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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

基本信息

批准号：
7367031
负责人：
JANARDAN P PANDEY
金额：
$ 18.69万
依托单位：
MEDICAL UNIVERSITY OF SOUTH CAROLINA
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-03-01 至 2010-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7367031
关键词：
Accounting Acute Affect Affinity African American Antibodies Antibody Formation Binding Biological Case-Control Studies Caucasians Caucasoid Race Clinical DNA Sequence Detection Enzyme-Linked Immunosorbent Assay Epitopes Ethnic group Experimental Models Frequencies Genes Genetic Genotype Haplotypes Health Hemagglutination Hepatitis C Hepatitis C virus Immune response Immunoglobulin Allotypes Immunoglobulin G Immunoglobulins Immunologic Surveillance Individual Infection Integration Host Factors Interferons Investigation Light Measures Methods Molecular Mimicry Monitor Outcome Persons Phenotype Play Population Population Study Property Race Reporting Risk Role Sampling Specificity Surface Plasmon Resonance System T-Lymphocyte Testing Thinking Variant Viral Viral Antigens Virus base comparative cytotoxicity design receptor receptor binding response sound virus pathogenesis

项目摘要

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.

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。人数急性感染HCV时，约15%会自发清除病毒。由于实验的限制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。临床和流行病学线索表明宿主因素至关重要。之中影响HCV感染结果的因素中，宿主遗传因素被认为发挥着重要作用占主导地位。免疫球蛋白 (Ig) GM 和 KM 同种异型——IgG 的遗传性抗原决定簇重链和 k 型轻链分别与病毒免疫特性相关，并且因此，这是用于研究以确定 HCV 风险因素的理想候选遗传系统发病。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，它们可能通过与 HCV 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。 Fcgamma 受体 (FcgammaR)。 GM 和 KM 同种异型也可以调节策略——Ig 分子该病毒利用拟态和 FcgammaR 样活性来逃避宿主免疫监视。测试我们的假设是，病例对照研究的设计目的如下：（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在非裔美国人中； (2) 确定GM和KM同种异型是否与HCV结果相关白种人感染； (3)测定HCV体液免疫反应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到以下因素的影响 GM 和 KM 同种异型； (4) 确定HCV编码的FcgammaR是否与IgG分子有差异结合携带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。 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是通过表面等离子体共振检测进行监测。这项调查的结果将推动我们了解宿主遗传因素在丙型肝炎病毒感染清除和持续存在中的作用。