Rosa Domenico, Saletti Giulietta, De Gregorio Ennio, Zorat Francesca, Comar Consuelo, D'Oro Ugo, Nuti Sandra, Houghton Michael, Barnaba Vincenzo, Pozzato Gabriele, Abrignani Sergio
Chiron Vaccines, 53100 Siena, Italy.
Proc Natl Acad Sci U S A. 2005 Dec 20;102(51):18544-9. doi: 10.1073/pnas.0509402102. Epub 2005 Dec 9.
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.
丙型肝炎病毒（HCV）感染是慢性肝病的主要病因，可与B淋巴细胞增殖性疾病相关，如混合性冷球蛋白血症和非霍奇金淋巴瘤。HCV的主要包膜蛋白（HCV-E2）以高亲和力结合CD81，CD81是一种在多种细胞类型上表达的四跨膜蛋白。在此，我们表明，HCV-E2和抗CD81单克隆抗体共同作用于人类B细胞上的CD81，可触发JNK通路，并导致幼稚（CD27-）B细胞亚群优先增殖。同时，我们发现绝大多数慢性丙型肝炎患者的B淋巴细胞被激活，且幼稚细胞比记忆（CD27+）B淋巴细胞显示出更高水平的激活标志物。此外，干扰素治疗消除HCV感染与激活标志物表达的正常化相关。我们提出，体外CD81介导的B细胞激活概括了体内HCV与B细胞CD81结合的效应，并且幼稚B淋巴细胞的多克隆增殖是HCV相关B淋巴细胞疾病发生发展的关键起始因素。
