外泌体诱导T淋巴细胞失衡在自身免疫甲状腺炎发病中的研究

Autoimmune thyroiditis (AIT) is a common organ-specific autoimmune disease,of which the pathogenesis is not well verified yet. It has been reported that the damages to thyrocytes induced by high iodine, the presentation of autoantigens by dendritic cells (DCs) and thyrocyte itself can lead to break down of immune tolerance, and the imbalanced differentiations of auto-reactive T lymphocytes are also involved in the development of AIT. Exosomes, with the diameter of 30-100nm, containing proteins,lipids and nucleic acids, derive from diverse types of cells and play important roles in antigen presentation, immunity activation and tumor metastasis. It has been found in some autoimmune diseases including type 1 diabetes and rheumatoid arthritis that damaged target cells-derived exosomes carrying with the ligands of TLRs can promote DCs maturation via the NF-kappa B pathway and consequently disturb the balenced differentiation of the CD4+T cells. This study aims at exploring the roles and mechanisms of exosomes derived from damaged thyrocytes of AIT in the aspects of antigen presentation, DCs activation and T lymphocytes differentiation and trying to provide theoretical basis for finding novel therapeutic strategies of AIT through blocking TLR signaling in DCs or inhibiting the exosomes secretion of thyrocytes.

自身免疫甲状腺炎（AIT）是器官特异性自身免疫病，发病机制仍未明。碘致甲状腺细胞损伤，树突状细胞（DCs）以及甲状腺细胞本身呈递自身抗原打破免疫耐受，自身反应性T细胞分化失衡是AIT重要的免疫学发病机制。外泌体是直径30-100 nm间的微泡，由不同类型细胞分泌，其内囊括蛋白质、核酸、脂类等成分，在抗原呈递、免疫激活、肿瘤转移等方面发挥重要作用。损伤细胞来源的外泌体中含有Toll样受体(TLRs)的配体，激活NF-κB通路促进DCs成熟，诱导CD4+T细胞分化失衡。1型糖尿病、类风湿性关节炎等多种自身免疫病中均发现受累靶细胞来源的外泌体呈递自身抗原，激活DCs，诱导T细胞分化。本课题将探究受损甲状腺细胞来源的外泌体在自身抗原提呈、DCs激活、T细胞分化失衡等环节的作用及其参与AIT发生发展的具体机制；阻断DC细胞TLR通路或抑制甲状腺细胞外泌体分泌可能为寻找新的AIT治疗策略提供理论依据。

自身免疫甲状腺炎（Autoimmune thyroiditis，AIT）是典型的器官特异性自身免疫病，以甲状腺内炎性细胞浸润，产生针对甲状腺自身抗原的特异性抗体：甲状腺过氧化物酶抗体（ Thyroiperoxidase antibody ，TPOAb）和甲状腺球蛋白（Thyroiglobulin antibody，TgAb）为特征。AIT的主要危害是甲状腺功能异常导致的多器官系统受累，在育龄妇女还可引起流产、不育、甚至损害后代的神经智力发育。AIT有如此严重的危害，但是它的发病机制并不是十分明确。本课题研究结论如下：1、HT患者血清中的外泌体高表达甲状腺特异性抗原TPO、抗原递呈分子MHC-II类分子和炎症因子HSP60，可与DCs的TLR2/3结合，通过TLR2/MyD88/NF-κB 和 TLR3/TRIF/NF-κB 途径激活 DCs，并导致 CD4+T淋巴细胞的分化失衡。TLR2/3 抑制剂可部分逆转上述结果。2、甲状腺细胞来源的外泌体不能直接诱导CD4+T 淋巴细胞的细胞因子表达和释放，需要先激活 DCs。外泌体抑制剂 GW4869 抑制 IFN-γ 刺激的甲状腺滤泡细胞释放的外泌体后，阻断了甲状腺滤泡细胞对 DCs 的活化，提示外泌体在抗原递呈炎症反应中发挥关键作用。 3、GW4869未降低AIT小鼠血清TgAb水平及改善甲状腺的炎症，T淋巴细胞各亚群的比率也无明显差异。本课题为探究AIT的发病机制提供实验基础，为AIT的治疗提供新思路。