Th9细胞在多发性大动脉炎中损伤主动脉内皮细胞的作用及其分子机制

Takayasu arteritis (TA) is a severe autoimmune large vessel vasculitis. T lymphocyte infiltration and induced vascular endothelial cell injury play a crucial role in the pathogenesis of TA. The related exact immune mechanisms remain to be elucidated. Latest research suggested T helper（Th）9 cells, a new subset of T cells and interleukin (IL)-9 (main cytokine secreted by Th9) may increase the inflammatory response in promoting a variety of autoimmune diseases. Th9 cells can mediate CD8 + T cells activation and then induce tissue damage. Our preliminary results showed that the sera level of IL-9 and the percentage of Th9 cells in TA patients were significantly elevated, IL-9 expression and CD8+T cells infiltration were showed in aorta tissue of TA patients, which suggested that Th9 cells may play an important role in the pathogenesis in TA. However, whether Th9 cells can promote aorta endothelial cells lesions is unclear. Here, we hypothesize that Th9 cells secrete IL -9，which activate CD8 + T cells, and then aggravates the aortic injury in TA patients. In this study, we plan to validate our hypothesis in 3 aspects:（1）To test the levels of IL-9 and Th9 cells in patients with TA and to evaluate their relationships with disease activity of TA. （2）To find the roles of Th9 cells in promoting cytotoxicity of CD8+T cells. （3）To investigate how the cytotoxic CD8+T cells activated by IL-9 producing Th9 cells injure the aorta endothelial cells. In this study, we anticipate to explore a novel therapeutic target of TA.

多发性大动脉炎（Takayasu Arteritis，TA）是一种严重危害人类健康的自身免疫性疾病，T淋巴细胞浸润和血管内皮细胞损伤是其重要的病理基础。TA免疫紊乱的机制至今仍不清楚。研究发现，一种新的T细胞亚群，Th9细胞与多种自身免疫病密切相关，并可促进CD8+T细胞的杀伤功能造成组织损伤。本课题组前期研究发现，TA患者外周血及病变部位Th9细胞和IL-9水平显著升高，提示Th9细胞可能参与TA的发生发展。据此我们假设：Th9细胞分泌IL-9，促进 CD8+T细胞对TA患者主动脉内皮细胞的损伤。本研究拟对TA患者主动脉组织和外周血样本中Th9及IL-9与TA发病及疾病活动的关系进行评估，明确Th9细胞在多发性大动脉炎发生发展中的作用；通过体外细胞共培养明确Th9细胞对CD8+T细胞杀伤作用的调控，并探讨Th9细胞参与主动脉内皮细胞损伤的机制，以期为TA的诊治提供新的治疗靶点和依据。

多发性大动脉炎（Takayasu’s arteritis，TA）是累及主动脉及其分支的大血管炎，T淋巴细胞浸润和血管内皮细胞损伤在TA病理过程发挥重要作用，然而具体机制尚不清楚。研究发现白细胞介素（Interleukin，IL）-9和Th9细胞参与自身免疫性大血管炎如巨细胞动脉炎的病理过程。我们的前期研究也发现，TA患者血清IL-9水平和外周血Th9细胞比例显著升高，TA患者主动脉组织科检测到IL-9高表达，因此，我们假设Th9细胞和其分泌的主要细胞因子IL-9参与TA免疫紊乱。我们用流式液相多重蛋白定量（cytometric bead array，CBA）的方法检测了血清中细胞因子IL-4, IL-6, IL-8, IL-17, IL-10, TNF-α, IFN-γ和 IL-9，采用流式细胞术检测（peripheral blood mononuclear cells，PBMCs）中Th9细胞比例。结果发现，TA患者血清中IL-6, TNF-α和 IL-9水平显著高于健康对照组，TA患者PBMC中CD4+IL-9+T细胞，CD4+PU.1+T细胞显著高于健康对照组；CD4+T细胞中IL-9+ PU.1+ T 细胞比例也显著高于健康对照组；TA患者的血清IL-9水平与红细胞沉降率成正比。我们期望IL-9和Th9能成为TA治疗的潜在靶点。