炎症性树突状细胞通过ICOS/ICOSL信号对Graves病甲亢TRAb产生的机制研究

Graves' disease (GD) is organ-specific autoimmune disease caused by the production of thyrotropin receptor antibody (TRAb). The production of TRAb involves the interaction of various immune cells. New evidence indicated that inflammatory dendritic cells (infDCs) were the key factor to manipulate the differentiation of CD4+T cells in autoimmune disease. infDCs may be also the reason to maintain the autoimmune process in inflamed tissue. Our previous study found that the absolute counts and percentage of monocytes in peripheral blood in patients with GD were increased significantly and positively correlated with TRAb. Monocytes can be recruited to inflamed tissue and differentiated into infDCs in situ. InfDCs were found in thyroid tissue in patients with GD. T cells expressing the characteristic molecules ICOS and CXCR5 of Tfh cell were also infiltrated in GD thyroid tissue. Meanwhile, ICOSL was highly expressed on the surface of thyroid follicular cells in GD thyroid tissue. Based on our previous work, the proposed project is first to reveal the distribution and frequencies of infDCs in peripheral blood and thyroid tissue to explore the pathogenesis role of infDCs in GD. The correlation of infDCs, Th subsets and clinical parameters will be analyzed in GD patients before and after anti-thyroid treatment. In addition, the specific cytokines secreted by infDCs and the interaction of infDCs with thyroid cells and CD4+T cells will be determined. In vivo, ICOS/ICOSL in infDCs and specific molecular mechanisms will be investigated which might eventually offer a new therapy target for treatment of GD.

Graves病（Graves’disease, GD）是一种器官特异性自身免疫性疾病，促甲状腺素受体自身抗体（TRAb）是其主要病因。TRAb的产生涉及多种免疫细胞相互作用。炎症性树突状细胞（infDCs）是影响CD4+T细胞分化以及炎症维持的重要因素。本课题组前期研究发现初发GD患者外周血infDCs前体细胞单核细胞水平显著升高，且与TRAb水平显著正相关；同时GD甲状腺局部浸润有infDCs及T细胞，T细胞表达Tfh细胞特征表面分子ICOS及CXCR5，甲状腺滤泡上皮细胞表面高表达ICOSL。本课题拟以此工作为基础，从外周血和甲状腺组织两方面着手检测infDCs改变，分析其与临床资料及Th细胞亚群的相关性；围绕infDCs与甲状腺细胞、CD4+T细胞的相互作用，探讨ICOS/ICOSL信号作用及TRAb产生的相关分子机制，从而最终为阐释GD发病机制及治疗提供新思路。

Graves病（Graves’ Disease, GD）又称毒性弥漫性甲状腺肿,是一种器官特异性自身免疫性疾病，深入研究GD自身免疫反应过程以及TRAb的产生机制对于寻找新的治疗靶点尤为必要。本课题通过对GD甲亢患者进行临床随访，从外周和甲状腺组织局部两方面入手，初步讨论了infDCs及其前体细胞单核细胞在Graves病甲亢TRAb产生的作用。在外周infDCs前体细胞通过分泌BAFF等炎症因子促进TRAb的产生；在炎症因子的作用下，infDCs及其前体细胞可趋化至甲状腺局部，通过JAK-STAT、mTORC、NF-κB等信号通路激活参与Th1/Th2/Th17等细胞的激活过程。此外，我们发现CD4+T细胞表面ICOS及CD19+B细胞表面的ICOSL表达显著升高，与TRAb滴度有一定的相关性。在甲状腺组织局部观察到类生发中心的形成，infDCs可能通过ICOS/ICOSL信号参与Tfh细胞的分化、成熟及辅助B细胞产生抗体过程。通过本项目的研究可以为GD甲亢患者的免疫靶向治疗提供依据和方向。