Wang Richard Y, Bare Patricia, De Giorgi Valeria, Matsuura Kentaro, Salam Kazi Abdus, Grandinetti Teresa, Schechterly Cathy, Alter Harvey J
Department of Transfusion Medicine, Clinical Center, National Institutes of Health, Bethesda, MD.
Instituto de Investigaciones Hematológicas, Instituto de Medicina Experimental, CONICET, Academia Nacional de Medicina, Buenos Aires, Argentina.
Hepatology. 2016 Dec;64(6):1900-1910. doi: 10.1002/hep.28842. Epub 2016 Oct 24.
Extrahepatic disease manifestations are common in chronic hepatitis C virus (HCV) infection. The mechanism of HCV-related lymphoproliferative disorders is not fully understood. Recent studies have found that HCV in peripheral blood mononuclear cells from chronically infected patients is mainly associated with cluster of differentiation 19-positive (CD19 ) B cells. To further elucidate this preferential association of HCV with B cells, we used in vitro cultured virus and uninfected peripheral blood mononuclear cells from healthy blood donors to investigate the necessary serum components that activate the binding of HCV to B cells. First, we found that the active serum components were present not only in HCV carriers but also in HCV recovered patients and HCV-negative, healthy blood donors and that the serum components were heat-labile. Second, the preferential binding activity of HCV to B cells could be blocked by anti-complement C3 antibodies. In experiments with complement-depleted serum and purified complement proteins, we demonstrated that complement proteins C1, C2, and C3 were required to activate such binding activity. Complement protein C4 was partially involved in this process. Third, using antibodies against cell surface markers, we showed that the binding complex mainly involved CD21 (complement receptor 2), CD19, CD20, and CD81; CD35 (complement receptor 1) was involved but had lower binding activity. Fourth, both anti-CD21 and anti-CD35 antibodies could block the binding of patient-derived HCV to B cells. Fifth, complement also mediated HCV binding to Raji cells, a cultured B-cell line derived from Burkitt's lymphoma.
In chronic HCV infection, the preferential association of HCV with B cells is mediated by the complement system, mainly through complement receptor 2 (CD21), in conjunction with the CD19 and CD81 complex. (Hepatology 2016;64:1900-1910).
肝外疾病表现在慢性丙型肝炎病毒（HCV）感染中很常见。HCV相关淋巴增殖性疾病的机制尚未完全了解。最近的研究发现，慢性感染患者外周血单个核细胞中的HCV主要与分化簇19阳性（CD19）B细胞相关。为了进一步阐明HCV与B细胞的这种优先关联，我们使用体外培养的病毒和来自健康献血者的未感染外周血单个核细胞来研究激活HCV与B细胞结合的必需血清成分。首先，我们发现活性血清成分不仅存在于HCV携带者中，也存在于HCV康复患者以及HCV阴性的健康献血者中，并且血清成分对热不稳定。其次，HCV与B细胞的优先结合活性可被抗补体C3抗体阻断。在使用补体缺失血清和纯化补体蛋白的实验中，我们证明补体蛋白C1、C2和C3是激活这种结合活性所必需的。补体蛋白C4部分参与了这一过程。第三，使用针对细胞表面标志物的抗体，我们表明结合复合物主要涉及CD21（补体受体2）、CD19、CD20和CD81；CD35（补体受体1）也参与其中，但结合活性较低。第四，抗CD－21和抗CD35抗体均可阻断患者来源的HCV与B细胞的结合。第五，补体也介导HCV与Raji细胞的结合，Raji细胞是一种源自伯基特淋巴瘤的培养B细胞系。
在慢性HCV感染中，HCV与B细胞的优先关联由补体系统介导，主要通过补体受体2（CD21），并与CD19和CD81复合物结合。（《肝脏病学》2016年；64：1900 - 1910）
