Immunoglobulin Allotypes in Hepatitis C Virus Infection

丙型肝炎病毒（HCV）是一种主要的健康问题，影响着全球超过1.7亿人。人 急性感染HCV后，约有15%的人会自发清除病毒。由于实验的局限性， 模型和自然急性感染的罕见认识，病毒清除的机制是 不太了解。有临床和流行病学线索表明宿主因素至关重要。之间 HCV感染预后的影响因素中，宿主遗传因素被认为是影响HCV感染预后的重要因素。 主导作用。免疫球蛋白（IG）GM和KM同种异型？IgG的遗传抗原决定簇 重链和k型轻链分别与病毒免疫学特性相关， 因此，它们是研究确定HCV风险因子的理想候选遗传系统 发病机制我们假设GM和KM同种异型可能有助于HCV感染的结果 通过它们可能影响同种异型限制性抗体对病毒抗原的反应。此外，本发明还 它们可能通过与HCV的不同相互作用影响抗体依赖性T细胞对HCV的细胞毒性。 Fc γ受体（Fc γ R）。GM和KM同种异型也可以调节IG分子的策略 这种病毒利用模仿和Fc γ R样活性来逃避宿主免疫监视。测试 我们的假设，病例对照研究已经设计了以下具体目标：（1）进一步 确定HCV感染结果与IG GM和KM同种异型之间的关联程度 （2）确定GM和KM同种异型是否与HCV的结局相关 （3）检测对HCV的体液免疫应答的特异性和滴度 抗原（核心，E1，E2，NS 3，NS 4，NS 5），并确定这些抗体的产生是否受到 GM和KM同种异型;（4）确定HCV编码的Fc γ R是否与IgG分子差异结合 携带着不同的转基因同种异型GM和KM同种异型分型将通过血凝抑制直接进行 DNA测序和PCR-RFLP方法。将通过ELISA测量HCV抗原的IgG抗体。 不同GM同种异型的IgG分子与HCV-Fc γ R的结合和比较亲和力将在下文中描述。 通过表面等离子体共振检测监测。这次调查的结果将推动我们的 了解宿主遗传因素在清除和持续丙型肝炎病毒感染中的作用。

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.