HLA-DR/DQ等位在慢性HBV感染免疫损伤中的作用及机制研究

慢性HBV感染是我国最主要的慢性病毒感染，机体免疫应答导致的肝损伤是其致病机制的关键问题，目前认为病毒特异性的CD4 T细胞应答是免疫损伤的关键环节，但具体启动机制并不清楚。我们前期GWAS研究发现，HLA- DR/DQ是决定乙型肝炎重度损伤的关键分子。我们推测，HLA-DR/DQ等位可能通过表位提呈选择CD4 T细胞repertoire，确定了病毒准种的表位漂移、个体患者免疫耐受打破的阈值和免疫应答的偏向性。本课题拟精细解析HLA-DR/DQ等位分子限制的病毒特征变异（HBV全长序列变异模式）、特征表位（S、C、P、X蛋白表位肽作图）、特征CD4 T细胞极化（in vitro、ex vivo亚群、损伤/保护效应、TCR repertoire）、限制表位的交叉/等位之间的交互作用（HLA-DR/DQ-HBV转基因小鼠in vivo模型）四个层次，揭示乙型肝炎免疫损伤的机制。

Chronic hepatitis B virus (HBV) infection is the major human viral infection in China, immune injury is the key step for HBV pathogenesis. Recent studies show that HBV-specific CD4 T cell responses play an important role on the immune injury, however, the exact mechanism is not clear. Our preliminary genome-wide association study revealed the HLA-DR/DQ region was the only injury associated locus. We hypothesize the highly polymorphic HLA-DR/DQ alleles may select the CD4 T cell repertoire via epitope presentation, and restrict the epitope drift of viral quasispecies, breaking threshold of individual immune tolerance, and the bias of immune responses. In this project, we expect to dissect the mechanism involved in immune injury of chronic HBV infection based on four aspects: the viral variation pattern (full-length HBV genomic levels), viral antigen epitopes (epitope-mapping on S, C, P, X protein), CD4 T cell polarization (in vitro and ex vivo cell phenotypes, injury / protection effects, TCR repertoire) and interaction between epitopes / DR/DQ alleles (in vivo HLA-DR/DQ-HBV transgenic mice model).