雄激素信号调控HLA-II差异表达介导Kupffer细胞促炎效应及机制研究

慢性乙型肝炎病毒（HBV）感染后，肝脏微环境免疫应答及调控是炎症活化与消退的关键环节，但其确切调控机制尚不清楚。最新全基因组关联研究提示，HLA-Ⅱ类基因是影响慢性HBV感染转归最显著的基因。Kupffer细胞在肝脏持续性炎症过程中具有中心调控作用，可表达HLA-Ⅱ类分子提呈抗原，激活CD4 T细胞。雄激素可促进HLA-Ⅱ类分子表达，我们前期发现HLA-Ⅱ类基因启动子存在雄激素反应元件，具有性激素差异转录调控基础。我们推测，雄激素信号可能在转录水平调控HLA-Ⅱ类分子差异表达，进而调控CD4 T细胞极化和Kupffer细胞表型可塑性。本课题拟从雄激素水平、HLA-Ⅱ类分子差异转录、Kupffer细胞表型可塑性调控、CD4 T细胞极化效应等层次，探索雄激素调控Kupffer细胞表达HLA-Ⅱ分子及其促炎效应的机制，以期对肝脏持续性炎症的转归机制产生新认识，为慢性乙型肝炎防治提供有效干预靶点。

HBV-specific CD4 T response and its regulation in liver microenvironment is thought as the key procedure for patients with chronic hepatitis B virus (HBV) infection. However, the exact mechanisms have not been well elucidated. Recently, the genome-wide association studies of ours and other investigators had indicated that HLA class Ⅱ genomic region was the most significant locus for HBV-related chronic liver disease. Kupffer cells are the major regulator in persistent inflammation, which express HLA class Ⅱ molecules and present antigen to CD4 T cells. Androgen could promote the expression of HLA-II molecules, with immunomodulatory effect in the liver microenvironment. Additionally, our preliminary study also showed that there were androgen response elements in the promoter of HLA class Ⅱ gene. So, we hypothesized that the plasticity of HLA-Ⅱ expression (quantity, species, patterns and differentiated allelic combinations) may regulate the plasticity of Kupffer cells and the polarization of CD4 T cells during the persistent inflammation in an androgen-dependent manner. In this project, we investigate the regulations of expression patterns of HLA class II on plasticity of Kupffer cells, the androgen-specific transcription of HLA-II molecules, and differential polarization effects of HLA-II molecules on CD4 T cells. This study may elucidate novel mechanisms involved in the outcomes of persistent inflammations in patients with chronic HBV infection, and find out some new targets for the prevention and intervention of chronic liver diseases.