These are representative sample records from Science.gov related to your search topic.
For comprehensive and current results, perform a real-time search at Science.gov.
1

Occult B-cell lymphoproliferative disorders.  

PubMed

The term monoclonal B-cell lymphocytosis (MBL) was recently introduced to identify individuals with a population of monoclonal B cells in the absence of other features that are diagnostic of a B-cell lymphoproliferative disorder. MBL is often identified through hospital investigation of a mild lymphocytosis, and approximately 1% of such individuals develop progressive disease requiring treatment per year. However, in population studies using high-sensitivity flow cytometry, MBL may be detectable in more than 10% of adults aged over 60 years, and clinical progression is rare. The majority of MBL cases have features that are characteristic of chronic lymphocytic leukaemia, but an increasing amount of information is becoming available about MBL with the features of other B-cell lymphoproliferative disorders. In addition to flow cytometry findings, the incidental detection of an occult B-cell lymphoproliferative disorder is also occurring in a significant proportion of tissue biopsy samples. In this review, the clinical and biological relationship between MBL and B-cell lymphoproliferative disorders will be discussed, with a focus on identifying the differences between low levels of peripheral blood or bone marrow involvement with lymphoma and the monoclonal B-cell populations that commonly occur in elderly adults. PMID:21261685

Rawstron, Andy C

2011-01-01

2

B cell lymphoproliferative disorders following hematopoietic stem cell transplantation: risk factors, treatment and outcome  

Microsoft Academic Search

Twenty-six cases of B cell lymphoproliferative disorder (BLPD) were identified among 2395 patients following hematopoietic stem cell transplants (HSCT) for which an overall incidence of BLPD was 1.2%. The true incidence was probably higher, since 9\\/26 of the diagnoses were made at autopsy. No BLPD was observed following autologous HSCT, so risk factor analyses were confined to the 1542 allogeneic

TG Gross; M Steinbuch; T DeFor; RS Shapiro; P McGlave; NKC Ramsay; JE Wagner; AH Filipovich

1999-01-01

3

Clinicopathologic Features of CDK6 Translocation-Associated B-Cell Lymphoproliferative Disorders  

PubMed Central

Cyclin-dependent protein kinase 6 (CDK6), in cooperation with cyclin Ds, drives cell cycle progression from G1 to S phase through phosphorylation and subsequent inactivation of Retinoblastoma 1 protein (Rb). Alteration of this pathway results in both non-hematologic and hematologic malignancies, which include a small subset of B-cell lymphoproliferative disorders (BLPDs). We identified 5 cases of BLPD that carried CDK6 chromosomal translocations and characterized their clinical, pathologic, immunophenotypic, and genetic features. Common clinical characteristics included marked neoplastic lymphocytosis, systemic lymphadenopathy, splenomegaly, and bone marrow involvement. Three patients were diagnosed with low-grade B-cell lymphoma and had an indolent clinical course, and 2 patients (one who transformed to large B-cell lymphoma and another who was initially diagnosed with a high-grade B-cell lymphoma) had an aggressive clinical course. Immunophenotypically, the neoplastic B-cells expressed CD5, CDK6, and cytoplasmic Rb in all cases, expressed phospho-RB, p27kip1, and cyclin D2 in most cases, and uniformly lacked expression of all other cyclins. In four cases, the CDK6 translocation partner was kappa immunoglobulin light-chain gene (IGK); and in the fifth case, the CDK6 translocation partner was unknown. These distinct clinicopathologic and cytogenetic features distinguish the CDK6 translocation-associated BLPDs (CDK6-BLPDs) from other mature B-cell lymphomas. PMID:19145199

Chen, Dong; Law, Mark E.; Theis, Jason D.; Gamez, Jeffrey D.; Caron, Lynn B.; Vrana, Julie A.; Dogan, Ahmet; Remstein, Ellen D.

2009-01-01

4

Plasmablastic transformation of low-grade CD5+ B-cell lymphoproliferative disorder with MYC gene rearrangements.  

PubMed

Plasmablastic transformation of low-grade B-cell lymphoproliferative disorders is rarely reported, particularly in cases with clonal evolution. Moreover, the relationship of these 2 morphologically and immunophenotypically distinctive neoplasms remains elusive. Here, we report 2 exceptional cases of plasmablastic transformation with apparently direct transformation from their preceding low-grade B-cell lymphoproliferative disorder. In both cases, the plasmablastic transformation and low-grade lymphoproliferative disorder shared the same immunoglobulin heavy chain gene rearrangements and an identical chromosomal translocation. Notably, both plasmablastic transformation cases also carried MYC gene rearrangements on chromosome 8q24, which have been frequently identified in de novo plasmablastic lymphoma. Therefore, our data suggest that dysregulation of MYC gene may play a critical role in the pathogenesis of plasmablastic transformation. PMID:23791008

Pan, Zenggang; Xie, Qingmei; Repertinger, Susan; Richendollar, Bill G; Chan, Wing C; Huang, Qin

2013-10-01

5

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

PubMed Central

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

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

2013-01-01

6

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

PubMed Central

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

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

2015-01-01

7

Post-transplant Lymphoproliferative Disorders.  

PubMed

Post-transplant lymphoproliferative disorders (PTLD) are a serious complication after solid organ or allogeneic hematopoietic stem cell transplantation and include a range of diseases from benign proliferations to malignant lymphomas. Risk factors for developing PTLD include Epstein-Barr virus (EBV) infection, recipient age, transplanted organ, type of immunosuppression, and genetics. Uncontrolled proliferation of EBV-infected B cells is implicated in EBV-positive PTLD, whereas the pathogenesis of EBV-negative PTLD may be similar to non-Hodgkin's lymphoma in the general population. The World Health Organization (WHO) classifies PTLD into four categories: early lesions, polymorphic PTLD, monomorphic PTLD, and classical Hodgkin's lymphoma (cHL). Treatment is aimed at cure of PTLD, while maintaining transplanted organ function. However, there are no established guidelines for the treatment of PTLD. Immune suppression reduction (ISR) is the first line of treatment in most cases, with more recent data suggesting early use of rituximab. In more aggressive forms of PTLD, upfront chemotherapy may offer a better and more durable response. Sequential therapy using rituximab followed by chemotherapy has demonstrated promising results and may establish a standard of care. Novel therapies including anti-viral agents, adoptive immunotherapy, and monoclonal antibodies targeting cytokines require further study in the prevention and treatment of PTLD. PMID:25655616

Singavi, Arun K; Harrington, Alexandra M; Fenske, Timothy S

2015-01-01

8

Hepatitis C virus-related lymphoproliferative disorders: An overview  

Microsoft Academic Search

Hepatitis C virus (HCV) is a global health problem affecting 3% of the world's population (about 180 million) and a cause of both hepatic and extrahepatic diseases. B-cell lymphoproliferative disorders, whose prototype is mixed cryoglobulinemia, represent the most closely related as well as the most investigated HCV- related extrahepatic disorder. The association between extrahepatic (lymphoma) as well as hepatic malignancies

Anna Linda Zignego; Carlo Giannini; Ferri Francoise; Lunel Fabiani; Clodoveo Ferri; Reggio Emilia; Ferri C. Hepatitis

2007-01-01

9

?-HHVs and HHV-8 in Lymphoproliferative Disorders  

PubMed Central

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

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

2011-01-01

10

KSHV- and EBV-associated germinotropic lymphoproliferative disorder.  

PubMed

Kaposi sarcoma-associated herpesvirus (KSHV) is known to be associated with 3 distinct lymphoproliferative disorders: primary effusion lymphoma (PEL), multicentric Castleman disease (MCD), and MCD-associated plasmablastic lymphoma. We report 3 cases of a previously undescribed KSHV-associated lymphoproliferative disorder. The disease presented as localized lymphadenopathy and showed a favorable response to chemotherapy or radiotherapy. Histologically, the lymphoproliferation is characterized by plasmablasts that preferentially involved germinal centers of the lymphoid follicles, forming confluent aggregates. They were negative for CD20, CD27, CD79a, CD138, BCL6, and CD10 but showed monotypic kappa or lambda light chain. Clusters of CD10(+)CD20(+) residual follicle center cells were identified in some of the follicles. The plasmablasts were positive for both KSHV and EBV, and most of them also expressed viral interleukin-6 (vIL-6). Unexpectedly, molecular analysis of whole tissue sections or microdissected KSHV-positive aggregates demonstrated a polyclonal or oligoclonal pattern of immunoglobulin (Ig) gene rearrangement. The plasmablasts showed somatic mutation and intraclonal variation in the rearranged Ig genes, and one case expressed switched Ig heavy chain (IgA), suggesting that they originated from germinal center B cells. We propose calling this distinctive entity "KSHV-associated germinotropic lymphoproliferative disorder." PMID:12384445

Du, Ming-Qing; Diss, Tim C; Liu, Hongxiang; Ye, Hongtao; Hamoudi, Rifat A; Cabeçadas, José; Dong, Henry Y; Harris, Nancy Lee; Chan, John K C; Rees, John W; Dogan, Ahmet; Isaacson, Peter G

2002-11-01

11

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

12

Lymphoproliferative disorders following allogeneic bone marrow transplantation: the Vancouver experience  

Microsoft Academic Search

Between June 1988 and May 1996, 428 patients underwent allogeneic BMT (288 related donor (RD) and 140 unrelated donor (UD)) at the Vancouver General Hospital. Eight patients (UD six and RD two) developed a post-transplant lymphoproliferative disorder (PTLD). Median age at BMT was 38 years (range 22–51). Five of the six UD allografts were T cell depleted. Cyclosporine ± methotrexate

INM Micallef; M Chhanabhai; JD Shepherd; HC Fung; SH Nantel; CL Toze; H-G Klingemann; HJ Sutherland; DE Hogge; TJ Nevill; A Le; MJ Barnett

1998-01-01

13

EBV-associated lymphoproliferative disorder of CNS associated with the use of mycophenolate mofetil  

PubMed Central

Epstein-Barr virus (EBV)–associated lymphoid proliferations are a well-recognized complication of congenital or acquired systemic immunosuppression. The CNS is a frequent site for development of such lymphoid proliferations. We describe the clinical, imaging, and pathologic observations of a CNS disorder histologically similar to posttransplantation lymphoproliferative disorder that occurred in four patients with autoimmune disease treated with mycophenolate mofetil (MM). Two patients had polymorphous lymphoplasmacytic infiltration of brain parenchyma, and two had monomorphous infiltrations consistent with diffuse large B-cell lymphoma. In situ hybridization for EBV-encoded RNA was positive in all four patients. All patients improved after MM withdrawal and the use of rituximab. Because of a favorable toxicity profile, MM is now being used as steroid-sparing immunomodulatory therapy in autoimmune disorders. Based on our experience presented herein, we recommend caution in patient selection for MM and strict surveillance of those patients with autoimmune disorders who receive MM. PMID:17522336

O’Neill, Brian Patrick; Vernino, Steven; Dogan, Ahmet; Giannini, Caterina

2007-01-01

14

A rare cause of ulcerative colitis - diarrhoea and perianal bleeding due to posttransplant lymphoproliferative disorder (PTLD).  

PubMed

Post-transplant lymphoproliferative disorder (PTLD) is characterised by frequent extranodal manifestation, in 20 - 25 % including the gastrointestinal tract. This entity, which is more frequent after solid organ transplantation, rarely occurs after bone marrow transplantation (BMT). We report the case of a 43-year-old male presenting with a short history of rectal bleeding, diarrhoea and weight loss. He had received a bone marrow transplant two years previously for an acute lymphocytic leukaemia of B-cell origin. On sigmoidoscopy, deep ulcerations of the rectal and sigmoideal mucosa were found. Further investigations revealed a diffuse infiltration of the liver, spleen, both kidneys and lungs. Histologically, a monomorphic post-transplant lymphoproliferative disorder was diagnosed, the subtype was a high grade diffuse-large cell Non-Hodgkin's lymphoma of B-cell origin. The biopsies showed that a major proportion of cells expressed Epstein-Barr virus encoded proteins typical for latent as well as lytic EBV infection. This is a common feature of PTLD and possibly plays a critical role in its pathogenesis. The current therapeutic approach to the subtype of PTLD we saw in this patient is CHOP chemotherapy, comprising the anti-CD 20 antibody rituximab if CD 20-positivity is present. This patient had a fatal course of the disease and died a few days after the first chemotherapy cycle due to severe multiple organ failure. PMID:19280542

Godt, C; Regnery, A; Schwarze, B; Junker, K; Porschen, R

2009-03-01

15

Epstein-Barr virus-related lymphoproliferative disorder induced by equine anti-thymocyte globulin therapy.  

PubMed

Post-transplant lymphoproliferative disorder (PTLD) is generally caused by an uncontrolled B-cell proliferation induced by Epstein-Barr virus (EBV) in the setting of impaired EBV-specific T-cell immunity. PTLD has been described in allogeneic hematopoietic stem cell transplant (HSCT) and rarely in autologous HSCT. Anti-thymocyte globulin (ATG) is being increasingly utilized for acute rejection in organ transplantation, severe autoimmune diseases and aplastic anemia. Mainly, the use of rabbit ATG has been associated with PTLD, which is considered to be more immunosuppressive than equine ATG. The sole administration of equine ATG has rarely been associated with PTLD. Due to the increased use of these potent and novel immunosuppressive agents, it is paramount to be aware of these complications. We present a 55-year-old man with an autologous HSCT who presented with an unusual case of monoclonal plasmacytic PTLD. His lymphoproliferative disorder occurred 3 years after his HSCT and 1 month after the use of equine ATG administered for severe aplastic anemia. We review current concepts of EBV-PTLD, including risk factors, the potential for preemptive therapy and various management strategies. PMID:20680523

Viola, George M; Zu, Youli; Baker, Kelty R; Aslam, Saima

2011-12-01

16

Lymphocyte markers and clinical expression of lymphoproliferative disorders with moderate lymphocytosis.  

PubMed Central

Lymphoproliferative syndrome with well differentiated lymphocytes and moderate lymphocytosis in the peripheral blood includes a heterogeneous group of disorders, that present often difficulties in classification. We have studied the lymphocyte markers (ER, EMR, sIg and T3, T4, T8 antigens) in 36 cases who had lymphocytic infiltration in the bone marrow and peripheral lymphocyte counts less than 15 X 10(9) l-1. Four cases (11.1%) had the characteristics of T8 lymphocytosis and 31 had a B cell monoclonal proliferation in the peripheral blood. Of these, four were sIg-, EMR+, 19 were sIg+, EMR+ and 8 were sIg+, EMR-. Most patients (17/32) had the clinical picture of stage 0 and I B-CLL. Six cases presented as pure splenomegalic form of CLL, three had the features of immunocytic lymphoma and five had the features of lymphocytic lymphoma. It is concluded that the majority of lymphoproliferative disorders presenting with moderate lymphocytosis represent early forms of B-CLL. Occasionally cases of lymphocytic or immunocytic lymphoma may present problems of differential diagnosis since there may be a dissociation of phenotypic characteristics of lymphocytes between tissues and peripheral blood. PMID:3490873

Economidou, J.; Choremi, H.; Konstantinidou, N.; Kofina, A.; Psarra, K.; Stefanoudaki, K.; Papayannis, A.; Economopoulos, F.; Dervenoulas, J.; Vlachos, J.

1986-01-01

17

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

PubMed

Post-transplant lymphoproliferative disorder (PTLD) can occur after solid organ transplantation (SOT) or hematopoietic stem cell transplantation (HSCT). The majority of PTLDs are related to the reactivation of Epstein-Barr virus (EBV) in the lymphoid organs. PLTDs in HSCT recipients tend to present with systemic involvement, and isolated PTLD in these patients is rare. Only 14 isolated cerebral PTLDs have been reported in HSCT recipients, and none have been reported in lymphoma patients. When diagnosing PTLD in a lymphoma patient, it is challenging to discriminate between a PTLD that originated from previous disease and a newly developed clone and to distinguish between donor and recipient origin. In this report, we present the first case of a B-cell lymphoma patient who developed isolated PTLD in the CNS, and we confirmed that the PTLD originated in a distinct clone and from a different origin. Furthermore, the role of EBV-DNA monitoring in such patients is discussed. PMID:24126003

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

2013-01-01

18

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

19

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

20

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

PubMed

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

Liebman, Howard A

2009-01-01

21

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

PubMed Central

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

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

2015-01-01

22

Atypical hydroa vacciniforme-like epstein-barr virus associated T/NK-cell lymphoproliferative disorder.  

PubMed

Epstein-Barr virus (EBV)-associated T-cell/natural killer (NK)-cell lymphoproliferative disorders (EBV-T/NK-LPDs) accompany severe chronic active EBV infection (CAEBV) or comprise the CAEBV disease entity. The CAEBV disease entity has the common feature of lymphoproliferation of T or NK cells (primarily), and B cells (rarely), with chronic activation of EBV infection. The disease is rare and seems to be more prevalent in East Asian countries. The CAEBV disease entity encompasses heterogenous disorders, including hydroa vacciniforme (HV), hypersensitivity to mosquito bites, EBV-associated hemophagocytic syndrome, NK/T-cell lymphoma, and NK-cell leukemia. Atypical HV-like eruptions are present on sun-exposed and nonexposed areas with facial edema, fever, and hepatosplenomegaly, unlike classic HV. Recently, it has been suggested that classic HV and atypical HV-like eruptions are variants within the same disease spectrum of EBV-T/NK-LPD. We report a Korean boy with an atypical HV-like eruption and various systemic manifestations, including fever, sore throat, abdominal pain, headaches, seizures, and hematologic abnormalities for 2 years. After the initial mild eruption, which resembled a viral exanthem, ulceronecrotic skin lesions gradually developed and were associated with a high-grade fever and constitutional symptoms. He had a CAEBV infection, which showed a predominant proliferation of NK cells with high EBV DNA levels in the peripheral blood. However, in the skin lesions, there were nonneoplastic CD4 T-cell infiltrations predominantly showing a monoclonal T-cell receptor-? gene rearrangement and positive EBV in situ hybridization. PMID:23169419

Lee, Hye Young; Baek, Jin Ok; Lee, Jong Rok; Park, Sang Hui; Jeon, In Sang; Roh, Joo Young

2012-12-01

23

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

Microsoft Academic Search

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

R. Garand; N. Robillard

1997-01-01

24

Immunophenotyping of selected hematologic disorders--focus on lymphoproliferative disorders with more than one malignant cell population.  

PubMed

Currently, clinical laboratories face increasing demand for flow cytometry testing combined with limited funding. Therefore, many laboratories search for panels that would provide sufficient immunophenotyping information and meet economical requirements. At the Flow Cytometry Laboratory, University Health Network, Toronto, ON, Canada, we apply two 10-color tubes of surface markers for diagnosis of lymphoproliferative disorders (LPDs). These tubes contain most of the mandatory B- and T-cell markers according to European Leukemia Net (www.leukemia-net.org) recommendations. The B-cell-oriented panel includes the following antibodies: Kappa-FITC/lambda-PE/CD19-ECD/CD38-PC5.5/CD20-PC7/CD34-APC/CD23 APC-AF700/CD10 APC-AF750/CD5-PB/CD45-KO. A different combination is applied to detect cytoplasmic Ig light chain expression and aberrant immunophenotype of plasma cells. The T-cell panel allows enumeration of various T- and NK-cell subsets: CD57-FITC/CD11c-PE/CD8-ECD/CD3-PC5.5/CD2-PC7/CD56-APC/CD7-APC-AF700/CD4-APC-AF750/CD5-PB/CD45-KO. The reported overall incidence of B-cell chronic LPDs presenting with more than one aberrant population is approximately 5%. Multicolor analysis facilitates the detection of multiple aberrant populations in the same sample because expression of multiple antigens can be studied simultaneously in each defined population. Examples of LPDs with multiple aberrant populations are presented. PMID:23590655

Porwit, A

2013-06-01

25

An inherited disorder of lymphocyte apoptosis: the autoimmune lymphoproliferative syndrome.  

PubMed

The autoimmune lymphoproliferative syndrome (ALPS) affords novel insights into the mechanisms that regulate lymphocyte homeostasis and underlie the development of autoimmunity. This syndrome arises early in childhood in persons who inherit mutations in genes that mediate apoptosis, or programmed cell death. The timely deletion of lymphocytes is a way to prevent their accumulation and the persistence of cells that can react against the body's own antigens. In ALPS, defective lymphocyte apoptosis permits chronic, nonmalignant adenopathy and splenomegaly; the survival of normally uncommon "double-negative" CD3+ CD4- CD8- T cells; and the development of autoimmune disease. Most cases of ALPS involve heterozygous mutations in the lymphocyte surface protein Fas that impair a major apoptotic pathway. Detailed immunologic investigations of the cellular and cytokine profiles in ALPS show a prominent skewing toward a T-helper 2 phenotype; this provides a rational explanation for the humoral autoimmunity typical of patients with ALPS. Prospective evaluations of 26 patients and their families show an ever-expanding spectrum of ALPS and its major complications: hypersplenism, autoimmune hemolytic anemia, thrombocytopenia, and neutropenia. Defective apoptosis may also contribute to a heightened risk for lymphoma. PMID:10189330

Straus, S E; Sneller, M; Lenardo, M J; Puck, J M; Strober, W

1999-04-01

26

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

27

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

PubMed

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

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

2015-01-01

28

Primary cutaneous CD30 positive T-cell lymphoproliferative disorders with aberrant expression of PAX5: report of three cases.  

PubMed

Accurate diagnosis of lymphoma includes the assessment of lineage-specific markers. Hematopoietic and lymphoid tissues express PAX5 exclusively in pro-B-cell to mature B-cell stages. However, some mature PAX5+ T-cell lymphomas have been reported. We report three cases of primary cutaneous CD30+ T-cell lymphoproliferative disorders (LPDs) with PAX5 expression: one cutaneous anaplastic large cell lymphoma (ALCL) and two cases of lymphomatoid papulosis (LyP). The three patients were 26 years old and female, 75 years old and female, and 65 years old and male. In all cases, Hodgkin's and Reed-Sternberg-like large lymphoid cells were present, positive for CD30, fascin, and PAX5, and negative for CD3, CD4, CD8, CD20, CD45RO, CD56, cytotoxic markers, and Epstein-Barr virus. The ALCL was accompanied by lymphadenopathy; the patient died of progressive disease 5 months after diagnosis. The LyP cases were localized in the skin with spontaneous regression. One case was diagnosed during pregnancy, transformed to ALCL, and ended in death 32 months after diagnosis despite multi-agent chemotherapy. This study is the first to address the clinical significance of PAX5+ primary cutaneous CD30+ T-cell LPDs. These cases were distinct regarding PAX5 expression and a relatively aggressive clinical course versus conventional primary cutaneous CD30+ T-cell LPDs. PMID:22449230

Hagiwara, Masahiro; Tomita, Akihiro; Takata, Katsuyoshi; Shimoyama, Yoshie; Yoshino, Tadashi; Tomita, Yasushi; Nakamura, Shigeo

2012-04-01

29

Comparison of non-myeloablative conditioning regimens for lymphoproliferative disorders.  

PubMed

Hematopoietic cell transplantation (HCT) with non-myeloablative (NMA) conditioning for lymphoproliferative diseases (LD) includes fludarabine with and without low-dose TBI. Transplant outcomes were compared among patients aged ?40 years with LD who received a HCT with TBI (N=382) or no-TBI (N=515) NMA from 2001 to 2011. The groups were comparable except for donor, graft, prophylaxis for GVHD, disease status and year of HCT. Cumulative incidences of grades II-IV GVHD at 100 days were 29% and 20% (P=0.001) and of chronic GVHD at 1 year were 54% and 44% (P=0.004) for TBI and no-TBI, respectively. Multivariate analysis of progression/relapse, treatment failure and mortality showed no outcome differences by conditioning. Full donor chimerism at day 100 was observed in 82% vs 64% in the TBI and no-TBI groups, respectively (P=0.006). Subsets of the four most common conditioning/GVHD prophylaxis combinations demonstrated higher rates of grades II-IV acute (P<0.001) and chronic GVHD (P<0.001) among recipients of TBI-mycophenolate mofetil (MMF) compared with other combinations. TBI-based NMA conditioning induces faster full donor chimerism, but overall survival outcomes are comparable to no-TBI regimens. Combinations of TBI and MMF are associated with higher rates of GVHD without impact on survival outcomes in patients with LD.Bone Marrow Transplantation advance online publication, 1 December 2014; doi:10.1038/bmt.2014.269. PMID:25437248

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

2014-12-01

30

Early gene expression changes by Epstein-Barr virus infection of B-cells indicate CDKs and survivin as therapeutic targets for post-transplant lymphoproliferative diseases.  

PubMed

Lymphoproliferative diseases (LPDs) associated with Epstein-Barr virus (EBV) infection cause significant morbidity and mortality in bone marrow and solid organ transplant recipients. To gain insight into LPD pathogenesis and to identify potential effective therapeutic approaches, we investigated early molecular events leading to B-cell transformation by gene expression profiling of EBV-infected B-cells from tonsils by Affymetrix microarray 72 hr postinfection when the B-cells hyperproliferation phase starts. Cell cycle and apoptosis were the most significantly affected pathways and enriched gene sets. In particular, we found significantly increased expression of cyclin-dependent kinase (CDK)1 and CCNB1 (cyclin B1) and of one of their downstream targets BIRC5 (survivin). Importantly, the strong upregulation of the antiapoptotic protein survivin was confirmed in lymphoblastoid cell lines (LCLs) and 71% of EBV-positive post-transplant EBV-LPD lesions scored positive for survivin. The validity of early transforming events for the identification of therapeutic targets for EBV-LPD was confirmed by the marked antiproliferative effect of the CDK inhibitor flavopiridol on LCLs and by the strong induction of apoptosis by survivin inhibition with YM155 or terameprocol. Our results suggest that targeting of CDKs and/or survivin in post-transplant EBV-LPD by specific inhibitors might be an important approach to control and eliminate EBV-transformed B-cells that should be further considered. PMID:23640782

Bernasconi, Michele; Ueda, Seigo; Krukowski, Patricia; Bornhauser, Beat C; Ladell, Kristin; Dorner, Marcus; Sigrist, Juerg A; Campidelli, Cristina; Aslandogmus, Roberta; Alessi, Davide; Berger, Christoph; Pileri, Stefano A; Speck, Roberto F; Nadal, David

2013-11-15

31

T cell lymphoproliferative disorders associated with anti-tumor necrosis factor alpha antibody therapy for ulcerative colitis: literature summary.  

PubMed

The enhanced risk of development of lymphoproliferative disorders in patients with inflammatory bowel disease has been attributed to immunosuppressive/immunomodulatory therapies. Infliximab is a chimeric monoclonal immunoglobulin G1 antibody directed against tumor necrosis factor alpha (TNF-?) that was approved by the Food and Drug Administration (FDA) in 1998 as an effective therapeutic agent against inflammatory bowel disease. Malignant lymphomas of both B and T cell lineage have been described in patients undergoing therapy involving TNF-? blockade. To date, eight cases of Epstein-Barr virus (EBV)-negative hepatosplenic T cell lymphoma associated with infliximab have been reported to the FDA's Adverse Event Reporting System, as well as several other T cell lymphoproliferative disorders with aggressive clinical outcomes. We present the histologic, immunophenotypic, and molecular features of a T cell lymphoproliferative disorder involving the axillary lymph node of a 33-year-old male following infliximab treatment for ulcerative colitis. These EBV-negative lymphomas suggest that lymphoproliferative disorders following infliximab treatment for inflammatory bowel disease may involve EBV-independent immune dysregulation. The spectrum of lymphoproliferative disorders associated with infliximab and the potential mechanisms by which they occur are discussed. PMID:19669196

Schmidt, Lindsay A; Lim, Megan S

2009-07-01

32

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

PubMed Central

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.

2013-01-01

33

Rituximab therapy in a patient with low grade B-cell lymphoproliferative disease and concomitant acquired angioedema  

PubMed Central

Acquired angioedema is often associated with significant morbidity. An underlying lymphatic malignancy, autoimmune disorder, adenocarcinoma, or other malignancy may be present. Screening for these disorders should occur in all patients with acquired angioedema as treatment may result in resolution of angioedema. PMID:25506230

Kaur, Ravdeep; Williams, Aerik Anthony; Swift, Catherine Baker; Caldwell, Jason W

2014-01-01

34

Case report: successful treatment of posttransplant lymphoproliferative disorder and quiescence of dermatomyositis with rituximab and sirolimus.  

PubMed

Posttransplant lymphoproliferative disorder (PTLD) remains one of the most important complications of intensive immunosuppressive therapy. A 65-year-old Caucasian woman received a primary en bloc kidney transplant from a deceased 2-year-old donor. After antithymocyte globulin induction she was treated with a maintenance regimen including cyclosporine and mycophenylate mofetil (MMF). She had a history of recurrent dermatomyositis, suggesting a flawed immune system. After a benign course for 9 months and after an increase in MMF from 2 to 3 g daily, she presented with pneumonia owing to Candida albicans, which was responsive to antibiotics, as was the PTLD. Persistent fever led to a diagnosis of PTLD. The immunosuppressive regimen was converted to sirolimus (SRL) and rituximab, with over 90% necrosis of the neoplasm at 1 month. However, owing to concern at exploration, the allografts were extirpated. This case documented the benefit of the rituximab-SRL combination to treat PTLD while maintaining dermatomyositis in remission. PMID:18589184

Kaposztas, Z; Etheridge, W B; Kahan, B D

2008-06-01

35

The vacuolated glycogen-laden leukemic lymphocytes of a T-cell lymphoproliferative disorder.  

PubMed

In this report, we present a case of peripheral T-cell leukemia/lymphoma having mostly small- to medium-sized cells with abundant clear cytoplasmic vacuoles. The presentation at the time of diagnosis was one of leukemia/lymphoma. The phenotype of the leukemic cells of the peripheral blood was T1+, T11+, TQ1+, interleukin-2+, T3-, T4-, and T8-. The cells in the peripheral blood as well as those obtained from lymph node biopsy were strongly periodic acid-Schiff positive; the positivity was diastase sensitive. Electron microscopy confirmed the presence of glycogen in the cytoplasmic vacuoles. Serologic tests were negative for human T-cell lymphotropic virus type 1 antibody. The data presented in this article support the existence of a vacuolated variant of peripheral T-cell leukemia/lymphoma and further expand the morphological spectrum of T-cell lymphoproliferative disorders. PMID:2787977

Krauss, J S; Pantazis, C G; Spurlock, B O; Price, L M; Neeley, A E

1989-08-01

36

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

37

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

PubMed

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

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

2014-12-11

38

Intrathecal therapy with rituximab in central nervous system involvement of post-transplant lymphoproliferative disorder.  

PubMed

Post-transplant lymphoproliferative disorder (PTLD) caused by Epstein-Barr virus (EBV) is a severe complication in high-risk allogeneic hematopoietic stem cell transplant (HSCT) recipients. Central nervous system (CNS) involvement of PTLD is a very rare event in patients with HSCT. As no established standard therapy in CNS-EBV-PTLD is available, the aim of this study was analysis of the safety and efficacy of intrathecal rituximab therapy in a group of eight children and adolescents with CNS-EBV-PTLD. Seven patients responded to therapy: all clinical symptoms and EBV-DNA viral load resolved after a median 2 (range: 1-7) doses of rituximab. However, some magnetic resonance imaging (MRI) changes in brain scan persisted in two patients. In all patients, except one, no adverse events of the therapy were observed. In conclusion, intrathecal rituximab administration seems to be an effective and safe method of treatment of CNS-EBV-PTLD in pediatric stem cell recipients. We recommend this treatment modality for further investigation. PMID:22873830

Czyzewski, Krzysztof; Styczynski, Jan; Krenska, Anna; Debski, Robert; Zajac-Spychala, Olga; Wachowiak, Jacek; Wysocki, Mariusz

2013-03-01

39

Adapted treatment of Epstein-Barr virus infection to prevent posttransplant lymphoproliferative disorder after heart transplantation.  

PubMed

Up to 35% of posttransplant lymphoproliferative disorder (PTLD) cases occur within 1 year of transplantation, and over 50% are associated with Epstein-Barr virus (EBV). EBV primary infection and reactivation are PTLD predictive factors, but there is no consensus for their treatment. We conducted a prospective single-center study on 299 consecutive heart-transplant patients treated with the same immunosuppressive regimen and monitored by repetitive EBV viral-load measurements and endomyocardial biopsies to detect graft rejection. Immunosuppression was tapered on EBV reactivation with EBV viral loads >10(5) copies/mL or primary infection. In the absence of response at 1 month or a viral load >10(6) copies/mL, patients received one rituximab infusion (375 mg/m(2) ). All patients responded to treatment without increased graft rejection. One primary infection case developed a possible PTLD, which completely responded to diminution of immunosuppression, and one patient, whose EBV load was unevaluable, died of respiratory complications secondary to PTLD. Compared with a historical cohort of 820 patients, PTLD incidence was decreased (p = 0.033) by a per-protocol analysis. This is the largest study on EBV primary infection/reactivation treatment, the first using rituximab following solid organ transplantation to prevent PTLD and the first to demonstrate an acceptable tolerability profile in this setting. PMID:24666832

Choquet, S; Varnous, S; Deback, C; Golmard, J L; Leblond, V

2014-04-01

40

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

PubMed

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

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

2015-01-01

41

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

PubMed Central

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

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

2014-01-01

42

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

43

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

PubMed

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

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

2015-03-01

44

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

45

In non-follicular lymphoproliferative disorders, IGH/BCL2-fusion is not restricted to chronic lymphocytic leukaemia.  

PubMed

The translocation t(14;18) and its t(2;18) and t(18,22) variants, which involve the BCL2 genetic hallmark for follicular lymphoma (FL), have been reported in several cases of chronic B-cell lymphoproliferative disease (CLPD) and frequently in chronic lymphocytic leukaemia (CLL). We describe here the clinical, morphological, immunological, cytogenetic and molecular findings from 37 cases of t(14;18)-positive CLPD, identified from our series of non-FL B-cell neoplasms (n=993) that were routinely analysed in peripheral blood by conventional cytogenetics analyses. The FL diagnosis was excluded by morphology and immunology (the samples were CD10 negative in all cases). The BCL2 translocations were observed in 22 CLL cases, including 7 monoclonal B-cell lymphocytosis (MBL) cases re-classified according to the new International Workshop on CLL criteria, six small lymphocytic lymphoma (SLL) cases, 1 splenic marginal zone lymphoma (SMZL) case and eight cases of unclassifiable CLPD with overlapping CLL/MZL features. In the CLL cases, the IGH/BCL2 fusion was remarkably associated with trisomy 12 (13/22) and mutated IGHV status (20/21) and did not affect the outcome. Moreover, most of these CLLs harboured a low mutation load of BCL6 gene and unmutated FAS (CD95) loci, which points to a post-germinal-centre cellular origin. PMID:22686190

Baseggio, Lucile; Geay, Marie-Odile; Gazzo, Sophie; Berger, Françoise; Traverse-Glehen, Alexandra; Ffrench, Martine; Hayette, Sandrine; Callet-Bauchu, Evelyne; Verney, Aurélie; Morel, Dominique; Jallades, Laurent; Magaud, Jean-Pierre; Salles, Gilles; Felman, Pascale

2012-08-01

46

Anti-CD20 B-cell depletion enhances monocyte reactivity in neuroimmunological disorders  

PubMed Central

Background Clinical trials evaluating anti-CD20-mediated B-cell depletion in multiple sclerosis (MS) and neuromyelitis optica (NMO) generated encouraging results. Our recent studies in the MS model experimental autoimmune encephalomyelitis (EAE) attributed clinical benefit to extinction of activated B-cells, but cautioned that depletion of naïve B-cells may be undesirable. We elucidated the regulatory role of un-activated B-cells in EAE and investigated whether anti-CD20 may collaterally diminish regulatory B-cell properties in treatment of neuroimmunological disorders. Methods Myelin oligodendrocyte glycoprotein (MOG) peptide-immunized C57Bl/6 mice were depleted of B-cells. Functional consequences for regulatory T-cells (Treg) and cytokine production of CD11b+ antigen presenting cells (APC) were assessed. Peripheral blood mononuclear cells from 22 patients receiving anti-CD20 and 23 untreated neuroimmunological patients were evaluated for frequencies of B-cells, T-cells and monocytes; monocytic reactivity was determined by TNF-production and expression of signalling lymphocytic activation molecule (SLAM). Results We observed that EAE-exacerbation upon depletion of un-activated B-cells closely correlated with an enhanced production of pro-inflammatory TNF by CD11b+ APC. Paralleling this pre-clinical finding, anti-CD20 treatment of human neuroimmunological disorders increased the relative frequency of monocytes and accentuated pro-inflammatory monocyte function; when reactivated ex vivo, a higher frequency of monocytes from B-cell depleted patients produced TNF and expressed the activation marker SLAM. Conclusions These data suggest that in neuroimmunological disorders, pro-inflammatory APC activity is controlled by a subset of B-cells which is eliminated concomitantly upon anti-CD20 treatment. While this observation does not conflict with the general concept of B-cell depletion in human autoimmunity, it implies that its safety and effectiveness may further advance by selectively targeting pathogenic B-cell function. PMID:22027448

2011-01-01

47

Treatment of rare co-occurrence of Epstein-Barr virus-driven post-transplant lymphoproliferative disorder and hemophagocytic lymphohistiocytosis after allogeneic stem cell transplantation.  

PubMed

In both conditions, post-transplant lymphoproliferative disorder (PTLD) and hemophagocytic lymphohistiocytosis (HLH), infection with Epstein-Barr virus (EBV) is a key mechanism: almost all PTLD in allogeneic stem cell transplantation (alloSCT) is caused by EBV-related neoplastic lymphoproliferation, and secondary HLH is most frequently triggered by EBV infection. Therefore, concomitant EBV-driven PTLD and HLH early after alloSCT require an approach to eliminate EBV and balance immune activation simultaneously. We report on a patient who developed simultaneous PTLD and signs of HLH on day 64 after alloSCT. Treatment was comprised of stopping cyclosporine, short-course dexamethasone, and 3 courses of rituximab. The patient showed full recovery and complete remission of lymphadenopathy. This result indicates that immediate reduction in EBV-carrying B cells by rituximab, suppression of general inflammation, and parallel support of reconstitution of long-term T-cell function, might be an appropriate therapeutic approach in this rare situation. PMID:25179757

Weber, T; Wickenhauser, C; Monecke, A; Gläser, C; Stadler, M; Desole, M; Ligeti, K; Behrmann, C; Müller-Tidow, C; Müller, L P

2014-12-01

48

Translational Mini-Review Series on B Cell-Directed Therapies: Recent advances in B cell-directed biological therapies for autoimmune disorders  

PubMed Central

B cell-directed therapies are promising treatments for autoimmune disorders. Besides targeting CD20, newer B cell-directed therapies are in development that target other B cell surface molecules and differentiation factors. An increasing number of B cell-directed therapies are in development for the treatment of autoimmune disorders. Like rituximab, which is approved as a treatment for rheumatoid arthritis (RA), many of these newer agents deplete B cells or target pathways essential for B cell development and function; however, many questions remain about their optimal use in the clinic and about the role of B cells in disease pathogenesis. Other therapies besides rituximab that target CD20 are the furthest along in development. Besides targeting CD20, the newer B cell-directed therapies target CD22, CD19, CD40–CD40L, B cell activating factor belonging to the TNF family (BAFF) and A proliferation-inducing ligand (APRIL). Rituximab is being tested in an ever-increasing number of autoimmune disorders and clinical studies of rituximab combined with other biological therapies are being pursued for the treatment of rheumatoid arthritis (RA). B cell-directed therapies are being tested in clinical trials for a variety of autoimmune disorders including RA, systemic lupus erythematosus (SLE), Sjögren's syndrome, vasculitis, multiple sclerosis (MS), Graves' disease, idiopathic thrombocytopenia (ITP), the inflammatory myopathies (dermatomyositis and polymyositis) and the blistering skin diseases pemphigus and bullous pemphigoid. Despite the plethora of clinical studies related to B cell-directed therapies and wealth of new information from these trials, much still remains to be discovered about the pathophysiological role of B cells in autoimmune disorders. PMID:19604259

Levesque, M C

2009-01-01

49

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

PubMed Central

It is well recognized that patients with immunodeficiency have a high risk of development of lymphoproliferative disorders (LPDs), and Epstein-Barr virus (EBV) is associated with the occurrence of LPDs. Methotrexate (MTX) is one of the common cause of iatrogenic-associated LPD, and approximately 40-50% of MTX-related LPD cases occur in extranodal sites. However, the occurrence of MTX-related LPD in the gingiva is extremely rare. Herein, we report the fourth documented case of MTX-related EBV-associated LPD occurring in the gingiva of a patient with rheumatoid arthritis (RA). A 76-year-old Japanese female with a 10-year history of RA, who was treated with MTX and infliximab, presented with a tumorous lesion in the gingiva. Biopsy of the gingiva tumor revealed diffuse proliferation of large-sized lymphoid cells with cleaved nuclei containing conspicuous nucleoli. These lymphoid cells were CD20- and EBER-positive. Therefore, a diagnosis of MTX-related EBV-associated LPD showing features of diffuse large B-cell lymphoma (DLBCL) that occurred in the gingiva was made. Although the occurrence of LPD in the oral region, as seen in the present case, is rare, the prevalence of this disorder may be on the rise due to the increased number of patients undergoing immunosuppression therapy. Moreover, immunosenescence can also be a cause of EBV-associated LPD. Therefore, recognition of the occurrence of this disorder in the oral cavity and consideration of the clinical history can facilitate the correct diagnosis. PMID:24133604

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

2013-01-01

50

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

PubMed Central

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

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

2008-01-01

51

Clinicopathological characteristics of four cases of EBV positive T-cell lymphoproliferative disorders of childhood in China.  

PubMed

A new category, "EBV positive T-cell lymphoproliferative disorders (LPD) of childhood", was proposed in the 2008 World Health Organization's (WHO) classifications of lymphoma. This series of lymphoproliferative disorders is rare. There are two major types of this series of disorders: systemic EBV positive T-cell LPD of childhood and hydroa vacciniforme-like lymphoma (HVLL). In this study, we describe the distinct features of four cases of EBV positive T-cell LPD of childhood in China. Two were systemic EBV positive T-cell LPD of childhood, one was HVLL and one was chronic active EBV (CAEBV). The main manifestations were lymphadenopathy, fever, hepatosplenomegaly and skin rashes. The structure of the lymph nodes in the patients ranged from preserved to partially or totally destroyed. Small- to medium-sized, atypical T cells had infiltrated the lymph nodes. In HVLL, the neoplastic cells had infiltrated the dermis and subcutaneous region surrounding sweat glands and nerves. All of the cases tested positive for CD8, other T cells, cytotoxic markers and EBV-encoded RNA (EBER) without CD56 expression. Molecular analysis was performed in three cases. All of the three analyses showed a TCR? rearrangement and one case also had an IGH rearrangement. One of the patients with systemic EBV positive T-cell LPD of childhood experienced rapid evolved and died within five months of onset. CAEBV, systemic EBV-positive T-cell LPD of childhood and HVLL are distinct but overlapping diseases within the category of EBV-positive T-cell LPD of childhood. They constitute a continuous spectrum of EBV-infected associated disorders. PMID:25197370

Huang, Wenting; Lv, Ning; Ying, Jianming; Qiu, Tian; Feng, Xiaoli

2014-01-01

52

Hepatitis C infection and lymphoproliferative disease: Accidental comorbidities?  

PubMed Central

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

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

2014-01-01

53

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

54

A unique case of rituximab-related posterior reversible encephalopathy syndrome in a heart transplant recipient with posttransplant lymphoproliferative disorder.  

PubMed

Rituximab is commonly used as a first line therapy to treat posttransplant lymphoproliferative disorders (PTLDs). It has also proved useful in the management of refractory antibody mediated graft rejection. We report an unusual case in which a heart transplant recipient being treated with rituximab for PTLD developed altered mental status, hallucinations and visual symptoms and magnetic resonance imaging (MRI) findings of symmetrical enhancement suggestive of posterior reversible leukoencephalopathy syndrome (PRES). Resolution of these clinical symptoms and radiological findings after discontinuation of therapy confirmed the diagnosis. This is the first case of PRES seen due to rituximab in a heart transplant recipient. Another unique feature of the case is the development of PRES after second cycle of rituximab as compared to prior reports in nonheart transplant patients in which the syndrome developed after first dose administration. The objective of this case report is to increase the awareness of this rare entity amongst immunocompromised transplant patients. PMID:25648447

Jaiswal, A; Sabnani, I; Baran, D A; Zucker, M J

2015-03-01

55

Occurrence of gammopathies and lymphoproliferative disorders in liver transplant recipients randomized to tacrolimus (FK506)- or cyclosporine-based immunosuppression.  

PubMed

Lymphoproliferative disorders (LPDs) are a serious side effect of immunosuppression after liver transplantation, and the introduction on the market of a new immunosuppressive drug has been associated with an increased risk of these disorders. To compare the effect of cyclosporine A (CSA) and FK506 in a clinical setting, the incidence of monoclonal or oligoclonal gammopathies known to often precede the appearance of LPDs was evaluated. A total of 88 adult patients was analyzed, 46 were prospectively randomized to CSA and 42 to FK506 for immunosuppression. None of these patients had gammopathy before transplantation. All the patients were tested for immunoglobulin abnormalities five to nine times during a period of 1 year and then two to four times per year thereafter from December 1990 until March 1997. The same incidence of serum immunoglobulin (Ig) abnormalities was observed in both groups (13%) with a mean delay of appearance of 11.1 +/- 5.9 versus 7.6 +/- 3.6 months for CSA and FK506, respectively (P > .05). In each group, the gammopathies were transient in 3 patients and persisted in 2. The class of Ig involved was IgG, and a monoclonal component was documented in 2 patients treated with CSA and in 3 patients with FK506. One patient treated with FK506 developed an LPD localized to the lymph nodes 8 months after the occurrence of serum protein abnormalities. The lymphoproliferative lesions subsequently disappeared with the reduction of immunosuppression. In this study, an immunosuppressive regimen of FK506 has not shown an increased incidence of lymphoproliferation compared with CSA in adult liver transplant patients. PMID:9516567

Pham, H; Lemoine, A; Salvucci, M; Azoulay, D; Frenoy, N; Samuel, D; Reynès, M; Bismuth, H; Debuire, B

1998-03-01

56

Posttransplant diffuse large B-cell lymphoma of \\  

Microsoft Academic Search

The exact relationship between lymphomatoid granulomatosis (LyG) and posttransplant lymphoproliferative disorders (PTLDs) is not clear. Both are observed in immunodeficient patients and are Epstein-Barr virus driven. These disorders are, however, considered distinct based upon the immune response elicited; LyG is T-cell rich while PTLDs are T-cell poor. We describe a case of LyG-type diffuse large B-cell lymphoma (DLBCL) in a

A. Saxena; K. M. Dyker; S. Angel; O. Moshynska; S. Dharampaul; D. W. Cockroft

2002-01-01

57

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

58

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

59

Haploinsufficiency of the Hmga1 gene causes cardiac hypertrophy and myelo-lymphoproliferative disorders in mice.  

PubMed

The HMGA1 protein is a major factor in chromatin architecture and gene control. It plays a critical role in neoplastic transformation. In fact, blockage of HMGA1 synthesis prevents rat thyroid cell transformation by murine transforming retroviruses, and an adenovirus carrying the HMGA1 gene in the antisense orientation induces apoptotic cell death in anaplastic human thyroid carcinoma cell lines, but not in normal thyroid cells. Moreover, both in vitro and in vivo studies have established the oncogenic role of the HMGA1 gene. In this study, to define HMGA1 function in vivo, we examined the consequences of disrupting the Hmga1 gene in mice. Both heterozygous and homozygous mice for the Hmga1-null allele show cardiac hypertrophy due to the direct role of HMGA1 on cardiomyocytic cell growth regulation. These mice also developed hematologic malignancies, including B cell lymphoma and myeloid granuloerythroblastic leukemia. The B cell expansion and the increased expression of the RAG1/2 endonuclease, observed in HMGA1-knockout spleen tissues, might be responsible for the high rate of abnormal IgH rearrangements observed in these neoplasias. Therefore, the data reported here indicate the critical role of HMGA1 in heart development and growth, and reveal an unsuspected antioncogenic potential for this gene in hematologic malignancies. PMID:16510570

Fedele, Monica; Fidanza, Vincenzo; Battista, Sabrina; Pentimalli, Francesca; Klein-Szanto, Andres J P; Visone, Rosa; De Martino, Ivana; Curcio, Antonio; Morisco, Carmine; Del Vecchio, Luigi; Baldassarre, Gustavo; Arra, Claudio; Viglietto, Giuseppe; Indolfi, Ciro; Croce, Carlo M; Fusco, Alfredo

2006-03-01

60

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

61

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

PubMed Central

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

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

2014-01-01

62

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. PMID:25324869

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

2014-01-01

63

Long-term survival in post-transplant lymphoproliferative disorders with a dose-adjusted ACVBP regimen.  

PubMed

Post-transplant lymphoproliferative disorders (PTLD) are severe complications after solid organ transplantation with no consensus on best treatment practice. Chemotherapy is a therapeutic option with a high response and a significant relapse rate leading to a low long-term tolerance rate. Currently, most centres use anthracycline-based drug combinations, such as CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone). We assessed the efficacy and safety of a dose-adjusted ACVBP (doxorubicin reduced to 50 mg/m(2), cyclophosphamide adjusted to renal function, vindesine, bleomycin, prednisone) regimen in patients failing to respond to a reduction in immunosuppressive therapy. Favourable responses were observed in 24 (73%) of the 33 treated patients. Fourteen (42%) patients died, mostly from PTLD progression. Actuarial survival was 60% at 5 years and 55% at 10 years. Survival prognostic factors were: number of involved sites (P = 0.007), clinical stage III/IV (P = 0.004), bulky tumour (P < 0.0001), B symptoms (P = 0.03), decreased serum albumin (P = 0.03) and poor performance status (P = 0.06). Both the international and the PTLD prognostic index were predictive for survival (P = 0.001 and P = 0.002, respectively). Overall 128 cycles were given. Grade 3 or 4 neutropenia was recorded after 26 (20%) chemotherapy cycles in 19 (58%) patients. Forty-one (32%) infections were recorded in 26 (79%) patients. This study demonstrated that an individual dose-adjustment of ACVBP regimen was manageable in PTLD patients and favourably impacted on long-term survival. PMID:16889621

Fohrer, Cécile; Caillard, Sophie; Koumarianou, Argyro; Ellero, Bernard; Woehl-Jaeglé, Marie-Lorraine; Meyer, Carole; Epailly, Eric; Chenard, Marie-Pierre; Lioure, Bruno; Natarajan-Ame, Shanti; Maloisel, Frédéric; Lutun, Philippe; Kessler, Romain; Moulin, Bruno; Bergerat, Jean-Pierre; Wolf, Philippe; Herbrecht, Raoul

2006-09-01

64

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

65

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. PMID:25066638

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

2014-11-01

66

In vivo intratumoral Epstein-Barr virus replication is associated with XBP1 activation and early-onset post-transplant lymphoproliferative disorders with prognostic implications.  

PubMed

Post-transplant lymphoproliferative disorders are life-threatening complications following hematopoietic or solid organ transplantation. They represent a spectrum of mostly EBV-driven lymphoplasmacytic proliferations. While the oncogenic effect of EBV is related to latent infection, lytic infection also has a role in lymphomagenesis. In vitro, EBV replication is linked to plasma cell differentiation and XBP1 activation, although this phenomenon has never been addressed in vivo. We analyzed for the first time latent and lytic intratumoral EBV infection in a series of 35 adult patients with a diagnosis of post-transplant lymphoproliferative disorder (26M/9F, median age 54 years). A complete EBV study was performed including the analysis of the latent EBER, latent membrane protein-11, and EBV nuclear antigens as well as the immediate-early BZLF1/ZEBRA and early BMRF1/EADE31 lytic genes. XBP1 activation was assessed by nuclear protein expression. EBV infection was observed in 28 (80%) cases being latency II and III the most frequently observed 22 (79%). Intratumoral EBV replication was detected in 17 (60%) cases. Among these, XBP1 activation was observed in 11/12 evaluable cases associated with strong cytoplasmic immunoglobulin expression consistent with plasma cell differentiation. Intriguingly, the combination of latency III infection and EBV replication identified a high-risk subgroup of patients with significantly shorter survival (overall survival at 1 year 18% vs 48%) and early-onset (median of 7 vs 26 months) post-transplant lymphoproliferative disorder. Moreover, these patients appear to be more heavily immunosuppressed, so they exhibit lower rates of rejection and graft vs host disease but higher rates of cytomegalovirus reactivation. In conclusion, EBV replication is associated with plasma cell differentiation and XBP1 activation with prognostic implications. Both latency III and lytic EBV infection are related to aggressive and early-onset post-transplant lymphoproliferative disorder. These results suggest that immunohistochemical study of latent and lytic EBV genes in the clinical practice may help to select higher-risk patients to new therapies including antiviral treatments. PMID:24762547

Gonzalez-Farre, Blanca; Rovira, Jordina; Martinez, Daniel; Valera, Alexandra; Garcia-Herrera, Adriana; Marcos, Maria Angeles; Sole, Carla; Roue, Gael; Colomer, Dolors; Gonzalvo, Elena; Ribera-Cortada, Imma; Araya, Monica; Lloreta, Josep; Colomo, Luis; Campo, Elias; Lopez-Guillermo, Armando; Martinez, Antonio

2014-12-01

67

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

68

Successful treatment of a child with late-onset T-cell post-transplant lymphoproliferative disorder/lymphoma.  

PubMed

We report a novel regimen for refractory post-transplant T-cell lymphoma (PTL). Our patient presented with non-Epstein-Barr virus (EBV) related, T-cell post-transplant lymphoproliferative disease (PTLD) 3.5 years after liver transplantation. Initially diagnosed as polyclonal PTLD, the disease progressed to a monoclonal, T-cell PTL that was refractory to several chemotherapy regimens but responded to a regimen consisting of fludarabine, cyclophosphamide, cytarabine, and alemtuzumab. Consolidation therapy included high-dose chemotherapy, autologous hematopoietic stem cell rescue, and radiation therapy. She remains in remission 2.5 years later. T-cell PTL is a rare disease with a poor prognosis; this regimen provides a novel, potentially curative approach for its treatment. PMID:17318876

Williams, Kirsten M; Higman, Meghan A; Chen, Allen R; Schwartz, Cindy L; Wharam, Moody; Colombani, Paul; Arceci, Robert J

2008-03-01

69

ONLINE FIRST OBSERVATION Cutaneous B-Cell Neoplasms Mimicking  

E-print Network

disorders have a limited clinical spectrum of skin involvement. Cutaneous B-cell neoplasms mimicking rosacea or rhinophyma are rare. Observations: We described 12 patients with B-cell lymphoproliferative neoplasms presenting with a facial eruption clinically mimicking rosacea or rhinophyma. Eleven patients were women; ages ranged from 36 to 81 years. The clinical presentation included small papules on the nose and cheeks and around the eyes mimicking granulomatous rosacea; nodules on the nose, cheeks, chin, or forehead mimicking phymatous rosacea; or a combination of both. Three patients had preexisting erythematotelangiectatic rosacea and 1 had rhinophyma. Based on a clinicopathologic correlation and B-cell clonality analysis, the diagnosis was primary cutaneous follicular center B-cell lymphoma in 4 cases, primary cutaneous marginal zone lymphoma in 6, and skin involvement of chronic lymphocytic leukemia in 2. All patients had an indolent course as expected for their disease. Conclusions: Cutaneous involvement of B-cell neoplasms may mimic granulomatous rosacea or rhinophyma. This unusual clinical presentation is more common in women and appears in the setting of preexisting rosacea or as a new eruption. Proliferative B-cell disorders should be added to the differential diagnosis of symmetric papular or papulonodular eruptions of the face.

Granulomatous Rosacea Or Rhinophyma; Hilla Tabibian-keissar; Phd Ninette Amarilgio; Phd Emmilia Hodak; Arch Dermatol

2012-01-01

70

Epstein-Barr virus Associated B-cell lymphomas: Pathogenesis and Clinical Outcomes  

PubMed Central

Epstein-Barr virus (EBV) is a ubiquitous human ?-herpesvirus that establishes a life-long asymptomatic infection in immunocompetent hosts. It is also found to be frequently associated with a broad spectrum of B-cell lymphomas predominantly seen in immunodeficient patients. In spite of many resemblances, these EBV-linked lymphoproliferative disorders display heterogeneity at the clinical as well as the molecular level. Moreover, EBV-associated lymphoproliferative diseases differ in their differential expression patterns of the EBV-encoded latent antigens which are directly related to their interactions with the host. EBV-driven primary B-cell immortalization is linked to the cooperative functions of these latent proteins that are critical for perturbing many important cell-signaling pathways maintaining B-cell proliferation. Additionally, it is used as a surrogate model to explore the underlying mechanisms involved in the development of B-cell neoplasms. Recent discoveries have revealed that a number of sophisticated mechanisms exploited by EBV during cancer progression. This will be instrumental in the design of novel approaches for therapeutic interventions against EBV associated B-cell lymphomas. This review limits the discussion to the biology and pathogenesis of EBV associated B-cell lymphomas and the related clinical implications. PMID:21372216

Saha, Abhik; Robertson, Erle S.

2014-01-01

71

Lymphoproliferative Disease Presenting as Obstructive Uropathy After Renal Transplantation  

Microsoft Academic Search

Lymphoproliferative disorders occur with a greater frequency in recipients of solid organ transplants. Unlike in the general population, these tumors tend to arise in extranodal sites and are often confined to a single organ. We report on a patient with lymphoproliferative disease confined to the hilum of the renal allograft. The only clinical clue to the presence of the tumor

Biff F. Palmer; Arthur I. Sagalowsky; Dwayne A. McQuitty; Ingemar Dawidson; Miguel A. Vazquez; Christopher Y. Lu

1995-01-01

72

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

2014-11-07

73

Autoimmune lymphoproliferative syndrome.  

PubMed

Autoimmune lymphoproliferative syndrome arises early in childhood in people who inherit mutations in genes that mediate lymphocyte apoptosis, or programmed cell death. In the immune system, antigen-induced lymphocyte apoptosis maintains immune homeostasis by limiting lymphocyte accumulation and minimizing reactions against self-antigens. In autoimmune lymphoproliferative syndrome, defective lymphocyte apoptosis manifests as chronic, nonmalignant adenopathy and splenomegaly; the expansion of an unusual population of CD4-CD8- T cells; and the development of autoimmune disease. Most cases of autoimmune lymphoproliferative syndrome involve heterozygous mutations in the lymphocyte surface protein Fas (CD95, Apo1) that impair a major apoptotic pathway. Prospective evaluations of patients and their families have revealed an ever-expanding spectrum of autoimmune lymphoproliferative syndrome and its major complications. PMID:12819469

Sneller, Michael C; Dale, Janet K; Straus, Stephen E

2003-07-01

74

Interleukin-6 production in posttransplant lymphoproliferative disease.  

PubMed Central

IL-6, a multifunctional cytokine produced by monocytes, fibroblasts, and endothelial cells, promotes the growth of EBV-immortalized B cells in vitro and renders these cells tumorigenic in athymic mice. In the present study, serum/plasma IL-6 bioactivity was found to be abnormally elevated, albeit transiently, in 17 of 18 solid organ transplant recipients with posttransplant lymphoproliferative disease (PTLD), with a mean maximal level of 196.7 U/ml. This represents a 16.4 increase above the normal mean (11.3 U/ml). In contrast, only 3 of 10 solid organ transplant recipients with uncomplicated courses posttransplant had abnormally elevated serum/plasma IL-6 bioactivity (mean maximal level 41.4 U/ml, P = 0.0007). When transferred to single cell culture, the 11 PTLD tissues produced 640 to 1.25 x 10(6) IL-6 U/ml in the culture supernatant, with a mean maximal level of 35,025 IL-6 U/ml. Cell separation experiments demonstrated that the adherent cells, identified as non-B cells, were the principal source of IL-6 production in vitro by PTLD tissue. Control cultures of inflammatory lymphoid tissue negative for lymphoproliferative disease as well as of PBL from patients with acute EBV-induced infectious mononucleosis consistently produced < 10 IL-6 U/ml. Thus, IL-6 is produced at high levels by PTLD tissues and may play a critical role in the pathogenesis of PTLD. PMID:8514888

Tosato, G; Jones, K; Breinig, M K; McWilliams, H P; McKnight, J L

1993-01-01

75

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

76

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

PubMed Central

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

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

2014-01-01

77

X-Linked Lymphoproliferative Disease  

PubMed Central

2B4 is a surface molecule involved in activation of the natural killer (NK) cell–mediated cytotoxicity. It binds a protein termed Src homology 2 domain–containing protein (SH2D1A) or signaling lymphocyte activation molecule (SLAM)-associated protein (SAP), which in turn has been proposed to function as a regulator of the 2B4-associated signal transduction pathway. In this study, we analyzed patients with X-linked lymphoproliferative disease (XLP), a severe inherited immunodeficiency characterized by critical mutations in the SH2D1A gene and by the inability to control Epstein-Barr virus (EBV) infections. We show that, in these patients, 2B4 not only fails to transduce triggering signals, but also mediates a sharp inhibition of the NK-mediated cytolysis. Other receptors involved in NK cell triggering, including CD16, NKp46, NKp44, and NKp30, displayed a normal functional capability. However, their activating function was inhibited upon engagement of 2B4 molecules. CD48, the natural ligand of 2B4, is highly expressed on the surface of EBV+ B cell lines. Remarkably, NK cells from XLP patients could not kill EBV+ B cell lines. This failure was found to be the consequence of inhibitory signals generated by the interaction between 2B4 and CD48, as the antibody-mediated disruption of the 2B4–CD48 interaction restored lysis of EBV+ target cells lacking human histocompatibility leukocyte antigen (HLA) class I molecules. In the case of autologous or allogeneic (HLA class I+) EBV+ lymphoblastoid cell lines, restoration of lysis was achieved only by the simultaneous disruption of 2B4–CD48 and NK receptor–HLA class I interactions. Molecular analysis revealed that 2B4 molecules isolated from either XLP or normal NK cells were identical. As expected, in XLP-NK cells, 2B4 did not associate with SH2D1A, whereas similar to 2B4 molecules isolated from normal NK cells, it did associate with Src homology 2 domain–containing phosphatase 1. PMID:10934222

Parolini, Silvia; Bottino, Cristina; Falco, Michela; Augugliaro, Raffaella; Giliani, Silvia; Franceschini, Roberta; Ochs, Hans D.; Wolf, Hermann; Bonnefoy, Jean-Yves; Biassoni, Roberto; Moretta, Lorenzo; Notarangelo, Luigi D.; Moretta, Alessandro

2000-01-01

78

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

79

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

ClinicalTrials.gov

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

2014-11-26

80

IDEC-C2B8 anti-CD20 (rituximab) immunotherapy in patients with low-grade non-Hodgkin's lymphoma and lymphoproliferative disorders: evaluation of response on 48 patients.  

PubMed

This study focused on the efficacy of IDEC-C2B8 (chimeric anti-CD20) immunotherapy relative to specific subtypes of low-grade lymphoproliferative disorders/non-Hodgkin's lymphomas (LPD/NHL). Forty-eight patients with resistant or relapsed disease completed the IDEC-C2B8 infusion schedule of 375 mg/m2/wk x 4 wk. The LPD/NHL subtypes included: (a) follicular centre cell lymphoma (FCC) in 22 patients; (b) mantle cell lymphoma (MCL) in 10; (c) 1 diffuse large cell lymphoma (DLCL); and (d) the category of small lymphocytic lymphoma/chronic lymphocytic leukaemia (SLL/CLL) and related disorders in 15 patients. No patient obtained a complete remission. Ten patients (21%) achieved partial remission: 6 FCC, 2 MCL, 1 DLCL and 1 patient from the SLL/CLL group. Twenty-eight patients had stable disease and 10 progressed during immunotherapy. In patients with CLL and MCL in leukaemic phase, there was no correlation between the marked decrease in circulating neoplastic cells following antibody infusions and amelioration of the tumour burden. The results suggest that the subtype of LPD/NHL and the intensity of CD20 on the tumour cells influence the effectiveness of IDEC-C2B8. The antibody was most efficacious against FCC lymphoma. The efficacy (at the dose schedule of 375 mg/m2/wk x 4) against MCL and SLL/CLL appeared to be limited, however. PMID:10052709

Nguyen, D T; Amess, J A; Doughty, H; Hendry, L; Diamond, L W

1999-02-01

81

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

82

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

PubMed

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

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

2006-02-01

83

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

PubMed Central

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

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

2014-01-01

84

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

85

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

PubMed Central

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

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

2010-01-01

86

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

87

How I treat autoimmune lymphoproliferative syndrome  

PubMed Central

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

Oliveira, João Bosco

2011-01-01

88

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

89

Polyclonal B-cell lymphocytosis with binucleated lymphocytes (PPBL).  

PubMed

Persistent polyclonal B-cell lymphocytosis (PPBL) is a rare and recently described entity. The review of the literature show PPBL is diagnosed predominantly but not exclusively in women, usually smokers. PPBL is recognized by a moderate, chronic and absolute lymphocytosis (>4 × 10(9)/l) in the peripheral blood. In 10% of cases without lymphocytosis, the PPBL diagnosis has to be suggested by peripheral blood examination showing in all cases atypical binucleated lymphocytes. A polyclonal serum IgM is also associated and HLA-DR7 expression is present in most cases. Contrary to B-cell chronic lymphoproliferative disorders (B-CLPD), peripheral B cells are polyclonal with kappa and lambda light-chain expression and no clonal rearrangement of immunoglobulin heavy chain genes is usually demonstrated. The detection of an extra isochromosome for the long arm of chromosome 3 +i(3)(q10) has to be considered as a specific marker of PPBL. We performed conventional cytogenetic analysis (CCA) in 111 patients with typical PPBL we followed-up more than 4 years. +i(3q) was detected in 34% (33/98), PCC in 8% (8/98) and both abnormalities in 31% (30/98). CCA showed neither +i(3q) nor PCC in 28% (27/98). Fluorescence in situ hybridization (FISH) was also performed in 84 cases and +i(3q) was detected in 71% (60/84). When combining both procedures in 84 patients, +i(3q) was detected in 17 patients with negative CCA and was confirmed in 43 patients with positive CCA. CCA and FISH were both negative in 24 cases. Whether patients with PPBL are at increased risk of hematological malignancy remains unclear. After a median follow-up of 4.4 years, most PPBL patients presented a stable clinical and biological course. Six patients died from pulmonary cancer, myocardial infarction, cerebral aneurysm rupture or diffuse large B-cell lymphoma. Two patients had IgM monoclonal gammopathy of undetermined significance (MGUS) at the time of PPBL diagnosis and two other patients developed IgM MGUS respectively 12 and 22 years after PPBL diagnosis. A malignant non Hodgkin's lymphoma (NHL) appeared in 3 additional patients: two patients presented diffuse large B cell lymphoma and 1 patient a splenic marginal zone lymphoma. In conclusion, the possibility of PPBL to evolve toward a clonal proliferation, malignant lymphoma or secondary solid cancer lead us to consider PPBL not as a benign pathology. We recommend a careful and continued clinical and biological long-term follow-up in all PPBL patients. PMID:21127753

Troussard, Xavier; Cornet, Edouard; Lesesve, Jean-François; Kourel, Carine; Mossafa, Hossein

2008-01-01

90

Polyclonal B-cell lymphocytosis with binucleated lymphocytes (PPBL)  

PubMed Central

Persistent polyclonal B-cell lymphocytosis (PPBL) is a rare and recently described entity. The review of the literature show PPBL is diagnosed predominantly but not exclusively in women, usually smokers. PPBL is recognized by a moderate, chronic and absolute lymphocytosis (>4 × 109/l) in the peripheral blood. In 10% of cases without lymphocytosis, the PPBL diagnosis has to be suggested by peripheral blood examination showing in all cases atypical binucleated lymphocytes. A polyclonal serum IgM is also associated and HLA-DR7 expression is present in most cases. Contrary to B-cell chronic lymphoproliferative disorders (B-CLPD), peripheral B cells are polyclonal with kappa and lambda light-chain expression and no clonal rearrangement of immunoglobulin heavy chain genes is usually demonstrated. The detection of an extra isochromosome for the long arm of chromosome 3 +i(3)(q10) has to be considered as a specific marker of PPBL. We performed conventional cytogenetic analysis (CCA) in 111 patients with typical PPBL we followed-up more than 4 years. +i(3q) was detected in 34% (33/98), PCC in 8% (8/98) and both abnormalities in 31% (30/98). CCA showed neither +i(3q) nor PCC in 28% (27/98). Fluorescence in situ hybridization (FISH) was also performed in 84 cases and +i(3q) was detected in 71% (60/84). When combining both procedures in 84 patients, +i(3q) was detected in 17 patients with negative CCA and was confirmed in 43 patients with positive CCA. CCA and FISH were both negative in 24 cases. Whether patients with PPBL are at increased risk of hematological malignancy remains unclear. After a median follow-up of 4.4 years, most PPBL patients presented a stable clinical and biological course. Six patients died from pulmonary cancer, myocardial infarction, cerebral aneurysm rupture or diffuse large B-cell lymphoma. Two patients had IgM monoclonal gammopathy of undetermined significance (MGUS) at the time of PPBL diagnosis and two other patients developed IgM MGUS respectively 12 and 22 years after PPBL diagnosis. A malignant non Hodgkin's lymphoma (NHL) appeared in 3 additional patients: two patients presented diffuse large B cell lymphoma and 1 patient a splenic marginal zone lymphoma. In conclusion, the possibility of PPBL to evolve toward a clonal proliferation, malignant lymphoma or secondary solid cancer lead us to consider PPBL not as a benign pathology. We recommend a careful and continued clinical and biological long-term follow-up in all PPBL patients. PMID:21127753

Troussard, Xavier; Cornet, Edouard; Lesesve, Jean-François; Kourel, Carine; Mossafa, Hossein

2008-01-01

91

Pathological findings in human autoimmune lymphoproliferative syndrome.  

PubMed

The defects in lymphocyte apoptosis that underlie the autoimmune lymphoproliferative syndrome (ALPS) are usually attributable to inherited mutations of the CD95 (Fas) gene. In this report, we present the histopathological and immunophenotypic features seen in the lymph nodes (n = 16), peripheral blood (n = 10), bone marrow (n = 2), spleen (n = 3), and liver (n = 2) from 10 patients with ALPS. Lymph nodes showed marked paracortical hyperplasia. Interfollicular areas were expanded and populated by T cell receptor-alphabeta CD3+ CD4-CD8- (double-negative, DN) T cells that were negative for CD45RO. CD45RA+ T cells were increased in all cases studied. The paracortical infiltrate was a result of both reduced apoptosis and increased proliferation, as measured by in situ detection of DNA fragmentation and staining with MIB-1, respectively. The paracortical proliferation may be extensive enough to suggest a diagnosis of malignant lymphoma. Many of the paracortical lymphocytes expressed markers associated with cytotoxicity, such as perforin, TIA-1, and CD57. CD25 was negative. In addition, most lymph nodes exhibited florid follicular hyperplasia, often with focal progressive transformation of germinal centers; in some cases, follicular involution was seen. A polyclonal plasmacytosis also was present. The spleens were markedly enlarged, more than 10 times normal size. There was expansion of both white pulp and red pulp, with increased DN T cells. DN T cells also were observed in liver biopsies exhibiting portal triaditis. In the peripheral blood, the T cells showed increased expression of HLA-DR and CD57 but not CD25. CD45RA+ T cells were increased in the four cases studied. Polyclonal B cell lymphocytosis with expansion of CD5+ B cells was a characteristic finding. Taken together, the histopathological and immunophenotypic findings, particularly in lymph nodes and peripheral blood, are sufficiently distinctive to suggest a diagnosis of ALPS. Of note, two affected family members of one proband developed lymphoma (T-cell-rich B-cell lymphoma and nodular lymphocyte predominance Hodgkin's disease, respectively). PMID:9811346

Lim, M S; Straus, S E; Dale, J K; Fleisher, T A; Stetler-Stevenson, M; Strober, W; Sneller, M C; Puck, J M; Lenardo, M J; Elenitoba-Johnson, K S; Lin, A Y; Raffeld, M; Jaffe, E S

1998-11-01

92

The development of lymphomas in families with autoimmune lymphoproliferative syndrome with germline Fas mutations and defective lymphocyte apoptosis.  

PubMed

Lymphomas were studied in kindreds with autoimmune lymphoproliferative syndrome (ALPS; Canale-Smith syndrome), a disorder of lymphocyte homeostasis usually associated with germline Fas mutations. Fas (CD95/APO-1) is a cell surface receptor that initiates programmed cell death, or apoptosis, of activated lymphocytes. Lymphoma phenotype was determined by immunohistochemistry, frequency of CD3(+)CD4(-)CD8(-) T-cell-receptor alpha/beta cells by flow cytometry, nucleotide sequences of the gene encoding Fas (APT1, TNFRSF6), and the percentage of lymphocytes undergoing apoptosis in vitro. Of 223 members of 39 families, 130 individuals possessed heterozygous germline Fas mutations. Eleven B-cell and T-cell lymphomas of diverse types developed in 10 individuals with mutations in 8 families, up to 48 years after lymphoproliferation was first documented. Their risk of non-Hodgkin and Hodgkin lymphomas, respectively, was 14 and 51 times greater than expected (each P <.001). Investigation of these 10 patients and their relatives with Fas mutations revealed that all had defective lymphocyte apoptosis and most had other features of ALPS. The tumor cells retained the heterozygous Fas mutations found in the peripheral blood and manifested defective Fas-mediated killing. These data implicate a role for Fas-mediated apoptosis in preventing B-cell and T-cell lymphomas. Inherited defects in receptor-mediated lymphocyte apoptosis represent a newly appreciated risk factor for lymphomas. PMID:11418480

Straus, S E; Jaffe, E S; Puck, J M; Dale, J K; Elkon, K B; Rösen-Wolff, A; Peters, A M; Sneller, M C; Hallahan, C W; Wang, J; Fischer, R E; Jackson, C M; Lin, A Y; Bäumler, C; Siegert, E; Marx, A; Vaishnaw, A K; Grodzicky, T; Fleisher, T A; Lenardo, M J

2001-07-01

93

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

PubMed Central

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

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

2014-01-01

94

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

2014-12-09

95

Autoimmune lymphoproliferative syndrome with neonatal onset.  

PubMed

We describe 2 cases of autoimmune lymphoproliferative syndrome (ALPS), which is a rare disorder of auto-immunity, chronic persistent or recurrent lymphadenopathy, splenomegaly, hepatomegaly and hyper gamma globulinemia (1gG, 1gA). Both cases presented in neonatal period which is a rare age of presentation in this disease. A 20 days old female neonate presented with respiratory symptoms which rapidly progressed needing ventilatory support. There was hepatomegaly and no auscultatory findings in the chest. Serial CBCs (complete blood counts) showed persistent leucocytosis with predominant lymphocytosis. Her chest X-ray showed left sided consolidation which responded poorly to antibiotics. Her prompt clinical response to steroids raised the suspicion of autoimmunity and the diagnosis was established after a negative bone marrow examination for leukemia and a positive result for ALPS on flow cytometry. The second case presented with anemia, thrombocytopenia starting in neonatal period followed by persistent lymphadenopathy, hepatosplenomegaly and recurrent infections which responded poorly to antibiotics. Diagnosis was delayed due to low index of suspicion, and finally achieved with multiple radiological studies, histopathology and flow cytometry. PMID:24906264

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

2014-05-01

96

New immunohistochemistry for B-cell lymphoma and hodgkin lymphoma.  

PubMed

Context .- B-cell non-Hodgkin lymphoma is a heterogeneous group of lymphoproliferative malignancies with different clinical behaviors and treatments. It is important to differentiate individual B-cell lymphoma to apply the best treatment and management. Morphology and immunohistochemistry are the primary tools used for diagnosing lymphoma. There is a characteristic pattern of expression with immunohistochemical antibodies in most well-defined B-cell lymphomas. Some cases of B-cell lymphoma, however, show unusual morphologic and immunophenotypic features. The new and sometimes more specific antibodies have been developed recently, which may further define those lymphomas. Only with use of the antibodies over time does their true nature and specificity become evident. Objectives .- To present new antibodies for B-cell lymphoma that enhance the probability for diagnosis or can act as alternate markers in unusual cases, in which a B-cell lymphoma does not present with characteristic immunohistochemical staining, and to present prognostic markers that allow for better management of patients with specific B-cell lymphomas. Data Sources .- Data were obtained from literature review and figures from slides in personal practice. Conclusions .- The immunohistochemical antibodies presented in this article increase our ability to understand, diagnosis, and manage patients with B-cell lymphoma. PMID:25427044

Zhang, Xiaohong Mary; Aguilera, Nadine

2014-12-01

97

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

SciTech Connect

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

Peddanna, N.; Gogineni, S.K.; Rosenthal, C.J. [Long Island College Hospital, Brooklyn, NY (United States)] [and others

1994-09-01

98

Acute inflammatory neuropathy with monoclonal anti-GM2 IgM antibodies, IgM-? paraprotein and additional autoimmune processes in association with a diffuse large B-cell non-Hodgkin's lymphoma  

PubMed Central

Lymphoproliferative disorders are often associated with autoimmune processes preceding or following the occurrence of a lymphoma. Here, we describe a patient with a history of recurrent diffuse large B-cell non-Hodgkin's lymphoma who suffered from an acute inflammatory neuropathy with specific monoclonal anti-GM2 IgM antibodies and associated IgM-? paraprotein. It was possible in this case to prove that both, anti-GM2 IgM antibodies and IgM-? paraprotein, share the same binding characteristic. In addition, the patient possibly suffered from an immune thrombocytopenia and an early-stage bullous pemphigoid with anti-BP-230 IgG antibodies. Intravenous immunoglobulin and plasmapheresis alleviated the acute neuropathy and thrombocytopenia, while the bullous pemphigoid has been aggravated. In summary, the simultaneous occurrence of multiple autoimmune processes was a sign of a dysfunctional immune system preceding the relapse of a B-cell non-Hodgkin's lymphoma. PMID:23341581

Milnik, Annette; Roggenbuck, Dirk; Conrad, Karsten; Bartels, Claudius

2013-01-01

99

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

PubMed Central

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

Chadha, S. Nicole; Amrol, David

2010-01-01

100

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; Lucafò, Marianna; Mansilla, Eduardo; Garrovo, Chiara; Marín, Gustavo H.; Baj, Gabriele; Gattei, Valter; Pozzato, Gabriele; Núñez, Luis; Macor, Paolo

2013-01-01

101

Peripheral B cell subsets  

PubMed Central

Summary Our understanding of the origins and the biological functions of different peripheral B cell subsets continues to evolve. Some understanding has been obtained regarding the synergy between BCR derived signals and other receptors and signaling pathways that drive the development of follicular, marginal zone and B-1 B cells, but this remains a complex and poorly understood issue. More recent information regarding the origins of B-1 and B-2 B cells, the ability of follicular B cells to mature both in the bone marrow and the spleen, the existence of a definable precursor for MZ B cells, and the ability of follicular B cells to occupy two distinct niches are all highlighted in this review. PMID:18434123

Allman, David; Pillai, Shiv

2008-01-01

102

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

PubMed Central

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

Néron, Sonia; Darveau, André; Delage, Robert

2014-01-01

103

Aggressive large B-cell lymphoma in a systemic lupus erythematosus patient with chronic active Epstein-Barr virus infection: a case report.  

PubMed

A link between Epstein-Barr Virus (EBV) infection, systemic lupus erythematosus (SLE) and non-Hodgkin's lymphoma (NHL) has been recently reported in literature. Here we report a case of diffuse large B-cell lymphoma (DLBCL) with a particularly aggressive clinical course in an SLE patient with EBV infection. A 49-year-old woman with a long history of SLE was admitted to the Department of Experimental and Clinical Medicine and dramatically died a few hours later. The autopsy described no evidence of active lymphoproliferative disorder. Instead, histological examination demonstrated an atypical lymphocitic proliferation in lymph node, kidneys, pericardium and uterus. Immunoistochemically, the lymphomatous cells were positive with CD19, CD20, CD22 and CD79a, which was consistent with a DLBCL. The cells were also reactive to EBV markers, indicating the possible role of previous EBV infection in DLBCL pathogenesis. PMID:22230415

Abenavoli, L; Pennacchia, I; Stigliano, E; Carbone, A; Vecchio, F M; Arena, V

2011-01-01

104

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

PubMed

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

2014-08-01

105

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

PubMed

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

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

2013-02-01

106

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

107

PCR analysis of the immunoglobulin heavy chain gene in polyclonal processes can yield pseudoclonal bands as an artifact of low B cell number.  

PubMed

Polymerase chain reaction (PCR)-based analysis for detecting immunoglobulin heavy chain gene (IgH) rearrangements in lymphoproliferative disorders is well established. The presence of one or two discrete bands is interpreted as a monoclonal proliferation, whereas a smear pattern represents a polyclonal population. Prompted by our observation of discrete bands in histologically reactive processes with a relative paucity of B cells, we sought to determine whether low numbers of B cells in biopsy specimens could artifactually produce pseudomonoclonal bands. We performed IgH PCR analysis on serially diluted DNA samples from 5 B cell non-Hodgkin's lymphomas (B-NHLs), 5 reactive lymph nodes, 5 reactive tonsils and 10 microdissected germinal centers from a lymph node with follicular hyperplasia. We also assessed multiple aliquots of DNA samples from small biopsy specimens of reactive lymphocytic processes from the stomach (5 cases). PCR products were evaluated using high resolution agarose or polyacrylamide gels, and DNA sequencing was performed on IgH PCR products from two reactive germinal centers, which yielded monoclonal bands of identical size. All 5 B-NHLs harboring monoclonal B cell populations yielded single discrete bands, which were maintained in all dilutions. By contrast, all of the reactive lesions with polyclonal patterns at 50 ng/microl starting template concentration showed strong pseudomonoclonal bands at dilutions of 1:1,000 to 1:1,500 in placental DNA. Two of the microdissected reactive germinal centers that showed bands of identical size on duplicate reactions were proven to have different IgH sequences by sequencing. We conclude that specimens containing low numbers of polyclonal B cells may produce pseudomonoclonal bands on IgH PCR analysis. IgH PCR analysis should be performed on multiple aliquots of each DNA sample, and only samples that yield reproducible bands of identical size can be reliably interpreted as monoclonal. PMID:11272894

Elenitoba-Johnson, K S; Bohling, S D; Mitchell, R S; Brown, M S; Robetorye, R S

2000-05-01

108

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

PubMed Central

Mutations affecting the SLAM-associated protein (SAP) are responsible for the X-linked lympho-proliferative syndrome (XLP), a severe primary immunodeficiency syndrome with disease manifestations that include fatal mononucleosis, B cell lymphoma and dysgammaglobulinemia. It is well accepted that insufficient help by SAP?/? CD4+ T cells, in particular during the germinal center reaction, is a component of dysgammaglobulinemia in XLP patients and SAP?/? animals. It is however not well understood whether in XLP patients and SAP?/? mice B cell functions are affected, even though B cells themselves do not express SAP. Here we report that B cell intrinsic responses to haptenated protein antigens are impaired in SAP?/? mice and in Rag?/? mice into which B cells derived from SAP?/? mice together with wt CD4+ T cells had been transferred. This impaired B cells functions are in part depending on the genetic background of the SAP?/? mouse, which affects B cell homeostasis. Surprisingly, stimulation with an agonistic anti-CD40 causes strong in vivo and in vitro B cell responses in SAP?/? mice. Taken together, the data demonstrate that genetic factors play an important role in the SAP-related B cell functions. The finding that anti-CD40 can in part restore impaired B cell responses in SAP?/? mice, suggests potentially novel therapeutic interventions in subsets of XLP patients. PMID:23806511

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

2013-01-01

109

Familial Lymphoproliferative Malignancies and Tandem Duplication of NF1 Gene  

PubMed Central

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

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

2014-01-01

110

Distinct chromosome 3 abnormalities in persistent polyclonal B-cell lymphocytosis.  

PubMed

Persistent polyclonal B-cell lymphocytosis (PPBL) is a rare entity of unknown etiology characterized by a polyclonal expansion of B-lymphocytes with typical bilobulated forms, elevated serum IgM, and an additional isochromosome for the long arm of chromosome 3 as the sole change. In the present study, we investigated four cases of PPBL by means of conventional cytogenetic analysis and FISH. In all patients, the polyclonality of the lymphoproliferation was demonstrated by immunophenotypic studies, and PCR analysis failed to demonstrate clonal IGH rearrangements in three evaluated cases. In two patients, in addition to +i(3)(q10), banding techniques identified unrelated clones with trisomy 3. FISH studies using a chromosome 3 long arm-specific probe provided evidence that all cases had both +i(3)(q10) and +3. To determine more precisely the distribution of the chromosomal abnormalities within the peripheral lymphocyte population, we investigated two of these cases using a technique of simultaneous fluorescence immunophenotyping and interphase cytogenetics (FICTION). We demonstrated that both abnormalities were randomly distributed among the B-lymphocytes, independently of the kappa or lambda light chain isotype and the nuclear aspect. These data lead us to conclude that trisomy 3 represents, in addition to +i(3)(q10), another recurrent cytogenetic change in PPBL, suggesting that this lymphoproliferative disorder is associated with an increased frequency of chromosome 3 instability. PMID:10502320

Callet-Bauchu, E; Gazzo, S; Poncet, C; Pagès, J; Morel, D; Alliot, C; Coiffier, B; Coeur, P; Salles, G; Felman, P

1999-11-01

111

[Relevance of cytological and immunophenotypical analysis for the diagnosis of B-cell chronic lymphocytic leukaemia].  

PubMed

The objective of this study was to describe the cytological and immunophenotypical parameters evocative of B-cell Chronic Lymphocytic Leukaemia (B-CLL) and their ability to participate to the differential diagnosis of other B-chronic lymphoproliferatives disorders with blood dissemination (B-CLD). Two groups of pathology included 92 patients, 79 patients had a B-CLL and the 13 other had a B-CLD (1 Prolymphocytic Leukaemia, 12 non- Hodgkin's Lymphoma in which 4 Splenic Lymphoma with Villous Lymphocytes or SLVL). The lymphoid morphology was studied on blood smear stained with May Gr nwald Giemsa and the immunophenotypical analysis was performed by flow cytometry. The 72 patients with B-CLL were characterized by a predominance of small mature lymphocytes with a Matutes's CLL score 3 (generally CD5+, CD23+, SmIg poor expression). 4 out of B-CLL with cleaved lymphocytes 5 % showed the same immunological characteristics than the typical B-CLL cases. 3 cases of B-CLL with prolymphocytes between 5 and 55 % showed in 2 cases an immunophenotyping compatible with the diagnosis of B-CLD. The presence of shadow cells of Gumprecht was highly evocative of B-CLL. In conclusion, the cytological analysis remains at the root of any diagnosis and can be sufficient in most cases of typical CLL with the presence of shadow cells of Gumprecht on the blood smear. In case of presence of cleaved lymphocytes, the immunophenotyping becomes essential to confirme the diagnosis of B-CLL. In prolymphocytic cases, the differential diagnosis between mixed CLL and B-CLD (especially Mantle Cell Lymphoma and Marginal Zone B-Cell Lymphoma without villous lymphocytes) needs a multidisciplinary approach (clinical, cytogenetical and histological). PMID:12446231

Guillaume, N; Alimardani, G; Capiod, J C; Claisse, J F

2002-01-01

112

Will Jill come tumbling after? The case for a JAK2-type mutation as a prequel to the connective tissue disorders.  

PubMed

The JAK2 [V617F] mutation has recently been recognised as critical to the pathogenesis of the myeloproliferative disorders (MPDs). Thus, a common mutation affecting a haematopoietic precursor stem cell is capable of giving rise to diverse clinical phenotypes. In this hypothesis paper, we propose that a similar mutation affecting a stem cell precursor, most likely of the B cell lineage, could underlie the development of the connective tissue disorders which could be regarded as "lymphoproliferative" disorders. Consistent with this hypothesis is the observation that there are similarities between the myeloproliferative disorders and the connective tissue disorders in terms of their biological behaviour. Diseases within each family can transform into each other and sometimes into haematological malignancies (most often B cell origin non-Hodgkins lymphoma for the connective tissue disorders and acute myeloid leukemia for the myeloproliferative disorders). The timecourse for development of the connective tissue disorders involves a long latent period when autoantibodies are present (anti-CCP and ANA) possibly reflecting production by a B cell clone. A similar time-dependent increase in clonal dominance has been described in erythroblastic clones taken from the bone marrow of polycythemia vera patients, long before the onset of clinical disease. Evidence of B cell clonality has been described in bone marrow samples from rheumatoid arthritis patients and from glandular biopsies from those with Sjogren's syndrome. Moreover, pseudofollicles containing activated B cells are features of rheumatoid synovial membrane and have also recently been described in subchondral bone where they are associated with macrophages, T cells and osteoclasts. The success of B cell depletion therapy in rheumatoid arthritis and systemic lupus erythematosus is also strong circumstantial evidence for this hypothesis. PMID:19482442

McQueen, Fiona M; Dalbeth, Nicola

2009-11-01

113

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. PMID:25360073

Chang, Jae-Hoon

2014-01-01

114

Monoclonal antibodies IPO-3 and IPO-10 against human B cell differentiation antigens.  

PubMed

Monoclonal antibodies (mAbs) IPO-3 and IPO-10 were generated following immunization of a BALB/c mice with human cell lines RPMI-1788 and Daudi respectively. The reactivity of these mAbs was studied by indirect immunofluorescence technique with 10 human cell lines, blood cells of healthy persons and patients with the malignant lymphoproliferative diseases. Studies of normal and neoplastic B cells suggest that mAbs IPO-3 and IPO-10 which recognize antigens are B lineage restricted. The presence of an antigen defined by the mAb IPO-10 appears to include most but not all the stages of B cell differentiation, whereas IPO-3 detected antigen is not represented on resting B cells and has a very limited expression on activated B lymphocytes. The results obtained with mAbs IPO-3 and IPO-10 are discussed in relation to other known B cell surface markers. PMID:3265315

Pinchouk, V G; Sidorenko, S P; Gluzman, D F; Vetrova, E P; Berdova, A G; Schlapatskaya, L N

1988-01-01

115

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

Microsoft Academic Search

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.

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

116

B cell receptor signal strength determines B cell fate  

Microsoft Academic Search

B cell receptor (BCR)-mediated antigen recognition is thought to regulate B cell differentiation. BCR signal strength may also influence B cell fate decisions. Here, we used the Epstein-Barr virus protein LMP2A as a constitutively active BCR surrogate to study the contribution of BCR signal strength in B cell differentiation. Mice carrying a targeted replacement of Igh by LMP2A leading to

Kevin L Otipoby; Marat Alimzhanov; Sibille Humme; Nathalie Uyttersprot; Jeffery L Kutok; Michael C Carroll; Stefano Casola; Klaus Rajewsky

2004-01-01

117

Human peripheral blood B-cell compartments: a crossroad in B-cell traffic.  

PubMed

A relatively high number of different subsets of B-cells are generated through the differentiation of early B-cell precursors into mature B-lymphocytes in the bone marrow (BM) and antigen-triggered maturation of germinal center B-cells into memory B-lymphocytes and plasmablasts in lymphoid tissues. These B-cell subpopulations, which are produced in the BM and lymphoid tissues, recirculate through peripheral blood (PB), into different tissues including mucosa and the BM, where long-living plasma cells produce antibodies. These circulating PB B-cells can be classified according to their maturation stage into i) immature/transitional, ii) naïve, and iii) memory B-lymphocytes, and iv) plasmablasts/plasma cells. Additionally, unique subsets of memory B-lymphocytes and plasmablasts/plasma cells can be identified based on their differential expression of unique Ig-heavy chain isotypes (e.g.: IgM, IgD, IgG, IgA). In the present paper, we review recent data reported in the literature about the distribution, immunophenotypic and functional characteristics of these cell subpopulations, as well as their distribution in PB according to age and seasonal changes. Additional information is also provided in this regard based on the study of a population-based cohort of 600 healthy adults aged from 20 to 80 years, recruited in the Salamanca area in western Spain. Detailed knowledge of the distribution and traffic of B-cell subsets through PB mirrors the immune status of an individual subject and it may also contribute to a better understanding of B-cell disorders related to B-cell biology and homeostasis, such as monoclonal B-cell lymphocytosis (MBL). PMID:20839338

Perez-Andres, M; Paiva, B; Nieto, W G; Caraux, A; Schmitz, A; Almeida, J; Vogt, R F; Marti, G E; Rawstron, A C; Van Zelm, M C; Van Dongen, J J M; Johnsen, H E; Klein, B; Orfao, A

2010-01-01

118

Basic science for the clinician 38: B cells, factories, and immunomodulators.  

PubMed

In a previous article in this series, we explored how developing pre-T cells learn how to be well-behaved T cells that recognize and honor the "self versus nonself" dichotomy of the universe. B cells do much of the same sort of thing, with multipotent stem cells becoming committed to ultimately becoming B cells within the bone marrow and then, after judicious culling of the flock, going off to the spleen to learn the final lessons needed to become "well-behaved" B cells. Like with T cells, there are a large number of things that can, and do, go wrong. If there is a failure of the system and B cells do not develop properly, hypogammaglobulinemia may develop as a result of a number of immune deficiency syndromes that can be quite devastating. If autoreactive cells survive to emerge into the periphery, autoimmunity, either organ-specific or more global, may occur. If B cells in the periphery proliferate in an uncontrolled fashion, a variety of B cell lymphoproliferative syndromes may develop, recognizable by the phenotypic markers of their originating B cell lineage level of differentiation. The full details of how autoreactive B cells survive and thrive, only to cause disease, are not yet clear, but identification of many of the phenotypic surface markers and circulating growth factors identified to this point have borne therapeutic fruit. PMID:16755249

Sigal, Leonard H

2006-06-01

119

Murine Gamma-herpesvirus Immortalization of Fetal Liver-Derived B Cells Requires both the Viral Cyclin D Homolog and Latency-Associated Nuclear Antigen  

Microsoft Academic Search

Human gammaherpesviruses are associated with the development of lymphoproliferative diseases and B cell lymphomas, particularly in immunosuppressed hosts. Understanding the molecular mechanisms by which human gammaherpesviruses cause disease is hampered by the lack of convenient small animal models to study them. However, infection of laboratory strains of mice with the rodent virus murine gammaherpesvirus 68 (MHV68) has been useful in

Xiaozhen Liang; Clinton R. Paden; Francine M. Morales; Ryan P. Powers; Joshy Jacob; Samuel H. Speck

2011-01-01

120

An unusual case of indolent B-cell lymphoma with distinct chronic lymphocytic leukemia and marginal zone differentiation according to the site of involvement.  

PubMed

The immunological profile of lymphoproliferative disorders is usually conserved whatever the involved site, thus allowing a reliable diagnosis from peripheral blood analysis, especially in small lymphocytic lymphoma/chronic lymphocytic lymphoma (SLL/CLL). Here we present a case wherein the cytology and immunophenotype of blood specimen and bone marrow argue in favor of SLL/CLL with a typical Matutes score (5/5), whereas the cyto-histology and immunophenotype of spleen specimen led to the diagnosis of splenic marginal zone B-cell lymphoma (SMZL). Moreover genomic analysis showed that the splenic cells displayed a SMZL signature. Whereas these data suggested the presence of 2 B-cell clones, the study of the mutational status of IgVH gene in blood and spleen demonstrated the presence of a single clone, which likely developed simultaneously along two distinct ways of differentiation according to the anatomic site suggesting here the predominant role of a micro-environmental factor in cell differentiation. Although rare, this kind of event must be kept in mind as a cause of discrepancies between diagnoses from different sites. PMID:16109617

Baseggio, Lucile; Gazzo, Sophie; Callet-Bauchu, Evelyne; Traverse-Glehen, Alexandra; Thieblemont, Catherine; Bryon, Paul-André; Magaud, Jean-Pierre; Berger, Françoise; Felman, Pascale

2005-09-01

121

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

PubMed

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

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

2014-08-21

122

Intravascular large B cell lymphoma  

PubMed Central

Intravascular large B cell lymphoma (IVBCL) is a rare type of extranodal large B cell lymphoma characterized by selective growth of lymphoma cells within the microvasculature. We present an illustrative case of intravascular B cell lymphoma suspected by the presence of a very small monoclonal B cell population identified by immunophenotype and polymerase chain reaction in bone marrow. The diagnosis was confirmed by skin biopsy. PMID:24596677

García-Muñoz, Ricardo; Rubio-Mediavilla, Susana; Robles-de-Castro, Diego; Muñoz, Aura; Herrera-Pérez, Pilar; Rabasa, Pilar

2014-01-01

123

MicroRNAs, Major Players in B Cells Homeostasis and Function  

PubMed Central

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

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

2014-01-01

124

Spontaneous remission of epstein-barr virus-positive diffuse large B-cell lymphoma of the elderly.  

PubMed

A 94-year-old female patient presented with anorexia and left axillar lymphadenopathy on admission. Her past history was angina pectoris at 83 years of age and total gastrectomy due to gastric cancer at 87 years. The family history revealed that her son had had a malignant lymphoma, the histopathological diagnosis of which was diffuse large B-cell lymphoma. A physical examination showed both cervical, axillar, and inguinal lymphadenopathy without tenderness. She had elevated lactate dehydrogenase, ferritin, and soluble interleukin-2 receptor (sIL-2R). Whole-body computed tomography confirmed the cervical, axillary, and inguinal lymphadenopathy. Gallium-68 imaging revealed positive accumulation in these superficial lymph nodes. A right inguinal lymph node biopsy showed features of Epstein-Barr virus-associated lymphoproliferative disorder. Immunohistological studies on this lymph node biopsy showed CD20-positive large cells, CD3-positive small cells, and CD30-partly-positive large cells. In situ hybridization showed Epstein-Barr virus-positive, LMP-partly-positive, and EBNA2-negative cells. She refused chemotherapy as her son had died from hematemesis during chemotherapy. She received intravenous hyperalimentation for 1 month after admission. No palpable lymph nodes were identified by physical examination or computed tomography 3 months after admission, and regression of lactate dehydrogenase, ferritin, and sIL-2R was observed. She recovered from anorexia and was discharged. She died from pneumonia 10 months later after initial symptoms of anorexia. The autopsy showed no superficial lymphadenopathy. PMID:23741222

Mizuno, T; Ishigaki, M; Nakajima, K; Matsue, T; Fukushima, M; Minato, H; Nojima, N; Atsushi, Saito; Ishigami, K; Atsumi, H; Ito, T; Iguchi, M; Usuda, D; Okamura, H; Urashima, S; Asano, M; Fukuda, A; Izumi, Y; Takekoshi, N; Kanda, T

2013-05-01

125

Lymphoproliferative disease virus in wild turkeys in southeast United States  

Technology Transfer Automated Retrieval System (TEKTRAN)

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

126

ALPS: an autoimmune human lymphoproliferative syndrome associated with abnormal lymphocyte apoptosis.  

PubMed

Apoptosis of activated lymphocytes is critical to immune homeostasis. The cell surface receptor Fas is an important mediator of lymphocyte apoptosis; defective Fas expression causes accumulation of lymphocytes and autoimmune disease in mice. Apoptosis defects due to mutations of Fas have also been found in a rare human autoimmune lymphoproliferative syndrome (ALPS). Nine unrelated children with ALPS had lymphadenopathy, autoimmunity and expansion of a normally infrequent population of CD4-CD8-T cells. All nine exhibited impaired lymphocyte apoptosis in vitro, and eight had heterozygous Fas gene mutations. Thus genetic defects in apoptosis pathways are implicated in the pathogenesis of at least one human autoimmune disorder. PMID:9106310

Puck, J M; Sneller, M C

1997-02-01

127

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

128

Epstein-Barr virus LMP2A signaling in statu nascendi mimics a B cell antigen receptor-like activation signal  

PubMed Central

Background The latent membrane protein (LMP) 2A of Epstein-Barr virus (EBV) is expressed during different latency stages of EBV-infected B cells in which it triggers activation of cytoplasmic protein tyrosine kinases. Early studies revealed that an immunoreceptor tyrosine-based activation motif (ITAM) in the cytoplasmic N-terminus of LMP2A can trigger a transient increase of the cytosolic Ca2+ concentration similar to that observed in antigen-activated B cells when expressed as a chimeric transmembrane receptor. Even so, LMP2A was subsequently ascribed an inhibitory rather than an activating function because its expression seemed to partially inhibit B cell antigen receptor (BCR) signaling in EBV-transformed B cell lines. However, the analysis of LMP2A signaling has been hampered by the lack of cellular model systems in which LMP2A can be studied without the influence of other EBV-encoded factors. Results We have reanalyzed LMP2A signaling using B cells in which LMP2A is expressed in an inducible manner in the absence of any other EBV signaling protein. This allowed us for the first time to monitor LMP2A signaling in statu nascendi as it occurs during the EBV life cycle in vivo. We show that mere expression of LMP2A not only stimulated protein tyrosine kinases but also induced phospholipase C-?2-mediated Ca2+ oscillations followed by activation of the extracellular signal-regulated kinase (Erk) mitogen-activated protein kinase pathway and induction of the lytic EBV gene bzlf1. Furthermore, expression of the constitutively phosphorylated LMP2A ITAM modulated rather than inhibited BCR-induced Ca2+ mobilization. Conclusion Our data establish that LMP2A expression has a function beyond the putative inhibition of the BCR by generating a ligand-independent cellular activation signal that may provide a molecular switch for different EBV life cycle stages and most probably contributes to EBV-associated lymphoproliferative disorders. PMID:22472181

2012-01-01

129

B cell biology: an overview.  

PubMed

In this review we summarize recent insights into the development of human B cells primarily by studying immunodeficiencies. Development and differentiation of B cells can be considered as a paradigm for many other developmental processes in cell biology. However, it differs from the development of many other cell types by phases of extremely rapid cell division and by defined series of somatic recombination and mutation events required to assemble and refine the B cell antigen receptors. Both somatic DNA alteration and proliferation phases take place in defined sites but in different organs. Thus, cell migration and timely arrival at defined sites are additional features of B cell development. By comparing experimental mouse models with insights gained from studying defined genetic defects leading to primary immunodeficiencies and hypogammaglobulinemia, we address important features that are characteristic for human B cells. We also summarize recent advances made by developing improved in vitro and in vivo systems allowing the development of human B cells from hematopoietic stem cells. Combined with genetic and functional studies of immunodeficiencies, these models will contribute not only to a better understanding of disease affecting the B lymphocyte compartment, but also to designing better and safer novel B cell-targeted therapies in autoimmunity and allergy. PMID:24633618

Eibel, Hermann; Kraus, Helene; Sic, Heiko; Kienzler, Anne-Kathrin; Rizzi, Marta

2014-05-01

130

Autoimmune lymphoproliferative syndrome with defective Fas: genotype influences penetrance.  

PubMed

Autoimmune lymphoproliferative syndrome (ALPS) is a disorder of lymphocyte homeostasis and immunological tolerance. Most patients have a heterozygous mutation in the APT1 gene, which encodes Fas (CD95, APO-1), mediator of an apoptotic pathway crucial to lymphocyte homeostasis. Of 17 unique APT1 mutations in unrelated ALPS probands, 12 (71%) occurred in exons 7-9, which encode the intracellular portion of Fas. In vitro, activated lymphocytes from all 17 patients showed apoptotic defects when exposed to an anti-Fas agonist monoclonal antibody. Similar defects were found in a Fas-negative cell line transfected with cDNAs bearing each of the mutations. In cotransfection experiments, Fas constructs with either intra- or extracellular mutations caused dominant inhibition of apoptosis mediated by wild-type Fas. Two missense Fas variants, not restricted to patients with ALPS, were identified. Variant A(-1)T at the Fas signal-sequence cleavage site, which mediates apoptosis less well than wild-type Fas and is partially inhibitory, was present in 13% of African American alleles. Among the ALPS-associated Fas mutants, dominant inhibition of apoptosis was much more pronounced in mutants affecting the intracellular, versus extracellular, portion of the Fas receptor. Mutations causing disruption of the intracellular Fas death domain also showed a higher penetrance of ALPS phenotype features in mutation-bearing relatives. Significant ALPS-related morbidity occurred in 44% of relatives with intracellular mutations, versus 0% of relatives with extracellular mutations. Thus, the location of mutations within APT1 strongly influences the development and the severity of ALPS. PMID:10090885

Jackson, C E; Fischer, R E; Hsu, A P; Anderson, S M; Choi, Y; Wang, J; Dale, J K; Fleisher, T A; Middelton, L A; Sneller, M C; Lenardo, M J; Straus, S E; Puck, J M

1999-04-01

131

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

Technology Transfer Automated Retrieval System (TEKTRAN)

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

132

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

133

B-type suppression: a role played by "regulatory B cells" or "regulatory plasma cells"?  

PubMed

B-cell depletion can improve disease in some patients with rheumatoid arthritis or multiple sclerosis, indicating the pathogenic contribution of B cells to autoimmunity. However, studies in mice have demonstrated that B cells have immunosuppressive functions as well, with IL-10 being a critical mediator of B-cell-mediated suppression. IL-10-secreting B cells have been shown to promote disease remission in some mouse models of autoimmune disorders. Human B cells also produce IL-10, and evidence is accumulating that human IL-10-producing B cells might inhibit immunity. There is considerable interest in identifying the phenotype of B cells providing IL-10 in a suppressive manner, which would facilitate the analysis of the molecular mechanisms controlling this B-cell property. Here, we review current knowledge on the B-cell subpopulations found to provide suppressive functions in mice, considering both the pathological context in which they were identified and the signals that control their induction. We discuss the phenotype of B cells that have IL-10-dependent regulatory activities in mice, which leads us to propose that antibody-secreting cells are, in some cases at least, the major source of B-cell-derived regulatory IL-10 in vivo. Anti-inflammatory cytokine production by antibody-secreting cells offers a novel mechanism for the coordination of innate and humoral immune responses. PMID:24615065

Ries, Stefanie; Hilgenberg, Ellen; Lampropoulou, Vicky; Shen, Ping; Dang, Van Duc; Wilantri, Siska; Sakwa, Imme; Fillatreau, Simon

2014-05-01

134

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

135

Intravenous immunoglobulin replacement therapy in common variable immunodeficiency induces B cell depletion through differentiation into apoptosis-prone CD21(low) B cells.  

PubMed

Intravenous immunoglobulin (IVIG), besides its use as replacement therapy in patients with antibody deficiencies, is broadly used as an immunomodulatory agent for the treatment of autoimmune and inflammatory disorders. The mechanisms of action of IVIG include Fc receptor blockade, inhibition of cytokines and growth factors, modulation of macrophages and dendritic cells, enhancement of regulatory T cells, and modulation of B cells through the Fc?RIIB receptor and CD22. Recent studies suggest that in vitro exposure of human B cells to IVIG determines functional changes reminiscent of anergy and that IVIG treatment of patients with common variable immunodeficiency (CVID) induces in B cells ERK activation, a feature of anergy. Here, we show that IVIG therapy drives the B cells of patients with CVID to down-regulate CD21 expression and to assume the peculiar phenotype of the anergic-like, apoptosis-prone CD21(low) B cells that are spontaneously expanded in a subset of CVID and in some other immunological disorders. The CD21(low) B cells newly generated after IVIG infusion undergo spontaneous apoptosis upon in vitro culture. Furthermore, IVIG infusion is rapidly followed by a significant, although discrete, decrease in the number of circulating B cells, but not of T cells or of natural killer cells. These findings suggest that IVIG therapy may constrain antibody responses by inducing B cell depletion through differentiation into CD21(low) B cells that undergo accelerated apoptosis. PMID:25407649

Mitrevski, Milica; Marrapodi, Ramona; Camponeschi, Alessandro; Lazzeri, Cristina; Todi, Laura; Quinti, Isabella; Fiorilli, Massimo; Visentini, Marcella

2014-12-01

136

Induction of apoptosis and effect on CD20+ using rituximab on autologous peripheral blood stem cell harvests from patients with B cell lymphomas.  

PubMed

Purging of neoplastic cells for autologous stem cell transplantation is usually done in vivo by administering chemotherapy and/or other agents before harvesting. It is also possible to decrease malignant cells counts directly in the cell harvest. In this study, we ascertained the effect of anti-CD20 monoclonal antibody and rituximab administration on peripheral blood hematopoietic stem cells. Five samples of stem cell harvests from different patients with B cell lymphoma were obtained. Each sample was divided in two tubes with calcium gluconate (20 mEq/50 microl). Rituximab (1 mg/600,000 mononuclear cells) was added to one of the tubes. Using flow cytometry, CD19, CD20 (B cell markers), and CD95 (apoptosis marker), expression was measured at baseline and 24 h after the addition of rituximab. A one-sided t-test with equal variances was used to analyze the results. Immediately after rituximab addition, CD20 expression became null. No significant difference in variation of CD19 expression was detected after the addition of rituximab (-3.64% control vs. 0.63% rituximab, p = 0.69). Mean variations of percentage of CD95 expression were 2.9% (controls) and 10.52% (rituximab tubes) (p = 0.06). We conclude that rituximab is capable of initiating apoptosis in vitro. We found no decrease in the CD19+ cell count, used as a surrogate marker for CD20+ cells, meaning that, at least in 24 h, apoptosis activation is not capable of decreasing CD20+ cell numbers. In vitro purging of peripheral blood stem cells harvests with rituximab could be part of a broader therapeutic strategy to be offered to lymphoproliferative disorder patients. PMID:15186735

Borbolla-Escoboza, Jose R; Leon, Maria I; Collados, Maria T; Baez, Enrique; Baltasar, Severiano; Hernández, Roberto; Rojas, Julio C

2004-04-01

137

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

138

Mechanisms of B-cell lymphoma pathogenesis  

Microsoft Academic Search

Chromosomal translocations involving the immunoglobulin loci are a hallmark of many types of B-cell lymphoma. Other factors, however, also have important roles in the pathogenesis of B-cell malignancies. Most B-cell lymphomas depend on the expression of a B-cell receptor (BCR) for survival, and in several B-cell malignancies antigen activation of lymphoma cells through BCR signalling seems to be an important

Ralf Küppers

2005-01-01

139

Homing and antigenic characterization of a human non-Hodgkin's lymphoma B cell line in severe combined immunodeficient (SCID) mice.  

PubMed

The dissemination pattern of a human non-Hodgkin's lymphoma (NHL) B cell line (DoHH2) carrying the t(14;18) translocation was analyzed in severe combined immunodeficient (SCID) mice, using different routes of administration. When engrafted intraperitoneally (i.p.) the DoHH2 cells showed a local infiltration into intra- and retroperitoneal mouse tissues, and disseminated to bone marrow and lymph nodes. In contrast, after subcutaneous (s.c.) or intravenous (i.v.) transfer the DoHH2 cells displayed a hematogenous spread, and disseminated predominantly to hematopoietic and lymphoid organs including bone marrow, peripheral blood, spleen, peripheral lymph nodes, and liver. No involvement of the gut and mesenteric lymph nodes was observed, suggesting a specific homing pattern, bypassing the mucosa-associated lymphoid tissue (MALT). This pattern is reminiscent of the human disease. Phenotypic analysis, cytogenetic analysis, and minor histocompatibility antigen (mHA) typing using mHA-specific cytotoxic T-lymphocyte (CTL) clones performed on the original DoHH2 cell line and on DoHH2 cells recovered from mouse tissue, showed that in vivo passage did not alter the characteristics of the DoHH2 cells. After i.v. administration, the survival time of the SCID mice directly correlated with the number of DoHH2 cells inoculated. This model of dissemination of the DoHH2 cell line may be useful for studying the efficacy of (immunotherapeutic) treatment of human lymphoproliferative disorders in vivo. PMID:8057678

de Kroon, J F; Kluin, P M; Kluin-Nelemans, H C; Willemze, R; Falkenburg, J H

1994-08-01

140

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

141

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

142

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

PubMed Central

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

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

2009-01-01

143

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

2012-01-01

144

The Roles of Regulatory B Cells in Cancer  

PubMed Central

Regulatory B cells (Bregs), a newly described subset of B cells, have been proved to play a suppressive role in immune system. Bregs can inhibit other immune cells through cytokines secretion and antigen presentation, which give them the role in the pathogenesis of autoimmune diseases and cancers. There are no clear criteria to identify Bregs; different markers were used in the different experimental conditions. Massive researches had described the functions of immune cells such as regulatory T cells (Tregs), dendritic cells (DCs), and B cells in the autoimmune disorder diseases and cancers. More and more researches focused on the roles of Bregs and the cytokines such as Interleukin-10 (IL-10) and transforming growth factor beta (TGF-?) secreted by Bregs. The aim of this review is to summarize the characteristics of Bregs and the roles of Bregs in cancer. PMID:24991577

Qian, Hongyan; Liu, Yuan; Li, Yan; Shi, Guixiu

2014-01-01

145

Expansion of Murine Gammaherpesvirus Latently Infected B Cells Requires T Follicular Help  

PubMed Central

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.

2014-01-01

146

Monoclonal B-Cell Lymphocytosis  

PubMed Central

Monoclonal B-cell lymphocytosis (MBL) is an asymptomatic hematologic condition defined by the presence of a small (<5 x 109/L) clonal B-cell population in the peripheral blood in the absence of lymph-node enlargement, cytopenias or autoimmune diseases. It is found in approximately 3-12% of normal persons depending on the accuracy of analytical techniques applied. According to the immunophenotypic profile of clonal B-cells, the majority of MBL cases (75%) are classified as chronic lymphocytic leukemia (CLL)-like. This form may progress into CLL at a rate of 1–2% per year. It is thought that CLL is always preceded by MBL. The remaining MBL cases are defined as atypical CLL-like (CD5+/CD20bright) and CD5- MBL. The MBL clone size is quite heterogenous. Accordingly, two forms of MBL are identified: i) high-count, or ‘clinical’ MBL, in which an evidence of lymphocytosis (<5 x 109/L clonal B-cells) is seen, and ii) a low-count MBL, in which a normal leukocyte count is found and that is identified only in population-screening studies. Both forms of MBL may carry the cytogenetic abnormalities that are the hallmark of CLL, including 13q-, 17p- and trisomy 12. Consistent with the indolent phenotype of this condition, genetic lesions, such as TP53, ATM, NOTCH1 and SF3B1 mutations, usually associated with high-risk CLL, are rarely seen. Overall, no prognostic indicator of evolution of MBL to overt CLL has been found at present time. However, taking into account this possibility, a clinical and lab monitoring (at least annually), is recommended. PMID:24779000

D’Arena, G.; Musto, P.

2014-01-01

147

B-cell memory: are subsets necessary?  

Microsoft Academic Search

B-cell memory is provided by populations of quiescent memory B cells and long-lived plasma cells. Whereas it is clear that both of these cell populations arise from germinal centres, the signals and circumstances that trigger germinal-centre B cells to enter and then persist in memory compartments are poorly defined. Here, I propose that germinal centres produce memory B cells and

David Tarlinton

2006-01-01

148

Identification of a sub-population of B cells that proliferates after infection with epstein-barr virus  

PubMed Central

Background Epstein-Barr virus (EBV)-driven B cell proliferation is critical to its subsequent persistence in the host and is a key event in the development of EBV-associated B cell diseases. Thus, inquiry into early cellular events that precede EBV-driven proliferation of B cells is essential for understanding the processes that can lead to EBV-associated B cell diseases. Methods Infection with high titers of EBV of mixed, primary B cells in different stages of differentiation occurs during primary EBV infection and in the setting of T cell-immunocompromise that predisposes to development of EBV-lymphoproliferative diseases. Using an ex vivo system that recapitulates these conditions of infection, we correlated expression of selected B cell-surface markers and intracellular cytokines with expression of EBV latency genes and cell proliferation. Results We identified CD23, CD58, and IL6, as molecules expressed at early times after EBV-infection. EBV differentially infected B cells into two distinct sub-populations of latently infected CD23+ cells: one fraction, marked as CD23hiCD58+IL6- by day 3, subsequently proliferated; another fraction, marked as CD23loCD58+, expressed IL6, a B cell growth factor, but failed to proliferate. High levels of LMP1, a critical viral oncoprotein, were expressed in individual CD23hiCD58+ and CD23loCD58+ cells, demonstrating that reduced levels of LMP1 did not explain the lack of proliferation of CD23loCD58+ cells. Differentiation stage of B cells did not appear to govern this dichotomy in outcome either. Memory or naïve B cells did not exclusively give rise to either CD23hi or IL6-expressing cells; rather memory B cells gave rise to both sub-populations of cells. Conclusions B cells are differentially susceptible to EBV-mediated proliferation despite expression of viral gene products known to be critical for continuous B cell growth. Cellular events, in addition to viral gene expression, likely play a critical role in determining the outcome of EBV infection. By indentifying cells predicted to undergo EBV-mediated proliferation, our study provides new avenues of investigation into EBV pathogenesis. PMID:21352549

2011-01-01

149

IFN-gamma gene polymorphisms associate with development of EBV+ lymphoproliferative disease in hu PBL-SCID mice.  

PubMed

Posttransplantation lymphoproliferative disorder (PTLD) is a devastating post-transplantation complication often associated with Epstein-Barr virus (EBV). Although the type and length of immunosuppression are risk factors, a patient's inherent immune capacity also likely contributes to this disorder. This report uses severe-combined immunodeficient mice given injections of human peripheral blood leukocytes (hu PBL-SCID [Severe Combined Immunodeficient] mice) to test the hypothesis that cytokine genotype associates with the development of EBV-associated lymphoproliferative disease (LPD). We observed that the A/A (adenosine/adenosine) genotype for base + 874 of the interferon gamma (IFN-gamma) gene was significantly more prevalent in PBLs producing rapid, high-penetrance LPD in hu PBL-SCID mice, compared to PBLs producing late, low-penetrance LPD or no LPD. In examining the relationship between genotype and cytolytic T-lymphocyte (CTL) function, transforming growth factor beta (TGF-beta) inhibited restimulation of CTLs in PBLs with adenosine at IFNG base + 874, but not in PBLs homozygous for thymidine. Importantly, neutralization of TGF-beta in hu PBL-SCID mice injected with A/A genotype PBLs resulted in reduced LPD development and expanded human CD8(+) cells. Thus, our data show that TGF-beta may promote tumor development by inhibiting CTL restimulation and expansion. Further, our data indicate that IFNG genotype may provide valuable information for both identifying transplant recipients at greater risk for PTLD and developing preventive and curative strategies. PMID:15498860

Dierksheide, Julie E; Baiocchi, Robert A; Ferketich, Amy K; Roychowdhury, Sameek; Pelletier, Ronald P; Eisenbeis, Charles F; Caligiuri, Michael A; VanBuskirk, Anne M

2005-02-15

150

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

2015-01-29

151

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

152

Phagocytic B cells in a reptile  

PubMed Central

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

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

2010-01-01

153

B cell depletion for autoimmune diseases in paediatric patients  

Microsoft Academic Search

Data on B cell depletion therapy in severe autoimmune diseases in paediatric patients are very limited. We conducted a retrospective\\u000a cohort study and recruited patients who were treated with rituximab (RTX) and followed up for at least 6 months through the\\u000a German societies of paediatric rheumatology and nephrology. The aim was to describe the spectrum of autoimmune disorders for\\u000a which RTX

Annette F. Jansson; Claudia Sengler; Jasmin Kuemmerle-Deschner; Bernd Gruhn; A. Birgitta Kranz; Hartwig Lehmann; Daniela Kleinert; Lars Pape; Hermann J. Girschick; Ivan Foeldvari; Dieter Haffner; Johannes P. Haas; Dagmar Moebius; Dirk Foell; Joachim Peitz; Veit Grote

2011-01-01

154

IL-17 Enhances Chemotaxis of Primary Human B Cells during Asthma  

PubMed Central

IL-17 is a pro-inflammatory mediator that is believed to play a critical role in regulating tissue inflammation during asthma, COPD, as well as other inflammatory disorders. The level of expression of IL-17 has been shown to be upregulated in lung bronchial tissue of asthmatic patients. Several reports have provided further evidence that this cytokine could play a key role in enhancing the migration of inflammatory as well as structural cells of the bronchial lung tissue during asthma and COPD. B cell infiltration to sites of inflammation during inflammatory disorders such as bowel disease, asthma and COPD has been reported. Accordingly, in this study we hypothesized that IL-17 may exert a chemotactic effect on primary B cells during asthma. We observed that B cells from asthmatic patients expressed significantly higher levels of IL-17RA and IL-17RC, compared to those of healthy subjects. Using an in-vitro migration assay, B cells were shown to migrate towards both IL-17A and IL-17F. Interestingly, blocking IL-17A and IL-17F signaling using either anti-IL-17R antibodies or MAP kinase inhibitors prevented in vitro migration of B cell towards IL-17. These observations indicate a direct chemotactic effect of IL-17 cytokines on primary peripheral blood B cells with higher effect being on asthmatic B cells. These findings revealed a key role for IL-17 in enhancing the migration of B cells to the lung tissue during asthma or COPD. PMID:25494178

Halwani, Rabih; Al-Kufaidy, Roua; Vazquez-Tello, Alejandro; Pureza, Mary Angeline; BaHammam, Ahmed S.; Al-Jahdali, Hamdan; Alnassar, Sami A.; Hamid, Qutayba; Al-Muhsen, Saleh

2014-01-01

155

Memory B cells in mouse models.  

PubMed

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

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

2013-08-01

156

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

PubMed

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

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

2014-12-01

157

Epstein-Barr virus infection in vitro can rescue germinal center B cells with inactivated immunoglobulin genes.  

PubMed

Immunoglobulin genotyping of Epstein-Barr virus (EBV)-positive posttransplantation lymphoproliferative disease has suggested that such lesions often arise from atypical post-germinal center B cells, in some cases carrying functionally inactivated immunoglobulin genes. To investigate whether EBV can rescue cells that are failed products of the somatic hypermutation process occurring in germinal centers (GCs), we isolated GC cells from tonsillar cell suspensions and exposed them to EBV in vitro. Screening more than 100 EBV-transformed cell lines of GC origin identified 6 lines lacking surface immunoglobulin, a phenotype never seen among lines derived from circulating naive or memory B cells. Furthermore, 3 of the 6 surface immunoglobulin-negative GC lines carried inactivating mutations in the immunoglobulin H (IgH) variable gene sequence. The ability of EBV to rescue aberrant products of the germinal center reaction in vitro strengthens the probability that a parallel activity contributes to EBV's lymphomagenic potential in vivo. PMID:16123211

Chaganti, Sridhar; Bell, Andrew I; Pastor, Noelia Begue; Milner, Anne E; Drayson, Mark; Gordon, John; Rickinson, Alan B

2005-12-15

158

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

PubMed Central

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

Jacob, Noam; Stohl, William

2009-01-01

159

B-cell malignancies in microRNA E?-miR-17?92 transgenic mice  

PubMed Central

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

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

2013-01-01

160

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

Technology Transfer Automated Retrieval System (TEKTRAN)

The eight cases described herein represent the first reports of lymphoproliferative disease virus (LPDV) infection in wild turkeys and the first identification of LPDV in North America. Systemic lymphoproliferative disease was presumably the cause of morbidity and mortality in five of the eight turk...

161

New Advances in the Diagnosis and Treatment of Autoimmune Lymphoproliferative Syndrome (ALPS)  

PubMed Central

Purpose of Review Autoimmune Lymphoproliferative Syndrome (ALPS) is a disorder of disrupted lymphocyte homeostasis, resulting from mutations in the Fas apoptotic pathway. Clinical manifestations include lymphadenopathy, splenomegaly, and autoimmune cytopenias. A number of new insights have improved the understanding of the genetics and biology of ALPS. These will be discussed in this review. Recent Findings A number of key observations have been made recently that better define the pathophysiology of ALPS, including the characterization of somatic FAS variant ALPS, the identification of haploinsufficiency as a mechanism of decreased Fas expression, and the description of multiple genetic hits in FAS in some families that may explain the variable penetrance of the disease. In addition, ALPS has been shown to be a more common condition, as patients diagnosed with other disorders, including Evans syndrome and common variable immune deficiency have been found to have ALPS. Finally, the treatment of the disease has changed as splenectomy and rituximab have been shown to have unexpected ALPS specific toxicities, and mycophenolate mofetil and sirolimus have been demonstrated to have marked activity against the disease. Summary Based on novel advances the diagnostic algorithm and recommended treatment for ALPS have changed significantly, improving quality of life for many patients. PMID:22157362

Teachey, David T.

2012-01-01

162

Clincal, immunologic, and genetic features of an autoimmune lymphoproliferative syndrome associated with abnormal lymphocyte apoptosis.  

PubMed

Programmed cell death (apoptosis) of activated lymphocytes is critical to immune homeostasis. The cell surface protein Fas (CD95) and its ligand play a pivotal role in regulating lymphocyte apoptosis, and defective expression of either Fas or Fas ligand results in marked over accumulation of mature lymphocytes and autoimmune disease in mice. The results of recent studies suggest that defective lymphocyte apoptosis caused by mutations of the Fas gene can result in a severe autoimmune lymphoproliferative syndrome (ALPS) in humans. To define the clinical, genetic, and immunologic spectrum of ALPS, 9 patients and their families were extensively evaluated with routine clinical studies, lymphocyte phenotyping, genotyping, and in vitro assays for lymphocyte apoptosis. Individual patients were followed up for 3 months to 6 years. ALPS was identified in 9 unrelated children as manifested by moderate to massive splenomegaly and lymphadenopathy, hypergammaglobulinemia, autoimmunity, B-cell lymphocytosis, and the expansion of an unusual population of CD4- CD8- T cells that express the alpha/beta T-cell receptor (TCR). All patients showed defective lymphocyte apoptosis in vitro. Heterozygous mutations of the Fas gene were detected in 8 patients. One ALPS patient lacked a Fas gene mutation. Healthy relatives with Fas mutations were identified in 7 of 8 ALPS kindreds. These relatives also showed in vitro abnormalities of Fas-mediated lymphocyte apoptosis, but clinical features of ALPS were not present in the vast majority of these individuals. ALPS is a unique clinical syndrome in which in vitro abnormalities of lymphocyte apoptosis are associated with abnormal lymphoproliferation and autoimmunity. These findings provide evidence that apoptosis of activated lymphocytes is an important mechanism for maintaining immunologic homeostasis and self-tolerance in humans. Fas gene mutations account for impaired lymphocyte apoptosis in only a subset of patients with ALPS. PMID:9028957

Sneller, M C; Wang, J; Dale, J K; Strober, W; Middelton, L A; Choi, Y; Fleisher, T A; Lim, M S; Jaffe, E S; Puck, J M; Lenardo, M J; Straus, S E

1997-02-15

163

Targeting Notch signaling in autoimmune and lymphoproliferative disease  

PubMed Central

Patients with autoimmune lymphoproliferative syndrome (ALPS) and systemic lupus erythematosis (SLE) have T-cell dysregulation and produce abnormal, activated T lymphocytes and an atypical peripheral T-cell population, termed double negative T cells (DNTs). T-cell functions, including DNT transition in T-cell development and T-cell activation, are critically dependent on Notch signaling. We hypothesized that inhibiting Notch signaling would be effective in ALPS and SLE by reducing the production of abnormal DNTs and by blocking aberrant T-cell activation. We tested this hypothesis using murine models of ALPS and SLE. Mice were randomized to treatment with the notch pathway inhibitor (gamma-secretase inhibitor), N-S-phenyl-glycine-t-butyl ester (DAPT), or vehicle control. Response to treatment was assessed by measurement of DNTs in blood and lymphoid tissue, by monitoring lymph node and spleen size with ultrasound, by quantifying cytokines by bead-array, by ELISA for total IgG and anti–double-stranded DNA (dsDNA) specific antibodies, and by histopathologic assessment for nephritis. We found a profound and statistically significant decrease in all disease parameters, comparing DAPT-treated mice to controls. Using a novel dosing schema, we avoided the reported toxicities of gamma-secretase inhibitors. Inhibiting the Notch signaling pathway may thus present an effective, novel, and well-tolerated treatment for autoimmune and lymphoproliferative diseases. PMID:17925488

Seif, Alix E.; Brown, Valerie I.; Bruno, Marlo; Bunte, Ralph M.; Chang, Yueh J.; Choi, John K.; Fish, Jonathan D.; Hall, Junior; Reid, Gregor S.; Ryan, Theresa; Sheen, Cecilia; Zweidler-McKay, Patrick; Grupp, Stephan A.

2008-01-01

164

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

PubMed

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

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

2014-02-15

165

Enhancement of the B-cell response to Staphylococcus aureus Cowan strain 1 by natural human gamma interferon.  

PubMed Central

The effects of interferon (IFN) on the B-cell response to Staphylococcus aureus Cowan strain 1 (SAC) were studied comparatively with natural human IFN-alpha, IFN-beta, and IFN-gamma, employing equal units of their anti-viral activity. First, the response was investigated in peripheral mononuclear cells obtained from healthy individuals, and next, confirmed in cultures employing B-cell enriched populations derived from tonsils obtained at tonsillectomy from patients with chronic tonsillitis. B cells were purified by rosetting out T cells with sheep red cells followed by the removal of adherent cells on a plastic surface. The results show that the SAC-stimulated lymphoproliferative response was enhanced in the presence of IFN-gamma in a dose-related manner, at concentrations ranging from 10 to 1000 IU/ml, both in peripheral mononuclear cells and tonsillar B-cell enriched fractions. In contrast, IFN-alpha and IFN-beta did not enhance or suppress SAC-stimulated blastogenesis in either lymphocyte preparation. The enhancing effects specific to IFN-gamma were more remarkable in cultures stimulated with a suboptimal dose (0.002%) of SAC than when the optimal dose (0.005%) was employed. PMID:3102351

Aoki, N; Ohno, Y

1987-01-01

166

Regulation of B-cell proliferation and differentiation by pre-B-cell receptor signalling  

Microsoft Academic Search

The pre-B-cell receptor (pre-BCR) is expressed following the productive recombination of the immunoglobulin heavy chain gene. Signals through the pre-BCR are required for initiating diverse processes in pre-B cells, including proliferation and recombination of the light chain gene, which eventually lead to the differentiation of pre-B cells to immature B cells. However, the molecular mechanisms by which the pre-BCR promotes

Sebastian Herzog; Michael Reth; Hassan Jumaa

2009-01-01

167

Restimulation-induced apoptosis of T cells is impaired in patients with X-linked lymphoproliferative disease caused by SAP deficiency  

PubMed Central

X-linked lymphoproliferative disease (XLP) is a rare congenital immunodeficiency that leads to an extreme, usually fatal increase in the number of lymphocytes upon infection with EBV. It is most commonly defined molecularly by loss of expression of SLAM-associated protein (SAP). Despite this, there is little understanding of how SAP deficiency causes lymphocytosis following EBV infection. Here we show that T cells from individuals with XLP are specifically resistant to apoptosis mediated by TCR restimulation, a process that normally constrains T cell expansion during immune responses. Expression of SAP and the SLAM family receptor NK, T, and B cell antigen (NTB-A) were required for TCR-induced upregulation of key pro-apoptotic molecules and subsequent apoptosis. Further, SAP/NTB-A signaling augmented the strength of the proximal TCR signal to achieve the threshold required for restimulation-induced cell death (RICD). Strikingly, TCR ligation in activated T cells triggered increased recruitment of SAP to NTB-A, dissociation of the phosphatase SHP-1, and colocalization of NTB-A with CD3 aggregates. In contrast, NTB-A and SHP-1 contributed to RICD resistance in XLP T cells. Our results reveal what we believe to be novel roles for NTB-A and SAP in regulating T cell homeostasis through apoptosis and provide mechanistic insight into the pathogenesis of lymphoproliferative disease in XLP. PMID:19759517

Snow, Andrew L.; Marsh, Rebecca A.; Krummey, Scott M.; Roehrs, Philip; Young, Lisa R.; Zhang, Kejian; van Hoff, Jack; Dhar, Deepali; Nichols, Kim E.; Filipovich, Alexandra H.; Su, Helen C.; Bleesing, Jack J.; Lenardo, Michael J.

2009-01-01

168

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

PubMed

A case is described of malignant B-cell lymphoma with scleroderma-like manifestation. Using different monoclonals as B-cell markers the tumor appeared to be positive for surface immunoglobulins (SmIg) and for B2-antigen, but negative for intracytoplasmic immunoglobulin (CIg), BA2- and FMC7-antigens. Therefore, the tumor could be determined as a highly differentiated Sm-positive early B-cell type of B-cell lymphoma. In this clinically rare manifestation of cutaneous B-cell lymphoma aspects of the cell morphology and of cellular mediated immunity are briefly discussed. PMID:6335153

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

1984-12-01

169

The immune potential and immunopathology of cytokine-producing B cell subsets: A comprehensive review.  

PubMed

B lymphocytes are generally recognized for their potential to mediate humoral immunity by producing different antibody isotypes and being involved in opsonization and complement fixation. Nevertheless, the non-classical, antibody-independent immune potential of B cell subsets has attracted much attention especially in the past decade. These B cells can release a broad variety of cytokines (such as IL-2, IL-4, IL-6, IL-10, IL-17, IFN-?, IFN-?, TNF-?, TGF-?, LT), and can be classified into distinct subsets depending on the particular cytokine profile, thus emerging the concept of cytokine-producing B cell subsets. Although there is still controversy surrounding the key cell surface markers, intracellular factors and cellular origins of cytokine-producing B cell subsets, accumulating evidence indicates that these B cells are endowed with great potential to regulate both innate and adaptive arms of immune system though releasing cytokines. On the one hand, they promote immune responses through mounting Th1/Th2/Th17 and neutrophil response, inducing DC maturation and formation of lymphoid structures, increasing NK cell and macrophage activation, enhancing development of themselves and sustaining antibody production. On the other hand, they can negatively regulate immune responses by suppressing Th cell responses, inhibiting Tr1 cell and Foxp3(+) Treg differentiation, impairing APC function and pro-inflammatory cytokine release by monocytes, and inducing CD8(+) T cell anergy and CD4(+) T cell apoptosis. Therefore, cytokine-producing B cell subsets have multifunctional functions in health and diseases, playing pathologic as well as protective roles in autoimmunity, infection, allergy, and even malignancy. In this review, we revisit the history of discovering cytokine-producing B cells, describe the identification of cytokine-producing B cell subsets, introduce the origins of cytokine-producing B cell subsets as well as molecular and cellular mechanisms for their differentiation, and summarize the recent progress made toward understanding the unexpectedly complex and potentially opposing roles of cytokine-producing B cells in immunological disorders. PMID:24794622

Bao, Yan; Cao, Xuetao

2014-12-01

170

Eosinophilia is associated with a higher mortality rate among patients with autoimmune lymphoproliferative syndrome.  

PubMed

Autoimmune lymphoproliferative syndrome (ALPS) is a disorder associated with heritable defects in lymphocyte apoptosis that result in chronic nonmalignant lymphadenopathy, splenomegaly, and autoimmunity. To examine the prevalence, mechanisms, and potential implications of eosinophilia in ALPS, we reviewed data retrospectively from 187 consecutive ALPS patients and their family members studied at the National Institutes of Health. ALPS patients with eosinophilia were compared with ALPS patients without eosinophilia with respect to their clinical and immunologic phenotype. Potential mechanisms for the eosinophilia, including abnormal Fas-mediated eosinophil apoptosis, increased production of eosinophilopoietic cytokines, and presence of anti-eosinophilic autoantibodies were also explored in a small number of patients from whom samples were available. Analysis of data from 68 ALPS patients and 119 of their relatives identified a distinct subgroup of patients with prominent and persisting eosinophilia that proved to be associated with increased numbers of peripheral blood leukocytes (PBL) of multiple lineages and a trend towards increased serum IgE levels. Eosinophilic ALPS patients also had a significantly higher risk of death due to infectious complications. Although the specific etiology of the eosinophilia in these patients remains uncertain, it does not appear to be associated with an altered serum cytokine profile, increased survival responsiveness of eosinophils to IL-5, defective Fas-mediated eosinophil apoptosis, or anti-eosinophil antibodies. Eosinophilia defines a distinct subgroup of ALPS patients with increased serum IgE levels, increased numbers of PBL of multiple lineages, and higher mortality from infectious complications. PMID:17266055

Kim, Yae-Jean; Dale, Janet K; Noel, Pierre; Brown, Margaret R; Nutman, Thomas B; Straus, Stephen E; Klion, Amy D

2007-07-01

171

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

PubMed Central

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

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

2007-01-01

172

Human adipose tissue-derived mesenchymal stem cells abrogate plasmablast formation and induce regulatory B cells independently of T helper cells.  

PubMed

Mesenchymal stem cells (MSC) interact with cells of the immune system in multiple ways. Modulation of the immune system by MSC is believed to be a therapeutic option for autoimmune disease and transplant rejection. In recent years, B cells have moved into the focus of the attention as targets for the treatment of immune disorders. Current B cell targeting treatment is based on the indiscriminate depletion of B cells. The aim of this study was to examine whether human adipose tissue-derived MSC (ASC) interact with B cells to affect their proliferation, differentiation and immune function. ASC supported the survival of quiescent B cells predominantly via contact-dependent mechanisms. Co-culture of B cells with activated T helper cells led to proliferation and differentiation of B cells into CD19(+) CD27(high) CD38(high) antibody producing plasmablasts. ASC inhibited the proliferation of B cells and this effect was dependent on the presence of T cells. In contrast, ASC directly targeted B cell differentiation, independently of T cells. In the presence of ASC, plasmablast formation was reduced and IL-10 producing CD19(+) CD24(high) CD38(high) B cells, known as regulatory B cells, were induced. These results demonstrate that ASC affect B cell biology in vitro, suggesting that they can be a tool for the modulation of the B cell response in immune disease. Stem Cells 2014. PMID:25376628

Franquesa, M; Mensah, F K; Huizinga, R; Strini, T; Boon, L; Lombardo, E; DelaRosa, O; Laman, J D; Grinyó, J M; Weimar, W; Betjes, M G H; Baan, C C; Hoogduijn, M J

2014-11-01

173

Fludarabine, cyclophosphamide, doxorubicin (FCD), and rituximab: a remission induction therapy for aggressive pediatric post-transplant lymphoproliferative disease (PTLD).  

PubMed

Management of aggressive, usually late-occurring, post-transplant lymphoproliferative disorders (PTLDs), a life-threatening complication after solid organ transplants, remains controversial. Four children affected by aggressive CD20+ PTLDs received a chemo-immunotherapy regimen for remission induction based on fludarabine, cyclophosphamide, doxorubicin, and rituximab, associated with a rapid discontinuation of immunosuppression (IS). Subsequent consolidation chemotherapy consisted of Berlin-Frankfurt-Münster-modified blocks. All patients achieved a complete remission, which persisted for 25, 68+, 80+, and 103+ months after diagnosis. Therapy was well tolerated. No patients developed allograft rejection during PTLD treatment. Our experience suggests that this chemo-immunotherapeutic approach may be an effective treatment strategy while allowing for a concomitant discontinuation of IS. PMID:21294246

Giraldi, Eugenia; Provenzi, Massimo; Fiocchi, Roberto; Colledan, Michele; Cornelli, Pieremilio; Torre, Giuliano; Rambaldi, Alessandro; Conter, Valentino

2011-08-01

174

Stat5 Is Essential for the Myelo- and Lymphoproliferative Disease Induced by TEL\\/JAK2  

Microsoft Academic Search

STAT5 is activated in a broad spectrum of human hematologic malignancies. We addressed whether STAT5 activation is necessary for the myelo- and lymphoproliferative disease induced by TEL\\/JAK2 using a genetic approach. Whereas mice transplanted with bone marrow transduced with retrovirus expressing TEL\\/JAK2 develop a rapidly fatal myelo- and lymphoproliferative syndrome, reconstitution with bone marrow derived from Stat5ab-deficient mice expressing TEL\\/JAK2

Juerg Schwaller; Evan Parganas; Demin Wang; Danielle Cain; Jon C. Aster; Ifor R. Williams; Chien-Kuo Lee; Rachel Gerthner; Toshio Kitamura; Julie Frantsve; Ema Anastasiadou; Mignon L. Loh; David E. Levy; James N. Ihle; D. Gary Gilliland

2000-01-01

175

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

176

Primary Hepatosplenic Large B-Cell Lymphoma  

Microsoft Academic Search

Diffuse large B-cell lymphoma is the most common form of lymphoma. It usually begins in the lymph nodes; up to 40% may have an extranodal presentation. According to a definition of primary extranodal lymphoma with presentation only in extranodal sites, there are reports of large B-cell lymphomas limited to liver or spleen as separate entities, and to date there have

M. R. Morales-Polanco; R. Drijansky-Morgenstern; E. Murillo-Meza; E. Gómez-Morales

2008-01-01

177

Tolerogenicity of Resting and Activated B Cells  

Microsoft Academic Search

Summary Antigen presentation by resting splenic B cells has been shown previously to induce T helper I cell (Thl) anergy. In contrast to expectations, it was found here that B cells treated with F(ab')2 goat anti-mouse immunoglobulin (IgM) for 24 or 48 h also presented antigen (Ag) to Thl cells in a manner that induced dramatic Ag-specific proliferative inactivation. The

Kathleen M. Gilbert; William O. Weigle

178

Isotype Control of B Cell Signaling  

NSDL National Science Digital Library

The B cell receptor (BCR) consists of an antigen-binding membrane immunoglobulin (mIg) associated with the CD79α and CD79β heterodimer. Nai¨ve B cells express the IgM and IgD isotypes, which have very short cytoplasmic tails and therefore depend on CD79α and CD79β for signal transduction. After antigenic stimulation, B cells undergo isotype switching to yield IgG, IgE, or IgA. Recent research suggests that the ability of the B cell coreceptor CD22 to regulate BCR signaling depends on the isotype of the mIg cytoplasmic tail. Cell lines that express a BCR with the cytoplasmic tail from IgG, the isotype found in memory B cells, are not subject to CD22 regulation, whereas cell lines that express BCRs with IgM cytoplasmic tails are subject to CD22 regulation. Moreover, stimulation through BCRs containing an IgG cytoplasmic tail causes increased numbers of antigen-specific clones to accumulate. These observations are a valuable step toward understanding the difference in B cell signaling between nai¨ve and memory cells. Here, we discuss the implications of these findings for CD22 regulation and signaling through the mIgG-containing BCR.

Karlee Silver (Headington;Nuffield Department of Clinical Medicine, University of Oxford, John Radcliffe Hospital REV); Richard J. Cornall (Headington;Nuffield Department of Clinical Medicine, University of Oxford, John Radcliffe Hospital REV)

2003-05-27

179

p53-mediated apoptosis prevents the accumulation of progenitor B cells and B-cell tumors  

Microsoft Academic Search

We propose that the apoptotic function of p53 has an important role in B-cell homeostasis, which is important for the prevention of B-cell lymphomas. We created a mouse model (m?pro) that lacked residues 58–88 of the proline-rich domain of p53. m?pro is defective for apoptosis, but is able to arrest cell-cycle progression in hematopoietic tissues. m?pro develops late-onset B-cell lymphoma,

T L Slatter; P Ganesan; C Holzhauer; R Mehta; C Rubio; G Williams; M Wilson; J A Royds; M A Baird; A W Braithwaite

2010-01-01

180

B cell reconstitution after rituximab treatment of lymphoma recapitulates B cell ontogeny.  

PubMed

The long-term immunologic effects of B cell depletion with rituximab and the characteristics of the reconstituting B cell pool in lymphoma patients are not well defined, despite the widespread usage of this therapy. Here we report that during the B cell reconstitution phase a majority of the peripheral blood B cells have an immature transitional phenotype (47.8%+/-25.2% vs. 4.4%+/-2.4% for normal controls, p<0.0001), similar to what has been described during the original ontogeny of the immune system and following bone marrow transplantation. Moreover, the recovery of the CD27+ memory B cell pool was delayed compared to normal B cell ontogeny, remaining below normal controls at 1 year post-rituximab (4.4%+/-3% vs. 31%+/-7%, p<0.0001). Expansion of functionally immature B cells and decreased memory B cells may contribute to an immunodeficient state in patients recovering from rituximab mediated B cell depletion, particularly with repeated treatment. PMID:17008130

Anolik, Jennifer H; Friedberg, Jonathan W; Zheng, Bo; Barnard, Jennifer; Owen, Teresa; Cushing, Emily; Kelly, Jennifer; Milner, Eric C B; Fisher, Richard I; Sanz, Iñaki

2007-02-01

181

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

182

Characterising B cell numbers and memory B cells in HIV infected and uninfected Malawian adults  

PubMed Central

Background Untreated human immunodeficiency virus (HIV) disease disrupts B cell populations causing reduced memory and reduced naïve resting B cells leading to increases in specific co-infections and impaired responses to vaccines. To what extent antiretroviral treatment reverses these changes in an African population is uncertain. Methods A cross-sectional study was performed. We recruited HIV-uninfected and HIV-infected Malawian adults both on and off antiretroviral therapy attending the Queen Elizabeth Central hospital in Malawi. Using flow cytometry, we enumerated B cells and characterized memory B cells and compared these measurements by the different recruitment groups. Results Overall 64 participants were recruited - 20 HIV uninfected (HIV-), 30 HIV infected ART naïve (HIV+N) and 14 HIV-infected ART treated (HIV+T). ART treatment had been taken for a median of 33 months (Range 12-60 months). Compared to HIV- the HIV+N adults had low absolute number of naïve resting B cells (111 vs. 180 cells/?l p = 0.008); reduced memory B cells (27 vs. 51 cells/?l p = 0.0008). The HIV+T adults had B-cell numbers similar to HIV- except for memory B cells that remained significantly lower (30 vs. 51 cells/?l p = 0.02). In the HIV+N group we did not find an association between CD4 count and B cell numbers. Conclusions HIV infected Malawian adults have abnormal B-cell numbers. Individuals treated with ART show a return to normal in B-cell numbers but a persistent deficit in the memory subset is noted. This has important implications for long term susceptibility to co-infections and should be evaluated further in a larger cohort study. PMID:20860822

2010-01-01

183

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

PubMed

Intravenous immunoglobulin (IVIG) is used as replacement therapy in patients with antibody deficiencies and at higher dosages in immune-mediated disorders. Although different mechanisms have been described in vitro, the in vivo immunomodulatory effects of IVIG are poorly understood. Different studies have suggested that IVIG modulates B-cell functions as activation, proliferation, and apoptosis. Recently, it was shown that IVIG induces in vitro B-cell unresponsiveness similar to anergy. In accord with this, we recently reported that IVIG therapy in patients affected by common variable immunodeficiency (CVID) interferes in vivo with the B-cell receptor (BCR) signaling by increasing constitutive ERK activation and by reducing the phosphorylated ERK increment induced by BCR cross-linking. Moreover, we observed that IVIG induces in CVID patients an increase of circulating CD21(low) B-cells, an unusual population of anergic-like B-cells prone to apoptosis. Therefore, IVIG at replacement dose in vivo could prime B-cells to an anergic, apoptotic program. Here, we discuss these recent findings, which may improve our understanding of the immunomodulatory effects of IVIG, individualizing single involved molecules for more specific treatments. PMID:25657650

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

2015-01-01

184

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

PubMed Central

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

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

2014-01-01

185

Innate control of B cell responses  

PubMed Central

Mature B cells generate protective immunity by undergoing immunoglobulin (Ig) class switching and somatic hypermutation, two Ig gene-diversifying processes that usually require cognate interactions with T cells that express CD40 ligand. This T cell-dependent pathway provides immunological memory but is relatively slow to occur. Thus it must be integrated with a faster, T cell-independent pathway for B cell activation through CD40 ligand-like molecules that are released by innate immune cells in response to microbial products. Here we discuss recent advances in our understanding of the interplay between the innate immune system and B cells, particularly at the mucosal interface. We also review the role of innate signals in the regulation of Ig diversification and production PMID:21419699

Cerutti, Andrea; Puga, Irene; Cols, Montserrat

2011-01-01

186

B cell lymphoma in hiv transgenic mice  

PubMed Central

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

2013-01-01

187

Homeostasis of Peripheral B Cells in the Absence of B Cell Influx from the Bone Marrow  

PubMed Central

To study homeostasis of peripheral B lymphocytes in the absence of B cell influx from the bone marrow, we generated a mouse mutant in which the recombination-activating gene (RAG)-2 can be inducibly deleted. When RAG-2 was deleted at the age of 8–10 wk, splenic naive follicular B cells were gradually lost over a year of observation, with a half-life of ?4.5 mo. By contrast, the pool of marginal zone B cells in the spleen and of B-1 cells in the peritoneal cavity were kept at normal level. In lymph nodes, ?90% of the B cells were lost within 4 mo, and B cell numbers remained constant thereafter. Mice in which RAG-2 was deleted at birth maintained a small population of activated B cells with an increased proportion of marginal zone B cells. Additionally, an increase of the pool of IgM secreting cells and B-1a cells was observed. PMID:11602643

Hao, Zhenyue; Rajewsky, Klaus

2001-01-01

188

B Cells and Humoral Immunity in Atherosclerosis  

PubMed Central

Insights into the important contribution of inflammation and immune functions in the development and progression of atherosclerosis have greatly improved our understanding of this disease. Although the role of T cells has been extensively studied for decades, only recently has the role of B cells gained more attention. Recent studies have identified differential effects of different B-cell subsets and helped to clarify the still poorly understood mechanisms by which these act. B1 cells have been shown to prevent lesion formation, whereas B2 cells have been suggested to promote it. Natural IgM antibodies, mainly derived from B1 cells, have been shown to mediate atheroprotective effects, but the functional role of other immunoglobulin classes, particularly IgG, still remains elusive. In this review, we will focus on recent insights on the role of B cells and various immunoglobulin classes and how these may mediate their effects in atherosclerotic lesion formation. Moreover, we will highlight potential therapeutic approaches focusing on B-cell depletion that could be used to translate experimental evidence to human disease. PMID:24855199

Tsiantoulas, Dimitrios; Diehl, Cody J.; Witztum, Joseph L.; Binder, Christoph J.

2014-01-01

189

Dopamine targets cycling B cells independent of receptors/transporter for oxidative attack: Implications for non-Hodgkin’s lymphoma  

PubMed Central

Human B lymphocytes and derived lines from a spectrum of B cell malignancy were studied for expression of dopaminergic pathway components and for their cytostatic response to the catecholamine and related, potentially therapeutic compounds. Proliferating normal lymphocytes and dividing malignant clones rapidly arrested on exposure to dopamine in the low (?10 ?M) micromolar range. The antiparkinsonian drugs l-DOPA and apomorphine (particularly) were similarly antiproliferative. With the exception of D4, dopamine receptors D1–D5 were variably expressed among normal and neoplastic B cell populations, as was the dopamine transporter. Transcripts for D1 and D2 were frequently found, whereas D3 and D5 revealed restricted expression; dopamine transporter was detected in most cases. Nevertheless, pharmacological analysis disclosed that dopamine targeted cycling B cells independent of these structures. Rather, oxidative stress constituted the primary mechanism: the catecholamine’s actions being mimicked by hydrogen peroxide and reversed by exogenous catalase, and evidence for the intracellular redox protein thioredoxin contributing protection. Among proliferating clones, growth arrest was accompanied by cell death in populations deplete in antiapoptotic Bcl-2: resting lymphocytes escaping low micromolar dopamine toxicity. Dysregulated bcl-2 expression, although preventing oxidative-induced caspase-dependent apoptosis, by itself conferred only minor protection against dopamine cytostasis. The selective impact of dopamine on lymphocytes that are in active cycle indicates an axis for therapeutic intervention not only in B cell neoplasia but also in lymphoproliferative disturbances generally. Rational tailoring of drug delivery systems already in development for Parkinson’s disease could provide ideal vehicles for carrying the oxidative hit directly to the target populations. PMID:16938864

Meredith, Elizabeth J.; Holder, Michelle J.; Rosén, Anders; Lee, Adrian Drake; Dyer, Martin J. S.; Barnes, Nicholas M.; Gordon, John

2006-01-01

190

Germinal center B cells and mixed leukocyte reactions  

SciTech Connect

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

Monfalcone, A.P.; Kosco, M.H.; Szakal, A.K.; Tew, J.G. (Virginia Commonwealth Univ., Richmond (USA))

1989-09-01

191

A role for IRF8 in B cell anergy  

PubMed Central

B cell central tolerance is a process through which self-reactive B cells are removed from the B cell repertoire. Self-reactive B cells are generally removed by receptor editing in the bone marrow and by anergy induction in the periphery. Interferon regulatory factor 8 (IRF8) is a critical transcriptional regulator of immune system development and function. A recent study has shown that marginal zone B cells and B1 B cells population are dramatically increased in the IRF8 deficient mice, indicating that there are B cell developmental defects in the absence of IRF8. Here, we report that mice deficient for IRF8 produced anti-dsDNA antibodies. Using hen egg lysozyme double transgenic model, we further demonstrate that B cell anergy was breached in the IRF8 deficient mice. While anergic B cells in the IRF8 proficient background were blocked at the transitional stage of development, anergic B cells in the IRF8 deficient background were able to further mature which allow them to regain responses to antigen stimulation. Interestingly, our results show that IRF8 deficient B cells were more sensitive to antigen stimulation and were resistant to antigen induced cell death. Moreover, our results show that IRF8 was expressed at a high level in the anergic B cells and elevated level of IRF8 promoted apoptosis in the transitional B cells. Thus, our findings presented here reveal a previously unrecognized function of IRF8 in B cell anergy induction. PMID:24218455

Pathak, Simanta; Ma, Shibin; Shukla, Vipul; Lu, Runqing

2013-01-01

192

B cell repopulation after alemtuzumab induction-transient increase in transitional B cells and long-term dominance of naïve B cells.  

PubMed

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

2012-07-01

193

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

PubMed

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

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

2002-02-01

194

Calcium ultracytochemistry in pancreatic B-cells.  

PubMed

Ultracytochemical studies in B-cells using the pyroantimonate technique in combination with x-ray microanalysis demonstrated calcium deposits in association with structures of functional importance. In a series of experiments precipitate distribution has been shown to depend on the functional state of the B-cell. Increased calcium precipitation during stimulation of insulin secretion occurred at the cell membranes, in the ground plasma and the halos of the secretory granules. If these data bear functional relevance and are not only concomitant effects of the activated secretory apparatus on pyroantimonate precipitation, they may point to a direct involvement of calcium in some early steps of exocytosis and in granule transport mechanisms. PMID:7005053

Klöppel, G; Bommer, G; Lenzen, S

1980-01-01

195

B cells in HIV infection and disease  

PubMed Central

In recent years, intense research efforts have been dedicated to elucidating the pathogenic mechanisms of HIV-associated disease progression. In addition to the progressive depletion and dysfunction of CD4+ T cells, HIV infection also leads to extensive defects in the humoral arm of the immune system. The lack of immune control of the virus in almost all infected individuals is a great impediment to the treatment of HIV-associated disease and to the development of a successful HIV vaccine. This Review focuses on advances in our understanding of the mechanisms of B-cell dysfunction in HIV-associated disease and discusses similarities with other diseases that are associated with B-cell dysfunction. PMID:19319142

Moir, Susan; Fauci, Anthony S.

2009-01-01

196

Primary mediastinal B-cell lymphoma.  

PubMed

Primary mediastinal B-cell lymphoma is a discrete clinicopathologic entity. Molecular analysis reveals it to be distinct from other types of large B-cell lymphoma, and retrospective analysis suggests that it may respond better to multi-agent chemotherapy regimens than to the more commonly used CHOP. The addition of rituximab may mitigate such differences, and may also diminish the role of consolidation radiotherapy, which is often used to treat residual mediastinal masses. For the future the role of FDG-PET scanning requires prospective examination, and it is hoped that this may allow the de-escalation of treatment if it can be shown to yield reliable prognostic information. The relative rarity of this type of lymphoma necessitates international collaboration in clinical trials, with a prospective clinicopathologic study, IELSG 26, already underway. PMID:19074109

Johnson, Peter W M; Davies, Andrew J

2008-01-01

197

B-cell deficiency and severe autoimmunity caused by deficiency of protein kinase C ?.  

PubMed

Primary B-cell disorders comprise a heterogeneous group of inherited immunodeficiencies, often associated with autoimmunity causing significant morbidity. The underlying genetic etiology remains elusive in the majority of patients. In this study, we investigated a patient from a consanguineous family suffering from recurrent infections and severe lupuslike autoimmunity. Immunophenotyping revealed progressive decrease of CD19(+) B cells, a defective class switch indicated by low numbers of IgM- and IgG-memory B cells, as well as increased numbers of CD21(low) B cells. Combined homozygosity mapping and exome sequencing identified a biallelic splice-site mutation in protein C kinase ? (PRKCD), causing the absence of the corresponding protein product. Consequently, phosphorylation of myristoylated alanine-rich C kinase substrate was decreased, and mRNA levels of nuclear factor interleukin (IL)-6 and IL-6 were increased. Our study uncovers human PRKCD deficiency as a novel cause of common variable immunodeficiency-like B-cell deficiency with severe autoimmunity. PMID:23319571

Salzer, Elisabeth; Santos-Valente, Elisangela; Klaver, Stefanie; Ban, Sol A; Emminger, Wolfgang; Prengemann, Nina Kathrin; Garncarz, Wojciech; Müllauer, Leonhard; Kain, Renate; Boztug, Heidrun; Heitger, Andreas; Arbeiter, Klaus; Eitelberger, Franz; Seidel, Markus G; Holter, Wolfgang; Pollak, Arnold; Pickl, Winfried F; Förster-Waldl, Elisabeth; Boztug, Kaan

2013-04-18

198

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

199

B-cell deficiency and severe autoimmunity caused by deficiency of protein kinase C ?  

PubMed Central

Primary B-cell disorders comprise a heterogeneous group of inherited immunodeficiencies, often associated with autoimmunity causing significant morbidity. The underlying genetic etiology remains elusive in the majority of patients. In this study, we investigated a patient from a consanguineous family suffering from recurrent infections and severe lupuslike autoimmunity. Immunophenotyping revealed progressive decrease of CD19+ B cells, a defective class switch indicated by low numbers of IgM- and IgG-memory B cells, as well as increased numbers of CD21low B cells. Combined homozygosity mapping and exome sequencing identified a biallelic splice-site mutation in protein C kinase ? (PRKCD), causing the absence of the corresponding protein product. Consequently, phosphorylation of myristoylated alanine-rich C kinase substrate was decreased, and mRNA levels of nuclear factor interleukin (IL)-6 and IL-6 were increased. Our study uncovers human PRKCD deficiency as a novel cause of common variable immunodeficiency-like B-cell deficiency with severe autoimmunity. PMID:23319571

Salzer, Elisabeth; Santos-Valente, Elisangela; Klaver, Stefanie; Ban, Sol A.; Emminger, Wolfgang; Prengemann, Nina Kathrin; Garncarz, Wojciech; Müllauer, Leonhard; Kain, Renate; Heitger, Andreas; Arbeiter, Klaus; Eitelberger, Franz; Seidel, Markus G.; Holter, Wolfgang; Pollak, Arnold; Pickl, Winfried F.

2013-01-01

200

Hepatitis C and B-cell lymphoma  

Microsoft Academic Search

The association between the hepatitis C virus and B-cell non-Hodgkin's lymphomas is controversial. We review the epidemiological evidence behind the association, and look at the reasons behind the variation in study findings. There is increasing evidence of the pathogenesis of hepatitis C-associated lymphoma. Treatment of the hepatitis C virus with antiviral therapy may lead to the regression of some low-grade

N. C. Turner; G. Dusheiko; A. Jones

2003-01-01

201

Human B cell defects in perspective  

PubMed Central

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

2012-01-01

202

NKT Cell Responses to B Cell Lymphoma  

PubMed Central

Natural killer T (NKT) cells are a unique subset of CD1d-restricted T lymphocytes that express characteristics of both T cells and natural killer cells. NKT cells mediate tumor immune-surveillance; however, NKT cells are numerically reduced and functionally impaired in lymphoma patients. Many hematologic malignancies express CD1d molecules and co-stimulatory proteins needed to induce anti-tumor immunity by NKT cells, yet most tumors are poorly immunogenic. In this study, we sought to investigate NKT cell responses to B cell lymphoma. In the presence of exogenous antigen, both mouse and human NKT cell lines produce cytokines following stimulation by B cell lymphoma lines. NKT cell populations were examined ex vivo in mouse models of spontaneous B cell lymphoma, and it was found that during early stages, NKT cell responses were enhanced in lymphoma-bearing animals compared to disease-free animals. In contrast, in lymphoma-bearing animals with splenomegaly and lymphadenopathy, NKT cells were functionally impaired. In a mouse model of blastoid variant mantle cell lymphoma, treatment of tumor-bearing mice with a potent NKT cell agonist, ?-galactosylceramide (?-GalCer), resulted in a significant decrease in disease pathology. Ex vivo studies demonstrated that NKT cells from ?-GalCer treated mice produced IFN-? following ?-GalCer restimulation, unlike NKT cells from vehicle-control treated mice. These data demonstrate an important role for NKT cells in the immune response to an aggressive hematologic malignancy like mantle cell lymphoma. PMID:24955247

Li, Junxin; Sun, Wenji; Subrahmanyam, Priyanka B.; Page, Carly; Younger, Kenisha M.; Tiper, Irina V.; Frieman, Matthew; Kimball, Amy S.; Webb, Tonya J.

2014-01-01

203

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

204

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

Technology Transfer Automated Retrieval System (TEKTRAN)

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

205

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

206

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

PubMed Central

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

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

2014-01-01

207

Characterization of Epstein-Barr virus (EBV)-infected cells in EBV-associated hemophagocytic lymphohistiocytosis in two patients with X-linked lymphoproliferative syndrome type 1 and type 2  

PubMed Central

Background X-linked lymphoproliferative syndrome (XLP) is a rare inherited immunodeficiency by an extreme vulnerability to Epstein-Barr virus (EBV) infection, frequently resulting in hemophagocytic lymphohistiocytosis (HLH). XLP are now divided into type 1 (XLP-1) and type 2 (XLP-2), which are caused by mutations of SH2D1A/SLAM-associated protein (SAP) and X-linked inhibitor of apoptosis protein (XIAP) genes, respectively. The diagnosis of XLP in individuals with EBV-associated HLH (EBV-HLH) is generally difficult because they show basically similar symptoms to sporadic EBV-HLH. Although EBV-infected cells in sporadic EBV-HLH are known to be mainly in CD8+ T cells, the cell-type of EBV-infected cells in EBV-HLH seen in XLP patients remains undetermined. Methods EBV-infected cells in two patients (XLP-1 and XLP-2) presenting EBV-HLH were evaluated by in EBER-1 in situ hybridization or quantitative PCR methods. Results Both XLP patients showed that the dominant population of EBV-infected cells was CD19+ B cells, whereas EBV-infected CD8+ T cells were very few. Conclusions In XLP-related EBV-HLH, EBV-infected cells appear to be predominantly B cells. B cell directed therapy such as rituximab may be a valuable option in the treatment of EBV-HLH in XLP patients. PMID:22325832

2012-01-01

208

Transfer of Small Resting B Cells into Immunodeficient Hosts Results in the Selection of a Self-renewing Activated B Cell Population  

Microsoft Academic Search

Summary We studied the role of bone marrow B cell production in the renewal of peripheral B cells and the feedback mechanisms that control the entry of newly formed B cells into the peripheral B cell pools. When resting lymph node B cells are injected into B cell-deficient hosts, a fraction of the transferred cells expands and constitutes a highly

Fabien Agenès; António A. Freitas

209

B-cell development: one problem, multiple solutions  

Microsoft Academic Search

Interspecies variations in the processes of B-cell development and repertoire generation contrast with the greater consistency of T-cell development. B-cell development in mice and humans, with postnatal B-cell generation of new repertoire in the bone marrow throughout life, is regarded as the ‘standard’ pattern. In contrast, accounts of B cells in birds, sheep, cattle, rabbits and pigs (the ‘other’ species)

Noorjahan Banu Alitheen; Susan McClure; Peter McCullagh

2010-01-01

210

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

211

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

PubMed Central

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

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

2012-01-01

212

Gastrointestinal B-cell lymphomas: From understanding B-cell physiology to classification and molecular pathology  

PubMed Central

The gut is the most common extranodal site where lymphomas arise. Although all histological lymphoma types may develop in the gut, small and large B-cell lymphomas predominate. The sometimes unexpected finding of a lymphoid lesion in an endoscopic biopsy of the gut may challenge both the clinician (who is not always familiar with lymphoma pathogenesis) and the pathologist (who will often be hampered in his/her diagnostic skill by the limited amount of available tissue). Moreover, the past 2 decades have spawned an avalanche of new data that encompasses both the function of the reactive B-cell as well as the pathogenic pathways that lead to its neoplastic counterpart, the B-cell lymphoma. Therefore, this review aims to offer clinicians an overview of B-cell lymphomas in the gut, and their pertinent molecular features that have led to new insights regarding lymphomagenesis. It addresses the question as how to incorporate all presently available information on normal and neoplastic B-cell differentiation, and how this knowledge can be applied in daily clinical practice (e.g., diagnostic tools, prognostic biomarkers or therapeutic targets) to optimalise the managment of this heterogeneous group of neoplasms. PMID:23443141

Sagaert, Xavier; Tousseyn, Thomas; Yantiss, Rhonda K

2012-01-01

213

Successful treatment with recombinant thrombomodulin for B-cell lymphoma-associated hemophagocytic syndrome complicated by disseminated intravascular coagulation  

PubMed Central

We report here a 47-year-old male with the diagnosis of high-grade B-cell lymphoma and hemophagocytosis accompanying disseminated intravascular coagulation (DIC). Lymphoma-associated hemophagocytic syndrome (LAHS) is a life-threatening disorder, and LAHS secondary to B-cell lymphoma is relatively rare compared to that secondary to T- or NK/T-cell lymphoma in Western countries. T- or NK/T-cell LAHS is sometimes combined with DIC, which makes patients’ outcomes even worse, but few reports of B-cell LAHS accompanying DIC has been published so far. We successfully treated a patient with this condition with recombinant thrombomodulin (rTM), a novel agent for DIC. We believe that rTM is a therapeutic option in cases with B-cell LAHS accompanying DIC. PMID:23696942

Uni, Masahiro; Yoshimi, Akihide; Maki, Hiroaki; Maeda, Daichi; Nakazaki, Kumi; Nakamura, Fumihiko; Fukayama, Masashi; Kurokawa, Mineo

2013-01-01

214

Successful treatment with recombinant thrombomodulin for B-cell lymphoma-associated hemophagocytic syndrome complicated by disseminated intravascular coagulation.  

PubMed

We report here a 47-year-old male with the diagnosis of high-grade B-cell lymphoma and hemophagocytosis accompanying disseminated intravascular coagulation (DIC). Lymphoma-associated hemophagocytic syndrome (LAHS) is a life-threatening disorder, and LAHS secondary to B-cell lymphoma is relatively rare compared to that secondary to T- or NK/T-cell lymphoma in Western countries. T- or NK/T-cell LAHS is sometimes combined with DIC, which makes patients' outcomes even worse, but few reports of B-cell LAHS accompanying DIC has been published so far. We successfully treated a patient with this condition with recombinant thrombomodulin (rTM), a novel agent for DIC. We believe that rTM is a therapeutic option in cases with B-cell LAHS accompanying DIC. PMID:23696942

Uni, Masahiro; Yoshimi, Akihide; Maki, Hiroaki; Maeda, Daichi; Nakazaki, Kumi; Nakamura, Fumihiko; Fukayama, Masashi; Kurokawa, Mineo

2013-01-01

215

disorder disorder Co disorder  

E-print Network

disorder disorder RKKY Co 10 Co disorder disorder disorder Kondo-like Co 3 BiSb BiSb 4 BiSb Bi(001) Bi(001) Bi(001) 1 m 1, 000 % Bi 10 % Bi/Ag(111) Rashba #12;2 Ag(111) Bi 1/3 Ag(111) 3 Ã? 3-Bi 1 ps Rashba ( ) [1] K. He, T. Hirahara, T. Okuda, S. Hasegawa, A. Kakizaki, and I. Matsuda: Spin-polarization

Hasegawa, Shuji

216

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

E-print Network

Human blood IgM "memory" B cells are circulating splenic marginal zone B cells harboring cell subsets, that blood IgM IgD CD27 cells correspond to circulating splenic marginal zone B cells and Cell Biology10 University of Marburg, DE G n tique Humaine des Maladies Infectieuses11 é é INSERM : U

Boyer, Edmond

217

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

E-print Network

1 Immunobiology Human blood IgM "memory" B cells are circulating splenic marginal zone B cells expression profiling of the different blood and splenic B cell subsets, that blood IgM+ IgD+ CD27+ cells cells in human Sandra Weller1 , Moritz C. Braun1 , Bruce K. Tan2 , Andreas Rosenwald2 , Corinne Cordier3

Paris-Sud XI, Université de

218

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

PubMed

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

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

2014-06-01

219

B cell receptor-induced apoptosis in primary transitional murine B cells: signaling requirements and modulation by T cell help  

Microsoft Academic Search

Self-reactive immature B cells may be eliminated in the bone marrow (BM) after B cell receptor (BCR) engagement in a process known as negative selection. Immature B cells emigrating from the BM, the so-called transitional cells, remain sensitive to negative selection and are likely to be important targets of tolerance towards peripheral antigens. Transitional cells are deleted through apoptosis after

Richard A. Sater; Peter C. Sandel; John G. Monroe

1998-01-01

220

Increases in circulating and lymphoid tissue interleukin-10 in autoimmune lymphoproliferative syndrome are associated with disease expression.  

PubMed

Autoimmune lymphoproliferative syndrome (ALPS) is an inherited disorder in which genetic defects in proteins that mediate lymphocyte apoptosis, most often Fas, are associated with enlargement of lymph nodes and the spleen and a variety of autoimmune manifestations. Some patients with ALPS have relatives with these same apoptotic defects, however, who are clinically well. This study showed that the circulating levels of interleukin 10 (IL-10) were significantly higher (P <.001) in 21 patients with ALPS than in healthy controls. Moreover, the peripheral blood mononuclear cells (PBMCs) and lymphoid tissues of these patients with ALPS contained significantly higher levels of IL-10 messenger RNA (mRNA; P <.001 and P <.01, respectively). By fractionating PBMC populations, disproportionately high concentrations of IL-10 mRNA were found in the CD4(-)CD8(-) T-cell population, expansion of which is virtually pathognomonic for ALPS. Immunohistochemical staining showed intense IL-10 protein signals in lymph node regions known to contain CD4(-)CD8(-) T cells. Nonetheless, in vitro studies showed no influence of IL-10 on the survival of CD4(-)CD8(-) T cells. Overexpression of IL-10 in patients with inherited apoptotic defects is strongly associated with the overt manifestations of ALPS. PMID:11342444

Lopatin, U; Yao, X; Williams, R K; Bleesing, J J; Dale, J K; Wong, D; Teruya-Feldstein, J; Fritz, S; Morrow, M R; Fuss, I; Sneller, M C; Raffeld, M; Fleisher, T A; Puck, J M; Strober, W; Jaffe, E S; Straus, S E

2001-05-15

221

A Novel Molecular Complex Expressed on Immature B Cells: A Possible Role in T Cell-Independent B Cell Development  

PubMed Central

To identify surface molecules that may play a role in regulating ileal Peyer's patch (PP) B cell growth, we generated monoclonal antibodies (mAbs) and then selected them for a unique reactivity with ileal PP B cells. Flow cytometric analysis identified a mAb (SIC4.8R) that labeled 97% of ileal and 50–60% of jejunal PP sIgM+B cells. SIC4.8R also labeled a subpopulation of cortical thymocytes but few B or T cells in other lymphoid tissues, including bone marrow. Immunohistochemistry revealed intense SIC4.8R staining of B cells in the cortex of ileal PP follicles. SIC4.8R also labeled bovine PP B cells, a murine pro-B cell line, and pre-B cells in human bone marrow. Protein chemistry revealed that a structurally similar molecular complex was expressed on sheep ileal PP B cells and thymocytes and murine pro-B cells. Addition of soluble SIC4.8R to cultured ileal PP B cells reduced apoptotic cell death, elevated proliferative responses, partially inhibited anti-Ig-induced cell death, and induced IL-4 responsiveness. In contrast, soluble SIC4.8R had an antiproliferative effect on a mouse pro-B cell line. Finally, SIC4.8R labeling declined following the stimulation of ileal PP B cells with CD40 ligand. In conclusion, the present investigation determined that SIC4.8R identified a novel molecular complex that is expressed at several stages of T cell-independent B cell development in a variety of mammalian species. This observation confirmed that PP B cells are developmentally distinct from other B cell populations in sheep and suggested that the bone marrow may not be a site of B lymphopoiesis in young lambs. PMID:8828012

Ghia, Paolo; Grawunder, Ulf; Ferrari, Giorgio

1996-01-01

222

Bone biopsy in haematological disorders.  

PubMed Central

Bone marrow biopsies are now widely used in the investigation and follow-up of many diseases. Semi-thin sections of 8216 undecalcified biopsies of patients with haematological disorders were studied. Observations were made on the cytopenias and the myelodysplastic syndromes, the acute leukaemias the myeloproliferative disorders, Hodgkin's disease and the malignant lymphomas including multiple myeloma, hairy cell leukaemia and angioimmunoblastic lymphadenopathy. Bone marrow biopsies are essential for the differential diagnosis of most cytopenias and for the early recognition of fibrosis which most frequently occurred as a consequence of megakaryocytic proliferation in the myeloproliferative disorders. Different patterns of bone marrow involvement were found in the lymphoproliferative disorders and both their type and extent constituted factors of prognostic significance. A survey of the literature is given and the conclusion is drawn that bone marrow biopsies provide indispensible information for the diagnostic evaluation and the follow-up of patients with haematological disorders. Images PMID:7040489

Burkhardt, R; Frisch, B; Bartl, R

1982-01-01

223

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

224

Alemtuzumab in chronic lymphocytic leukaemia, other lymphoproliferative disease and autoimmune disorders  

Microsoft Academic Search

Summary  Alemtuzumab is a humanized IgG1 antibody targetting the CD52 antigen which is primarily present on normal and neoplastic lymphoid\\u000a cells. In a number of studies, its therapeutic efficacy was shown in the treatment of certain lymphomas including chronic\\u000a lymphocytic leukaemia (B-CLL). In this indication, it was registered in 2001 with patients refractory towards fludarabine.\\u000a In 2007, it was also registered

M. Fiegl; G. Gastl; G. Hopfinger; K. Eigenberger; A. Zabernigg; T. Schenk; F. Falkner; A. Falkner; S. Sodia; M. Doubek; Y. Brychtova; A. Panovska; R. Greil; J. Mayer

2008-01-01

225

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

Microsoft Academic Search

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

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

1995-01-01

226

The Roles of B Cells and Their Interactions with Fibroblast-Like Synoviocytes in the Pathogenesis of Rheumatoid Arthritis  

Microsoft Academic Search

Rheumatoid arthritis (RA) is a chronic, systemic inflammatory disorder that may affect many tissues and organs but principally attacks synovial joints. The pathogenesis of RA is complex and encompasses many cell types, including T cells, B cells and fibroblast-like synoviocytes (FLSs); each is believed to play a significant role in the process of RA. Interactions between T cells and B

Qingtong Wang; Yukun Ma; Dandan Liu; Lingling Zhang; Wei Wei

2011-01-01

227

Spontaneous B cell hyperactivity in autoimmune-prone MRL mice.  

PubMed

The MRL-lpr/lpr mouse strain is a commonly used model of the human autoimmune disease systemic lupus erythematosus (SLE). Although much is known about the contribution of the lpr Fas mutation to B cell tolerance breakdown, the role of the genetic background of the MRL strain itself is less well explored. In this study, we use the MD4 anti-hen egg lysozyme Ig (IgHEL) transgenic system to explore B cell function in MRL+/+ and non-autoimmune mice. We demonstrate that MRL IgHEL B cells show spontaneous hyperactivity in the absence of self-antigen, which is associated with low total B cell numbers but an expansion of the marginal zone B cell population. However, B cell anergy is normal in the presence of soluble lysozyme [soluble hen egg lysozyme (sHEL)], and MRL IgHEL B cells undergo normal elimination in the presence of sHEL when competing with a polyclonal C57BL/6 B cell repertoire. We conclude that B cell hyperactivity may contribute to the autoimmune phenotype of MRL+/+ and MRL-lpr/lpr strains when it initiates antibody responses to rare or sequestered antigens that are below the threshold for tolerance induction, but that there is no B cell intrinsic defect in anergy in MRL mice. PMID:16735376

Nijnik, Anastasia; Ferry, Helen; Lewis, Graham; Rapsomaniki, Eleni; Leung, Janson C H; Daser, Angelika; Lambe, Teresa; Goodnow, Christopher C; Cornall, Richard J

2006-07-01

228

Childhood sarcoidosis: A rare but fascinating disorder  

PubMed Central

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

229

CD19 Expression in B Cells Regulates Atopic Dermatitis in a Mouse Model  

PubMed Central

Atopic dermatitis is an inflammatory cutaneous disorder characterized by dry skin and relapsing eczematous skin lesions. Besides antibody production, the contribution of B cells to the pathogenesis of atopic dermatitis is unclear. In mice, repeated epicutaneous sensitization with ovalbumin induces inflamed skin lesions resembling human atopic dermatitis and therefore serves as an experimental model for this condition. To investigate the role of B cells in a murine model of atopic dermatitis, ovalbumin-sensitized allergic skin inflammation was assessed in mice lacking CD19. In ovalbumin-sensitized skin from CD19-deficient mice, the number of eosinophils and CD4+ T cells was reduced, and both epidermal and dermal thickening were decreased. Following in vitro stimulation with ovalbumin, CD19 deficiency significantly reduced the proliferation of CD4+, but not CD8+, T cells from spleen and draining lymph nodes. Furthermore, splenocytes and draining lymph node cells from ovalbumin-sensitized CD19-deficient mice secreted significantly less IL-4, IL-13, and IL-17 than ovalbumin-sensitized wild-type mice. These results suggest that CD19 expression in B cells plays a critical role in antigen-specific CD4+ T-cell proliferation and T helper 2 and 17 responses in a murine model of atopic dermatitis. Furthermore, the present findings may have implications for B-cell–targeted therapies for the treatment of atopic dermatitis. PMID:23583649

Yanaba, Koichi; Kamata, Masahiro; Asano, Yoshihide; Tada, Yayoi; Sugaya, Makoto; Kadono, Takafumi; Tedder, Thomas F.; Sato, Shinichi

2014-01-01

230

Transcriptional analysis of the B cell germinal center reaction  

PubMed Central

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

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

2003-01-01

231

AID expression during B-cell development: searching for answers  

Microsoft Academic Search

Expression of activation-induced cytidine deaminase (AID) by germinal center (GC) B cells drives the processes of immunoglobulin\\u000a (Ig) somatic hypermutation (SHM) and class switch recombination (CSR) necessary for the generation of high affinity IgG serum\\u000a antibody and the memory B-cell compartment. Increasing evidence indicates that AID is also expressed at low levels in developing\\u000a B cells but to date, this

Masayuki Kuraoka; Laurie McWilliams; Garnett Kelsoe

2011-01-01

232

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

233

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

234

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

235

Tolerant Anti-insulin B Cells are Effective APCs1  

PubMed Central

Autoreactive B lymphocytes that are not culled by central tolerance in the bone marrow frequently enter the peripheral repertoire in a state of functional impairment, termed anergy. These cells are recognized as a liability for autoimmunity, but their contribution to disease is not well-understood. Insulin-specific 125Tg B cells support T cell-mediated Type 1 diabetes (T1D) in nonobese diabetic (NOD) mice, despite being anergic to B cell mitogens and T cell dependent immunization. Using this model, the potential of anergic, autoreactive B cells to present antigen and activate T cells was investigated. The data show that: a) insulin is captured and rapidly internalized by 125Tg BCRs, b) these antigen-exposed B cells are competent to activate both experienced and naïve CD4+ T cells, c) anergic 125Tg B cells are more efficient than naïve B cells at activating T cells when antigen is limiting, and d) 125Tg B cells are competent to generate low-affinity insulin B chain epitopes necessary for activation of diabetogenic anti-insulin BDC12-4.1 T cells, indicating the pathological relevance of anergic B cells in T1D. Thus, phenotypically tolerant B cells that are retained in the repertoire may promote autoimmunity by driving activation and expansion of autoaggressive T cells via antigen-presentation. PMID:23396943

Kendall, Peggy L.; Case, James B.; Sullivan, Allison M.; Holderness, Jeff S.; Wells, K. Sam; Liu, Edwin; Thomas, James W.

2013-01-01

236

Expression of T cell receptor genes in human B cells  

PubMed Central

We analyzed the transcription and rearrangement of the T cell antigen receptor (Ti) genes Ti alpha and Ti beta in human B cell, T cell, and myeloid cell lines, as well as in purified tonsillar B and T cells. All four B cell lines examined, as well as one of two myeloid cell lines, expressed low levels of truncated Ti beta transcripts, as did freshly purified tonsillar B cells. Two of the B cell lines and one of the myeloid lines also expressed truncated Ti alpha transcripts, while tonsillar B cells did not. Sequence analysis of cDNA clones from a B cell line demonstrated that these truncated Ti alpha and Ti beta transcripts were composed of unrearranged J and C gene segments. Comparison of cDNA clones from T and B cells suggests that D alpha genes or N regions contribute to the formation of Ti alpha transcripts in T cells but not in B cells. None of the B cell or myeloid cell lines in this study showed evidence of Ti beta gene rearrangements by Southern blotting. Our data, and other studies of gene rearrangements in human tumors, demonstrate that the level of Ti beta transcriptional activity and the frequency of Ti beta gene rearrangements are correlated in all cell types examined. Thus, our data support the accessibility model of antigen receptor gene rearrangement, whereby the susceptibility of gene segments to recombination enzymes is correlated with their transcriptional activity. PMID:2431093

1986-01-01

237

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

PubMed Central

The human peripheral B cell compartment displays a large population of IgM+IgD+CD27+ “memory” B cell carrying a mutated Ig receptor. We show here, by phenotypic analysis, CDR3 spectratyping during a T-independent response and gene expression profiling of the different blood and splenic B cell subsets, that blood IgM+IgD+CD27+ cells correspond to circulating splenic marginal zone B cells. Furthermore, analysis of this peripheral subset in normal children below 2 years shows that these B cells develop and mutate their Ig receptor during ontogeny, prior to their differentiation into T-independent antigen-responsive cells. It is therefore proposed that these IgM+IgD+CD27+ B cells provide the splenic marginal zone with a diversified and protective pre-immune repertoire in charge of the responses against encapsulated bacteria. PMID:15191950

Weller, Sandra; Braun, Moritz C.; Tan, Bruce K.; Rosenwald, Andreas; Cordier, Corinne; Conley, Mary Ellen; Plebani, Alessandro; Kumararatne, Dinakhanta S.; Bonnet, Damien; Tournilhac, Olivier; Tchernia, Gil; Steiniger, Birte; Staudt, Louis M.; Casanova, Jean-Laurent; Reynaud, Claude-Agnès; Weill, Jean-Claude

2004-01-01

238

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

PubMed Central

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

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

2014-01-01

239

B-Cell Maturation Protein, Which Binds the Tumor Necrosis Factor Family Members BAFF and APRIL, Is Dispensable for Humoral Immune Responses  

Microsoft Academic Search

B-cell maturation protein (BCMA) is a member of the tumor necrosis factor (TNF) receptor family and is expressed in B lymphocytes. BCMA binds two TNF family members, BAFF and APRIL, that stimulate cellular proliferation. BAFF in particular has been shown to influence B-cell survival and activation, and transgenic mice overexpressing BAFF have a lupus-like autoimmune disorder. We have inactivated BCMA

SHENGLI XU; KONG-PENG LAM

2001-01-01

240

Establishment and Characterization of Human B-Cell Lymphoma Cell Lines Using B-Cell Growth Factor  

Microsoft Academic Search

B-cell non-Hodgkin's lymphomas (NHL-B) have been diffi- cult to establish in long-term cell culture using standard techniques. We report the establishment of five represen- tative cell lines from high grade NHL-B using B-cell growth factor (BCGF). The five NHL-B cell lines display the morpho- logic, immunophenotypic, genotypic, and biologic character- istics of the lymphoma cells present in the original diagnos-

Richard J. Ford; Angela Goodacre; Irma Ramirez; Shashikant R. Mehta; Fernando Cabanillas

1990-01-01

241

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

242

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

PubMed Central

Background Primary HIV-infected patients display severe and irreversible damage to different blood B-cell subsets which is not restored by highly efficient anti-retroviral therapy (HAART). Because longitudinal investigations of primary HIV-infection is limited by the availability of lymphoid organs, we studied the tissue-specific B-cell dysfunctions in acutely simian immunodeficiency virus (SIV) mac251-infected Cynomolgus macaques. Methods and Findings Experiments were performed on three groups of macaques infected for 14, 21 or 28 days and on three groups of animals treated with HAART for two-weeks either initiated at 4 h, 7 or 14 days post-infection (p.i.). We have simultaneously compared changes in B-cell phenotypes and functions and tissue organization of B-cell areas in various lymphoid organs. We showed that SIV induced a steady decline in SIgG-expressing memory (SIgD?CD27+) B-cells in spleen and lymph nodes during the first 4 weeks of infection, concomitant to selective homing/sequestration of B-cells to the small intestine and spleen. SIV non-specific Ig production was transiently increased before D14p.i., whereas SIV-specific Ig production was only detectable after D14p.i., coinciding with the presence of CD8+ T-cells and IgG-expressing plasma cells within germinal centres. Transient B-cell apoptosis on D14p.i. and commitment to terminal differentiation contributed to memory B-cell loss. HAART abrogated B-cell apoptosis, homing to the small intestine and SIV-specific Ig production but had minimal effect on early Ig production, increased B-cell proportions in spleen and loss of memory B-cells. Therefore, virus–B-cell interactions and SIV-induced inflammatory cytokines may differently contribute to early B-cell dysfunction and impaired SIV/HIV-specific antibody response. Conclusions These data establish tissue-specific impairments in B-cell trafficking and functions and a generalized and steady memory B-cell loss in secondary lymphoid organs. Characterization of underlying mechanisms would be helpful in designing new therapeutic strategies to dampen B-cell activation and increases HIV/SIV specific antibody response. PMID:19543531

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

2009-01-01

243

Interleukin-10+ Regulatory B Cells Arise Within Antigen-Experienced CD40+ B Cells to Maintain Tolerance to Islet Autoantigens.  

PubMed

Impaired regulatory B cell (Breg) responses are associated with several autoimmune diseases in humans; however, the role of Bregs in type 1 diabetes (T1D) remains unclear. We hypothesized that naturally occurring, interleukin-10 (IL-10)-producing Bregs maintain tolerance to islet autoantigens, and that hyperglycemic nonobese diabetic (NOD) mice and T1D patients lack these potent negative regulators. IgVH transcriptome analysis revealed that islet-infiltrating B cells in long-term normoglycemic (Lnglc) NOD, which are naturally protected from diabetes, are more antigen-experienced and possess more diverse B-cell receptor repertoires compared to those of hyperglycemic (Hglc) mice. Importantly, increased levels of Breg-promoting CD40(+) B cells and IL-10-producing B cells were found within islets of Lnglc compared to Hglc NOD. Likewise, healthy individuals showed increased frequencies of both CD40(+) and IL-10(+) B cells compared to T1D patients. Rituximab-mediated B-cell depletion followed by adoptive transfer of B cells from Hglc mice induced hyperglycemia in Lnglc human CD20 transgenic NOD mouse models. Importantly, both murine and human IL-10(+) B cells significantly abrogated T-cell-mediated responses to self- or islet-specific peptides ex vivo. Together, our data suggest that antigen-matured Bregs may maintain tolerance to islet autoantigens by selectively suppressing autoreactive T-cell responses, and that Hglc mice and individuals with T1D lack this population of Bregs. PMID:25187361

Kleffel, Sonja; Vergani, Andrea; Tezza, Sara; Ben Nasr, Moufida; Niewczas, Monika A; Wong, Susan; Bassi, Roberto; D'Addio, Francesca; Schatton, Tobias; Abdi, Reza; Atkinson, Mark; Sayegh, Mohamed H; Wen, Li; Wasserfall, Clive H; O'Connor, Kevin C; Fiorina, Paolo

2015-01-01

244

ABSENCE OF SCLEROSTIN ADVERSELY AFFECTS B CELL SURVIVAL  

PubMed Central

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

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

2012-01-01

245

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

246

Relevant B Cell Epitopes in Allergic Disease  

PubMed Central

The 3-dimensional structure of an allergen defines the accessible parts on the surface of the molecule or epitopes that interact with antibodies. Mapping the antigenic determinants for IgE antibody binding has been pursued through strategies based on the use of overlapping synthetic peptides, recombinant allergenic fragments or unfolded allergens. These approaches led to the identification of mostly linear epitopes and are useful for food allergens that undergo digestion or food processing. For inhaled allergens, conformational epitopes appear to be the primary targets of IgE responses. Knowledge of the molecular structure of allergens alone and in complex with antibodies that interfere with IgE antibody binding is important to understand the immune recognition of B cell-antigenic determinants on allergens and the design of recombinant allergens for immunotherapy. Starting with the molecular cloning and expression of allergens, and with the advent of X-ray crystallography and nuclear magnetic resonance techniques, we have been able to visualize conformational epitopes on allergens. PMID:19940500

Pomés, Anna

2010-01-01

247

Generation of Functional Human Pancreatic b Cells In Vitro  

E-print Network

and quality of donor islets (Bellin et al., 2012). The generation of an unlimited supply of human b cells fromResource Generation of Functional Human Pancreatic b Cells In Vitro Felicia W. Pagliuca,1,3 Jeffrey in diabetes. However, insu- lin-producing cells previously generated from human pluripotent stem cells (h

Blackwell, Keith

248

Original Research B-cell Ligand Processing Pathways Detected  

E-print Network

) in elucidating biochemical pathways involved in complex signaling events in cells. Keywords: Ligand recognition and bacteria to the recognition of cancerous cells. B-cells act as the body's most effective line of defenseOriginal Research B-cell Ligand Processing Pathways Detected by Large-scale Comparative Analysis

Honavar, Vasant

249

Uptake and Presentation of Antigen by B Cells   

E-print Network

B cells internalize antigen in a specific manner through the B cell receptor (BCR). The antigen is processed into peptides that are loaded on to MHC class II molecules and presented to CD4+ T cells. I have investigated factors that affect how...

Brooks, Katharine E

250

B Cells: The Old New Players in Reproductive Immunology  

PubMed Central

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

251

Interleukin-10-producing B cells and the regulation of immunity.  

PubMed

B cells are usually considered primarily for their unique capacity to produce antibodies after differentiation into plasma cells. In addition to their roles as antibody-producing cells, it has become apparent during the last 10 years that B cells also perform important functions in immunity through the production of cytokines. In particular, it was shown that B cells could negatively regulate immunity through provision of interleukin (IL)-10 during autoimmune and infectious diseases in mice. Here, we review data on the suppressive functions of B cells in mice with particular emphasis on the signals controlling the acquisition of such suppressive functions by B cells, the phenotype of the B cells involved in the negative regulation of immunity, and the processes targeted by this inhibitory circuit. Finally, we discuss the possibility that human B cells might also perform similar inhibitory functions through the provision of IL-10, and review data suggesting that such B cell-mediated regulatory activities might be impaired in patients with autoimmune diseases. PMID:25004814

Hilgenberg, Ellen; Shen, Ping; Dang, Van Duc; Ries, Stefanie; Sakwa, Imme; Fillatreau, Simon

2014-01-01

252

Involvement of I-A-restricted B-B cell interaction in the polyclonal B cell differentiation induced by lipopolysaccharide  

SciTech Connect

The present study has examined a functional role of Ia molecules expressed on murine B cells in polyclonal B cell differentiation induced by lipopolysaccharide (LPS). Reverse, IgM PFC responses of unprimed B cells induced by LPS in the apparent absence of T cells and adherent accessory cells were markedly inhibited in a haplotype-specific manner by Fab monomer fragment of anti-class II (Ia) but not anti-class I MHC monoclonal antibody (mAb). However, the degree of inhibition of LPS responses of H-2-heterozygous F1 B cells expressing both parental I-A products by either one of anti-I-A mAb was at best half that of the parental B cells. Interestingly, when (B10 x B10.-BR)F1 (H-2b/k) B cells were fractionated into adherent and nonadherent populations by their ability to bind to parental B10 B cell monolayers, LPS responses of F1 B cells adherent to and nonadherent to the B10 B cell monolayers were selectively inhibited by anti-I-Ab and anti-I-Ak mAb, respectively. These results suggest that LPS-responsive F1 B cells comprise at least two separate populations with restriction specificity for only one of the parental I-A products expressed on B cells. In addition, it was demonstrated that the I-A-restriction specificity of LPS-responsive B cells is plastic and determined by H-2-genotype of bone marrow cells present during B cell ontogeny but not by that of radiation-resistant host elements. Namely, the LPS responses of B10-derived B cells from (B10 + B10.BR) (H-2b x H - 2k)F1 radiation bone marrow chimeras but not from B10 (H-2b x H-2k)F1 chimeras became sensitive to the inhibition of anti-I-Ak mAb in the presence of mitomycin C-treated I-Ak-positive B cells, supporting a notion of receptor-Ia molecules interactions rather than like-like interactions.

Takahama, Y.; Ono, S.; Ishihara, K.; Muramatsu, M.; Hamaoka, T. (Osaka Univ. Medical School (Japan))

1990-01-01

253

Memory B cells: effectors of long-lived immune responses.  

PubMed

Immunological memory is the phenomenon whereby B and T cells have the unique ability to respond with heightened kinetics and efficacy to subsequent encounter with Ag relative to the initial exposure. In this review, we examine recent developments in the phenotypic characterisation of memory B cells, with an emphasis on the definition and functional properties of memory B-cell subsets in humans. Gene expression differences are also considered in light of the unique functional and survival properties of memory B cells, and mutations that alter memory formation and function are also examined. Finally, we consider recent advances in the understanding of germinal center B-cell differentiation through analysis of transcription factor networks operating in these B cells. PMID:19637202

Tangye, Stuart G; Tarlinton, David M

2009-08-01

254

Protein Kinase C? Promotes Transitional B Cell-Negative Selection and Limits Proximal B Cell Receptor Signaling To Enforce Tolerance  

PubMed Central

Protein kinase C? (PKC?) deficiency causes autoimmune pathology in humans and mice and is crucial for the maintenance of B cell homeostasis. However, the mechanisms underlying autoimmune disease in PKC? deficiency remain poorly defined. Here, we address the antigen-dependent and -independent roles of PKC? in B cell development, repertoire selection, and antigen responsiveness. We demonstrate that PKC? is rapidly phosphorylated downstream of both the B cell receptor (BCR) and the B cell-activating factor (BAFF) receptor. We found that PKC? is essential for antigen-dependent negative selection of splenic transitional B cells and is required for activation of the proapoptotic Ca2+-Erk pathway that is selectively activated during B cell-negative selection. Unexpectedly, we also identified a previously unrecognized role for PKC? as a proximal negative regulator of BCR signaling that substantially impacts survival and proliferation of mature follicular B cells. As a consequence of these distinct roles, PKC? deficiency leads to the survival and development of a B cell repertoire that is not only aberrantly autoreactive but also hyperresponsive to antigen stimulation. PMID:24515435

Zikherman, Julie; Lau, Tannia; Leitges, Michael; Weiss, Arthur

2014-01-01

255

Aberrant B cell receptor signaling from B29 (Ig, CD79b) gene mutations of chronic lymphocytic leukemia B cells  

Microsoft Academic Search

Chronic lymphocytic leukemia (CLL) B cells characteristically exhibit low or undetectable surface B cell receptor (BCR) and diminished responses to BCR-mediated signaling. These features suggest that CLL cells may have sustained mutations affecting one or more of the BCR proteins required for receptor surface assembly and signal transduction. Loss of expression and mutations in the critical BCR protein B29 (Ig,

Melinda S. Gordon; Roberta M. Kato; Frederick Lansigan; Alexis A. Thompson; Randolph Wall; David J. Rawlings

2000-01-01

256

IL-21 regulates germinal center B cell differentiation and proliferation through a B cell–intrinsic mechanism  

PubMed Central

Germinal centers (GCs) are sites of B cell proliferation, somatic hypermutation, and selection of variants with improved affinity for antigen. Long-lived memory B cells and plasma cells are also generated in GCs, although how B cell differentiation in GCs is regulated is unclear. IL-21, secreted by T follicular helper cells, is important for adaptive immune responses, although there are conflicting reports on its target cells and mode of action in vivo. We show that the absence of IL-21 signaling profoundly affects the B cell response to protein antigen, reducing splenic and bone marrow plasma cell formation and GC persistence and function, influencing their proliferation, transition into memory B cells, and affinity maturation. Using bone marrow chimeras, we show that these activities are primarily a result of CD3-expressing cells producing IL-21 that acts directly on B cells. Molecularly, IL-21 maintains expression of Bcl-6 in GC B cells. The absence of IL-21 or IL-21 receptor does not abrogate the appearance of T cells in GCs or the appearance of CD4 T cells with a follicular helper phenotype. IL-21 thus controls fate choices of GC B cells directly. PMID:20142430

Zotos, Dimitra; Coquet, Jonathan M.; Zhang, Yang; Light, Amanda; D'Costa, Kathy; Kallies, Axel; Corcoran, Lynn M.; Godfrey, Dale I.; Toellner, Kai-Michael; Smyth, Mark J.; Nutt, Stephen L.

2010-01-01

257

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

258

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; Birnböck, Herbert F.; Richter, Wolfgang F.; Del Nagro, Christopher J.

2013-01-01

259

The pre-B cell Receptor in B Cell Development: Recent Advances, Persistent Questions and Conserved Mechanisms  

Microsoft Academic Search

5. The pre-B cell Receptor in B Cell Development: Recent Advances, Persistent Questions and Conserved Mechanisms\\u000a \\u000a M. R. Clark12 , A. B. Cooper12, L. D. Wang12 and I. Aifantis12\\u000a \\u000a \\u000a \\u000a (12) \\u000a Section of Rheumatology, University of Chicago, MC0930, 5841 S. Maryland Ave., Chicago, IL 60637, USA\\u000a \\u000a \\u000a Abstract\\u000a B cell development is a process tightly regulated by the orchestrated signaling of cytokine receptors, the pre-B cell receptor\\u000a (BCR) and the B cell

M. R. Clark; A. B. Cooper; L. D. Wang; I. Aifantis

260

Treatment with sirolimus results in complete responses in patients with autoimmune lymphoproliferative syndrome  

PubMed Central

Summary We hypothesized that sirolimus, an mTOR inhibitor, may be effective in patients with autoimmune lymphoproliferative syndrome (ALPS) and treated patients who were intolerant to or failed other therapies. Four patients were treated for autoimmune cytopenias; all had a rapid complete or near complete response. Two patients were treated for autoimmune arthritis and colitis, demonstrating marked improvement. Three patients had complete resolution of lymphadenopathy and splenomegaly and all patients had a reduction in double negative T cells, a population hallmark of the disease. Based on these significant responses, we recommend that sirolimus be considered as second-line therapy for patients with steroid-refractory disease. PMID:19208097

Teachey, David T.; Greiner, Robert; Seif, Alix; Attiyeh, Edward; Bleesing, Jack; Choi, John; Manno, Catherine; Rappaport, Eric; Schwabe, Dirk; Sheen, Cecilia; Sullivan, Kathleen E.; Zhuang, Hongming; Wechsler, Daniel S.; Grupp, Stephan A.

2010-01-01

261

Report of a factor VIII inhibitor in a patient with autoimmune lymphoproliferative syndrome.  

PubMed

The occurrence of factor VIII inhibitors in non-hemophilic patients is a rare event with a potentially lethal outcome. Despite its infrequent occurrence, the association of this inhibitor with multiple autoimmune diseases is well recognized. We report the case of a patient with the recently described autoimmune lymphoproliferative syndrome (ALPS) who developed an inhibitor to factor VIII. ALPS is a disease characterized by defective lymphocyte apoptosis due to inherited mutations in genes that regulate apoptosis, with the resulting enlargement of lymphoid organs and a variety of autoimmune manifestations. Published 2000 Wiley-Liss, Inc. PMID:10861820

Fang, B S; Sneller, M C; Straus, S E; Frenkel, L; Dale, J K; Rick, M E

2000-07-01

262

Activation of Ras overcomes B-cell tolerance to promote differentiation of autoreactive B cells and production of autoantibodies  

PubMed Central

Newly generated immature B cells are selected to enter the peripheral mature B-cell pool only if they do not bind (or bind limited amount of) self-antigen. We previously suggested that this selection relies on basal extracellular signal-regulated kinase (Erk) activation mediated by tonic B-cell antigen receptor (BCR) signaling and that this signal can be replaced by an active rat sarcoma (Ras), which are small GTPase proteins. In this study we compared the activity of Ras and Erk in nonautoreactive and autoreactive immature B cells and investigated whether activation of Ras can break tolerance. Our results demonstrate lower levels of active Erk and Ras in autoreactive immature B cells, although this is evident only when these cells display medium/high avidity for self-antigen. Basal activation of Erk in immature B cells is proportional to surface IgM and dependent on sarcoma family kinases, whereas it is independent of B-cell activating factor, IFN, and Toll-like receptor signaling. Ectopic expression of the constitutively active mutant Ras form N-RasD12 in autoreactive cells raises active Erk, halts receptor editing via PI3 kinase, and promotes differentiation via Erk, breaking central tolerance. Moreover, when B cells coexpress autoreactive and nonautoreactive BCRs, N-RasD12 leads also to a break in peripheral tolerance with the production of autoantibodies. Our findings indicate that in immature B cells, basal activation of Ras and Erk are controlled by tonic BCR signaling, and that positive changes in Ras activity can lead to a break in both central and peripheral B-cell tolerance. PMID:24958853

Teodorovic, Lenka S.; Babolin, Chiara; Rowland, Sarah L.; Greaves, Sarah A.; Baldwin, David P.; Torres, Raul M.; Pelanda, Roberta

2014-01-01

263

Regulatory B cells in autoimmune diseases and mucosal immune homeostasis  

PubMed Central

B lymphocytes contribute to physiological immunity through organogenesis of secondary lymphoid organs, presentation of antigen to T cells, production of antibodies, and secretion of cytokines. Their role in several autoimmune diseases, mainly as producers of pathogenic antibodies, is also well known. However, certain subsets of B cells are emerging as the important regulatory cell populations in both mouse and human. The regulatory functions of B cells have been demonstrated in a variety of mouse models of autoimmune diseases including collagen-induced arthritis (CIA), experiment autoimmune encephalomyelitis (EAE), anterior chamber-associated immune deviation (ACAID), diabetes, contact hypersensitivity (CHS), and intestinal mucosal inflammation. Accumulating evidence from both mouse and human studies confirms the existence of regulatory B cells, and is beginning to define their mechanisms of action. In this article, we first review the history of B cells with regulatory function in autoimmune diseases, and summarize the current understanding about the characterizations of such B-cell subsets. We then discuss the possible regulatory mechanisms of B cells, and specifically define the role of regulatory B cells in immune homeostasis in the intestine. PMID:20701454

LI, XIAOXIAO; BRAUN, JONATHAN; WEI, BO

2013-01-01

264

Regulatory B cells in autoimmune diseases and mucosal immune homeostasis.  

PubMed

B lymphocytes contribute to physiological immunity through organogenesis of secondary lymphoid organs, presentation of antigen to T cells, production of antibodies, and secretion of cytokines. Their role in several autoimmune diseases, mainly as producers of pathogenic antibodies, is also well known. However, certain subsets of B cells are emerging as the important regulatory cell populations in both mouse and human. The regulatory functions of B cells have been demonstrated in a variety of mouse models of autoimmune diseases including collagen-induced arthritis (CIA), experiment autoimmune encephalomyelitis (EAE), anterior chamber-associated immune deviation (ACAID), diabetes, contact hypersensitivity (CHS), and intestinal mucosal inflammation. Accumulating evidence from both mouse and human studies confirms the existence of regulatory B cells, and is beginning to define their mechanisms of action. In this article, we first review the history of B cells with regulatory function in autoimmune diseases, and summarize the current understanding about the characterizations of such B-cell subsets. We then discuss the possible regulatory mechanisms of B cells, and specifically define the role of regulatory B cells in immune homeostasis in the intestine. PMID:20701454

Li, Xiaoxiao; Braun, Jonathan; Wei, Bo

2011-02-01

265

Role of Bruton's Tyrosine Kinase in B Cell Development  

PubMed Central

X-linked agammaglobulinemia (XLA) is one of the most frequent inherited immunodeficiency diseases in man and is characterized by an almost complete arrest of B cell differentiation at the pre-B cell stage. The gene defective in XLA encodes the cytoplasmic signaling molecule Bruton's tyrosine kinase (Btk). Next to the CBA/N strain of mice, carrying a single amino acid substitution mutation in the Btk gene, which results in the X-linked immunodeficiency (xid) phenotype, additional mouse models have been developed to study the role of Btk in vivo. This review discusses the analyses of Btk null-mutants, obtained by gene targeting in embryonic stem cells, and transgenic mice that express wild-type or mutated forms of the Btk gene. These studies provided information on the function of Btk at several important checkpoints throughout B cell development. Analyses of the mouse models indicated that Btk is not essential for pre-B cell receptor signaling in the mouse. By contrast, Btk-mediated B cell receptor signaling appears to be required for the survival of immature B cells in the bone marrow, that have performed a successful immunoglobulin (Ig) L chain locus rearrangement, resultirig in the expression of a non-autoreactive Ig on the membrane. Btk is also shown to be involved in signaling pathways that govern the development of peripheral B cells, including follicular entry, follicular maturation and plasma cell differentiation. PMID:11785667

Maas, Alex

2001-01-01

266

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

267

PDK1 regulates B cell differentiation and homeostasis  

PubMed Central

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

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

2014-01-01

268

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

269

Intrinsic differences in the initiation of B cell receptor signaling favor responses of human IgG+ memory B cells over IgM+ naïve B cells  

PubMed Central

The acquisition of long-lived memory B cells (MBCs) is critical for the defense against many infectious diseases. Despite their importance, little is known about how antigens (Ags) trigger human MBCs, even though our understanding of the molecular basis of Ag activation of B cells in model systems has advanced considerably. Here, we use quantitative, high-resolution, live cell imaging at the single cell and single molecule levels to describe the earliest Ag-driven events in human isotype-switched, IgG-expressing MBCs and compare them to those in IgM-expressing naïve B cells. We show that human MBCs are more robust than naïve B cells at each step in the initiation of B cell receptor (BCR) signaling, including interrogation of Ag-containing membranes, formation of sub-microscopic BCR oligomers and recruitment and activation of signaling-associated kinases. Despite their robust response to Ag, MBCs remain highly sensitive to Fc?RIIB-mediated inhibition. We also demonstrate that in the absence of Ag, a portion of MBC receptors spontaneously oligomerized and phosphorylated kinases accumulated at the membrane and speculate that heightened constitutive signaling may play a role in maintaining MBC longevity. Using high-resolution imaging we have provided a description of the earliest events in the Ag activation of MBCs and evidence for acquired cell-intrinsic differences in the initiation of BCR signaling in human naïve and MBCs. PMID:22379037

Davey, Angel M.; Pierce, Susan K.

2012-01-01

270

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

Mahévas, Matthieu; Patin, Pauline; Huetz, François; 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-Agnès

2012-01-01

271

Epstein Barr virus-associated lymphoproliferative diseases: the virus as a therapeutic target  

PubMed Central

Epstein Barr virus (EBV)-associated lymphoproliferative diseases (LPDs) express all EBV latent antigens (type III latency) in immunodeficient patients and limited antigens (type I and II latencies) in immunocompetent patients. Post-transplantation lymphoproliferative disease (PTLD) is the prototype exhibiting type III EBV latency. Although EBV antigens are highly immunogenic, PTLD cell proliferation remains unchecked because of the underlying immunosuppression. The restoration of anti-EBV immunity by EBV-specific T cells of either autologous or allogeneic origin has been shown to be safe and effective in PTLDs. Cellular therapy can be improved by establishing a bank of human leukocyte antigen-characterized allogeneic EBV-specific T cells. In EBV+ LPDs exhibiting type I and II latencies, the use of EBV-specific T cells is more limited, although the safety and efficacy of this therapy have also been demonstrated. The therapeutic role of EBV-specific T cells in EBV+ LPDs needs to be critically reappraised with the advent of monoclonal antibodies and other targeted therapy. Another strategy involves the use of epigenetic approaches to induce EBV to undergo lytic proliferation when expression of the viral thymidine kinase renders host tumor cells susceptible to the cytotoxic effects of ganciclovir. Finally, the prophylactic use of antiviral drugs to prevent EBV reactivation may decrease the occurrence of EBV+ LPDs. PMID:25613733

Tse, Eric; Kwong, Yok-Lam

2015-01-01

272

Variations of the UNC13D Gene in Patients with Autoimmune Lymphoproliferative Syndrome  

PubMed Central

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

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

2013-01-01

273

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

274

B Cells in Pregnancy: Functional Promiscuity or Tailored Function?  

PubMed

During pregnancy, the maternal immune and endocrine systems undergo significant adaptations in order to maintain immune tolerance towards the semi-allogeneic fetus. Pregnancy related hormones, such as estradiol, progesterone and glucocorticoids soar, and leukocyte subsets of the innate and adaptive immune response systems functionally engage in ensuring successful implantation of the embryo, placentation and maintenance of pregnancy until term. Over the last two decades, a considerable amount of research has been devoted first to understand the functional role of natural killer (NK) cells, dendritic cells (DC) and T cells, and then to dissect potential cross talk between these cells and pregnancy-related hormones, decidual stroma cells and fetal trophoblast cells [1,2].It is now evident that immune responses against fetal antigens are suppressed by multiple pathways that lead to dampening of T effector cells, generation of regulatory T cells [3,4,5] and modulation of DC [6] and NK cell functions [7], along with epigenetic modifications of the decidual stroma [8]. Remarkably, the amalgamation of these pathways ensures pregnancy success, whereas single cell subsets or markers are largely redundant, as learned from reductionist approaches of single gene knock out or in vivo cellular depletion experiments [1]. This profound maternal adaptation to pregnancy has certain collateral effects on maternal health. These effects including both, health advantages, such as amelioration of certain autoimmune diseases including multiple sclerosis (MS) [9], as well as disadvantages, such as increased risk for certain infections, including influenza virus [10]. Considering the relevance of maternal immunological adaptation during pregnancy to autoimmunity, infectious disease and fetal health, the importance of understanding these changes has become increasingly clear. In this context, one leukocyte subset has largely been neglected in reproductive immunology: the B cells (Figure 1). As critical, non-redundant players in the adaptive immune response, B cells mediate humoral immunity by producing antibodies; more recently, research has unveiled antibody-independent immune-modulatory functions of certain B cell subsets. These findings have resulted in a re-classification of B cell subsets based on their potential to secrete a distinct cytokine profile [11]. Hereby, B cells activate or suppress immune responses via their interactions with DC, NK cells and T cells [12,13]. Furthermore, a wealth of evidence supports that B cell subsets can be functionally promiscuous, capable of maintaining health as well as aggravating immune pathologies [11, 14, 15]. The recent publication by Frederico Jensen and colleagues at the University of Greifswald in Germany has begun to close the gap in knowledge on the function and modifications of B cell subsets and their function during pregnancy [16]. In their study, the Greifswald group provides evidence that B cell development undergoes significant adaptations over the course of pregnancy in allogenically mated mice [16]. These adaptations include a gradual reduction in numbers of pre/pro and, to a lesser extent, immature B cells in the bone marrow early during gestation, prior to the completion of placentation. These findings overcome a limitation of previously published evidence, in which a similar suppression of B lymphopoiesis during gestation had also been observed, but cells from different gestational stages had been pooled [17].By mid gestation, the Greifswald group observed a clear reduction in numbers of B cell precursors together with an increase in numbers of mature B cells, which together suggest an a reduction in B cell lymphopoiesis. Subsequent in-depth analyses of B cell development in the periphery unveiled a preponderance of marginal zone B cells in the spleen. Splenic marginal zone B cells can give rise to antibody-secreting memory B cells and plasma cells, which are required to deal with infections such as the influenza A virus. Hence, it is possible that mechanisms are activated to overcome p

Arck, Petra Clara; Hecher, Kurt; Solano, María Emilia

2014-11-26

275

Modulation of B cell responses by Toll-like receptors.  

PubMed

B lymphocytes are well known because of their key role in mediating humoral immune responses. Upon encounter with antigen and on cognate interaction with T cells, they differentiate into antibody-secreting plasma cells, which are critical for protection against a variety of pathogens. In addition to their antibody-production function, B cells are efficient antigen-presenting cells and express a variety of pathogen recognition receptors (PRRs). Engagement of these PRRs with their respective ligands results in cytokine and chemokine secretion and the upregulation of co-stimulatory molecules. These events constitute innate immune responses. Toll-like receptor (TLR) activation provides a third signal for B cell activation and is essential for optimal antigen-specific antibody responses. In some situations, TLR activation in B cells can result in autoimmunity. The purpose of this review is to provide some insights into the way that TLRs influence innate and adaptive B cell responses. PMID:20824286

Booth, Jayaum; Wilson, Heather; Jimbo, Steve; Mutwiri, George

2011-01-01

276

COMPUTATION MODELING OF TCDD DISRUPTION OF B CELL TERMINAL DIFFERENTIATION  

EPA Science Inventory

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

277

Bad-deficient mice develop diffuse large B cell lymphoma  

E-print Network

02115; §Division of Neuroscience, Children's Hospital Boston and Department of Neurobiology, Harvard -irradiation resulted in an increased incidence of pre-T cell and pro- pre-B cell lymphoblastic leukemia

Datta, Sandeep Robert

278

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.

279

B-Cell waste classification sampling and analysis plan  

SciTech Connect

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

HOBART, R.L.

1999-09-22

280

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 Central

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

2014-01-01

281

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

282

The molecular biology of B-cell lymphoma: Clinicopathologic implications  

Microsoft Academic Search

Summary Nonrandom chromosomal translocations like the t(14;18), t(8;14), and t(11;14) are found in distinct types of B-cell malignancies. Recent molecular studies concerning their structure and origin showed that many translocations occur in early precursor B cells and may be interpreted as aberrant immunoglobulin gene rearrangements. The available data from in vitro experiments, transgenic mice, and normal human individuals indicate that

P. M. Kluin

1991-01-01

283

B cells: No longer the nondominant arm of multiple sclerosis  

Microsoft Academic Search

The role B cells and humoral immunity play in multiple sclerosis (MS) is continually evolving. Recent discoveries include\\u000a advances in lesion classification, identification of B cell clonal expansion in the central nervous system with evidence of\\u000a antigen targeting, identification of chemokines in MS lesions, and expansion of information on the roles of autoantibodies\\u000a and complement. Strong indications are accumulating that

Eric C. Klawiter; Anne H. Cross

2007-01-01

284

B-cell lymphoma-associated hemophagocytic syndrome: clinicopathological characteristics  

Microsoft Academic Search

Seven patients with peripheral B-cell lymphoma associated with hemophagocytic syndrome are reported. In all cases, the histologic\\u000a subtype was diffuse large B-cell lymphoma. Hemophagocytic features were noted in the bone marrow with lymphomatous infiltration.\\u000a Hemophagocytic syndrome occurred with presentation of the lymphoma and was characterized by high fever, cytopenias, and elevated\\u000a levels of lactate dehydrogenase, ferritin, C-reactive protein, and cytokines

M. Miyahara; M. Sano; K. Shibata; M. Matsuzaki; K. Ibaraki; Y. Shimamoto; O. Tokunaga

2000-01-01

285

Monoclonal B cell lymphocytosis--what does it really mean?  

PubMed

Monoclonal B cell Lymphocytosis (MBL) or similar terms have been used for decades to describe the presence of light-chain restricted B lymphocytes with uncertain clinical significance, usually having a phenotype consistent with chronic lymphocytic leukemia (CLL). As diagnostic technology improved, ever smaller monoclonal B cell populations were identifiable in the population, and approximately half of people over 90 years old have a minimal (<1 cell/?L) circulating CLL-like B cell population. These minimal CLL-like B cell populations share some molecular characteristics with CLL, but have no clinical significance. In contrast, CLL-like MBL cases detected through hospital investigations are biologically indistinguishable from early stage CLL, but the neoplastic B cell levels are usually stable over time and the risk of progressive disease requiring treatment is much lower than for early stage CLL. However, there is usually partial or complete depletion of normal B cells, with an increased relative risk of severe infection, comparable to early stage CLL, which may impair overall survival. PMID:23307471

Rawstron, Andy C

2013-03-01

286

Identification of the human mature B cell miRNome  

PubMed Central

The full set of microRNAs (miRNAs) in the human genome is not known. Because presently known miRNAs have been identified by virtue of their abundant expression in a few cell types, many tissue-specific miRNAs remain unrevealed. To understand the role of miRNAs in B-cell function and lymphomagenesis, we generated short-RNA libraries from normal human B cells at different stages of development (naïve, germinal-center, memory) and from a Burkitt lymphoma cell-line. A combination of cloning and computational analysis identified 178 miRNAs (miRNome) expressed in normal and/or transformed B-cell libraries. Most notably, the B-cell miRNome included 75 miRNAs which to our knowledge have not been previously reported and of which 66 have been validated by RNA blot and/or RT-PCR analyses. Numerous miRNAs were expressed in a stage- or transformation-specific fashion in B cells, suggesting specific functional or pathologic roles. These results provide a resource for studying the role of miRNAs in B-cell development, immune function, and lymphomagenesis. PMID:19446474

Basso, Katia; Sumazin, Pavel; Morozov, Pavel; Schneider, Christof; Maute, Roy L.; Kitagawa, Yukiko; Mandelbaum, Jonathan; Haddad, Joseph; Chen, Chang-Zheng; Califano, Andrea; Dalla-Favera, Riccardo

2009-01-01

287

Organisation of B-cell receptors on the cell membrane.  

PubMed

B-cell receptors (BCRs) have been reported to organise into oligomeric clusters on the B-cell surface, and mutations, that are likely to interfere with such clustering, result in B-cell unresponsiveness. This has led to the suggestion that pre-formed BCR clusters may be crucial for B-cell signalling. However, neither the size nor the fraction of BCRs organised in such clusters have yet been determined in experiments. Hence, the authors use a statistical approach to predict the membrane organisation of BCRs, based on available experimental data. For physiological parameters, most BCRs will organise into supramolecular polymers that comprise about five receptors where the non-covalent interactions are mediated by the IgH transmembrane helix. A reduction in the density of IgM to 2-5% of the normal density, a characteristic of anergic MD4 B cells, strongly reduces IgM polymerisation, and it is suggested that impaired BCR clustering may be responsible for the unresponsiveness of anergic B cells. PMID:16986327

Iber, D; Gruhn, T

2006-09-01

288

Resistance to CpG DNA–induced autoimmunity through tolerogenic B cell antigen receptor ERK signaling  

Microsoft Academic Search

CpG sequences in self-DNA are an important potential trigger for autoantibody secretion in systemic lupus and other systemic autoimmune disorders. It is not known how this ubiquitous threat may be controlled by active mechanisms for maintaining self tolerance. Here we show that two distinct mechanisms oppose autoantibody secretion induced by CpG DNA in anergic B cells that are constantly binding

Lixin Rui; Carola G Vinuesa; Julie Blasioli; Christopher C Goodnow

2003-01-01

289

Posterior reversible encephalopathy syndrome in a child with autoimmune lymphoproliferative syndrome: Case report and review of literature  

PubMed Central

Posterior reversible encephalopathy syndrome (PRES) is characterized by headache, nausea, vomiting, seizures and visual disturbances. PRES has been usually associated with hypertension, chronic renal disease, malignancy and chemotherapeutic agents. We report the association of PRES with Autoimmune lymphoproliferative syndrome, which to our best knowledge has not been reported before. PMID:23560015

Chandramohan, Vaishnavi; Nagarajan, Vinoth Ponnurangam; Sathyamoorthi, Muthamil Selvan; Kumar, Sathish; Shanmugasundaram, Chitrambalam; Periakaruppan, Gokulakrishnan; Scott, Julius Xavier

2012-01-01

290

TEN-like eruption in setting of EBV positive T-cell lymphoproliferative disease with HLH, in a child.  

PubMed

Haemophagocytic lymphohistiocytosis complicating Epstein-Barr virus positive T-cell lymphoproliferative disease of childhood is a rare and life-threatening entity. We report a child with this condition presenting with a toxic epidermal necrolysis-like eruption. PMID:23573996

Sharma, Niyati; Clark, Jonathan; Pham, Hiep; Efron, Daryl; MacGregor, Duncan; O'Keefe, Rodney; Orchard, David

2014-08-01

291

Adhesion receptor profile of thymic B-cell lymphoma.  

PubMed Central

Primary thymic B-cell lymphoma is clinically characterized by aleukemic, highly aggressive local growth, infrequent distant metastasis, and infrequent secondary lymph node involvement. VLA-1 to VLA-6 are cell surface molecules binding to matrix molecules such as collagen, fibronectin, epiligrin, and laminin. VLA-4 additionally binds to VCAM-1 and ICAM-2, thus mediating intercellular adhesion. Other molecules involved in cell/cell adhesion are LFA-1 (CD11a/CD18), Mac-1(CD11b/CD18) and their ligand ICAM-1 (CD54), p150,95 (CD11c/CD18), LFA-3 (CD58), CD44, and LECAM-1. Twenty-three tumors, together with normal lymphoid tissue, were immunohistochemically examined to investigate the expression pattern of these molecules in thymic B-cell lymphomas and in their putative normal counterparts, namely thymic medullary B cells. Thymic B-cell lymphomas consistently lacked VLA-1,-2,-3,-5,-6, and CD11b, expressed ICAM-1 in 21 of 23 cases but were heterogenous for VLA-4, LFA-1, CD11c, LFA-3, CD44, and LECAM-1. Presence of LFA-1 correlated with LFA-3 expression (P = 0.029). The receptor profile of thymic B-cell lymphoma was reminiscent of the expressional status of normal thymic medullary B cells in some aspects but deviated in others: Assuming that, in terms of differentiation, thymic B-cell lymphoma is related to the asteroid variant of thymic medullary B cells, a propensity to down-regulate/lose VLA-4, CD11a, CD44, and LECAM-1 would have to be supposed in conjunction with a tendency to overexpress ICAM-1 and LFA-3. Sclerosis as an inconsistent phenomenon in thymic B-cell lymphoma was absent in 8 of 23 tumors. Presence of sclerosis correlated with LECAM-1 expression of the tumor cells (P = 0.038). Recent studies suggest that a locally growing/aleukemic phenotype of a B-cell neoplasia might be determined by the phenotype VLAs-, LFA-1+, ICAM-1+, CD44-, and LECAM-1-. Our data corroborate this view. Images Figure 1 Figure 2 Figure 3 PMID:1381563

Eichelmann, A.; Koretz, K.; Mechtersheimer, G.; Möller, P.

1992-01-01

292

Personality disorders  

MedlinePLUS

... personality disorder Histrionic personality disorder Narcissistic personality disorder Obsessive-compulsive personality disorder Paranoid personality disorder Schizoid personality disorder Schizotypal personality disorder

293

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.; Günther, Thomas; Weidner-Glunde, Magdalena; Rothämel, Thomas; Grundhoff, Adam; Kellam, Paul

2013-01-01

294

G?q-containing G proteins regulate B cell selection and survival and are required to prevent B cell–dependent autoimmunity  

PubMed Central

Survival of mature B cells is regulated by B cell receptor and BAFFR-dependent signals. We show that B cells from mice lacking the G?q subunit of trimeric G proteins (Gnaq?/? mice) have an intrinsic survival advantage over normal B cells, even in the absence of BAFF. Gnaq?/? B cells develop normally in the bone marrow but inappropriately survive peripheral tolerance checkpoints, leading to the accumulation of transitional, marginal zone, and follicular B cells, many of which are autoreactive. Gnaq?/? chimeric mice rapidly develop arthritis as well as other manifestations of systemic autoimmune disease. Importantly, we demonstrate that the development of the autoreactive B cell compartment is the result of an intrinsic defect in Gnaq?/? B cells, resulting in the aberrant activation of the prosurvival factor Akt. Together, these data show for the first time that signaling through trimeric G proteins is critically important for maintaining control of peripheral B cell tolerance induction and repressing autoimmunity. PMID:20624888

Misra, Ravi S.; Shi, Guixiu; Moreno-Garcia, Miguel E.; Thankappan, Anil; Tighe, Michael; Mousseau, Betty; Kusser, Kim; Becker-Herman, Shirly; Hudkins, Kelly L.; Dunn, Robert; Kehry, Marilyn R.; Migone, Thi-Sau; Marshak-Rothstein, Ann; Simon, Melvin; Randall, Troy D.; Alpers, Charles E.; Liggitt, Denny

2010-01-01

295

Competition within the early B-cell compartment conditions B-cell reconstitution after hematopoietic stem cell transplantation in nonirradiated recipients.  

PubMed

Severe combined immunodeficiency (SCID) is characterized by a complete block in T-lymphocyte differentiation. Most SCID also affects B-cell development or function, although a normal pool of pro-B cells is detectable. Treatment of SCID consists of allogeneic hematopoietic stem cell transplantation (HSCT), but in the absence of a myeloablative conditioning regimen, only T cells, and in some cases, natural killer (NK) cells, are of donor origin, while all other leukocytes subsets are of host origin. We hypothesized that donor B-cell development success could be conditioned by the competitive ability of recipient B-cell precursors in the bone marrow. We therefore compared the outcome of unconditioned HSCT in mice that differed with respect to their pro-B-cell compartments. B-cell reconstitution was limited in recipient mice containing a normal pro-B-cell pool, whereas immature and mature B-cell numbers reached wild-type levels in mice with compromised early B-cell precursors. Interestingly, host NK cells did not modify the outcome of unconditioned HSCT as long as the early B-cell compartment was compromised. These observations suggest that recipient B-cell precursors condition the reconstitution of the donor B-cell pool and, if extrapolative to humans, suggest that conditioning regimens targeting host pro-B cells may help improve B-cell reconstitution after allogeneic HSCT. PMID:16614244

Liu, Allen; Vosshenrich, Christian A J; Lagresle-Peyrou, Chantal; Malassis-Seris, Michele; Hue, Christophe; Fischer, Alain; Di Santo, James P; Cavazzana-Calvo, Marina

2006-08-15

296

B-cell biomarkers in transplantation - from genes to therapy.  

PubMed

An increased understanding of the mechanisms by which the immune system mounts a response to transplanted organs has allowed the development of immunosuppressive regimens that limit acute T-cell-mediated rejection (TCMR). However, the treatment of acute and chronic antibody-mediated rejection (ABMR) in kidney transplants remains sub-optimal. The occurrence and severity of antibody-mediated graft pathology are variable, and genetic polymorphisms that affect the magnitude and nature of the B-cell response, as well as effector functions of antibody, are likely to contribute to such phenotypic variation. Here we review current efforts to understand and quantify the contribution of B cells to renal transplant pathology by studying variation in DNA, mRNA and proteins. Large genetic studies with information on B-cell-specific genetic variants are scarce. At a transcriptomic level, there is evidence that B cells are essential contributors to transplant tolerance and may protect against TCMR and ABMR. In contrast, at the protein level, the detection of donor-specific human leukocyte antigen (HLA) antibodies and an assessment of their capacity to bind complement allow patients of high immunological risk to be identified. Other biomarkers, such as serum B-cell-activating factor (BAFF) or interleukin (IL)-10-producing B cells, may allow this risk stratification to be refined. An increased understanding of the significance of these biomarkers should allow a more accurate assessment of how an individual patient's B cells will impact allograft responses and thereby allow clinicians to adjust therapeutic strategies appropriately. PMID:25626600

Banham, G D; Clatworthy, M R

2015-02-01

297

The LRF transcription factor regulates mature B cell development and the germinal center response in mice  

PubMed Central

B cells play a central role in immune system function. Deregulation of normal B cell maturation can lead to the development of autoimmune syndromes as well as B cell malignancies. Elucidation of the molecular features of normal B cell development is important for the development of new target therapies for autoimmune diseases and B cell malignancies. Employing B cell–specific conditional knockout mice, we have demonstrated here that the transcription factor leukemia/lymphoma-related factor (LRF) forms an obligate dimer in B cells and regulates mature B cell lineage fate and humoral immune responses via distinctive mechanisms. Moreover, LRF inactivation in transformed B cells attenuated their growth rate. These studies identify what we believe to be a new key factor for mature B cell development and provide a rationale for targeting LRF dimers for the treatment of autoimmune diseases and B cell malignancies. PMID:21646720

Sakurai, Nagisa; Maeda, Manami; Lee, Sung-Uk; Ishikawa, Yuichi; Li, Min; Williams, John C.; Wang, Lisheng; Su, Leila; Suzuki, Mai; Saito, Toshiki I.; Chiba, Shigeru; Casola, Stefano; Yagita, Hideo; Teruya-Feldstein, Julie; Tsuzuki, Shinobu; Bhatia, Ravi; Maeda, Takahiro

2011-01-01

298

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

PubMed Central

Lymphoproliferative disease virus (LPDV) is an exogenous oncogenic retrovirus that induces lymphoid tumors in some galliform species of birds. Historically, outbreaks of LPDV have been reported from Europe and Israel. Although the virus has previously never been detected in North America, herein we describe the widespread distribution, genetic diversity, pathogenesis, and evolution of LPDV in the United States. Characterization of the provirus genome of the index LPDV case from North America demonstrated an 88% nucleotide identity to the Israeli prototype strain. Although phylogenetic analysis indicated that the majority of viruses fell into a single North American lineage, a small subset of viruses from South Carolina were most closely related to the Israeli prototype. These results suggest that LPDV was transferred between continents to initiate outbreaks of disease. However, the direction (New World to Old World or vice versa), mechanism, and time frame of the transcontinental spread currently remain unknown. PMID:24503062

Allison, Andrew B.; Keel, M. Kevin; Philips, Jamie E.; Cartoceti, Andrew N.; Munk, Brandon A.; Nemeth, Nicole M.; Welsh, Trista I.; Thomas, Jesse M.; Crum, James M.; Lichtenwalner, Anne B.; Fadly, Aly M.; Zavala, Guillermo; Holmes, Edward C.; Brown, Justin D.

2014-01-01

299

Severe Puumala virus infection in a patient with a lymphoproliferative disease treated with icatibant.  

PubMed

Abstract Early identification of patients at risk of a severe course of hantaviral disease and lack of effective medication represent a global challenge in the treatment of this emerging infection. We describe a 67-year-old female patient with a history of chronic lymphoproliferative disease involving the spleen and an extremely severe acute Puumala hantavirus infection. She was treated with the bradykinin receptor antagonist icatibant and recovered. She is the second patient with a spleen abnormality and severe Puumala infection treated with icatibant in our hospital. We suggest that patients with spleen abnormalities may be more susceptible to severe hantavirus disease. The activation of the kinin-kallikrein system and the formation of bradykinin in hantavirus-infected endothelial cells indicate that the role of bradykinin receptor antagonist icatibant in the treatment of hantavirus disease is worth studying. PMID:25496418

Laine, Outi; Leppänen, Ilona; Koskela, Sirpa; Antonen, Jaakko; Mäkelä, Satu; Sinisalo, Marjatta; Vaheri, Antti; Mustonen, Jukka

2015-02-01

300

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

301

A Gammaherpesvirus Bcl-2 Ortholog Blocks B Cell Receptor-Mediated Apoptosis and Promotes the Survival of Developing B Cells In Vivo  

PubMed Central

Gammaherpesviruses such as Epstein-Barr virus (EBV) and Kaposi's sarcoma-associated herpesvirus (KSHV, HHV-8) establish lifelong latency in their hosts and are associated with the development of several types of malignancies, including a subset of B cell lymphomas. These viruses are thought to co-opt the process of B cell differentiation to latently infect a fraction of circulating memory B cells, resulting in the establishment of a stable latency setpoint. However, little is known about how this infected memory B cell compartment is maintained throughout the life of the host. We have previously demonstrated that immature and transitional B cells are long-term latency reservoirs for murine gammaherpesvirus 68 (MHV68), suggesting that infection of developing B cells contributes to the maintenance of lifelong latency. During hematopoiesis, immature and transitional B cells are subject to B cell receptor (BCR)-mediated negative selection, which results in the clonal deletion of autoreactive B cells. Interestingly, numerous gammaherpesviruses encode homologs of the anti-apoptotic protein Bcl-2, suggesting that virus inhibition of apoptosis could subvert clonal deletion. To test this, we quantified latency establishment in mice inoculated with MHV68 vBcl-2 mutants. vBcl-2 mutant viruses displayed a marked decrease in the frequency of immature and transitional B cells harboring viral genome, but this attenuation could be rescued by increased host Bcl-2 expression. Conversely, vBcl-2 mutant virus latency in early B cells and mature B cells, which are not targets of negative selection, was remarkably similar to wild-type virus. Finally, in vivo depletion of developing B cells during chronic infection resulted in decreased mature B cell latency, demonstrating a key role for developing B cells in the maintenance of lifelong latency. Collectively, these findings support a model in which gammaherpesvirus latency in circulating mature B cells is sustained in part through the recurrent infection and vBcl-2-mediated survival of developing B cells. PMID:24516386

Coleman, Carrie B.; McGraw, Jennifer E.; Feldman, Emily R.; Roth, Alexa N.; Keyes, Lisa R.; Grau, Katrina R.; Cochran, Stephanie L.; Waldschmidt, Thomas J.; Liang, Chengyu; Forrest, J. Craig; Tibbetts, Scott A.

2014-01-01

302

Valproic Acid (VPA), a Histone Deacetylase (HDAC) Inhibitor, Diminishes Lymphoproliferation in the Fas Deficient MRL/lpr?/? Murine Model of Autoimmune Lymphoproliferative Syndrome (ALPS)  

PubMed Central

Objective Autoimmune lymphoproliferative syndrome (ALPS) is a disorder of apoptosis, often presenting in childhood. Similarly, MRL/lpr?/? mice homozygous for Fas mutations develop an ALPS-like disease with autoimmunity, lymphadenopathy, splenomegaly, and expansion of double negative T (DNT) cells. Currently, there are no proven therapies with adequate safety margins for sustained abolition of the lymphoproliferation associated with ALPS. We sought to test the ability of valproic acid (VPA), a histone deacetylase inhibitor, to induce apoptosis and inhibit lymphoproliferation. Methods Human peripheral blood mononuclear cells (PBMCs) from patients with ALPS and normal controls were tested in vitro to determine the efficacy of VPA at inducing cell death. VPA was used in vivo to control lymphoproliferation in MRL/lpr?/? mice, a model for ALPS. Results VPA induced cell death in vitro, and was partially inhibited by the pan caspase inhibitor, Z-VAD-FMK. MRL/lpr?/? mice treated with VPA for 8 weeks showed significant reductions in spleen and lymph node weights and cellularity compared to controls. A concomitant decrease in DNT cells was observed in the spleen, lymph nodes, and peripheral blood. Serum levels of VPA peaked 1 hour after injection, and a 2.5 fold increase in histone acetylation was observed in the spleen at 4 hours after injection. Conclusion Based on our data, VPA is effective at reducing lymphoproliferation in mice, and is currently being studied in a clinical trial as a lympholytic agent in patients with ALPS. PMID:19217201

Dowdell, Kennichi C; Pesnicak, Lesley; Hoffmann, Victoria; Steadman, Kenneth; Remaley, Alan T.; Cohen, Jeffrey I.; Straus, Stephen E; Rao, V. Koneti

2009-01-01

303

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

PubMed Central

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

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

2013-01-01

304

Generation and identification of tumor-evoked regulatory B cells  

PubMed Central

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

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

2014-01-01

305

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

PubMed Central

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

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

2008-01-01

306

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

307

Diffuse large B-cell lymphomas with plasmablastic differentiation  

Microsoft Academic Search

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

Julie Teruya-Feldstein

2005-01-01

308

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

309

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

310

An age-related numerical and functional deficit in CD19(+) CD24(hi) CD38(hi) B cells is associated with an increase in systemic autoimmunity.  

PubMed

Autoimmunity increases with aging indicative of reduced immune tolerance, but the mechanisms involved are poorly defined. In recent years, subsets of B cells with immunoregulatory properties have been identified in murine models of autoimmune disorders, and these cells downregulate immune responses via secretion of IL10. In humans, immature transitional B cells with a CD19(+) CD24(hi) CD38(hi) phenotype have been reported to regulate immune responses via IL10 production. We found the frequency and numbers of CD19(+) CD24(hi) CD38(hi) cells were reduced in the PBMC pool with age. IL10 expression and secretion following activation via either CD40, or Toll-like receptors was also impaired in CD19(+) CD24(hi) CD38(hi) B cells from healthy older donors. When investigating the mechanisms involved, we found that CD19(+) CD24(hi) CD38(hi) B-cell function was compromised by age-related effects on both T cells and B cells: specifically, CD40 ligand expression was lower in CD4 T cells from older donors following CD3 stimulation, and signalling through CD40 was impaired in CD19(+) CD24(hi) CD38(hi) B cells from elders as evidenced by reduced phosphorylation (Y705) and activation of STAT3. However, there was no age-associated change in expression of costimulatory molecules CD80 and CD86 on CD19(+) CD24(hi) CD38(hi) cells, suggesting IL10-dependent immune suppression is impaired, but contact-dependent suppressive capacity is intact with age. Finally, we found a negative correlation between CD19(+) CD24(hi) CD38(hi) B-cell IL10 production and autoantibody (Rheumatoid factor) levels in older adults. We therefore propose that an age-related decline in CD19(+) CD24(hi) CD38(hi) B cell number and function may contribute towards the increased autoimmunity and reduced immune tolerance seen with aging. PMID:23755918

Duggal, Niharika A; Upton, Jane; Phillips, Anna C; Sapey, Elizabeth; Lord, Janet M

2013-10-01

311

Mental Disorders  

MedlinePLUS

... disorder, and phobias Bipolar disorder Depression Mood disorders Personality disorders Psychotic disorders, including schizophrenia There are many causes of mental disorders. Your genes and family history ...

312

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

313

Biclonal post-transplant B-cell lymphoma: report of a case with two distinct cell populations, XX,t(14;18) and XY,t(11;14).  

PubMed

Lymphoproliferative disorders are more likely to occur in transplant patients compared to the general population. Typically in these patients, lymphomas occur within 6-10 months following transplant and are Epstein-Barr virus (EBV) positive. We report a biclonal apparently EBV negative lymphoma occurring in a patient ten years after renal transplant, with karyotypes XX,t(14;18) and XY,t(11;14). Though the biclonal populations also had different sex chromosome compositions, complete evaluation showed that both clones most likely evolved from the patient's native lymphocytes. PMID:17321331

Dennis, Katie L; Wallentine, Steven L; Vanveldhuizen, Peter J; Persons, Diane L; Mathur, Sharad C

2007-03-01

314

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

315

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

PubMed

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

Frouin, Héloïse; Fortier, Marlène; Fournier, Michel

2010-04-11

316

Clonal analysis of B cells in the osteoarthritis synovium  

PubMed Central

OBJECTIVES—Cellular and humoral immunity to collagen and cartilage proteoglycan were shown in patients with osteoarthritis (OA). Inflammatory infiltration containing T and B lymphocytes and macrophages, which are HLA-DR positive, is often seen in the synovial membrane of patients with OA. An analysis of the DNA restriction enzyme patterns of T lymphocytes from the OA synovium showed an oligoclonal pattern of T cell receptor ? chain gene rearrangements. No similar studies of B cell clonality have previously been performed. This study aimed at determining the clonal characteristics of the B cells in the OA synovium.?METHODS—A reverse transcriptase-polymerase chain reaction of the immunoglobulin transcripts of B cells in the synovial membranes from six patients with OA was performed and the products were analysed by a single strand conformation polymorphism analysis.?RESULTS—Several dominant bands were seen in all samples and some of the dominant bands were common among the two or three separate regions of each synovial sample.?CONCLUSION—Infiltrated B cells are oligoclonal, and an antigen driven immune response may play a part in the progression of the disease process in OA.?? PMID:11454647

Shiokawa, S; Matsumoto, N; Nishimura, J

2001-01-01

317

RESEARCH Open Access B cells as biomarkers and  

E-print Network

-cell lymphotropic virus (HTLV-1) is the causative agent of the incapacitating, neuroinflammatory disease HTLV-1 quantified ex vivo and in vitro expression of CD80 and CD86 in PBMCs of healthy controls, HTLV-1-infected increased in all HTLV-1 infected individuals, but with a selective defect for B cell CD86 upregulation

Paris-Sud XI, Université de

318

Biogenesis of secretory organelles during B cell differentiation  

Microsoft Academic Search

The differentiation of B cells into Ig-secreting plasma cells requires the expansion of secretory organelles to cope with the increased cargo load. To evaluate the timeline of this process, we have quantitated the kinet- ics of secretory organelle expansion relative to Ig se- cretion and examined regulatory components of secre- tory transport following in vitro activation of human B lymphocytes.

Semra J. Kirk; Jacqueline M. Cliff; J. Alero Thomas; Theresa H. Ward

2009-01-01

319

B cells and tertiary lymphoid organs in renal inflammation  

Microsoft Academic Search

B lymphocytes are part of the inflammatory cells recruited to the human kidney in various disease settings. B cell infiltrates have been described in renal allografts, in acute and chronic interstitial nephritis, and the most common glomerular diseases like immunoglobulin A (IgA) and membranous nephropathy. These cells are almost exclusively recruited to the tubulointerstitium, but not the glomerular tuft. In

S Segerer; D Schlöndorff

2008-01-01

320

Mini-Review: Innate responses of B cells  

E-print Network

obvious potential side effect is that the patient becomes immuno-compromised and, therefore, susceptible cells. Antibodies are a first line defence against infection and most vaccines work because they elicit a protective antibody response. However, there is darker side to antibody production if the B cells have a BCR

MacDonald, Andrew

321

Inhibition of B cell development by kalanchosine dimalate.  

PubMed

Kalanchoe brasiliensis (Kb) is a medicinal plant from the Crassulaceae family, used in folk medicine to treat inflammatory and infectious diseases. Here we show that short-term treatment of mice with a highly purified compound named kalanchosine dimalate (KMC), obtained from Kb, led to a strong and selective inhibition of B cell development in the bone marrow, without affecting the myeloid lineage development. Numbers of mature B lymphocytes in bone marrow or peripheral lymphoid organs were preserved in KMC treated mice. The inhibitory effect of KMC was acute and rapidly reverted with the interruption of the treatment. In vitro, KMC, inhibited the interleukin-7 dependent proliferation of B cell precursors and do not induce cell death. Also in vitro, the maturation of B cell precursors was not affected by KMC. KMC does not inhibit the proliferative response to IL-3 or IL-2. These results suggest that KMC is selectively affecting B cell lymphopoiesis, possibly acting on the IL-7 signaling pathway, opening new perspectives for a potential therapeutic usage of Kb derived drugs. PMID:18442786

de Paiva, Luciana S; Hayashi, Elize A; De Melo, Giany O; Costa, Sonia S; Koatz, Vera Lúcia G; Nobrega, Alberto

2008-06-01

322

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

323

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

324

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

325

Bone marrow-induced Mef2c deficiency delays B-cell development and alters the expression of key B-cell regulatory proteins  

PubMed Central

The Mef2 family transcriptional regulator Mef2c (myocyte enhancer factor 2c) is highly expressed in maturing bone marrow and peripheral mature B-cells. To evaluate the role of this transcription factor in B-cell development, we generated a B-cell-specific conditional deletion of Mef2c using the Mb-1-Cre transgene that is expressed during the early stages of immunoglobulin rearrangement. Young mice possessing this defect demonstrated a significant impairment in B-cell numbers in bone marrow and spleen. This phenotype was evident in all B-cell subsets; however, as the animals mature, the deficit in the peripheral mature B-cell compartments was overcome. The absence of Mef2c in mature B-cells led to unique CD23+ and CD23? subsets that were evident in Mef2c knockout primary samples as well as Mef2c-deficient cultured, differentiated B-cells. Genome-wide expression analysis of immature and mature B-cells lacking Mef2c indicated altered expression for a number of key regulatory proteins for B-cell function including Ciita, CD23, Cr1/Cr2 and Tnfsf4. Chromatin immunoprecipitation analysis confirmed Mef2c binding to the promoters of these genes indicating a direct link between the presence (or absence) of Mef2c and altered transcriptional control in mature B-cells. PMID:23087187

Debnath, Irina; Roundy, Kirstin M.

2013-01-01

326

Aberrant B cell receptor signaling from B29 (Ig?, CD79b) gene mutations of chronic lymphocytic leukemia B cells  

PubMed Central

Chronic lymphocytic leukemia (CLL) B cells characteristically exhibit low or undetectable surface B cell receptor (BCR) and diminished responses to BCR-mediated signaling. These features suggest that CLL cells may have sustained mutations affecting one or more of the BCR proteins required for receptor surface assembly and signal transduction. Loss of expression and mutations in the critical BCR protein B29 (Ig?, CD79b), are prevalent in CLL and could produce the hallmark features of these leukemic B cells. Because patient CLL cells are intractable to manipulation, we developed a model system to analyze B29 mutations. Jurkat T cells stably expressing ?, ?, and mb1 efficiently assembled a functional BCR when infected with recombinant vaccinia virus bearing wild-type B29. In contrast, a B29 CLL mutant protein truncated in the transmembrane domain did not associate with ? or mb1 at the cell surface. Another B29 CLL mutant lacking the C-terminal immunoreceptor tyrosine activation motif tyrosine and distal residues brought the receptor to the surface as well as wild-type B29 but showed significant impairment in anti-IgM-stimulated signaling events including mitogen-activated protein kinase activation. These findings demonstrate that B29 mutations previously identified in CLL patients can affect BCR-dependent signaling and may contribute to the unresponsive B cell phenotype in CLL. Finally, the features of the B29 mutations in CLL predict that they may be generated by somatic hypermutation. PMID:10792036

Gordon, Melinda S.; Kato, Roberta M.; Lansigan, Frederick; Thompson, Alexis A.; Wall, Randolph; Rawlings, David J.

2000-01-01

327

B-cell Homeostasis in Chronic Hepatitis C Virus-Related Mixed Cryoglobulinemia is Maintained Through Naïve B-cell Apoptosis  

PubMed Central

Mixed cryoglobulinemia (MC) is the most common extrahepatic manifestation of chronic hepatitis C virus (HCV) infection. Although the formation of inflammation-triggering immune complexes is driven by clonal expansions of autoreactive B-cells we paradoxically found total B-cell numbers reduced in HCV-infected patients with MC. HCV patients with MC (n=17) also displayed a reduced number and a reduced frequency of naïve B-cells compared to HCV-infected patients without MC (n=19), HBV-infected patients (n=10) and uninfected controls (n=50). This was due to an increased sensitivity of naïve B-cells to apoptosis resulting in a reduction in the size of the naïve B-cell subset. In addition, four-fold expansion and skewing (lower T1/T2-ratio) of the immature B-cell subset was noted in MC patients suggesting that apoptosis of naïve B-cells triggered the release of B-cell precursors from the bone marrow in an attempt to maintain normal B-cell numbers. Following treatment of MC with the B-cell-depleting antibody Rituximab, the size of all B-cell subsets, the T1/T2-ratio and cyroglobulin levels normalized. Cryoglobulin levels correlated with in vivo proliferation of T2 B-cells, suggesting a link between the skewing of the T1/T2-ratio and the formation of immune complexes. Conclusion This study provides insight into the mechanisms maintaining B-cell homeostasis in HCV-induced MC, and the ability of Rituximab therapy to restore normal B-cell compartments. PMID:22556016

Holz, Lauren E.; Yoon, Joo Chun; Raghuraman, Sukanya; Moir, Susan; Sneller, Michael C.; Rehermann, Barbara

2012-01-01

328

Establishment of Murine Gammaherpesvirus Latency in B Cells Is Not a Stochastic Event  

PubMed Central

Murid ?-herpesvirus-4 (MuHV-4) promotes polyclonal B cell activation and establishes latency in memory B cells via unclear mechanisms. We aimed at exploring whether B cell receptor specificity plays a role in B cell susceptibility to viral latency and how this is related to B cell activation. We first observed that MuHV-4-specific B cells represent a minority of the latent population, and to better understand the influence of the virus on non-MuHV-4 specific B cells we used the SWHEL mouse model, which produce hen egg lysozyme (HEL)-specific B cells. By tracking HEL+ and HEL? B cells, we showed that in vivo latency was restricted to HEL? B cells while the two populations were equally sensitive to the virus in vitro. Moreover, MuHV-4 induced two waves of B cell activation. While the first wave was characterized by a general B cell activation, as shown by HEL+ and HEL? B cells expansion and upregulation of CD69 expression, the second wave was restricted to the HEL? population, which acquired germinal center (GC) and plasma cell phenotypes. Antigenic stimulation of HEL+ B cells led to the development of HEL+ GC B cells where latent infection remained undetectable, indicating that MuHV-4 does not benefit from acute B cell responses to establish latency in non-virus specific B cells but relies on other mechanisms of the humoral response. These data support a model in which the establishment of latency in B cells by ?-herpesviruses is not stochastic in terms of BCR specificity and is tightly linked to the formation of GCs. PMID:25079788

Fontinha, Diana; Marques, Sofia; Simas, J. Pedro

2014-01-01

329

Early lymphoid development and microenvironmental cues in B-cell acute lymphoblastic leukemia.  

PubMed

B-cell acute lymphoblastic leukemia (B-ALL) is a hematological disorder characterized by malignant and uncontrolled proliferation of B-lymphoid precursor cells in bone marrow. Over the last few years remarkable advances have been made in identifying genetic aberrations, patterns of abnormal transcriptional activity controlling early fate decisions and environmental cues that may influence leukemic development. In this review we focus on the structure of the early lymphoid system and the current knowledge about cell composition and function of the hematopoietic microenvironment that might control progenitor cell activity and lead to differentiation, proliferation and survival of developing B leukemic precursors. Learning the biology of special leukemic niches is central to understanding the pathogenesis of B-ALL and for the development of novel therapies. PMID:22480783

Purizaca, Jessica; Meza, Isaura; Pelayo, Rosana

2012-02-01

330

Retroperitoneal fibrosis due to B-cell non-Hodgkin lymphoma: Responding to rituximab!  

PubMed

Retroperitoneal fibrosis is a rare disease manifesting as chronic soft tissue fibrosis in the retroperitoneum, with potential anatomic and/or functional compromise of adjacent organs. It can be primary (idiopathic) or secondary to other conditions such as cancers, autoimmune disorders, or drugs. We report herein a 66-year-old patient with symptomatic retroperitoneal fibrosis leading to bilateral hydronephrosis and renal failure, in whom, after a complex diagnostic work-up and protracted clinical course, a B-cell non-Hodgkin lymphoma in the retroperitoneal space and several vertebral bodies was identified. The patient was treated with radiation therapy and weekly rituximab infusions, with resolution of hydronephrosis and lower back pain. We include a thorough literature review on etiopathogenesis, diagnosis, therapy, and prognosis of retroperitoneal fibrosis. A meticulous search for malignancy is necessary in this rare condition that, if positive, may have significant therapeutic and prognostic implications. PMID:25013186

Alvarez Argote, Juliana; Bauer, Frank A; Posteraro, Anthony F; Dasanu, Constantin A

2014-07-01

331

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

332

Latest advances in connective tissue disorders  

PubMed Central

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

Rao, Vijay

2013-01-01

333

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

334

Differential impact of Toll-like receptor signaling on distinct B cell subpopulations  

PubMed Central

B cells exhibit a range of functional responses following TLR engagement including immunoglobulin and cytokine production, proliferation, antigen presentation and migration. However, B cell intrinsic TLR responses appear to be precisely programmed based upon the developmental stage of the cell. B cell subpopulations classified as innate immune cells including marginal zone and B-1 B cells exhibit robust responses to TLR stimulation. In contrast, activation of other B cell subsets is constrained via a variety of developmentally regulated events. In this review we provide an overview of TLR responses in murine and human B cells and specifically highlight patterns of TLR expression and developmentally regulated functional responses. PMID:22201817

Meyer-Bahlburg, Almut; Rawlings, David J.

2013-01-01

335

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, João Bosco; Puck, Jennifer M.; Jaffe, Elaine S.; Pittaluga, Stefania; Cohen, Jeffrey I.; Fleisher, Thomas A.; Rao, V. Koneti

2010-01-01

336

Detection of lymphoproliferative disease virus by an enzyme-linked immunosorbent assay.  

PubMed Central

Hitherto, detection of lymphoproliferative disease virus (LPDV), a C-type retrovirus of turkeys, has proved difficult since no tissue culture or serological assay has been available. Development of serological tests has been hampered by the problems of raising virus-specific antisera. An indirect enzyme-linked immunosorbent assay (ELISA) is reported, using a viral antiserum raised with bromelain-digested virus. The assay specifically detected purified virus at a concentration of 250 ng/ml or greater. In an experiment to detect virus in plasma from turkeys over a period of 4 weeks following LPDV infection, ELISA results correlated closely with the viral reverse transcriptase activity. Both assays were of similar sensitivity and detected small amounts of virus in high-speed pellets of turkey plasma. Evidence is presented indicating that LPDV-infected or hyperimmunized turkeys do not produce readily detectable circulating viral antibodies. In reciprocal ELISA tests, using antibodies to group-specific antigens of other avian retrovirus groups (avian sarcoma-leukosis (ASLV) and reticuloendotheliosis (REV] no antigenic cross-reaction was found between LPDV, ASLV and REV. PMID:2448156

Patel, J. R.; Shilleto, R. W.

1987-01-01

337

Heterogeneity of B cell responsiveness to interleukin 4, interleukin 6 and low molecular weight B cell growth factor in discrete stages of B cell activation in patients with systemic lupus erythematosus.  

PubMed Central

To investigate the differential stages of B cell activation in patients with systemic lupus erythematosus (SLE), the effects of recombinant interleukin-4 (rIL-4) interleukin-6 (rIL-6), and low mol. wt BCGF (1-BCGF) on B cell proliferation and differentiation were evaluated. In a co-stimulatory assay with anti-IgM, proliferative response to rIL-4 and 1-BCGF showed no significant differences between SLE patients and healthy controls. In a restimulation assay, after pre-activation with anti-IgM for 3 days, proliferative response to rIL-4 and 1-BCGF was significantly decreased in SLE patients compared with normal healthy controls (P less than 0.01). With regard to rIL-6 induced B cell differentiation, SAC-pre-activated low density, large B cells from both SLE patients and healthy controls differentiated well, whereas high density B cells did not differentiate at all. Of particular interest, low density B cells from active patients directly differentiated into Ig secreting cells in response to rIL-6 without SAC activation. These data indicate that heterogeneity of B cell responsiveness to B cell-tropic interleukins resulted from the discrete stages of B cell activation in SLE. PMID:2788539

Kitani, A; Hara, M; Hirose, T; Norioka, K; Harigai, M; Hirose, W; Suzuki, K; Kawakami, M; Kawagoe, M; Nakamura, H

1989-01-01

338

Waldenstrom Macroglobulinemia with CD5+ Expression Presented as Cryoglobulinemic Glomerulonephropathy: A Case Report  

PubMed Central

Waldenstrom macroglobulinemia (WM) is a B-cell lymphoproliferative disorder associated with bone marrow involvement of lymphoplasmacytic lymphoma (LPL) and an IgM monoclonal gammopathy. Generally B-lymphocytes in LPL do not express CD5 that is important for differential diagnosis of B-cell lymphoproliferative disorders. In WM, various renal diseases and type I cryoglobulinemia are well described separately, but cryoglobulinemic glomerulonephropathy is very rarely reported. A 61-yr-old woman complained of generalized edema, cyanosis of the extremities in cold weather, visual disturbance, and pancytopenia. Bone marrow and renal biopsy showed CD5+ expressing B-cells and cryoglobulinemic glomerulonephropathy. With the diagnosis of WM, she received cyclophosphamide, doxorubicin, vincristine and prednisolone chemotherapy and got complete remission. Here, we report a rare case of WM associated with unusual expression of CD5+ B-lymphocytes and cryoglobulinemic glomerulonephropathy, and emphasize the importance of the clinical features in differentiating CD5+ B-cell lymphoproliferative disorders. PMID:21655071

Kim, You Lim; Hwang, Young Hwan; Joo, Jong Eun; Cho, Young Uk; Lee, Jung Ae; Sung, Su Ah; Lee, So Young; Kim, Nae Yoo

2011-01-01

339

del(7q) in chronic B-cell lymphoid malignancies  

Microsoft Academic Search

Twelve patients with diagnosis of B-cell non-Hodgkin's lymphoma\\/leukemia and del(7q) were studied for their clinical, cytogenetic, and molecular characteristics. Eleven patients were classified as small cell lymphoma whereas one had a diffuse large cell lymphoma. Lymphoplasmacytic features were observed in six out of eleven small cell lymphomas. Morphologically and immunologically these small cell lymphomas could be classified as chronic lymphocytic

Jesús María Hernandez; Cristina Mecucci; Lucienne Michaux; Arnold Criel; Michel Stul; Peter Meeus; Iwona Wlodarska; Angeline Van Orshoven; Jean-Jacques Cassiman; Christiane De Wolf-Peeters; Herman Van Den Berghe

1997-01-01

340

B-cell-directed therapies for autoimmune disease  

Microsoft Academic Search

Approval of the anti-CD20 antibody rituximab for the treatment of moderate-to-severe rheumatoid arthritis in patients who fail to respond to anti-tumor-necrosis-factor agents has raised interest in B-cell-directed therapy for this disease. A number of direct and indirect modalities with distinct mechanisms of action are being investigated, including anti-CD20 and anti-CD22 therapies, and new approaches for blocking members of the tumor

Andreas Radbruch; Gerd R. Burmester; Thomas Dörner

2009-01-01

341

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

342

Interaction of Btk and Akt in B cell signaling.  

PubMed

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 by visualizing the co-localization of Btk and Akt in the perinuclear region and membrane ruffles in COS-7 cells. We have also shown the involvement of phosphatidylinositol 3-kinase (PI 3-K) and Btk in the phosphorylation of Akt following stimulation by hydrogen peroxide (H2O2). Interestingly, Akt phosphorylation was found in the presence of Btk even in the absence of oxidative stress. In addition, we have investigated the involvement of PI 3-K in the MAPKs and ERK and JNK phosphorylation, in the presence or absence of Btk. Phosphorylation of both ERK and JNK increased when the PI 3-K pathway was inhibited and both pathways were modulated positively by Btk. Taken together, based on the study of endogenous conditions, we show the novel interaction of Btk and Akt in H2O2 signaling in B cells. PMID:12054657

Lindvall, Jessica; Islam, Tahmina C

2002-05-24

343

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

344

Ia-restricted B-B cell interaction. I. The MHC haplotype of bone marrow cells present during B cell ontogeny dictates the self-recognition specificity of B cells in the polyclonal B cell activation by a B cell differentiation factor, B151-TRF2  

SciTech Connect

We have demonstrated that B cell recognition of Ia molecules is involved in polyclonal B cell differentiation by B151-TRF2. The present study was undertaken to examine the Ia recognition specificity of B151-TRF2-responsive B cells in fully major histocompatibility complex (MHC)-allogeneic P1----P2, semiallogeneic P1----(P1 x P2)F1, and double donor (P1 + P2)----(P1 x P2)F1 and (P1 + P2)----P1 radiation bone marrow chimeras. The B cells from both P1----P2 and P1----(P1 x P2)F1 chimeras could give rise to in vitro immunoglobulin M-producing cells upon stimulation with B151-TRF2 comparable in magnitude to that of normal P1 B cells, and their responses were inhibited by anti-I-AP1 but not by anti-I-AP2 monoclonal antibody even in the presence of mitomycin C-treated T cell-depleted P2 spleen cells as auxiliary cells. In contrast, the B151-TRF2 responses of P1 B cells isolated from both (P1 + P2)----(P1 x P2)F1 and (P1 + P2)----P1 double bone marrow chimeras became sensitive to the inhibition of not only anti-I-AP1 but also anti-I-AP2 monoclonal antibody only when the culture was conducted in the presence of P2 auxiliary cells, demonstrating that they adaptively differentiate to recognize as self-structures allogeneic as well as syngeneic Ia molecules. Moreover, the experiments utilizing B cells from H-2-congenic mice and B cell hybridoma clones as auxiliary cells revealed that B151-TRF2-responsive B cells recognize Ia molecules expressed on B cells. Taken together, these results demonstrate that B151-TRF2-responsive B cells recognize Ia molecules expressed by B cells as self-structures and that their self-recognition specificity is dictated by the MHC haplotype of bone marrow cells present during the B cell ontogeny but not by the MHC haplotype of a radiation-resistant host environment.

Ono, S.; Takahama, Y.; Hamaoka, T.

1987-11-15

345

Follicular Lymphoma Presenting with Leptomeningeal Disease  

PubMed Central

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

Costa, Ricardo; Costa, Renata

2014-01-01

346

Follicular lymphoma presenting with leptomeningeal disease.  

PubMed

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

Costa, Rubens; Costa, Ricardo; Costa, Renata

2014-01-01

347

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

348

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

PubMed Central

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

2014-01-01

349

Germinal center checkpoints in B cell tolerance in 3H9 transgenic mice  

Microsoft Academic Search

Regulation throughout B cell maturation and activation prevents autoreactive B cells from entering germinal center (GC) reactions. This study shows that a subset of autoreactive B cells in VH3H9m IgH transgenic mice escapes these serial checkpoints and proceeds into splenic GC. GC B cells isolated from these mice all express the transgenic VH3H9m heavy chain, some co-express light chains that

Elahna Paul; Johannes Lutz; Jan Erikson; Michael C. Carroll

2004-01-01

350

Receptor editing is the main mechanism of B cell tolerance toward membrane antigens  

Microsoft Academic Search

Self-reactive B cells specific for ubiquitous membrane-bound autoantigens are eliminated in the bone marrow by two mechanisms of tolerance: receptor editing and clonal deletion. However, the relative contributions of clonal deletion and receptor editing to B cell tolerance in a polyclonal B cell population have not been established. Here we show that tolerance toward a membrane antigen–reactive B cell clone

Regina Halverson; Raul M Torres; Roberta Pelanda

2004-01-01

351

The 'zinc knuckle' motif of Early B cell Factor is required for transcriptional activation of B cell-specific genes  

PubMed Central

Early B cell factor (EBF) is a critical regulator of B lymphocyte-specific gene transcription. EBF functions, in part, by binding to regulatory sites of genes required for the pre-B- and mature B cell receptors. These DNA targets include the promoters of the mb-1 and Vpreb1 genes that encode Ig-? and one of the components of surrogate light chain, respectively. The biochemical basis of DNA binding and gene activation by EBF is poorly understood. The DNA-binding domain (DBD) of EBF includes a putative zinc-binding motif (HX3CX2CX5C), which we have designated the 'Zn-knuckle'. The Zn-knuckle is required for binding of the mb-1 promoter site in EMSA, but it has not been demonstrated to be important for functional activities of EBF in B cells. Therefore, we expressed EBF with mutations in the Zn-knuckle motif or flanking sequences in plasmacytoma cells in which activation of endogenous mb-1 and Vpreb1 genes is dependent on EBF. EBF with mutations that prevent zinc coordination by the Zn-knuckle did not activate transcription of either target gene. Other mutations affected the sequence preference of DNA binding and differentially inhibited activation of these genes. Our results demonstrate the importance of the Zn-knuckle motif in EBF. These experiments also confirm that EBF can re-activate multiple genes of the early B cell program in plasmacytoma cells, which provide a useful cell-based assay for dissecting mechanisms involving EBF. PMID:18606452

Fields, Scott; Ternyak, Kristina; Gao, Hua; Ostraat, Rachel; Akerlund, Janie; Hagman, James

2008-01-01

352

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

Microsoft Academic Search

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

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

353

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

354

Follicular Lymphoma with Monocytoid B-Cell Proliferation: Molecular Assessment of the Clonal Relationship between the Follicular and Monocytoid B-Cell Components  

Microsoft Academic Search

Although a number of studies have recognized that follicular lymphomas may be accompanied by a prominent proliferation of monocytoid B-cells, the clonal relationship between these components has not been adequately assessed. Using laser capture microdissection, we isolated the follicular and monocytoid B-cell components from four well-characterized cases of follicular lymphoma with prominent monocytoid B-cells. DNA from each component was analyzed

Ryan S Robetorye; Sandra D Bohling; L Jeffrey Medeiros; Kojo S J Elenitoba-Johnson

2000-01-01

355

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

Microsoft Academic Search

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

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

2003-01-01

356

Selective inhibitors of phosphoinositide 3-kinase delta: modulators of B-cell function with potential for treating autoimmune inflammatory diseases and B-cell malignancies  

PubMed Central

The delta isoform of the p110 catalytic subunit (p110?) of phosphoinositide 3-kinase is expressed primarily in hematopoietic cells and plays an essential role in B-cell development and function. Studies employing mice lacking a functional p110? protein, as well as the use of highly-selective chemical inhibitors of p110?, have revealed that signaling via p110?-containing PI3K complexes (PI3K?) is critical for B-cell survival, migration, and activation, functioning downstream of key receptors on B cells including the B-cell antigen receptor, chemokine receptors, pro-survival receptors such as BAFF-R and the IL-4 receptor, and co-stimulatory receptors such as CD40 and Toll-like receptors (TLRs). Similarly, this PI3K isoform plays a key role in the survival, proliferation, and dissemination of B-cell lymphomas. Herein we summarize studies showing that these processes can be inhibited in vitro and in vivo by small molecule inhibitors of p110? enzymatic activity, and that these p110? inhibitors have shown efficacy in clinical trials for the treatment of several types of B-cell malignancies including chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma (NHL). PI3K? also plays a critical role in the activation, proliferation, and tissue homing of self-reactive B cells that contribute to autoimmune diseases, in particular innate-like B-cell populations such as marginal zone (MZ) B cells and B-1 cells that have been strongly linked to autoimmunity. We discuss the potential utility of p110? inhibitors, either alone or in combination with B-cell depletion, for treating autoimmune diseases such as lupus, rheumatoid arthritis, and type 1 diabetes. Because PI3K? plays a major role in both B-cell-mediated autoimmune inflammation and B-cell malignancies, PI3K? inhibitors may represent a promising therapeutic approach for treating these diseases. PMID:22936933

Puri, Kamal D.; Gold, Michael R.

2012-01-01

357

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

PubMed Central

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

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

2014-01-01

358

Cold antibody autoimmune hemolytic anemia and lymphoproliferative disorders: a retrospective study of 20 patients including clinical, hematological, and molecular findings.  

PubMed

A total of 20 patients with cold antibody hemolytic anemia were evaluated in a retrospective study of them, 15 had a monoclonal gammopathy of unknown significance (MGUS): 14 with MGUS of immunoglobulin M (IgM) subtype and 1 with immunoglobulin G subtype. One patient had smoldering Waldenström's macroglobulinemia, but four patients had no monoclonal protein and no evidence of lymphoma. However, in three of these patients, we were able to demonstrate a (mono-)clonal rearrangement of their immunoglobulin heavy and/or light chains. Of the 20 patients, 5 had IgHV34 nucleotide sequence indicating that the antibody was directed against the "I" antigen. Two patients exhibited a progressive increase of IgM over time, however without increasing hemolytic activity. Moreover, in two patients with long-term follow-up, we were able to correlate recurrent hemolytic activity with low environmental temperatures. Among four patients treated with rituximab, all four responded to treatment. However, treatment effect was only transient in all of them. PMID:24842748

Arthold, Cathrin; Skrabs, Cathrin; Mitterbauer-Hohendanner, Gerlinde; Thalhammer, Renate; Simonitsch-Klupp, Ingrid; Panzer, Simon; Valent, Peter; Lechner, Klaus; Jäger, Ulrich; Sillaber, Christian

2014-06-01

359

Quorum Sensing Contributes to Activated IgM-Secreting B Cell Homeostasis  

PubMed Central

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

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

2013-01-01

360

Quorum sensing contributes to activated IgM-secreting B cell homeostasis.  

PubMed

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

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

2013-01-01

361

B cells as under-appreciated mediators of non-autoimmune inflammatory disease  

PubMed Central

B lymphocytes play roles in many autoimmune diseases characterized by unresolved inflammation, and B cell ablation is proving to be a relatively safe, effective treatment for such diseases. B cells function, in part, as important sources of regulatory cytokines in autoimmune disease, but B cell cytokines also play roles in other non-autoimmune inflammatory diseases. B cell ablation may therefore benefit inflammatory disease patients in addition to its demonstrated efficacy in autoimmune disease. Current ablation drugs clear both pro- and anti-inflammatory B cell subsets, which may unexpectedly exacerbate some pathologies. This possibility argues that a more thorough understanding of B cell function in human inflammatory disease is required to safely harness the clinical promise of B cell ablation. Type 2 diabetes (T2D) and periodontal disease (PD) are two inflammatory diseases characterized by little autoimmunity. These diseases are linked by coincident presentation and alterations in Toll-like receptor (TLR)-dependent B cell cytokine production, which may identify B cell ablation as a new therapy for co-affected individuals. Further analysis of the role B cells and B cell cytokines play in T2D, PD and other inflammatory diseases is required to justify testing B cell depletion therapies on a broader range of patients. PMID:20382544

Nikolajczyk, Barbara S.

2010-01-01

362

B cells have distinct roles in host protection against different nematode parasites  

Technology Transfer Automated Retrieval System (TEKTRAN)

B cells may mediate protective responses against nematode parasites by supporting Th2 cell development and/or by producing antibodies. To examine this, B cell-deficient mice were inoculated with Nippostrongylus brasiliensis (Nb) or Heligmosomoides polygyrus (Hp). B cell-deficient and wild type (WT...

363

Autoimmune encephalomyelitis: simultaneous identification of T and B cells in the target organ.  

PubMed

Monoclonal antibodies to guinea pig T cells and antibodies to guinea pig immunoglobulin G were used in immunofluorescence studies to identify T and B cells in central nervous system tissue from guinea pigs with acute autoimmune encephalomyelitis. T cells appeared before B cells and were distributed within the white matter parenchyma, while B cells remained in perivascular spaces. PMID:7029715

Traugott, U; Shevach, E; Chiba, J; Stone, H J; Raine, C S

1981-12-11

364

Phenotyping of P105-Negative B Cell Subsets in Patients with Systemic Lupus Erythematosus  

PubMed Central

This study aimed to investigate phenotype of RP105(?) B cell subsets in patients with systemic lupus erythematosus (SLE). Flow cytometry was used for phenotyping RP105-negaive B cell subsets. Based on CD19, RP105, and CD138 expression, RP105(?) B cells consist of at least 5 subsets of late B cells, including CD19(+)RP105(int), CD19(+) RP105(?), CD19(low) RP105(?) CD138(?), CD19(low) RP105(?)CD138(int), and CD19(low) RP105(?) CD138(++) B cells. Especially, CD19(+)RP105(int) and CD19(low) RP105(?)CD138(int) B cells are significantly larger than other RP105(?) B cell subsets in SLE. By comparison of RP105(?) B cell subsets between patients with SLE and normal subjects, these subsets were detectable even in normal subjects, but the percentages of RP105(?) B cell subsets were significantly larger in SLE. The phenotypic analysis of RP105(?) B cell subsets suggests dysregulation of later B cell subsets in SLE and may provide new insights into understanding regulation of B cells in human SLE. PMID:21961021

Koarada, Syuichi; Tada, Yoshifumi; Suematsu, Rie; Soejima, Sachiko; Inoue, Hisako; Ohta, Akihide; Nagasawa, Kohei

2012-01-01

365

Mechanisms of B-Cell Synapse Formation Predicted by Monte Carlo Simulation  

E-print Network

as the ``immunological synapse'' at the contact region between B cells and antigen presenting cells appears to precede antigen (Ag) uptake by B cells. The mature B-cell synapse is characterized by a central cluster of BCR predicts the affinity-dependent mechanism needs to be complemented by a BCR signaling-driven shift in LFA-1

Simon, Scott I.

366

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

PubMed Central

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

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

2014-01-01

367

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

PubMed Central

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

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

2010-01-01

368

Inherited human Caspase 10 mutations underlie defective lymphocyte and dendritic cell apoptosis in autoimmune lymphoproliferative syndrome type II.  

PubMed

Caspases are cysteine proteases that mediate programmed cell death in phylogenetically diverse multicellular organisms. We report here two kindreds with autoimmune lymphoproliferative syndrome (ALPS) type II, characterized by abnormal lymphocyte and dendritic cell homeostasis and immune regulatory defects, that harbor independent missense mutations in Caspase 10. These encode amino acid substitutions that decrease caspase activity and interfere with death receptor-induced apoptosis, particularly that stimulated by Fas ligand and TRAIL. These results provide evidence that inherited nonlethal caspase abnormalities cause pleiotropic apoptosis defects underlying autoimmunity in ALPS type II. PMID:10412980

Wang, J; Zheng, L; Lobito, A; Chan, F K; Dale, J; Sneller, M; Yao, X; Puck, J M; Straus, S E; Lenardo, M J

1999-07-01

369

Mucosal immunoglobulins and B cells of Teleost fish  

PubMed Central

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

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

2012-01-01

370

Human innate B cells: a link between host defense and autoimmunity?  

PubMed Central

B cells play a variety of immunoregulatory roles through their antigen-presentation ability and through cytokine and chemokine production. Innate immune activation of B cells may play a beneficial role through the generation of natural cross-reactive antibodies, by maintaining B cell memory and by exercising immunomodulatory functions that may provide protection against autoimmunity. In this article, we review human B cell populations and their functional properties, with a particular focus on a population of inherently autoreactive B cells, which seem to play an important physiological role in innate immunity, but which, if selected into adaptive immune responses, appear to become pathogenic agents in systemic lupus erythematosus. PMID:15633016

Milner, Eric C. B.; Anolik, Jennifer; Cappione, Amedeo; Sanz, Iñaki

2005-01-01

371

Tumor-infiltrating B cells come into vogue  

PubMed Central

Lymphocyte infiltration into solid tumors has been recognized as a main determinator of positive prognosis. For the most part this is attributed to cytotoxic T cells capable of directly destroying malignant cells. However, when considering the complex composition of the human immune system, recent findings of Nielsen et al on a potentially central role of tumor-infiltrating B cells is not really surprising. In this commentary article, I want to highlight the enormous potential impact of this observation for basic and translational research, prognostic procedures and ultimately for the development of future therapeutic concepts. PMID:23326156

Linnebacher, Michael

2013-01-01

372

Management of relapsed-refractory diffuse large B cell lymphoma  

PubMed Central

Relapsed-Refractory Diffuse Large B Cell Lymphoma (RR DLBCL), which accounts for approximately one-third of patients with DLBCL, remains a major cause of morbidity and mortality. Managing RR DLBCL continues to be a challenge to the treating hemato-oncologist. Salvage high-dose chemotherapy followed by autologous stem cell transplantation is the standard of care for chemosensitive relapses in DLBCL. Various salvage regimens are available, but the quest for an optimal regimen continues. The addition of rituximab to the salvage regimen has improved the outcome of RR DLBCL. Several pertinent issues regarding the management of RR DLBCL are discussed in this short review. PMID:24665451

Raut, Lalit S.; Chakrabarti, Prantar P.

2014-01-01

373

Jejunal perforation: a rare presentation of B-cell lymphoma.  

PubMed

A 42-year-old man who was being treated for pneumonia developed severe, sudden-onset abdominal pain with features of shock and peritonism. The clinical picture combined with radiological investigations raised suspicion of a bowel perforation necessitating urgent surgical review and emergency laparotomy. This diagnosed a jejunal perforation with abnormal lymph nodes. Histological examination confirmed diffuse large B-cell lymphoma. The patient was subsequently started on a course of chemotherapy. While gastrointestinal perforation secondary to antilymphoma treatment is a well-recognised complication, primary perforation caused by the lymphoma itself must always be considered. PMID:24557479

Santharam, V; Kumar, P; Lee, L Y W

2014-01-01

374

Anxiety Disorders  

MedlinePLUS

... Here we discuss six different anxiety disorders: generalized anxiety disorder social phobia panic disorder post-traumatic stress disorder obsessive-compulsive disorder specific phobias. Generalized Anxiety Disorder (GAD) Click for more information ...

375

Spleen Disorders  

MedlinePLUS

... Blood Cell Disorders Plasma Cell Disorders Leukemias Lymphomas Myeloproliferative Disorders Spleen Disorders Topics in Spleen Disorders Overview ... Streptococcus pneumoniae Back to Top Previous: Overview of Myeloproliferative Disorders Next: Enlarged Spleen Audio Figures Photographs Pronunciations ...

376

B cell development undergoes profound modifications and adaptations during pregnancy in mice.  

PubMed

Pregnancy hides an immunological riddle combining two antagonistic characteristics of immunology: the existence of a tolerance that allows the gestation of a semiallogeneic fetus and proper protection against pathogens threatening the health of the immunocompromised mother. Despite the fundamental role that B cells play in orchestrating an immune response, their behavior in the context of pregnancy has been barely investigated. Here we demonstrate that numbers of pre/pro and immature B cells were progressively diminished in the bone marrow (BM) of pregnant mice, leading to a reduced influx of B cells in blood and spleen. Correspondingly, lower levels of B cell-activating factor of the TNF family were observed in serum of pregnant mice. In contrast to immature B cells, mature B cells were accumulated in the BM during pregnancy. Accordingly, higher numbers of mature B cells were observed in the lymph nodes draining the uterus as well as in the peritoneal cavity of pregnant mice, both tissues in close contact with the fetuses. Despite an increase in spleen size, pregnant mice showed lower numbers of splenic B cells, which was mirrored by lower numbers of immature and FO B cells. However, marginal zone B cells in the spleen increased during pregnancy. Additionally, serum IgM, IgA, and IgG3 titers were elevated in pregnant mice. Collectively, our data show how the B cell compartment adapts to the presence of the semiallogeneic fetus during gravidity. PMID:25210132

Muzzio, Damián O; Soldati, Rocío; Ehrhardt, Jens; Utpatel, Kirsten; Evert, Matthias; Zenclussen, Ana C; Zygmunt, Marek; Jensen, Federico

2014-11-01

377

Complement receptor 2/CD21? human naive B cells contain mostly autoreactive unresponsive clones  

PubMed Central

Complement receptor 2–negative (CR2/CD21?) B cells have been found enriched in patients with autoimmune diseases and in common variable immunodeficiency (CVID) patients who are prone to autoimmunity. However, the physiology of CD21?/lo B cells remains poorly characterized. We found that some rheumatoid arthritis (RA) patients also display an increased frequency of CD21?/lo B cells in their blood. A majority of CD21?/lo B cells from RA and CVID patients expressed germline autoreactive antibodies, which recognized nuclear and cytoplasmic structures. In addition, these B cells were unable to induce calcium flux, become activated, or proliferate in response to B-cell receptor and/or CD40 triggering, suggesting that these autoreactive B cells may be anergic. Moreover, gene array analyses of CD21?/lo B cells revealed molecules specifically expressed in these B cells and that are likely to induce their unresponsive stage. Thus, CD21?/lo B cells contain mostly autoreactive unresponsive clones, which express a specific set of molecules that may represent new biomarkers to identify anergic B cells in humans. PMID:20231422

Isnardi, Isabelle; Ng, Yen-Shing; Menard, Laurence; Meyers, Greta; Saadoun, David; Srdanovic, Iva; Samuels, Jonathan; Berman, Jessica; Buckner, Jane H.; Cunningham-Rundles, Charlotte

2010-01-01

378

Censoring of self-reactive B cells by follicular dendritic cell-displayed self-antigen  

PubMed Central

In the secondary lymphoid organs, intimate contact with follicular dendritic cells (FDCs) is required for B cell retention and antigen-driven selection during the germinal center response. However, selection of self-reactive B cells by antigen on FDCs has not been addressed. To this end, we generated a mouse model to conditionally express a membrane-bound self-antigen on FDCs, and monitor the fate of developing self-reactive B cells. Here, we show that self-antigen displayed on FDCs mediates effective elimination of self-reactive B cells at the transitional stage. Notwithstanding, some self-reactive B cells persist beyond this checkpoint, showing evidence of antigen experience and intact proximal BCR signaling, but they are short-lived and unable to elicit T cell help. These results implicate FDCs as an important component of peripheral B cell tolerance that prevent the emergence of naïve B cells capable of responding to sequestered self-antigens. PMID:23817432

Yau, Irene W.; Cato, Matthew H.; Jellusova, Julia; Hurtado de Mendoza, Tatiana; Brink, Robert; Rickert, Robert C.

2013-01-01

379

BACH2-BCL6 balance regulates selection at the pre-B cell receptor checkpoint.  

PubMed

At the pre-B cell receptor (BCR) checkpoint, developing pre-B cells are selected for successful rearrangement of V(H)-DJ(H) gene segments and expression of a pre-BCR. Reduced stringency at this checkpoint may obstruct the B cell repertoire with nonfunctional B cell clones. Earlier studies have described that activation of B cell lymphoma/leukemia (BCL)6 by a functional pre-BCR mediates positive selection of pre-B cells that have passed the checkpoint. This concept is now further elaborated by the recent finding that the BTB and CNC homology 1 basic leucine zipper transcription factor 2 (BACH2) induces negative selection and opposes BCL6 function prior to the pre-BCR checkpoint. Here, we discuss the antagonism between BCL6 and BACH2 during early B cell development, as well as its implications in both repertoire selection and counter-selection of premalignant clones for leukemia suppression. PMID:24332591

Swaminathan, Srividya; Duy, Cihangir; Müschen, Markus

2014-03-01

380

A Rare Case of Splenic Marginal Zone B-Cell Lymphoma Mimicking Relapsing Polychondritis of the Ear  

PubMed Central

Relapsing polychondritis (RPC) is a poorly understood phenomenon associated with cartilaginous inflammation of the ear, nose, tracheobronchial tree, and peripheral joints. Many cases of RPC respond to anti-inflammatories and resolve with no further complications. However, RPC has also been linked to more insidious conditions such as malignancies, autoimmune disorders, vasculitis, or underlying infections. Given the spectrum of associated disorders, patients with RPC may need to be monitored for more insidious underlying conditions. In this case, we report a unique case of bilateral auricular inflammation and nasal inflammation mimicking RPC as the only presenting symptom of splenic marginal zone B-cell lymphoma and we survey related cases in the literature. PMID:25544924

Huang, Gary J.; Mendes, Bryan; Sheykholeslami, Kianoush

2014-01-01

381

A rare case of splenic marginal zone B-cell lymphoma mimicking relapsing polychondritis of the ear.  

PubMed

Relapsing polychondritis (RPC) is a poorly understood phenomenon associated with cartilaginous inflammation of the ear, nose, tracheobronchial tree, and peripheral joints. Many cases of RPC respond to anti-inflammatories and resolve with no further complications. However, RPC has also been linked to more insidious conditions such as malignancies, autoimmune disorders, vasculitis, or underlying infections. Given the spectrum of associated disorders, patients with RPC may need to be monitored for more insidious underlying conditions. In this case, we report a unique case of bilateral auricular inflammation and nasal inflammation mimicking RPC as the only presenting symptom of splenic marginal zone B-cell lymphoma and we survey related cases in the literature. PMID:25544924

Huang, Gary J; Mendes, Bryan; Sheykholeslami, Kianoush

2014-01-01

382

B-cell receptor signal strength influences terminal differentiation.  

PubMed

B-cell terminal differentiation into antibody secreting plasma cells (PCs) features a transcriptional shift driven by the activation of plasma cell lineage determinants such as Blimp-1 and Xbp-1, together with the extinction of Pax5. Little is known about the signals inducing this change in transcriptional networks and the role of the B-cell receptor (BCR) in terminal differentiation remains especially controversial. Here, we show that tonic BCR signal strength influences PC commitment in vivo. Using immuno-globulin light chain transgenic mice expressing suboptimal surface BCR levels and latent membrane protein 2A knock-in animals with defined BCR-like signal strengths, we show that weak, antigen-independent constitutive BCR signaling facilitates spontaneous PC differentiation in vivo and in vitro in response to TLR agonists or CD40/IL-4. Conversely, increasing tonic signaling completely prevents this process that is rescued by lowering surface BCR expression or through the inhibition of Syk phosphorylation. These findings provide new insights into the role of basal BCR signaling in PC differentiation and point to the need to resolve a strong BCR signal in order to guarantee terminal differentiation. PMID:23280426

Lechouane, Fabien; Bonaud, Amélie; Delpy, Laurent; Casola, Stefano; Oruc, Zeliha; Chemin, Guillaume; Cogné, Michel; Sirac, Christophe

2013-03-01

383

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

384

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

385

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