Immunoglobulin Allotypes in Hepatitis C Virus Infection

丙型肝炎病毒(丙型肝炎病毒)是一个主要的健康问题，影响着全球超过1.7亿人。人的数量 急性感染丙型肝炎病毒的人中，大约15%的人会自发清除病毒。由于实验的局限性 模型和罕见的自然急性感染，病毒清除的机制是 人们对此知之甚少。有临床和流行病学线索表明宿主因素是关键因素。其中 影响丙型肝炎病毒感染结局的因素，宿主遗传因素被认为起作用 主要角色。免疫球蛋白(Ig)GM和KM同种异型免疫球蛋白遗传抗原决定簇 重链和k型轻链分别与病毒免疫学特性有关，以及 因此是研究丙型肝炎病毒致病因素的理想候选基因系统 发病机制。我们推测GM和KM等位基因可能与丙型肝炎病毒感染的结局有关。 通过它们对病毒抗原的同种异型限制性抗体反应的可能影响。另外， 它们可能通过与丙型肝炎病毒的不同相互作用而影响抗体依赖性T细胞对丙型肝炎病毒的杀伤作用 FcGamma受体(FcGammaR)。Gm和Km同种异型也可以调节Ig分子的策略 这种病毒利用拟态和FcGammaR样活性来逃避宿主的免疫监视。为了测试 我们的假设是病例对照研究，其具体目的如下：(1)进一步 建立丙型肝炎病毒感染结局与免疫球蛋白GM和KM同种异型之间的关联程度 在非裔美国人中；(2)确定GM和KM等位基因是否与丙型肝炎病毒的结局相关 (3)检测丙型肝炎病毒体液免疫应答的特异性和效价 抗原(核心、E1、E2、NS3、NS4、NS5)，并确定这些抗体的产生是否受 Gm和Km同种异型；(4)确定丙型肝炎病毒编码的FcGammaR是否与免疫球蛋白分子有差异结合 携带不同的转基因同种异型。Gm和Km等位基因分型将通过血凝抑制直接进行 DNA测序和聚合酶链式反应-限制性片段长度多态性方法。丙型肝炎病毒免疫球蛋白抗体将通过酶联免疫吸附试验检测。 不同GM同种异型的免疫球蛋白分子与丙型肝炎病毒FcGammaR的结合和亲和力的比较 通过表面等离子体共振检测进行监测。这次调查的结果将推进我们的 了解宿主遗传因素在丙型肝炎病毒感染清除和持续中的作用。

Hepatitis C virus (HCV) is a major health problem, affecting over 170 million people worldwide. Of persons acutely infected with HCV, about 15% spontaneously clear the virus. Because of limitations in experimental models and the infrequent recognition of natural acute infection, the mechanisms of viral clearance are poorly understood. There are clinical and epidemiologic clues that suggest host factors are critical. Among the factors influencing the outcome of HCV infection, the host genetic factors are thought to play a predominant role. Immunoglobulin (Ig) GM and KM allotypes¿hereditary antigenic determinants of IgG heavy chains and k-type light chains, respectively¿are associated with viral immunological properties, and thus are ideal candidate genetic systems for investigations to identify risk-conferring factors in HCV pathogenesis. We hypothesized that GM and KM allotypes may contribute to the outcome of HCV infection through their possible influence on allotype-restricted antibody responses to the viral antigens. Additionally, they may influence antibody dependent T cell cytotoxicity to HCV by their differential interaction with Fcgamma receptors (FcgammaR). GM and KM allotypes could also modulate the strategies¿Ig molecular mimicry and FcgammaR-like activity¿employed by this virus to evade host immune surveillance. To test our hypothesis, a case control study has been designed with the following specific aims: (1) to further establish the magnitude of association between the outcome of HCV infection and Ig GM and KM allotypes in African Americans; (2) to determine if GM and KM allotypes are associated with the outcome of HCV infection in Caucasians; (3) to measure the specificity and titer of the humoral immune responses to HCV antigens (core, E1,E2,NS3,NS4,NS5) and determine if the production of these antibodies is influenced by GM and KM allotypes; (4) to determine if HCV-encoded FcgammaR binds differentially with IgG molecules carrying different GM allotypes. GM and KM allotyping will be done by hemagglutination-inhibition, direct DNA sequencing, and PCR-RFLP methods. IgG antibodies to HCV antigens will be measured by an ELISA. Binding and comparative affinities of IgG molecules of different GM allotypes to HCV-FcgammaR will be monitored by surface plasmon resonance detection. Results of this investigation will advance our understanding of the role of host genetic factors in clearance and persistence of hepatitis C virus infection.