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

Università degli Studi di Trieste, Trst, Friuli Venezia Giulia, 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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    • "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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    • "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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