Immunoglobulin Allotypes in Hepatitis C Virus Infection

丙型肝炎病毒感染中的免疫球蛋白同种异型

• 批准号: 7029163
• 负责人: JANARDAN P PANDEY
• 金额: $ 19.6万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-03-01 至 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7029163
• 关键词: African American; CD antigens; antibody receptor; antiviral antibody; caucasian American; clinical research; cytotoxic T lymphocyte; enzyme linked immunosorbent assay; hemagglutination test; hepatitis C virus; host organism interaction; human genetic material tag; human tissue; humoral immunity; immune response; isoantibody; microorganism immunology; nucleic acid sequence; polymerase chain reaction; surface plasmon resonance; virus antigen

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：丙型肝炎病毒 (HCV) 是一个主要的健康问题，影响着全世界超过 1.7 亿人。在 HCV 急性感染者中，约 15% 会自发清除病毒。由于实验模型的局限性以及对自然急性感染的认识很少，人们对病毒清除的机制知之甚少。临床和流行病学线索表明宿主因素至关重要。在影响HCV感染结果的因素中，宿主遗传因素被认为起着主导作用。免疫球蛋白 (Ig) GM 和 KM 同种异型（分别是 IgG 重链和 k 型轻链的遗传性抗原决定簇）与病毒免疫特性相关，因此是研究确定 HCV 发病机制中风险因素的理想候选遗传系统。我们假设 GM 和 KM 同种异型可能通过影响同种异型限制性抗体对病毒抗原的反应而导致 HCV 感染的结果。此外，它们可能通过与 Fcgamma 受体 (FcgammaR) 的不同相互作用来影响抗体依赖性 T 细胞对 HCV 的细胞毒性。 GM 和 KM 同种异型还可以调节该病毒用来逃避宿主免疫监视的策略——Ig 分子拟态和 FcgammaR 样活性。为了检验我们的假设，设计了一项病例对照研究，其具体目的如下：（1）进一步确定非裔美国人中 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 同种异型是否与白种人 HCV 感染结果相关； (3) 测量针对HCV抗原（核心、E1、E2、NS3、NS4、NS5）的体液免疫反应的特异性和效价，并确定这些抗体的产生是否受到GM和KM同种异型的影响； (4)确定HCV编码的FcgammaR是否与携带不同GM同种异型的IgG分子有差异地结合。 GM 和 KM 同种异型分型将通过血凝抑制、直接 DNA 测序和 PCR-RFLP 方法完成。 HCV 抗原的 IgG 抗体将通过 ELISA 进行测量。不同GM同种异型的IgG分子与HCV-FcgammaR的结合和比较亲和力将通过表面等离子体共振检测来监测。这项调查的结果将增进我们对宿主遗传因素在丙型肝炎病毒感染清除和持续性中的作用的理解。