Activation of na ̈ve B lymphocytes via CD81, a pathogenetic mechanism for hepatitis C virus-associated B lymphocyte disorders

Chiron Vaccines, 53100 Siena, Italy.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 01/2006; 102(51):18544-9. DOI: 10.1073/pnas.0509402102
Source: PubMed


Infection with hepatitis C virus (HCV), a leading cause of chronic liver diseases, can associate with B lymphocyte proliferative disorders, such as mixed cryoglobulinemia and non-Hodgkin lymphoma. The major envelope protein of HCV (HCV-E2) binds, with high affinity CD81, a tetraspanin expressed on several cell types. Here, we show that engagement of CD81 on human B cells by a combination of HCV-E2 and an anti-CD81 mAb triggers the JNK pathway and leads to the preferential proliferation of the naïve (CD27-) B cell subset. In parallel, we have found that B lymphocytes from the great majority of chronic hepatitis C patients are activated and that naïve cells display a higher level of activation markers than memory (CD27+) B lymphocytes. Moreover, eradication of HCV infection by IFN therapy is associated with normalization of the activation-markers expression. We propose that CD81-mediated activation of B cells in vitro recapitulates the effects of HCV binding to B cell CD81 in vivo and that polyclonal proliferation of naïve B lymphocytes is a key initiating factor for the development of the HCV-associated B lymphocyte disorders.

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Available from: Gabriele Pozzato, Jan 29, 2015
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    • "On B cells CD81, as part of the costimulatory complex, including CD19 and CD21, can provide stimulatory signals that lower the threshold required for B cell to respond to antigens [Maecker and Levy, 1997; Levy et al., 1998]. The multimeric engagement of CD81 by recombinant E2 protein is sufficient to activate B lymphocytes even in the absence of B cell antigen receptor (BCR) [Rosa et al., 2005]. In addition, the B lymphocyte stimulator (BlyS) receptor–ligand system has been reported recently to be involved in HCV-induced B lymphocyte clonal disorders [Landau et al., 2009]. "
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    ABSTRACT: IgM antibodies bound to different cancer antigens have shown recently a higher diagnostic value, compared with the corresponding free molecule, giving rise to a new family of biomarkers. High or increasing levels of Squamous Cell Carcinoma Antigen (SCCA)-IgM immune complexes were associated with more advanced liver disease and increased risk of development of HCC. Rheumatoid factor (RF) represents a long-standing problem of interference for immunometric assays. The aim of the present study was to examine the specificity of SCCA-IgM in relation to the presence of RF reactivity in patients infected with hepatitis C virus (HCV). Sera of 73 patients with cirrhosis, infected with HCV, (mean age ± SD: 66 ± 13 years; M/F: 45/28), including 21 patients with HCC, were studied. SCCA-IgM immune complexes levels were measured by a commercial ELISA. To evaluate the possible interfering effect of RF, the standard calibrator, positive for SCCA-IgM, was spiked with serial dilutions of a RF positive or negative serum. SCCA-IgM immune complexes were positive in 35 out of 73 (48%) patients, while RF activity was found in 10 out of 73 (14%) patients. Patients with cirrhosis with RF activity had significantly higher levels of SCCA-IgM, compared to RF negative cases; however, no significant correlation between SCCA-IgM and RF values was observed. In samples created artificially the same results in terms of reactivity for SCCA-IgM were obtained, regardless of the presence of RF activity. These findings support the lack of correlation between the two parameters found in sera of patients infected with HCV. J. Med. Virol. 85: 1005-1008, 2013. © 2013 Wiley Periodicals, Inc.
    Journal of Medical Virology 06/2013; 85(6):1005-8. DOI:10.1002/jmv.23493 · 2.35 Impact Factor
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    • "Particular attention was focused on the E2 protein. It has been shown that E2 interacts with the tetraspannin CD81, present also on the B-cell surface and it has been suggested that this binding is responsible for a sustained polyclonal B-cell activation essentially by lowering the B-cell activation threshold [74,75]. In addition, E2 protein has been suggested to be the inciting antigen of HCV-related NHL [76]. "
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    ABSTRACT: The relationship between Hepatitis C Virus (HCV) infection and immunosuppression is complex and multifaceted. Although HCV-related hepatocytolysis is classically interpreted as secondary to the attack by cytotoxic T lymphocytes against infected cells, the liver disease is usually exacerbated and more rapidly evolutive in immunosuppressed patients. This generally occurs during the immunosuppression state, and not at the reconstitution of the host response after immunosuppressive therapy discontinuation. The field of immunosuppression and HCV infection is complicated both by the different outcome observed in different situations and/or by contrasting data obtained in the same conditions, with several still unanswered questions, such as the opportunity to modify treatment schedules in the setting of post-transplant follow-up. The complexity of this field is further complicated by the intrinsic tendency of HCV infection in itself to lead to disorders of the immune system. This review will briefly outline the current knowledge about the pathogenesis of both hepatic and extrahepatic HCV-related disorders and the principal available data concerning HCV infection in a condition of impairment of the immune system. Attention will be especially focused on some conditions - liver or kidney transplantation, the use of biologic drugs and cancer chemotherapy - for which more abundant and interesting data exist.
    Journal of Translational Medicine 08/2012; 10(1):158. DOI:10.1186/1479-5876-10-158 · 3.93 Impact Factor
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    • "It has been shown that E2 interacts with the tetraspanin CD81, present also on the B-cell surface. This binding has been suggested to be responsible for sustained polyclonal B-cell activation essentially by lowering the B-cell activation threshold [31, 32]. "
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    ABSTRACT: Hepatitis C virus (HCV) infection is a serious public health problem because of its worldwide diffusion and sequelae. It is not only a hepatotropic but also a lymphotropic agent and is responsible not only for liver injury--potentially evolving to cirrhosis and hepatocellular carcinoma--but also for a series of sometimes severely disabling extrahepatic diseases and, in particular, B-cell lymphoproliferative disorders. These latter range from benign, but prelymphomatous conditions, like mixed cryoglobulinemia, to frank lymphomas. Analogously with Helicobacter pylori related lymphomagenesis, the study of the effects of viral eradication confirmed the etiopathogenetic role of HCV and showed it is an ideal model for better understanding of the molecular mechanisms involved. Concerning these latter, several hypotheses have been proposed over the past two decades which are not mutually exclusive. These hypotheses have variously emphasized the important role played by sustained stimulation of the immune system by HCV, infection of the lymphatic cells, viral proteins, chromosomal aberrations, cytokines, or microRNA molecules. In this paper we describe the main hypotheses that have been proposed with the corresponding principal supporting data.
    Clinical and Developmental Immunology 07/2012; 2012(5):980942. DOI:10.1155/2012/980942 · 2.93 Impact Factor
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