. The novel discovery of the differential localisation of B-cells with distinct phenotypes and functions revealed the compartmentalisation of B-cells. This review thus aims to describe novel findings regarding the B-cell compartments found in the mouse as a model organism, and in human physiology and pathology. It must be emphasised that some differences are noticeable between the mouse and human systems, thus increasing the complexity of B-cell compartmentalisation. Special attention will be given to the (lymph node and spleen) marginal zones, which represent major crossroads for B-cell types and functions and a challenge for understanding better the role of B-cell specificities in innate and adaptive immunology. PMID:23194300

2012-01-01

325

New monoclonal antibodies against B-cell antigens: possible new strategies for diagnosis of primary cutaneous B-cell lymphomas.  

PubMed

Reactivities of the monoclonal antibodies (mAbs) of the 9th Human Leukocyte Differentiation Antigen Workshop, in order to define specific antigenic expression of the primary cutaneous B-cell lymphomas (PC-BCL), were analyzed by immunohistology on human tonsil and on PC-BCL, such as follicular centre B-cell lymphomas (FCL), marginal zone lymphomas (MZL) and diffuse large B-cells lymphomas leg-type (DLBL-LT). We identified some subgroups of mAbs that were exclusively or preferentially positive in one lymphoma cell type: the PC-FCL subgroup of mAbs includes PD1/CD279, GCET-1, hFCRL1/CD307a, FCRL2/CD307b, CXCR5/CD185, B7-DC/CD273, MRC/CD200, CD130, CXCR4/CD184, Siglec-5/14, CD150, on the other hand subgroup of mAbs in PC-MZL includes BTLA/CD272, BLIMP-1, hCD38. No specific subgroup of mAbs was found to label PC-DLBCL. This study may be useful to better define specific antigen profile of different PC-BCL entities leading to a correct diagnosis. PMID:20951741

Fanoni, D; Tavecchio, S; Recalcati, S; Balice, Y; Venegoni, L; Fiorani, R; Crosti, C; Berti, E

2011-01-30

326

XBP-1 regulates signal transduction, transcription factors and bone marrow colonization in B cells  

E-print Network

XBP-1, a transcription factor that drives the unfolded protein response (UPR), is activated in B cells when they differentiate to plasma cells. Here, we show that in the B cells, whose capacity to secrete IgM has been ...

Hu, Chih-Chi Andrew

327

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

PubMed

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

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

2013-12-01

328

HCV NS5A Protein Containing Potential Ligands for Both Src Homology 2 and 3 Domains Enhances Autophosphorylation of Src Family Kinase Fyn in B Cells  

PubMed Central

Hepatitis C virus (HCV) infects B lymphocytes and induces mixed cryoglobulinemia and B cell non-Hodgkin's lymphoma. The molecular mechanism for the pathogenesis of HCV infection-mediated B cell disorders remains obscure. To identify the possible role for HCV nonstructural 5A (NS5A) protein in B cells, we generated the stable B cell lines expressing Myc-His tagged NS5A. Immunoprecipitation study in the presence or absence of pervanadate (PV) implied that NS5A was tyrosine phosphorylated by pervanadate (PV) treatment of the cells. Therefore we examined pull-down assay by using glutathione S-transferase (GST)-fusion proteins of various Src homology 2 (SH2) domains, which associates with phosphotyrosine within a specific amino acid sequence. The results showed that NS5A specifically bound to SH2 domain of Fyn from PV-treated B cells in addition to Src homology 3 (SH3) domain. Substitution of Arg176 to Lys in the SH2 domain of Fyn abrogated this interaction. Deletion mutational analysis demonstrated that N-terminal region of NS5A was not required for the interaction with the SH2 domain of Fyn. Tyr334 was identified as a tyrosine phosphorylation site in NS5A. Far-western analysis revealed that SH2 domain of Fyn directly bound to NS5A. Fyn and NS5A were colocalized in the lipid raft. These results suggest that NS5A directly binds to the SH2 domain of Fyn in a tyrosine phosphorylation-dependent manner. Lastly, we showed that the expression of NS5A in B cells increased phosphorylation of activation loop tyrosine in the kinase domain of Fyn. NS5A containing ligand for both SH2 and SH3 domains enhances an aberrant autophosphorylation and kinase activity of Fyn in B cells. PMID:23077515

Nakashima, Kenji; Takeuchi, Kenji; Chihara, Kazuyasu; Horiguchi, Tomoko; Sun, Xuedong; Deng, Lin; Shoji, Ikuo; Hotta, Hak; Sada, Kiyonao

2012-01-01

329

IgG1+ ovalbumin-specific B-cell transnuclear mice show class switch recombination in rare allelically included B cells.  

PubMed

We used somatic cell nuclear transfer (SCNT) to generate a mouse from the nucleus of an IgG1(+) ovalbumin-specific B cell. The resulting OBI mice show generally normal B-cell development, with elevated percentages of marginal zone B cells and a reduction in B-1 B cells. Whereas OBI RAG1(-/-) mice have exclusively IgG1 anti-ovalbumin in their serum, OBI mice show elevated levels of anti-ovalbumin of nearly all isotypes 3' of the ?1 constant region in the IgH locus, indicating that class switch recombination (CSR) occurs in the absence of immunization with ovalbumin. This CSR is associated with the presence of IgM(+)IgG1(+) double producer B cells that represent <1% of total B cells, accumulate in the peritoneal cavity, and account for near-normal levels of serum IgM and IgG3. PMID:22869725

Dougan, Stephanie K; Ogata, Souichi; Hu, Chih-Chi Andrew; Grotenbreg, Gijsbert M; Guillen, Eduardo; Jaenisch, Rudolf; Ploegh, Hidde L

2012-08-21

330

Cytotherapy. Author manuscript Whole lymphoma B cells allow efficient cross-presentation of antigens by  

E-print Network

; cytology ; immunology ; virology ; Humans ; Immunologic Factors ; pharmacology ; Lymphocyte Activation ; immunology ; Lymphoma, B-Cell ; immunology ; Macrophages ; cytology ; immunology ; Orthomyxoviridae

Boyer, Edmond

331

In vivo detection of peripherin-specific autoreactive B cells during type 1 diabetes pathogenesis.  

PubMed

Autoreactive B cells are essential for the pathogenesis of type 1 diabetes. The genesis and dynamics of autoreactive B cells remain unknown. In this study, we analyzed the immune response in the NOD mouse model to the neuronal protein peripherin (PRPH), a target Ag of islet-infiltrating B cells. PRPH autoreactive B cells recognized a single linear epitope of this protein, in contrast to the multiple epitope recognition commonly observed during autoreactive B cell responses. Autoantibodies to this epitope were also detected in the disease-resistant NOR and C57BL/6 strains. To specifically detect the accumulation of these B cells, we developed a novel approach, octameric peptide display, to follow the dynamics and localization of anti-PRPH B cells during disease progression. Before extended insulitis was established, anti-PRPH B cells preferentially accumulated in the peritoneum. Anti-PRPH B cells were likewise detected in C57BL/6 mice, albeit at lower frequencies. As disease unfolded in NOD mice, anti-PRPH B cells invaded the islets and increased in number at the peritoneum of diabetic but not prediabetic mice. Isotype-switched B cells were only detected in the peritoneum. Anti-PRPH B cells represent a heterogeneous population composed of both B1 and B2 subsets. In the spleen, anti-PRPH B cell were predominantly in the follicular subset. Therefore, anti-PRPH B cells represent a heterogeneous population that is generated early in life but proliferates as diabetes is established. These findings on the temporal and spatial progression of autoreactive B cells should be relevant for our understanding of B cell function in diabetes pathogenesis. PMID:24610011

Garabatos, Nahir; Alvarez, Raimon; Carrillo, Jorge; Carrascal, Jorge; Izquierdo, Cristina; Chapman, Harold D; Presa, Maximiliano; Mora, Conchi; Serreze, David V; Verdaguer, Joan; Stratmann, Thomas

2014-04-01

332

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

PubMed Central

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

Fernandes, Fabiola; Eloy, Catarina; Carimo, Awa; Pinto, Paula; Graves, Susannah; Simoes, Joana; Carrilho, Carla; Lopes, Jose Manuel

2013-01-01

333

TLR2 activated B cells are phenotypically similar to the abnormal circulating B cells seen preceding the diagnosis of AIDS related non-Hodgkin lymphoma (NHL) diagnosis  

PubMed Central

Background AIDS-related non-Hodgkin lymphoma (AIDS-NHL) is a common AIDS-defining cancer. Prior studies suggest that chronic B cell activation precedes AIDS-NHL diagnosis. Activation of B cells by multiple factors, including Toll-like receptor (TLR) signaling, leads to the expression of activation-induced cytidine deaminase (AID), a DNA mutating molecule that can contribute to oncogene translocations/mutations, leading to NHL. The goal of this study was to determine whether surface markers expressed on activated and/or germinal center (GC) B cells, and AID expression, were elevated on circulating B cells preceding AIDS-NHL, as well as to determine if TLR signaling contributes to this activated B cell phenotype. Methods Stored viable peripheral blood mononuclear cell (PBMC) specimens, obtained prior to AIDS-NHL diagnosis, were assessed by multi-color flow cytometry. Additionally, B cells isolated from PBMC were exposed to TLR ligands in vitro, after which B cell phenotype was assessed by flow cytometry. Results An elevated fraction of B cells expressing CD10, CD71, or CD86 was seen in those who went on to develop AIDS-NHL. AID expression was detected in some who developed AIDS-NHL, but not in HIV+ or HIV? controls. TLR2- stimulated purified B cells exhibited the activated B cell phenotype observed in HIV+ subjects prior to AIDS-NHL diagnosis. Conclusions These results indicate that an elevated fraction of B cells display an activated/GC phenotype in those HIV+ subjects who go on to develop AIDS-NHL, and suggest that TLR2-mediated activation may play a role in HIV infection-associated B cell activation, potentially contributing to the genesis of AIDS-NHL. PMID:23722608

Guo, Yu; Siewe, Basile; Epeldegui, Marta; Detels, Roger; Landay, Alan; Martinez-Maza, Otoniel

2013-01-01

334

Annexin V Binds to Viable B Cells and Colocalizes with a Marker of Lipid Rafts upon B Cell Receptor Activation1  

E-print Network

Annexin V Binds to Viable B Cells and Colocalizes with a Marker of Lipid Rafts upon B Cell Receptor, is mobilized to co-cap with IgM on anti-IgM-treated B cells and to colocalize with GM1, a marker of lipid raftsAnV) has been used to identify apoptotic cells based on its ability to bind phosphatidylserine (PS

Schlissel, Mark S.

335

Lymphoproliferative response and T lymphocyte subsets in a medium-term multi-organ bioassay for carcinogenesis in Wistar rats  

Microsoft Academic Search

The lymphoproliferative response and T lymphocyte subsets were evaluated at different stages of carcinogenesis in male Wistar rats sequentially initiated with N-diethylnitrosamine (DEN), N-butyl-N-4(hydroxybutyl)nitrosamine (BBN), N-methyl-N-nitrosourea (MNU), dihydroxy-di-N-propylnitrosamine (DHPN) and N,N?-dimethylhydrazine (DMH) (DMBDD initiation). One group was evaluated at the 4th week and other initiated group at the 30th week. Two initiated groups were also exposed through diet to 2-acetylaminofluorene

Ana Lúcia Tozzi Spinardi-Barbisan; Ramon Kaneno; Maria Aparecida Marchesan Rodrigues; Daisy Maria Fávero Salvadori; Eduardo Luiz Trindade Moreira; Lu??s Fernando Barbisan; João Lauro Viana de Camargo

2000-01-01

336

B Cell: T Cell Interactions Occur within Hepatic Granulomas during Experimental Visceral Leishmaniasis  

Microsoft Academic Search

Hepatic resistance to Leishmania donovani infection in mice is associated with the development of granulomas, in which a variety of lymphoid and non-lymphoid populations accumulate. Although previous studies have identified B cells in hepatic granulomas and functional studies in B cell-deficient mice have suggested a role for B cells in the control of experimental visceral leishmaniasis, little is known about

John W. J. Moore; Lynette Beattie; Jane E. Dalton; Benjamin M. J. Owens; Asher Maroof; Mark C. Coles; Paul M. Kaye

2012-01-01

337

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

PubMed Central

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

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

2007-01-01

338

B Cell Antigen Receptor Signaling and Internalization Are Mutually Exclusive Events  

E-print Network

B Cell Antigen Receptor Signaling and Internalization Are Mutually Exclusive Events Ping Hou1, Massenburg D, et al. (2006) B cell antigen receptor signaling and internalization are mutually exclusive of polyvalent antigens by the B cell antigen receptor (BCR) initiates a complex web of signaling events

Dinner, Aaron

339

G-Rich Proto-Oncogenes Are Targeted for Genomic Instability in B-Cell Lymphomas  

E-print Network

from follicular lymphoma to the more aggressive dif- fuse large B-cell lymphoma (DLBCL), and PAX5/IgG-Rich Proto-Oncogenes Are Targeted for Genomic Instability in B-Cell Lymphomas Michelle L, University of Washington School of Medicine, Seattle, Washington Abstract Diffuse large B-cell lymphoma

Maizels, Nancy

340

Activated B cells in autoimmune diseases: the case for a regulatory role  

Microsoft Academic Search

B lymphocytes contribute to immunity through organogenesis of secondary lymphoid organs, presentation of antigen to T cells, production of antibodies, and secretion of cytokines. Their roles in autoimmune diseases are complex. Clinical trials have shown that depleting B cells can significantly ameliorate such diseases, underlining the contributions of B cells to pathogenesis. Conversely, B-cell depletion can lead to exacerbation of

Stephen M Anderton; Simon Fillatreau

2008-01-01

341

Polyclonal B cell activation in infections: infectious agents' devilry or defense mechanism of the host?  

Microsoft Academic Search

Polyclonal B cell activation is not a pe- culiar characteristic to a particular infection, as many viruses, bacteria, and parasites induce a strong polyclonal B cell response resulting in hy- per--globulinemia. Here, we discuss the different roles proposed for polyclonal B cell activation, which can be crucial for early host defense against rapidly dividing microorganisms by contributing antibodies specific for

Carolina L. Montes; E. V. Acosta-Rodriguez; Maria Cecilia Merino; Daniela A. Bermejo; Adriana Gruppi

2007-01-01

342

Expression of the Grb2-related protein of the lymphoid system in B cell subsets enhances B cell antigen receptor signaling through mitogen-activated protein kinase pathways.  

PubMed

Adapter proteins play a critical role in regulating signals triggered by Ag receptor cross-linking. These small molecules link receptor proximal events with downstream signaling pathways. In this study, we explore the expression and function of the Grb2-related protein of the lymphoid system (GrpL)/Grb2-related adaptor downstream of Shc adapter protein in human B cells. GrpL is expressed in naive B cells and is down-regulated following B cell Ag receptor ligation. By contrast, germinal center and memory B cells express little or no GrpL. Using human B cell lines, we detected constitutive interactions between GrpL and B cell linker protein, Src homology (SH)2 domain-containing leukocyte protein of 76 kDa, hemopoietic progenitor kinase 1, and c-Cbl. The N-terminal SH3 domain of GrpL binds c-Cbl while the C-terminal SH3 domain binds B cell linker protein and SH2 domain-containing leukocyte protein of 76 kDa. Exogenous expression of GrpL in a GrpL-negative B cell line leads to enhanced Ag receptor-induced extracellular signal-related kinase and p38 mitogen-activated protein kinase phosphorylation. Thus, GrpL expression in human B cell subsets appears to regulate Ag receptor-mediated signaling events. PMID:12496419

Yankee, Thomas M; Solow, Sasha A; Draves, Kevin D; Clark, Edward A

2003-01-01

343

Lentivirus-induced lymphoproliferative disease. Comparative pathogenicity of phenotypically distinct ovine lentivirus strains.  

PubMed Central

For investigation of the pathogenicity of lentivirus strains, which have distinctly different cytopathic phenotypes in synovial membrane cell culture, plaque-purified, lytic, and nonlytic ovine lentivirus (OvLV) isolates were inoculated intratracheally into two groups of neonatal lambs. Twelve lambs were inoculated with a lytic OvLV isolate and 3 lambs each with two nonlytic OvLV isolates. Five control lambs were inoculated with either virus-free medium or were left uninoculated. In 8 of 12 lambs inoculated with a lytic OvLV isolate mild to severe lesions of lymphoid interstitial pneumonia (LIP) and pulmonary lymphoid hyperplasia developed, 6 of 12 lambs had lesions of pulmonary lymph node follicular hyperplasia, 3 of 9 female lambs had lesions of lymphoproliferative mastitis, 3 of 10 lambs had lesions of lymphocytic/plasmacytic synovitis, and 3 lambs had no lesions. In 3 of 6 lambs inoculated with nonlytic OvLV isolates only mild LIP lesions developed, without concurrent mammary gland or joint lesions. Bronchoalveolar lavage samples from OvLV-diseased lambs contained on average 1.5-fold more numbers of total leukocytes, and 4-fold more numbers of lymphocytes, compared with bronchoalveolar lavage samples of normal lambs. Monoclonal antibodies to ovine lymphocyte surface markers showed that the SBU-T8+ lymphocyte (CD 8 equivalent) was the predominant lymphocyte subset (mean of 65% of total lavaged lymphocytes) in bronchoalveolar lavage samples of 3 diseased lambs. Ovine lentivirus was reisolated from multiple tissues of both groups of OvLV-inoculated lambs, but the percentage of individual tissues infected was greater in lambs inoculated with the lytic viral isolate. Control lambs had no lesions and failed to produce OvLV-specific antibodies or yield OvLV from tissues. All OvLV-inoculated lambs produced either low or undetectable serum virus neutralizing antibodies. In contrast, lambs inoculated with either lytic or nonlytic OvLV produced precipitating antibodies to OvLV glycoprotein and group-specific protein. However, initial detection of precipitating antibodies to OvLV glycoprotein was earlier (mean, 5.8 weeks after inoculation) in OvLV-infected lambs in which severe lymphoproliferative disease developed and delayed (mean, 10.2 weeks after inoculation) in OvLV-infected lambs with mild or no lesions. Together, these results suggest that lentivirus isolates produced disease in a virus strain-dependent manner and suggest that humoral immune responses against OvLV failed to prevent lesion development in lentivirus-infected lambs.(ABSTRACT TRUNCATED AT 400 WORDS) Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 PMID:3337213

Lairmore, M. D.; Poulson, J. M.; Adducci, T. A.; DeMartini, J. C.

1988-01-01

344

Natalizumab treatment perturbs memory- and marginal zone-like B-cell homing in secondary lymphoid organs in multiple sclerosis.  

PubMed

Natalizumab, an antibody against the ?4 subunit of ?4 integrins, has been approved for multiple sclerosis (MS) therapy based on its high efficacy and safety profile. However, natalizumab has been associated with the development of progressive multifocal leukoencephalopathy (PML), a disorder caused by JC virus (JCV) infection. In order to improve our understanding of the mechanism of action of natalizumab and to identify possible risk factors for PML development, we have characterized in detail the cell blood composition in MS patients treated with natalizumab for more than 30 months. Natalizumab induced the release of lymphoid- but not myeloid precursor cells, which resulted in a chronic increase ofT-, NK- and particularly B cells. While the percentage of recent thymic emigrants (RTEs), na?ve, effector or memory T cells remained unchanged during treatment, a higher percentage of memory- and marginal zone (MZ)-like, but not of na?ve B cells, was observed, which most likely is due to a decreased retention of these cells within the splenic MZ. The ability of natalizumab to influence B-cell migration and homeostasis through the splenic MZ, where JCV has been detected, adds to the list of natalizumab effects and may contribute to PML development by disseminating JCV. PMID:22144343

Planas, Raquel; Jel?i?, Ilijas; Schippling, Sven; Martin, Roland; Sospedra, Mireia

2012-03-01

345

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

PubMed

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

Nguyen, Thuy Vy; Riou, Lydia; Aoufouchi, Saïd; Rosselli, Filippo

2014-06-01

346

Factor VIII delivered by hematopoietic stem cell-derived B cells corrects the phenotype of hemophilia A mice  

PubMed Central

Summary The main impediments to clinical application of hematopoietic stem cell (HSC) gene therapy for treatment of hemophilia A are the bone marrow transplant-related risks and the potential for insertional mutagenesis caused by retroviral vectors. To circumvent these limitations, we have adapted a nonmyeloablative conditioning regimen and directed factor VIII (FVIII) protein synthesis to B lineage cells using an insulated lentiviral vector containing an immunoglobulin heavy chain enhancer-promoter. Transplantation of lentiviral vector-modified HSCs resulted in therapeutic levels of FVIII in the circulation of all transplanted mice for the duration of the study (6 months). Immunostaining of spleen cells showed that the majority of FVIII was synthesized by B220+ B cells and CD138+ plasma cells. Subsequent challenge with recombinant FVIII elicited at most a minor anti-FVIII antibody response, demonstrating induction of immune hyporesponsiveness. All transplant recipients exhibited clot formation and survived tail clipping, indicating correction of their hemophilic phenotype. Therapeutic levels of FVIII could be transferred to secondary recipients by bone marrow transplantation, confirming gene transfer into long-term repopulating HSCs. Moreover, short-term therapeutic FVIII levels could also be achieved in secondary recipients by adoptive transfer of HSC-derived splenic B cells. Our findings support pursuit of B cell-directed protein delivery as a potential clinical approach to treat hemophilia A and other disorders correctable by systemically distributed proteins. PMID:21264447

Ramezani, Ali; Zweier-Renn, Lynnsey A.; Hawley, Robert G.

2011-01-01

347

Polyspecificity of T cell and B cell Receptor Recognition  

PubMed Central

A recent workshop discussed the recognition of multiple distinct ligands by individual T cell and B cell receptors and the implications of this discovery for lymphocyte biology. The workshop recommends general use of the term polyspecificity because it emphasizes two fundamental aspects, the inherent specificity of receptor recognition and the ability to recognize multiple ligands. Many different examples of polyspecificity and the structural mechanisms were discussed, and the group concluded that polyspecificity is a general, inherent feature of TCR and antibody recognition. This review summarizes the relevance of polyspecificity for lymphocyte development, activation and disease processes. PMID:17398114

Wucherpfennig, Kai W.; Allen, Paul M.; Celada, Franco; Cohen, Irun R.; De Boer, Rob; Garcia, K. Christopher; Goldstein, Byron; Greenspan, Ralph; Hafler, David; Hodgkin, Philip; Huseby, Erik S.; Krakauer, David C.; Nemazee, David; Perelson, Alan S.; Pinilla, Clemencia; Strong, Roland K.; Sercarz, Eli E.

2007-01-01

348

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

PubMed

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

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

2014-01-01

349

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

PubMed Central

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

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

2014-01-01

350

Reduced-intensity conditioning hematopoietic cell transplantation is an effective treatment for patients with SLAM-associated protein deficiency/X-linked lymphoproliferative disease type 1.  

PubMed

X-linked lymphoproliferative disease type 1 (XLP1) is a rare immune deficiency caused by mutations in SH2D1A. Allogeneic hematopoietic cell transplantation (HCT) is often performed because of the morbidity and mortality associated with XLP1. There is limited experience using reduced-intensity conditioning (RIC) regimens for these patients. Here we report our 8-year single-center experience. Sixteen consecutive patients diagnosed with XLP1 underwent allogeneic HCT between 2006 and 2013 after a RIC regimen consisting of alemtuzumab, fludarabine, and melphalan. Patient phenotypes included hemophagocytic lymphohistiocytosis (HLH) after Epstein-Barr virus (n = 5) or human herpesvirus 6 (n = 1), macrophage activation syndrome (n = 1), interstitial pneumonitis and encephalitis (n = 1), B cell lymphoma (n = 8), and hypogammaglobulinemia (n = 2). One patient was asymptomatic. Fourteen of 16 patients received 8/8 HLA-matched unrelated or related bone marrow grafts, whereas 2 patients received mismatched unrelated grafts. Acute graft-versus-host disease (GVHD) prophylaxis consisted of methylprednisolone and cyclosporine in all but 1 patient, who additionally received methotrexate. All patients had hematopoietic recovery. There were no cases of hepatic veno-occlusive disease or pulmonary hemorrhage. One patient (6%) developed acute GVHD and later also developed chronic GVHD (6%). Five patients (31%) developed mixed chimerism. Only 1 patient with mixed chimerism (6%) experienced a decline of donor chimerism to less than 50% but returned to full donor chimerism after infusion of donor lymphocytes and a CD34(+) selected stem cell boost. Infectious complications were frequent, particularly viral reactivation. One-year survival estimated by Kaplan-Meier analysis was 80%, with long-term survival estimated at 71%. Survival was similar for patients with or without a history of HLH (86% versus 75%, respectively, P = .70). There were no occurrences of lymphoma or HLH after HCT. RIC HCT with alemtuzumab, fludarabine, and melphalan is an effective treatment for patients with XLP1, offering good survival rates regardless of prior disease manifestations, including HLH. PMID:24923536

Marsh, Rebecca A; Bleesing, Jack J; Chandrakasan, Shanmuganathan; Jordan, Michael B; Davies, Stella M; Filipovich, Alexandra H

2014-10-01

351

Somatic FAS mutations are common in patients with genetically undefined autoimmune lymphoproliferative syndrome  

PubMed Central

Autoimmune lymphoproliferative syndrome (ALPS) is characterized by childhood onset of lymphadenopathy, hepatosplenomegaly, autoimmune cytopenias, elevated numbers of double-negative T (DNT) cells, and increased risk of lymphoma. Most cases of ALPS are associated with germline mutations of the FAS gene (type Ia), whereas some cases have been noted to have a somatic mutation of FAS primarily in their DNT cells. We sought to determine the proportion of patients with somatic FAS mutations among a group of our ALPS patients with no detectable germline mutation and to further characterize them. We found more than one-third (12 of 31) of the patients tested had somatic FAS mutations, primarily involving the intracellular domain of FAS resulting in loss of normal FAS signaling. Similar to ALPS type Ia patients, the somatic ALPS patients had increased DNT cell numbers and elevated levels of serum vitamin B12, interleukin-10, and sFAS-L. These data support testing for somatic FAS mutations in DNT cells from ALPS patients with no detectable germline mutation and a similar clinical and laboratory phenotype to that of ALPS type Ia. These findings also highlight the potential role for somatic mutations in the pathogenesis of nonmalignant and/or autoimmune hematologic conditions in adults and children. PMID:20360470

Niemela, Julie E.; Price, Susan; Davis, Joie; Hornung, Ronald L.; Oliveira, Joao Bosco; Puck, Jennifer M.; Jaffe, Elaine S.; Pittaluga, Stefania; Cohen, Jeffrey I.; Fleisher, Thomas A.; Rao, V. Koneti

2010-01-01

352

Somatic FAS mutations are common in patients with genetically undefined autoimmune lymphoproliferative syndrome.  

PubMed

Autoimmune lymphoproliferative syndrome (ALPS) is characterized by childhood onset of lymphadenopathy, hepatosplenomegaly, autoimmune cytopenias, elevated numbers of double-negative T (DNT) cells, and increased risk of lymphoma. Most cases of ALPS are associated with germline mutations of the FAS gene (type Ia), whereas some cases have been noted to have a somatic mutation of FAS primarily in their DNT cells. We sought to determine the proportion of patients with somatic FAS mutations among a group of our ALPS patients with no detectable germline mutation and to further characterize them. We found more than one-third (12 of 31) of the patients tested had somatic FAS mutations, primarily involving the intracellular domain of FAS resulting in loss of normal FAS signaling. Similar to ALPS type Ia patients, the somatic ALPS patients had increased DNT cell numbers and elevated levels of serum vitamin B(12), interleukin-10, and sFAS-L. These data support testing for somatic FAS mutations in DNT cells from ALPS patients with no detectable germline mutation and a similar clinical and laboratory phenotype to that of ALPS type Ia. These findings also highlight the potential role for somatic mutations in the pathogenesis of nonmalignant and/or autoimmune hematologic conditions in adults and children. PMID:20360470

Dowdell, Kennichi C; Niemela, Julie E; Price, Susan; Davis, Joie; Hornung, Ronald L; Oliveira, João Bosco; Puck, Jennifer M; Jaffe, Elaine S; Pittaluga, Stefania; Cohen, Jeffrey I; Fleisher, Thomas A; Rao, V Koneti

2010-06-24

353

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

PubMed Central

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

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

1988-01-01

354

Cannabinoid receptor 2 positions and retains marginal zone B cells within the splenic marginal zone  

PubMed Central

Specialized B cells residing in the splenic marginal zone (MZ) continuously survey the blood for antigens and are important for immunity to systemic infections. However, the cues that uniquely attract cells to the MZ have not been defined. Previous work demonstrated that mice deficient in cannabinoid receptor 2 (CB2) have decreased numbers of MZ B cells but it has been unclear whether CB2 regulates MZ B cell development or positioning. We show that MZ B cells are highly responsive to the CB2 ligand 2-arachidonylglycerol (2-AG) and that CB2 antagonism rapidly displaces small numbers of MZ B cells to the blood. Antagonism for longer durations depletes MZ B cells from the spleen. In mice deficient in sphingosine-1-phosphate receptor function, CB2 antagonism causes MZ B cell displacement into follicles. Moreover, CB2 overexpression is sufficient to position B cells to the splenic MZ. These findings establish a role for CB2 in guiding B cells to the MZ and in preventing their loss to the blood. As a consequence of their MZ B cell deficiency, CB2-deficient mice have reduced numbers of CD1d-high B cells. We show that CB2 deficiency results in diminished humoral responses to a CD1d-restricted systemic antigen. PMID:21875957

Muppidi, Jagan R.; Arnon, Tal I.; Bronevetsky, Yelena; Veerapen, Natacha; Tanaka, Masato; Besra, Gurdyal S.

2011-01-01

355

A role for intrathymic B cells in the generation of natural regulatory T cells.  

PubMed

B cells inhabit the normal human thymus, suggesting a role in T cell selection. In this study, we report that B cells can modulate thymic production of CD4+ Foxp3+ T cells (regulatory T cells [Tregs]). Mice with transgenic expression of BAFF (BAFF-Tg) harbor increased numbers of Helios+ Foxp3+ thymic Tregs and, similar to some human autoimmune conditions, also exhibit increased numbers of B cells colonizing the thymus. Distinct intrathymic B cell subpopulations were identified, namely B220+, IgM+, CD23(hi), CD21(int) cells; B220+, IgM+, CD23(lo), CD21(lo) cells; and a population of B220+, IgM+, CD23(lo), CD21(hi) cells. Anatomically, CD19+ B cells accumulated in the thymic medulla region juxtaposed to Foxp3+ T cells. These intrathymic B cells engender Tregs. Indeed, thymic Treg development was diminished in both B cell-deficient BAFF-Tg chimeras, but also B cell-deficient wild-type chimeras. B cell Ag capture and presentation are critical in vivo events for Treg development. In the absence of B cell surface MHC class II expression, thymic expansion of BAFF-Tg Tregs was lost. Further to this, expansion of Tregs did not occur in BAFF-Tg/Ig hen egg lysozyme BCR chimeras, demonstrating a requirement for Ag specificity. Thus, we present a mechanism whereby intrathymic B cells, through the provision of cognate help, contribute to the shaping of the Treg repertoire. PMID:24872190

Walters, Stacey N; Webster, Kylie E; Daley, Stephen; Grey, Shane T

2014-07-01

356

Towards the Generation of B-Cell Receptor Retrogenic Mice  

PubMed Central

Transgenic expression of B- and T-cell receptors (BCRs and TCRs, respectively) has been a standard tool to study lymphocyte development and function in vivo. The generation of transgenic mice is time-consuming and, therefore, a faster method to study the biology of defined lymphocyte receptors in vivo would be highly welcome. Using 2A peptide-linked multicistronic retroviral vectors to transduce stem cells, TCRs can be expressed rapidly in mice of any background. We aimed at adopting this retrogenic technology to the in vivo expression of BCRs. Using a well characterised BCR specific for hen egg lysozyme (HEL), we achieved surface expression of the retrogenically encoded BCR in a Rag-deficient pro B-cell line in vitro. In vivo, retrogenic BCRs were detectable only intracellularly but not on the surface of B cells from wild type or Rag2-deficient mice. This data, together with the fact that no BCR retrogenic mouse model has been published in the 7 years since the method was originally published for TCRs, strongly suggests that achieving BCR-expression in vivo with retrogenic technology is highly challenging if not impossible. PMID:25296340

Freitag, Jenny; Heink, Sylvia; Roth, Edith; Wittmann, Jurgen; Jack, Hans-Martin; Kamradt, Thomas

2014-01-01

357

Interleukin-35 induces regulatory B cells that suppress autoimmune disease.  

PubMed

Interleukin-10 (IL-10)-producing regulatory B (Breg) cells suppress autoimmune disease, and increased numbers of Breg cells prevent host defense to infection and promote tumor growth and metastasis by converting resting CD4(+) T cells to regulatory T (Treg) cells. The mechanisms mediating the induction and development of Breg cells remain unclear. Here we show that IL-35 induces Breg cells and promotes their conversion to a Breg subset that produces IL-35 as well as IL-10. Treatment of mice with IL-35 conferred protection from experimental autoimmune uveitis (EAU), and mice lacking IL-35 (p35 knockout (KO) mice) or defective in IL-35 signaling (IL-12R?2 KO mice) produced less Breg cells endogenously or after treatment with IL-35 and developed severe uveitis. Adoptive transfer of Breg cells induced by recombinant IL-35 suppressed EAU when transferred to mice with established disease, inhibiting pathogenic T helper type 17 (TH17) and TH1 cells while promoting Treg cell expansion. In B cells, IL-35 activates STAT1 and STAT3 through the IL-35 receptor comprising the IL-12R?2 and IL-27R? subunits. As IL-35 also induced the conversion of human B cells into Breg cells, these findings suggest that IL-35 may be used to induce autologous Breg and IL-35(+) Breg cells and treat autoimmune and inflammatory disease. PMID:24743305

Wang, Ren-Xi; Yu, Cheng-Rong; Dambuza, Ivy M; Mahdi, Rashid M; Dolinska, Monika B; Sergeev, Yuri V; Wingfield, Paul T; Kim, Sung-Hye; Egwuagu, Charles E

2014-06-01

358

The Genetic Basis of Diffuse Large B Cell Lymphoma  

PubMed Central

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

Pasqualucci, Laura

2014-01-01

359

Mercury alters B-cell protein phosphorylation profiles.  

PubMed

Environmental exposure to mercury is suggested to contribute to human immune dysfunction. To shed light on the mechanism, we identified changes in the phosphoproteomic profile of the WEHI-231 B cell line after intoxication with Hg(2+). These changes were compared to changes in the phosphoproteome that were induced by pervanadate or okadaic acid exposure. Both 250 ?M HgCl2 and pervanadate, a known phosphotyrosine phosphatase inhibitor, caused an increase in the number of proteins identified after TiO2 affinity selection and LC-MS/MS analysis. Pervanadate treatment had a larger effect than Hg(2+) on the number of Scansite motifs that were tyrosine-phosphorylated, 17, and Ingenuity canonical signaling pathways activated, 4, with score >5.0. However, Hg(2+) had a more focused effect, primarily causing tyrosine-phosphorylation in src homology 2 domains in proteins that are in the B cell receptor signaling pathway. The finding that many of the changes induced by Hg(2+) overlap with those of pervanadate, indicates that at high concentrations Hg(2+) inhibits protein tyrosine phosphatases. PMID:24224561

Caruthers, Nicholas J; Stemmer, Paul M; Shin, Namhee; Dombkowski, Alan; Caruso, Joseph A; Gill, Randal; Rosenspire, Allen

2014-02-01

360

Multiplex peptide-based B cell epitope mapping.  

PubMed

B cell epitope mapping is widely applied to determine antibody-binding sites. Several methods exist to map B cell epitopes and here we describe three methods that are characterized by the simultaneous analysis of multiple peptides. In the first approach a microarray of overlapping synthetic peptides derived from an antigenic protein is used and the binding of the antibodies is analyzed by fluorescently labeled secondary antibodies. This method is particularly suited for the identification of linear epitopes of an established target protein. In the second approach the binding of antibodies to a random synthetic peptide library immobilized on microbeads is determined by enzyme-conjugated secondary antibodies and the selection of antibody-bound beads by a light microscope. This method can be applied when information on the identity of the antigenic protein is lacking. In the third method an antigen is proteolytically digested and antibody binding to the resulting peptides is analyzed by surface plasmon resonance imaging (iSPR). The latter method can be applied when the purified antigenic protein is available. PMID:25048131

Hensen, Sanne M M; Derksen, Merel; Pruijn, Ger J M

2014-01-01

361

Intravascular large B-cell lymphoma confirmed by lung biopsy  

PubMed Central

Intravascular lymphoma is a very rare form of large B-cell non-Hodgkin’s lymphoma which is characterized by selective growth of lymphoma cells within the lumina of small blood vessels. We report a 64-year-old woman visited hospital because of persistent cough, intermittent high fever as high as 38.7°C and occasional shortness of breath. Her chest CT showed left upper lobe pneumonia and tuberculosis skin test (PPD test) was positive. She was suspected with tuberculosis and treated with anti-tuberculosis drugs. However, her symptoms and general condition deteriorated, and she visited our hospital. She had no abnormal findings on physical examination, but had abnormal laboratory findings, including decreased hemoglobin, elevated LDH and C-reactive protein. Arterial blood gas analysis showed moderate hypoxaemia. A chest radiograph showed pneumonia in whole lung and CT showed diffused ground glass opacities in both lung fields. Lung biopsy confirmed a diagnosis of intravascular large B-cell lymphoma. Primary pulmonary manifestation is very rare. The diagnosis is based on the histopathology and immunohistochemistry. PMID:25337283

Liu, Chunli; Lai, Ning; Zhou, Ying; Li, Shiyue; Chen, Rongchang; Zhang, Nuofu

2014-01-01

362

Unaltered regulatory B-cell frequency and function in patients with multiple sclerosis.  

PubMed

Multiple sclerosis (MS) is a chronic disease of the central nervous system (CNS) typically characterized by the recruitment of T cells into the CNS. However, certain subsets of B cells have been shown to negatively regulate autoimmune diseases and some data support a prominent role for B cells in MS physiopathology. For B cells in MS patients we analyzed subset frequency, cytokine secretion ability and suppressive properties. No differences in the frequencies of the B-cell subsets or in their ability to secrete cytokines were observed between MS and healthy volunteers (HV). Prestimulated B cells from MS patients also inhibited CD4(+)CD25(-) T cell proliferation with a similar efficiency as B cells from HV. Altogether, our data show that, in our MS patient cohort, regulatory B cells have conserved frequency and function. PMID:25267439

Michel, Laure; Chesneau, Melanie; Manceau, Philippe; Genty, Athenais; Garcia, Alexandra; Salou, Marion; Elong Ngono, Annie; Pallier, Annaïck; Jacq-Foucher, Marylène; Lefrère, Fabienne; Wiertlewski, Sandrine; Soulillou, Jean-Paul; Degauque, Nicolas; Laplaud, David-Axel; Brouard, Sophie

2014-12-01

363

T Cell-B Cell Thymic Cross-Talk: Maintenance and Function of Thymic B Cells Requires Cognate CD40-CD40 Ligand Interaction.  

PubMed

Thymic development requires bidirectional interaction or cross-talk between developing T cells and thymic stromal cells, a relationship that has been best characterized for the interaction between thymocytes and thymic epithelial cells. We have characterized in this article the requirement for similar cross-talk in the maintenance and function of thymic B cells, another population that plays a role in selection of developing thymic T cells. We found that maintenance of thymic B cells is strongly dependent on the presence of mature single-positive thymocytes and on the interactions of these T cells with specific Ag ligand. Maintenance of thymic B cell number is strongly dependent on B cell-autonomous expression of CD40, but not MHC class II, indicating that direct engagement of CD40 on thymic B cells is necessary to support their maintenance and proliferation. Thymic B cells can mediate negative selection of superantigen-specific, self-reactive, single-positive thymocytes, and we show that CD40 expression on B cells is critical for this negative selection. Cross-talk with thymic T cells is thus required to support the thymic B cell population through a pathway that requires cell-autonomous expression of CD40, and that reciprocally functions in negative selection of autoreactive T cells. PMID:25344473

Fujihara, Chiharu; Williams, Joy A; Watanabe, Masashi; Jeon, Hyein; Sharrow, Susan O; Hodes, Richard J

2014-12-01

364

Molecular Diagnosis of Primary Mediastinal B Cell Lymphoma Identifies a Clinically Favorable Subgroup of Diffuse Large B Cell Lymphoma Related to Hodgkin Lymphoma  

Microsoft Academic Search

Using current diagnostic criteria, primary mediastinal B cell lymphoma (PMBL) cannot be distinguished from other types of diffuse large B cell lymphoma (DLBCL) reliably. We used gene expression profiling to develop a more precise molecular diagnosis of PMBL. PMBL patients were considerably younger than other DLBCL patients, and their lymphomas fre- quently involved other thoracic structures but not extrathoracic sites

Andreas Rosenwald; George Wright; Karen Leroy; Xin Yu; Philippe Gaulard; Randy D. Gascoyne; Wing C. Chan; Tong Zhao; Corinne Haioun; Timothy C. Greiner; Dennis D. Weisenburger; James C. Lynch; Julie Vose; James O. Armitage; Erlend B. Smeland; Stein Kvaloy; Harald Holte; Jan Delabie; Elias Campo; Emili Montserrat; Armando Lopez-Guillermo; German Ott; H. Konrad Muller-Hermelink; Joseph M. Connors; Rita Braziel; Thomas M. Grogan; Richard I. Fisher; Thomas P. Miller; Michael LeBlanc; Michael Chiorazzi; Hong Zhao; Liming Yang; John Powell; Wyndham H. Wilson; Elaine S. Jaffe; Richard Simon; Richard D. Klausner; Louis M. Staudt

365

B-cell maturation in chronic lymphocytic leukaemia. IV. T-cell-dependent activation of leukaemic B cells by staphylococcal enterotoxin 'superantigens'.  

PubMed Central

Staphylococcal enterotoxins (SE) are potent T-lymphocyte activators that stimulate T cells by directly cross-linking HLA-DR molecules on antigen-presenting cells with the V beta gene products of the T-cell receptor. The different SE activate all T cells expressing a given V beta, and, therefore, have been termed 'superantigens'. Here we show that SE are potent activators of leukaemic B cells from patients with chronic lymphocytic leukaemia (CLL). Purified B cells from seven of eight CLL patients with high WBC counts (greater than 80,000/microliters) responded to one or several of the tested SE (SEA, SEB, SEC1, SED, SEE) by proliferation ([3H]TdR incorporation) and/or Ig secretion. In several instances, the response of leukaemic B cells to SE was much stronger than was the response to other known B-cell activators including EBV, pokeweed mitogen (PWM), phorbolester (TPA), and Staphylococcus aureus Cowan I (SAC). The activation of leukaemic B cells by SE was strictly dependent on the addition of irradiated T cells isolated from healthy donors. FACS analysis of cultured cells ensured that the proliferating cells were indeed B cells. Taken together, these results demonstrate that SE are strong T-cell-dependent B-cell activators that, in some cases, can stimulate maturation of leukaemic B cells which are refractory to other activation signals. PMID:1572690

Duan, X; Nerl, C; Janssen, O; Kabelitz, D

1992-01-01

366

Selective activation of VH3A10+ rheumatoid factor producing B cells by staphylococcal enterotoxin D.  

PubMed

Staphylococcal enterotoxin D (SED) is a T cell superantigen which selectively targets alpha beta TCRs bearing particular V beta elements. A second function of SED relates to the preferential activation of a B cell subset characterized by a high frequency of rheumatoid factor (RF) producing B cells. To define the molecular basis of the SED-induced B cell repertoire shift, we have analyzed Ig heavy chain genes in B cell clones expanded after SED stimulation and compared them with B cell clones established in the presence of anti-CD3 stimulated helper cells. Gene segments of the VH3 family were most frequently utilized under both stimulation conditions (42% anti-CD3; 47% SED). Sequence analysis of VH3 gene segments demonstrated that the repertoire of VH3 elements in B cell clones from SED driven and anti-CD3 driven cultures were distinct (P = 0.01). RF activity was closely associated with the expression of selected VH3 elements. B cell clones stimulated with SED preferentially expressed VH3A10, whereas VH26 was the gene segment dominantly used in B cell clones expanded with anti-CD3 stimulated helper cells. The usage of JH and DH elements was indistinguishable in SED and anti-CD3 driven B cell clones, suggesting that SED targets VH3+ B cells through a VH-specific mechanism. Comparison of the closely related sequences of the SED responsive VH3A10 and the SED non-responsive VH26 element suggested a role of a sequence polymorphism in the CDR2 reminiscent of B cell reactivity to conventional antigens. In contrast to conventional antigens, SED can induce differentiation of a high frequency of naive B cells. Thus, this staphylococcal enterotoxin combines selective activation of T cells with selective activation of B cells and might be able to direct T cell help to RF producing B cells. PMID:7794822

Xie, C; Brühl, H; He, X; Weyand, C M; Goronzy, J J

1995-03-01

367

A molecular mechanism for TNF-?-mediated downregulation of B cell responses.  

PubMed

B cell function with age is decreased in class switch recombination (CSR), activation-induced cytidine deaminase (AID), and stability of E47 mRNA. The latter is regulated, at least in part, by tristetraprolin (TTP), which is increased in aged B cells and also negatively regulates TNF-?. In this study, we investigated whether B cells produce TNF-?, whether this changes with age, and how this affects their function upon stimulation. Our hypothesis is that in aging there is a feedback mechanism of autocrine inflammatory cytokines (TNF-?) that lowers the expression of AID and CSR. Our results showed that unstimulated B cells from old BALB/c mice make significantly more TNF-? mRNA and protein than do B cells from young mice, but after stimulation the old make less than the young; thus, they are refractory to stimulation. The increase in TNF-? made by old B cells is primarily due to follicular, but not minor, subsets of B cells. Incubation of B cells with TNF-? before LPS stimulation decreased both young and old B cell responses. Importantly, B cell function was restored by adding anti-TNF-? Ab to cultured B cells. To address a molecular mechanism, we found that incubation of B cells with TNF-? before LPS stimulation induced TTP, a physiological regulator of mRNA stability of the transcription factor E47, which is crucial for CSR. Finally, anti-TNF-? given in vivo increased B cell function in old, but not in young, follicular B cells. These results suggest new molecular mechanisms that contribute to reduced Ab responses in aging. PMID:22116831

Frasca, Daniela; Romero, Maria; Diaz, Alain; Alter-Wolf, Sarah; Ratliff, Michelle; Landin, Ana Marie; Riley, Richard L; Blomberg, Bonnie B

2012-01-01

368

Identification of a B cell-dependent subpopulation of multiple sclerosis by measurements of brain-reactive B cells in the blood.  

PubMed

B cells are increasingly coming into play in the pathogenesis of multiple sclerosis (MS). Here, we screened peripheral blood mononuclear cells (PBMC) from patients with clinically isolated syndrome (CIS), MS, other non-inflammatory neurological, inflammatory neurological or autoimmune diseases, and healthy donors for their B cell reactivity to CNS antigen using the enzyme-linked immunospot technique (ELISPOT) after 96 h of polyclonal stimulation. Our data show that nine of 15 patients with CIS (60.0%) and 53 of 67 patients with definite MS (79.1%) displayed CNS-reactive B cells, compared to none of the control donors. The presence of CNS-reactive B cells in the blood of the majority of patients with MS or at risk to develop MS along with their absence in control subjects suggests that they might be indicative of a B cell-dependent subpopulation of the disease. PMID:24607792

Kuerten, Stefanie; Pommerschein, Giovanna; Barth, Stefanie K; Hohmann, Christopher; Milles, Bianca; Sammer, Fabian W; Duffy, Cathrina E; Wunsch, Marie; Rovituso, Damiano M; Schroeter, Michael; Addicks, Klaus; Kaiser, Claudia C; Lehmann, Paul V

2014-01-01

369

Foxo3-/- mice demonstrate reduced numbers of pre-B and recirculating B cells but normal splenic B cell sub-population distribution.  

PubMed

B cell antigen receptor (BCR) cross-linking promotes proliferation and survival of mature B cells. Phosphoinositide-3-kinase-mediated down-regulation of pro-apoptotic and anti-mitogenic genes such as the Foxo family of transcription factors is an important component of this process. Previously, we demonstrated that BCR signaling decreases expression of transcripts for Foxo1, Foxo3 and Foxo4. We now show that BCR-induced down-regulation of Foxo3 and Foxo4 mRNA expression occurs via distinct mechanisms from those established for Foxo1. While Foxo1, Foxo3 and Foxo4 bind the same DNA sequence, the differential control of their expression upon B cell activation suggests that they may have unique functions in the B lineage. To begin to address this issue, we evaluated B cell development and function in Foxo3-/- mice. No effect of Foxo3 deficiency was observed with respect to the following parameters in the splenic B cell compartment: sub-population distribution, proliferation, in vitro differentiation and expression of the Foxo target genes cyclin G2 and B cell translocation gene 1. However, Foxo3-/- mice demonstrated increased basal levels of IgG2a, IgG3 and IgA. A significant reduction in pre-B cell numbers was also observed in Foxo3-/- bone marrow. Finally, recirculating B cells in the bone marrow and peripheral blood were decreased in Foxo3-/- mice, perhaps due to lower than normal expression of receptor for sphingosine-1 phosphate, which mediates egress from lymphoid organs. Thus, Foxo3 makes a unique contribution to B cell development, B cell localization and control of Ig levels. PMID:19502585

Hinman, Rochelle M; Nichols, Whitney A; Diaz, Tracy M; Gallardo, Teresa D; Castrillon, Diego H; Satterthwaite, Anne B

2009-07-01

370

A TNF-?-CCL20-CCR6 axis regulates Nod1-induced B cell responses.  

PubMed

Innate immune responses provoke the accumulation of leukocytes at sites of inflammation. In addition to monocytes and granulocytes, B cells also participate in antimicrobial innate immune responses; however, the mechanisms for accumulation of B cells to sites of inflammation are not well understood. To study B cell accumulation following systemic inflammation, we used a model synthetic ligand that stimulates a specific pattern recognition molecule, nucleotide-binding oligomerization domain-containing protein 1 (Nod1). Upon exposure to Nod1 agonists, both B cells and neutrophils rapidly accumulate within the spleen, and dendritic cells migrate into the periarterial lymphoid sheath. Nod1 stimulation led to a marked increase in several chemokines within the spleen, including CXCL13, CCL2, and CCL20. Whereas the lymphotoxin pathway was critical for the induction of the B cell chemoattractant CXCL13 in response to Nod1 agonists, B cell accumulation within the spleen following Nod1-induced systemic inflammation was independent of the lymphotoxin pathway. In contrast, a CCR6/CCL20 chemokine loop instructed rapid increase of B cells in the spleen in response to systemic administration of Nod1 agonists in a TNF-?-dependent manner. Moreover, CCR6 was required to regulate Nod1-mediated B cell responses. These results reveal a novel mechanism of B cells during inflammation and shed light on how B cells participate in innate immune responses to microbial stimulation. PMID:24534531

Paradis, Maude; Mindt, Barbara C; Duerr, Claudia U; Rojas, Olga L; Ng, Dennis; Boulianne, Bryant; McCarthy, Doug D; Yu, Mingxi Dennis; Summers deLuca, Leslie E; Ward, Lesley A; Waldron, James B; Philpott, Dana J; Gommerman, Jennifer L; Fritz, Jörg H

2014-03-15

371

Mast Cells Control the Expansion and Differentiation of IL-10-Competent B Cells.  

PubMed

The discovery of B cell subsets with regulatory properties, dependent on IL-10 production, has expanded our view on the mechanisms that control inflammation. Regulatory B cells acquire the ability to produce IL-10 in a stepwise process: first, they become IL-10 competent, a poised state in which B cells are sensitive to trigger signals but do not actually express the Il-10 gene; then, when exposed to appropriate stimuli, they start producing IL-10. Even if the existence of IL-10-competent B cells is now well established, it is not yet known how different immune cell types cross talk with B cells and affect IL-10-competent B cell differentiation and expansion. Mast cells (MCs) contribute to the differentiation and influence the effector functions of various immune cells, including B lymphocytes. In this study, we explored whether MCs could play a role in the expansion of IL-10-competent B cells and addressed the in vivo relevance of MC deficiency on the generation of these cells. We show that MCs can expand IL-10-competent B cells, but they do not directly induce IL-10 production; moreover, the absence of MCs negatively affects IL-10-competent B cell differentiation. Noteworthy, our findings reveal that the CD40L/CD40 axis plays a significant role in MC-driven expansion of IL-10-competent B cells in vitro and highlight the importance of MC CD40L signaling in the colon. PMID:25267976

Mion, Francesca; D'Incà, Federica; Danelli, Luca; Toffoletto, Barbara; Guarnotta, Carla; Frossi, Barbara; Burocchi, Alessia; Rigoni, Alice; Gerdes, Norbert; Lutgens, Esther; Tripodo, Claudio; Colombo, Mario P; Rivera, Juan; Vitale, Gaetano; Pucillo, Carlo E

2014-11-01

372

IL-4R?-Associated Antigen Processing by B Cells Promotes Immunity in Nippostrongylus brasiliensis Infection  

PubMed Central

In this study, B cell function in protective TH2 immunity against N. brasiliensis infection was investigated. Protection against secondary infection depended on IL-4R? and IL-13; but not IL-4. Protection did not associate with parasite specific antibody responses. Re-infection of B cell-specific IL-4R??/? mice resulted in increased worm burdens compared to control mice, despite their equivalent capacity to control primary infection. Impaired protection correlated with reduced lymphocyte IL-13 production and B cell MHC class II and CD86 surface expression. Adoptive transfer of in vivo N. brasiliensis primed IL-4R? expressing B cells into naïve BALB/c mice, but not IL-4R? or IL-13 deficient B cells, conferred protection against primary N. brasiliensis infection. This protection required MHC class II compatibility on B cells suggesting cognate interactions by B cells with CD4+ T cells were important to co-ordinate immunity. Furthermore, the rapid nature of these protective effects by B cells suggested non-BCR mediated mechanisms, such as via Toll Like Receptors, was involved, and this was supported by transfer experiments using antigen pulsed Myd88?/? B cells. These data suggest TLR dependent antigen processing by IL-4R?-responsive B cells producing IL-13 contribute significantly to CD4+ T cell-mediated protective immunity against N. brasiliensis infection. PMID:24204255

Hoving, Jennifer C.; Nieuwenhuizen, Natalie; McSorley, Henry J.; Ndlovu, Hlumani; Bobat, Saeeda; Kimberg, Matti; Kirstein, Frank; Cutler, Anthony J.; DeWals, Benjamin; Cunningham, Adam F.; Brombacher, Frank

2013-01-01

373

A two-scale model for correlation between B cell VDJ usage in zebrafish  

NASA Astrophysics Data System (ADS)

The zebrafish (Danio rerio) is one of the model animals for study of immunology. The dynamics of the adaptive immune system in zebrafish is similar to that in higher animals. In this work, we built a two-scale model to simulate the dynamics of B cells in primary and secondary immune reactions in zebrafish and to explain the reported correlation between VDJ usage of B cell repertoires in distinct zebrafish. The first scale of the model consists of a generalized NK model to simulate the B cell maturation process in the 10-day primary immune response. The second scale uses a delay ordinary differential equation system to model the immune responses in the 6-month lifespan of zebrafish. The generalized NK model shows that mature B cells specific to one antigen mostly possess a single VDJ recombination. The probability that mature B cells in two zebrafish have the same VDJ recombination increases with the B cell population size or the B cell selection intensity and decreases with the B cell hypermutation rate. The ODE model shows a distribution of correlation in the VDJ usage of the B cell repertoires in two six-month-old zebrafish that is highly similar to that from experiment. This work presents a simple theory to explain the experimentally observed correlation in VDJ usage of distinct zebrafish B cell repertoires after an immune response.

Pan, Keyao; Deem, Michael

2011-03-01

374

Stromal Cell-Independent B-Cell Development In Vitro: Generation and Recovery of Autoreactive Clones  

PubMed Central

We describe and characterize a stromal-cell independent culture system that efficiently supports pro-B cell to IgM+ B-cell development with near normal levels of IgH and Ig? diversity. Pro-B cells present in non-adherent bone marrow cells proliferate in the presence of IL-7 and subsequent to the removal of IL-7 and addition of BAFF, differentiate normally into IgM+ B cells. B-cell development in vitro closely follows the patterns of development in vivo with culture derived (CD) B cells demonstrating characteristic patterns of surface antigen expression and gene activation. IgM+ CD B cells respond to TLR stimulation by proliferation and differentiation into antibody-secreting cells. Self-reactive IgM+ B-cell development is blocked in 3H9 IgH knockin mice; however, cultures of 3H9 IgH knockin pro-B cells yields high frequencies of “forbidden”, autoreactive IgM+ B cells. Furthermore, serum IgG autoantibody exceeded that present in autoimmune, C4?/? animals following the reconstitution of RAG1?/? mice with IgM+ CD cells derived from BL/6 mice. PMID:20109461

Holl, T. Matt; Haynes, Barton F.; Kelsoe, Garnett

2013-01-01

375

Ex vivo characterization and isolation of rare memory B cells with antigen tetramers  

PubMed Central

Studying human antigen-specific memory B cells has been challenging because of low frequencies in peripheral blood, slow proliferation, and lack of antibody secretion. Therefore, most studies have relied on conversion of memory B cells into antibody-secreting cells by in vitro culture. To facilitate direct ex vivo isolation, we generated fluorescent antigen tetramers for characterization of memory B cells by using tetanus toxoid as a model antigen. Brightly labeled memory B cells were identified even 4 years after last immunization, despite low frequencies ranging from 0.01% to 0.11% of class-switched memory B cells. A direct comparison of monomeric to tetrameric antigen labeling demonstrated that a substantial fraction of the B-cell repertoire can be missed when monomeric antigens are used. The specificity of the method was confirmed by antibody reconstruction from single-cell sorted tetramer+ B cells with single-cell RT-PCR of the B-cell receptor. All antibodies bound to tetanus antigen with high affinity, ranging from 0.23 to 2.2 nM. Furthermore, sequence analysis identified related memory B cell and plasmablast clones isolated more than a year apart. Therefore, antigen tetramers enable specific and sensitive ex vivo characterization of rare memory B cells as well as the production of fully human antibodies. PMID:21551230

Franz, Bettina; May, Kenneth F.; Dranoff, Glenn

2011-01-01

376

Developmental Switches in Chemokine Response Profiles during B Cell Differentiation and Maturation  

PubMed Central

Developing B cells undergo dramatic changes in their responses to chemoattractant cytokines (chemokines) and in expression of chemokine receptors. Bone marrow pre–pro-B cells (AA4.1+/natural killer 1.1? Fraction A cells) and cells capable of generating pro-B colonies in the presence of interleukin 7 and flt3 ligand migrate to thymus-expressed chemokine (TECK), a response lost in later stages of B cell development. B cell–attracting chemokine 1 (BCA-1) responses correlate with CXC chemokine receptor (CXCR)5 expression, are first displayed by a pro-B cell subset, are lost in pre-B cells, and then are regained just before and