雄激素信号调控Th17应答介导乙型肝炎活化的效应及机制研究

There is male predominance for the clinical outcomes of chronic hepatitis B virus (HBV) infection, such as severe hepatitis B and liver cirrhosis. We had preliminary found that serum testosterone levels were significantly higher at hepatitis flare point than inactive phase, and the medium CAG repeats in AR gene exon 1 were associated with lower serum testosterone levels in asymptomatic HBV carriers and an increased susceptibility to HBV-related ALF. However, the exact functional role of androgen signal pathway on the male predominance remain unclear. Recent studies revealed that human CD4+ T cells exhibited a sex difference for polarization, and androgen augmented Th1 to Th17 shift via PPAR alpha in female patients with multiple sclerosis. We speculate that androgen-androgen receptor may regulate the polarizations and functions of CD4+ T cells through PPARα/PPARγ balance, leading to the sex difference of hepaitis B. In this project, we plan to observe the polariztion effect of androgen on CD4 T cells, study the regulation mechanisms of androgen-AR on PPARα/PPARγ balance, and PPARα/PPARγ balance on activation and function of Th17. Our study would provide novel evidence for the mechanisms of sex difference in immune activation for chronic hepatitis B patients.

慢性HBV感染相关重型肝炎、肝硬化等疾病转归存在显著的性别差异，男性发病风险显著高于女性。我们的前期发现，乙型肝炎活化时血清睾酮水平存在脉冲性上升，雄激素受体（AR）CAG重复与重型乙型肝炎显著相关，但其功能效应和介导性别差异的机制尚不清楚。最近发现CD4 T细胞极化存在性别差异，雄激素可通过PPAR促进多发性硬化女性患者发生Th1向Th17的偏移。我们推测，雄激素-AR信号通路可能通过PPARα/PPARγ调控CD4 T细胞极化和功能，导致了乙型肝炎患者发病风险的显著性别差异。本研究拟从患者CD4 T细胞ex vivo水平研究雄激素刺激/极化效应、H9 T细胞株水平研究雄激素-AR-PPAR亚型调控机制、基于ChIP-seq分析雄激素-AR/PPARα/γ调控网络，明确雄激素信号通路通过PPARα/PPARγ平衡调控Th17极化和功能的具体机制，以期认识乙型肝炎免疫活化的性别差异机制。

慢性HBV感染相关重型肝炎、肝硬化等疾病转归存在显著的性别差异，男性发病风险显著高于女性。我们前期发现，乙型肝炎活化时血清睾酮水平存在脉冲性上升，雄激素受体（AR）CAG重复与重型乙型肝炎显著相关，但其功能效应和介导性别差异的机制尚不清楚。最近发现CD4+T细胞极化存在性别差异，雄激素可通过PPAR促进多发性硬化女性患者发生Th1向Th17的偏移。我们推测，雄激素及其受体（AR）信号通路可能通过PPARα/PPARγ调控CD4+T细胞极化和功能，导致了乙型肝炎患者发病风险的显著性别差异。本项目从临床研究及疾病关联研究水平探讨了雄激素水平与HBV感染肝脏炎症的关系，以及CAG重复与急性肝衰竭疾病相关性，从遗传学及表观遗传学研究水平，探讨CAG重复对AR基因功能的影响和疾病关联，细胞和分子水平探讨雄激素及AR基因外显子CAG功能多态位点对AR转录活性及雄激素特异的免疫细胞刺激效应的影响及调控作用，从患者CD4+T细胞ex vivo水平研究雄激素刺激/极化效应、H9 T细胞株水平研究雄激素-AR-PPAR亚型调控机制，明确雄激素信号通路通过PPARα/PPARγ平衡调控Th17极化和功能的具体机制，可能为认识乙型肝炎免疫活化的性别差异机制提供新思路。