从PTPs相关蛋白对T淋巴细胞的调控作用探讨葡萄膜炎的发病机制

Behcet disease and Vogt-Koyanagi-Harada (VKH) syndrome are the two most common uvieitis entities leading to blindness in China, which are both considered to be immune-related disorders. However, the precise pathogenesis is still need to be elucidated. PTPN2 and PTPN22, which are involved in negative regulation of the T-cell-related pathway, have been shown to be associated with numbers of immune-mediated diseases. Our preliminary studies showed that an association of polymorphisms in PTPN2 gene with Behcet disease and an association of polymorphisms in PTPN22 gene with VKH syndrome, suggesting involvement of both PTPN2 and PTPN22 in the development of these two diseases. We have collected samples from patients (1000 patients with Behcet disease and 1000 patients with VKH syndrome) and controls (2000 healthy individuals) for the study. This project focusing on two genes (PTPN2 and PTPN22) and T cells with genetic and immunologic methods aims to: ①to investigate the association between PTPN2 or PTPN22 polymorphism and the susceptibility to these two uveitis entities in a large population of Chinese Han population; ②to examine the mRNA and protein expression of this gene in immune cells in order to determine the influence of polymorphisms on gene expression; ③to investigate the effect of PTPN2 and PTPN22 on T cell proliferation and activation and to further characterize the molecular basis of these two genes in immune responses involved in these two diseases. This project may clarify the mechanisms for involvement of PTPN2 and PTPN22 in the pathogenesis of Behcet disease and VKH syndrome, and may throw light on the prevention and individualized treatment for uvetitis.

Behcet病和Vogt-小柳原田（VKH）综合征是我国常见致盲性眼病，发病机制尚不完全清楚。PTPs家族的PTPN2和PTPN22同属T细胞信号通路的负性调控基因，与多种自身免疫炎症性疾病相关。我们前期实验发现PTPN2、PTPN22启动子多态分别与Behcet病、VKH综合征相关，提示它们可能参与这两种疾病的发生。本项目以PTPN2和PTPN22基因为切入点，用大样本进一步确定PTPN2及PTPN22基因多态与Behcet病和VKH综合征的相关性，从易感性层面揭示其作用；从分子水平探究基因多态对基因转录和蛋白翻译的影响，阐明其生物学功能；从细胞水平探讨基因多态及相关蛋白对T细胞数量和/或功能的影响，阐明其调控自身免疫炎症形成的分子机制。本项目的实施将可能揭示PTPN2及PTPN22通过何种机制参与Behcet病和VKH综合征的发生，为葡萄膜炎的个体化防治研究提供新的靶点。

Behcet病、VKH综合征和急性前葡萄膜炎是我国致盲率最高的葡萄膜炎类型。迄今为止，这三种疾病发生的分子机制尚不完全清楚。本项课题在中国汉族人群中利用候选基因关联研究分析Behcet病、VKH综合征和急性前葡萄膜炎的遗传易感基因，并探讨这些基因的遗传变异（单核苷酸多态性）影响疾病易感性的分子生物学机制，主要包括以下3个方面：1. 鉴定了PTPN22/ rs2488457多态与VKH综合征的遗传易感性显著相关，而与急性前葡萄膜炎的遗传易感性无显著相关；进一步研究发现，rs2488457位点的CC基因型样本与CG/GG基因型样本相比较，PTPN22的表达水平显著降低，IL-10的表达水平显著降低；2. 鉴定了PTPN2/ rs7234029多态与Behcet病的遗传易感性显著相关，IL-2Rβ基因多态与Behcet病的遗传易感性无显著相关；PTPN2/ rs7234029位点的GG基因型样本与AG/AA基因型样本相比较，PTPN2的表达水平显著增高；3. 鉴定了TNFSF15/ rs3810936多态与急性前葡萄膜炎的遗传易感性显著相关。综上所述，这些研究为葡萄膜炎的个体化防治提供了新的靶点。