SOCS1/3 对TLR3及T细胞分化的调控及其在桥本甲状腺炎中的作用

Hashimoto's thyroiditis, a common organ-specific autoimmune disease, is characterized by the production of autoantibodies against throid peroxidase (TPO) and thyroglobulin (Tg) and by intrsthyroidal mononuclear cell infiltration, often leading to the development of hypothyroidism. Until now, there wasn't an effective immune intervention for Hashimoto's thyroiditis. Latest papers and our preliminary study results prompted that the dysfunction of T helper cell might contribute to pathogenesis of Hashimoto's thyroiditis. In addition to it, viral infection is also reputed to serve as a trigger of Hashimoto's thyroiditis. Viral infection leads to an increase in TRL3 expression in thyroid cell and this receptor is up-regulated in thyroids from patients with Hashimoto's thyroiditis.. Suppressors of cytokine signalling (SOCS) proteins can negatively regulate the Janus kinase signal transducer and activator of transcription (JAK-STAT) signaling cascade. STAT proteins regulate the expression of many genes required for the differentiation of various CD4(+) T helper cell lineages, and there is now accumulating evidence that SOCS play essential roles in the regulation and maintenance of CD4(+) T-cell polarization. And SOCS1 and SOCS3 are negative regulators of virus mediated innate immune response, up-regulation requires a TLR3-independent pathway..So, we choose SOCS1 and SOCS3 as the objection of our study, to investigate the role of SOCS1/3 on the pathogenesis of Hashimoto's thyroiditis. Firstly, we search the relation SOCS1/3 with TLR3 and Treg and Th17 cells and follicular helper T (Tfh) cells in the patients of Hashimoto's thyroiditis, and with thyroid pathological lesion in the clinical levels. Secondly, we set up the SOCS1 or SOCS3 transgenic mice, and observe the effect of overexpression SOCS1 and SOCS3 proteins to TLR3 and T helper cell differentiation and TGAb and thyroid pathological lesion in this mice. Thirdly, the CD4(+) T cells and thyrocytes transfected with antisense RNA oligonucleotides directed to SOCS1 or SOCS3 or with a scrambled control oligonucleotide.We observe the effect of overexpression SOCS1 or SOCS3 proteins to T helper cell differentiation and autoantibodies and thyrocytes. .Thus, we maybe identify the role of SOCS1 and SOCS3 in the system immunity and thyroid tissue immunity of Hashimoto's thyroiditis, and develop new clinical treatment for it.

桥本甲状腺炎（HT）是一种自身免疫性疾病，其特征性改变是甲状腺内淋巴细胞浸润，血清TPOAb和／或TGAb水平升高，目前尚无任何确切有效的治疗方法。近年文献及我们的前期研究结果提示T细胞亚群异常、病毒感染与HT发病密切相关。本研究拟将可以负调控TLR3及T细胞分化的SOCS1/3引入HT的研究中，探讨其在HT发病机制中的作用：1、从临床水平明确HT患者体内SOCS1/3与TLR3、Treg、Th17细胞、Tfh细胞的关系，分析其与病理损害的相关性；2、建立SOCS1和SOCS3转基因小鼠，体内观察上调SOCS1和SOCS3表达对TLR3、T细胞分化、TGAb、甲状腺损害的影响；3、在细胞水平，采用基因转染技术上调SOCS1和SOCS3表达，观察其对T细胞分化、B细胞产生抗体及甲状腺细胞的影响。从而明确SOCS1/3在HT全身系统免疫及甲状腺局部免疫中所起的作用，为临床治疗HT提供新的靶点。