MeCP2在葡萄膜炎中对免疫系统的调节作用

Epigenetic modification plays an important role in regulating the functin of immune system. And MeCP2 is the critical epigenetic molecule that binds to methylated DNA and regulates gene expression. The previous work of the applicant has revealed that: in both MeCP2 overexpression mice and MECP2 duplication syndrome patients, MeCP2 overexpression resulted in decreased IFN-γ secretion and impaired Th1 responses, thus leading to immunodeficiency. Importantly, dysregulation of T helper cells is the critical underlying mechanisms for autoimmune diseases. However, the role of MeCP2 in autoimmune diseases still remain unknown. On the basis of previous work, our project will investigate the regulatory role of MeCP2 in autoimmune disease in the model of experimental autoimmune uveitis (EAU). We will (1) examine the pathogenesis of EAU in MeCP2 overexpression or knockout mice; (2) examine the effect of MeCP2 on the balance of T helper cell development, including Th1、Th17、Treg; (3)examine the effect of MeCP2 on the function of dendritic cells; (4) investigate the upstream regulatory mechanisms for MeCP2 function in T helper cells. This project will clarify the mechanisms by which epigenetic system regulates immune system in autoimmune diseases such as EAU. And the result will provide important theoretical basis for prevention and therapeutics of autoimmune diseases such as uveitis.

表观遗传修饰对免疫系统功能具有重要调节作用，MeCP2是关键的表观遗传修饰分子，通过结合甲基化DNA调控基因表达。申请人的前期工作发现：MeCP2过表达在小鼠和MECP2复制综合症患者中引起IFN-γ分泌降低，导致Th1分化缺陷，从而造成机体的免疫缺陷。辅助性T细胞功能与自身免疫性疾病致病密切相关，但MeCP2在自身免疫性疾病中的作用尚未明确。在前期工作基础上，本项目将以实验性葡萄膜炎（EAU）为模型研究MeCP2在自身免疫性疾病中的调控作用：(1) 观察MeCP2过表达或敲除小鼠中EAU的发病情况；(2)研究MeCP对Th1、Th17、Treg分化平衡及功能的调控作用；（3）研究MeCP2对树突细胞功能的影响；（4）探讨在辅助性T细胞中调控MeCP2功能及Th1分化的上游分子机制。 本项目将深入阐明表观遗传修饰在自身免疫性疾病中的调控机制，为葡萄膜炎等自身免疫性疾病的防治提供理论依据。

表观遗传修饰对免疫系统功能具有重要调节作用，MeCP2是关键的表观遗传修饰分子，通过结合甲基化DNA调控基因表达。本项目以实验性葡萄膜炎（EAU）为模型研究MeCP2在自身免疫性疾病中的调控作用。我们发现，MeCP2过表达小鼠中EAU发病情况减轻，相关炎症因子表达下降，T细胞增殖情况无显著变化。发现MeCP2敲除小鼠中EAU发病情况加重，相关炎症因子表达上升。MeCP2的过表达导致EAU发病中Th1细胞分化减少，MeCP2敲除导致EAU发病中Th1细胞分化增加，而Th17细胞的分化变化不明显。MeCP2过表达的抗原特异性Th1细胞致病性降低，MeCP2敲除小鼠Th1的致病性与对照相比无明显变化。发现miR-22对MeCP2的表达有重要调控作用。本研究揭示了MeCP2在葡萄膜炎中的重要调控作用，为葡萄膜炎等自身免疫性疾病的防治提供了理论依据。