系统性硬皮病（SSc）是以皮肤以及内脏器官结缔组织纤维化、硬化和萎缩为主要表现的自身免疫病。其具体发病机制尚不明了。异常活化的T细胞被认为在该病的发病中起关键作用。本课题组证实，羟甲基酶tet1高表达导致CD4+T 细胞基因组低甲基化，进而使CD40L、CD70等基因过度表达是引起其异常活化是SSc 发病的重要机制，但在硬皮病患者中Tet1异常激活的机制不明。近年来，干扰素通路在自身免疫性疾病中的作用受到越来越多的关注。我们初步研究发现，干扰素诱导蛋白Oasl及其下游转录因子IRF7在SSc患者CD4+T 细胞中表达水平明显增高；同时发现Tet1的转录调节区域含有IRF7结合原件。提示SSc患者Tet1高表达可能受干扰素通路调控。本课题拟在上述基础上，探讨Oasl/IRF7通路对CD4+T细胞病理性低甲基化的影响，进而探讨其在SSc发生、发展中的作用，并有望为SSc 的治疗提供新的思路和途

Systemic sclerosis (SSc) is an autoimmune disease that involves multiple systems characterized by autoantibody formation, vascular obliteration, excessive extracellular matrix deposition. The pathogenic mechanisms remain incompletely understood. Abnormal activation of T cells may play a central role in the pathogenesis of SSc. In our previous studies, we demonstrated that DNA demethylation of CD4+T cell results in overexpression of CD40L, CD70 and CD11a genes from patients with SSc. Overexpression of these genes results in T cell autoreactivity, B cell immunoglobulin overproduction and fibroblast's collagen synthesis. These may contribute to pathogenic mechanisms in SSc. The DNA demethylation of T cell is coused by a Demethylase Tet1. However, the mechanism that Tet1 is abnormally activated is unknown in patients with scleroderma. In our previous preliminary study, the expression level of a interferon induced protein Oasl and IRF7 increased significantly in CD4+T cell of SSc patients. IRF7 can bind the transcription site of Tet1. These results suggest that the increased Tet1 expression in SSc patient may be regulated by the Interferon Pathway. In this study, we tend to explore the Oasl/IRF7 pathway underlying DNA demethylation in SSc T cells. It will be possible to discover the key aspects and molecular mechanisms of pathological hypomethylation T cells and autoimmune reactions of SSc patients. These studies provide new insights into the mechanisms causing DNA demethylation in SSc T cells, and suggest novel approaches for the treatment of SSc and may be a target for more effective SSc treatment.