Distinct CD55 Isoform Synthesis and Inhibition of Complement-Dependent Cytolysis by Hepatitis C Virus.
Distinct CD55 Isoform Synthesis and Inhibition of Complement-Dependent Cytolysis by Hepatitis C Virus.
复制标题
丙型肝炎病毒对依赖补体依赖性胞溶性的独特CD55同工型合成。
DOI：
10.4049/jimmunol.1600631
复制
发表时间：
2016-08-15
期刊：
影响因子：
--
通讯作者：
Ray R
中科院分区：
文献类型：
--
作者：
Kwon YC;Kim H;Meyer K;Di Bisceglie AM;Ray R
已知补体激活（RCA）的调节因子之一的CD 55/CD 14通过加速C3转化酶的衰变来限制宿主细胞表面上的过量补体激活。我们以前曾报道过丙型肝炎病毒（HCV）感染或病毒核心蛋白表达上调CD 55的表达。CD 55与HCV颗粒结合，可能保护HCV在循环中免于裂解。HCV感染细胞表面CD 55的增加可抑制补体介导的细胞杀伤。在这项研究中，我们已经表明，针对癌细胞表面蛋白的抗体诱导补体依赖性细胞溶解（CDC）或抗体依赖性细胞介导的细胞毒性（ADCC）的永生化人肝细胞（IHH）在CD 55阻断抗体的存在下。CD 55具有通过选择性剪接产生的分泌型同种型（sCD 55）。我们已经观察到，sCD 55在HCV感染的或携带HCV复制子的细胞中以及在来自慢性HCV感染患者的肝活检样品中被诱导。HCV感染的肝癌细胞（Huh 7.5）的条件培养基或IHH抑制绵羊血红细胞的C3转化酶活性和CDC。慢性HCV感染的患者血清显示C3转化酶活性的抑制，进一步暗示HCV感染的人中补体功能的特异性损害。CD 55阻断抗体抑制条件培养液对红细胞的溶解作用，提示CD 55/sCD 55具有降低转化酶活性的作用。总之，我们已经表明，HCV感染诱导sCD 55在HCV感染的细胞培养条件培养基中的表达，并抑制C3转化酶活性。这可能在微环境和HCV携带细胞中调节补体介导的免疫功能方面具有意义。
CD55/DAF, one of the regulators of complement activation (RCA), is known to limit excess complement activation on the host cell surface by accelerating the decay of C3 convertase. We have previously reported that hepatitis C virus (HCV) infection or virus core protein expression upregulates CD55 expression. CD55 associates with HCV particles, potentially protecting HCV from lysis in circulation. An increase in CD55 on HCV infected cell surface may inhibit complement mediated cell killing. In this study, we have shown that antibodies against cancer cell surface proteins induce complement dependent cytolysis (CDC) or antibody-dependent cell-mediated cytotoxicity (ADCC) of immortalized human hepatocytes (IHH) in the presence of CD55 blocking antibody. CD55 has a secreted isoform (sCD55) generated by alternative splicing. We have observed that sCD55 is induced in HCV infected or HCV replicon harboring cells, and in liver biopsy samples from chronically HCV infected patients. Conditioned medium from HCV infected hepatoma cells (Huh7.5) or IHH inhibited C3 convertase activity and CDC of sheep blood erythrocytes. Chronically HCV infected patient sera displayed inhibition of C3 convertase activity, further implicating HCV specific impairment of complement function in infected humans. CD55 blocking antibody inhibited erythrocyte lysis by conditioned medium, suggesting CD55/sCD55 has a function for impairing convertase activity. Together, we have shown that HCV infection induces sCD55 expression in HCV infected cell culture conditioned medium, and inhibits C3 convertase activity. This may have implication in modulating complement mediated immune function in the microenvironment and on HCV harboring cells.