NLRP3/NLRP1炎性小体调控Th17细胞功能和分化在甲状腺相关眼病发病机制中的研究

Thyroid-associated ophthalmopathy (TAO) has the highest incidence among orbital diseases, which results in visual impairment, craniofacial malformation and physical discomfort, with a great negative impact on patients’ quality of life and social psychological state. We first uncovered Th17 cell-mediated autoimmune reaction and fibrosis in the development of TAO. Due to the specific characteristics of orbital immunologic microenvironment, we found that infiltrating Th17 cells in retrobulbar tissues had obvious heterogeneity and the expression of NLRP3/NLRP1 was increased in Th17 cells in orbital tissues. It has been proved that inflammasome is closely related to the function of Th17 cells. This project will focus on the mechanism of NLRP3/NLRP1 molecular network in the regulation of Th17 cell function and differentiation, causing TAO attack. We will identify the phenotypic atlas of immune microenvironment of orbital connective tissues in TAO patients, discuss how NLRP3/NLRP1 molecular network influences the biological behavior of Th17 cells, discover novel therapeutic targets, and provide theoretical basis for precise treatment of TAO.

甲状腺相关眼病（thyroid-associated ophthalmolpathy，TAO）是发病率最高的眼眶病，导致视功能损伤、颅面畸形和身体不适，对患者的生活质量和社会心理状态有着极大的负面影响。我们首次揭示了Th17细胞介导的自身免疫反应和纤维化变性在TAO发生发展中的作用。由于眼眶局部免疫微环境的特殊性，我们发现浸润球后组织的Th17细胞存在明显的异质性，并且炎性小体NLRP3/NLRP1在眼眶组织中的Th17细胞内表达升高。业已证明，炎性小体和Th17细胞的功能密切相关，本项目将深入研究NLRP3/NLRP1分子网络调控Th17细胞功能与分化，影响TAO发病的作用机制。识别和鉴定TAO患者眼眶脂肪结缔组织中的免疫微环境表型图谱，探讨NLRP3/NLRP1分子网络如何影响Th17细胞的生物学行为，力争发现TAO新的治疗靶点，为其精准治疗提供理论依据和基础。

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，其发病率居眼眶病的首位。TAO是自身免疫介导的眼眶炎症性疾病，发病机制复杂。本项目组前期揭示了T辅助细胞（T helper cell，Th）17功能异常参与TAO的发生发展，在此基础上，项目组揭示了TAO眼眶脂肪结缔组织免疫微环境由自然杀伤细胞，树突状细胞，巨噬细胞，T细胞，B细胞，浆细胞和CD34+眼眶成纤维细胞（orbital fibroblast，OF）组成。此外，TAO眼眶脂肪结缔组织中存在Th17、Th2细胞型免疫应答；眼眶中浸润的Th17细胞呈Th1细胞样表型。CD34+OF表达独特的细胞表面标志物，表达更多的TSHR、IGF-1R、CD80、CD86、CD40和MHC Ⅱ。CD34+OF通过前列腺素E2-EP2/EP4-cAMP信号转导途径促进Th17细胞表面IL-23R和IL-1R的表达。本项目的研究结果为深入理解Th17细胞免疫与TAO发病奠定了理论基础。在本项目的资助下，项目组已在J Clin Endocrinol Metab等领域内的重要期刊发表SCI收录论文5篇，协助培养本专业博士研究生4名。