系统性硬皮病(SSc)是一种多器官、多系统受累的自身免疫性疾病，其发病机制至今尚未完全明了。异常活化的T淋巴细胞被认为在该病的发病中起着关键作用。本课题组研究证实，CD4+T细胞DNA低甲基化导致CD40L、CD70等基因过度表达是引起其异常活化及SSc发病的重要机制之一，然而，其低甲基化的机制并不清楚。近年来，Tet蛋白家族因具有去甲基化酶的功能而倍受关注。我们的初步研究发现，Tet1在SSc患者CD4+T细胞中表达水平明显增高; 在转染Tet1质粒的正常人CD4+T细胞中，上述基因启动子区域则发生了低甲基化。提示 SSc患者该细胞DNA调控区域低甲基化可能与Tet1表达上调有关。本课题拟在上述基础上，探讨Tet1对CD40L和CD70基因的调控作用及机制, 进而探讨其在SSc发生、发展中的作用。有可能揭示该病中T细胞病理性低甲基化的分子机制，并有望为SSc的治疗提供新的思路和途径。

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 T cell results in overexpression of CD40L and CD70 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 molecular basis of DNA demethylation in SSc T cells are still unclear. Rencently, Many studies indicate that the human Tet(Ten-eleven translocation) protein family could catalyse the conversion of 5-methylcytosine(5mC) of DNA to 5-hydroxymethylcytosine (5hmC) raising the possibility that DNA demethylation may be a Tet-mediated process. Because of its demethylase function, Tet protein family play a key role in a variety of biological processes and have attracted much attention. In our previous preliminary study, elevated Tet1 mRNA and protein expression were observed in CD4+ T cells from SSc patients.The average level of methylation of the CD40L and CD70 promoter regions was significantly reduced in CD4(+)T cells transfected with pcDNA3.1-Tet1 as compared with blank plasmid-transfected controls.These results suggest that hypomethylation of CD40L and CD70 genes regulatory regions may be related to Tet1 upregulation in SSc patients. On the basis of preliminary experiments,this study is intended to explore Tet1 regulatory function of CD40L and CD70 gene methylation and its molecular mechanism. Furthermore, to reveal the role of upregulation of Tet1 protein contributing to the development of autoimmunity by promoting DNA demethylation in SSc CD4 +T cells.It will be possible to descover 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.