ITM2A调节Th17/Treg影响甲状腺相关眼病发生发展的作用机制

Thyroid-associated ophthalmopathy (TAO) has the highest incidence among orbital diseases in adult. It results in malformation, disability, and blindness, with serious impact on patients’ quality of life. TAO attacks the orbit and its surrounding tissues, with the manifestation of inflammation, proliferation and fibrosis of the eyelids, extraocular muscles, and retrobulbar fat tissues. T effect cells play a key role in the autoimmune disorder of TAO. We identified 5 susceptible genes, including HLA, FcRL3, CTLA-4, TSHR, and ITM2A upon GWAS studies of 2,130 TAO samples, in which ITM2A was involved in the regulation of Treg functions. This project will focus on the mechanism of ITM2A in the regulation of Th17/Treg involved in the development of TAO. We will identify different subsets of immune cells and their functions in blood and orbital connective tissues of TAO patients via CyTOF2, and discuss how ITM2A influences the balance of Th17/Treg, and unravel the changes of orbital fibroblast and fibrocyte biological activities in order to find the possible therapeutic targets and provide theoretical basis for precise clinical treatment of TAO.

甲状腺相关眼病（TAO）是成人发病率最高的眼眶病，致残、致盲，严重影响患者生活质量。病变累及眼眶及其周围组织，表现为眼睑、眼外肌和球后脂肪的炎症、增生及纤维化。效应T细胞在TAO的免疫反应中发挥重要作用。我们通过2,130例TAO样本的GWAS研究识别了HLA、FcRL3、CTLA-4、TSHR和ITM2A等5个易感基因，其中ITM2A主要参与Treg细胞功能的调节。本项目将深入研究ITM2A调控Th17/Treg影响TAO发生发展的作用机制。通过质谱流式技术识别和鉴定TAO患者外周血和眼眶脂肪结缔组织中免疫细胞的亚群及其功能图谱，探讨ITM2A调节Treg和Th17细胞功能的分子机制，揭示眼眶成纤维细胞和纤维细胞异常增殖分化的调控网络，力争发现TAO新的治疗靶点，为其精准治疗提供理论依据和实验基础。

甲状腺相关眼病（thyroid-associated ophthalmopathy，TAO）是一种自身免疫性眼病，病变累及眼睑、眼外肌及球后脂肪等，其发病率居成人眼眶病的首位，是弥漫性甲状腺肿伴甲状腺功能亢进症（Graves' disease，GD）最重要和最常见的甲状腺外表现。TAO发病机制复杂，涉及遗传、免疫和环境等多重因素作用，目前无针对病因的治疗方法。本项目首先对来自国内的TAO患者人群进行全基因组关联分析，识别了TAO可能致病易感区段内的55个单核苷酸多态性位点，发现ITM2A区段上的rs5912838位点与TAO相关（Pcombined =1.46×10-14, OR = 0.7482）。随后，本项目在TAO眼眶脂肪结缔组织中鉴定出由自然杀伤细胞，树突状细胞，巨噬细胞，T细胞，浆细胞和CD34+眼眶成纤维细胞组成的眼眶免疫微环境。其中，辅助性T细胞（T helper，Th）17和Th2细胞主要介导TAO自身免疫应答，尤其是Th17细胞在多因素回归分析中显示出和TAO发生发展密切相关。CD34+眼眶成纤维细胞能够促进Th17细胞表达IL-23R和IL-1R，以前列腺素E2-EP2/EP4-cAMP信号转导途维持Th17细胞表型。ITM2A的易感区段可能导致其功能失常，造成TAO患者外周血效应调节性T细胞（regulatory T cell，Treg）的数量明显低于健康人群，而患者的幼稚Treg细胞高表达CTLA-4。Th17细胞和Treg细胞的失衡可能在TAO的发病中起了重要作用，重建机体Th17/Treg细胞免疫平衡有望成为TAO对因治疗的新靶点。在本项目的资助下，项目组已在J Clin Endocrinol Metab，Invest Ophthalmol Vis Sci等领域内的重要期刊发表SCI收录论文7篇，协助培养本专业博士研究生5名。