基于“分子模拟”理论清道夫受体A参与类风湿关节炎发病及乌梢蛇干预机制研究

类风湿关节炎（RA）是一种常见自身免疫疾病，但发病机制尚不完全清楚。申请者前期研究发现清道夫受体A（SRA）基因敲除小鼠对胶原诱导性关节炎（CIA）抵抗；注射SRA蛋白能够激活Ⅱ型胶原（CⅡ）特异性T细胞应答，提高CIA发病率；抗风湿中药乌梢蛇CⅡ能够缓解CIA炎症，调控Th17/Treg平衡，但相关机制有待进一步阐明。鉴于SRA存在胶原样结构域，我们假说：SRA经抗原交叉反应诱导产生的自身反应性T细胞攻击机体自身CⅡ，引起/加剧RA；中药乌梢蛇通过分子模拟机制诱导免疫耐受，缓解RA。本项目拟在已建立SRA真核表达系统、获得SRA杂交瘤抗体以及SRA基因敲除小鼠等工作基础上：①鉴定SRA活化RA患者自身反应性T细胞的具体肽段；②评估靶向SRA治疗RA的转化医学价值；③阐明乌梢蛇缓解RA的免疫学机制。项目目标是阐明RA的病理机制和乌梢蛇的疗效机制，为RA防治药物的研发提供新的靶点。

Rheumatoid arthritis (RA) is a common autoimmune disease with high disability rate. Our preliminary study showed that scavenger receptor A (SRA) knock out mice were resistant to collagen-induced arthritis (CIA). Administration of SRA protein could induce type Ⅱ collagen (CⅡ) specific T cells response and aggravate CIA. Chinese medicine Zaocys could alleviate CIA and regulate Th17/Treg balance, the mechanism of which remained unclear. Based on the knowledge that there`s a collagen domain in the structure of SRA protein, we hypothesize that SRA functions as an cross-reacting antigen and induces autoreactive T cells attacking CⅡ, which cause or aggravate RA. Zaocys could induce immune tolerance through molecular mimicry and alleviate RA. Using our established technology, e.g. eucaryote cells protein expression system and hybridoma antibody technique, and SRA knock out mice, we are going to ①Identify the specific peptide of SRA which induces the autoreactive T cells in patients with RA. ② Determine the therapeutic potency of SRA in RA. ③ Based on the theory of " molecular mimicry and immune tolerance", elucidate the immunological mechanism of Zaocys in the treatment of RA. The completion of this project will be helpful to provide a new target for the prevention and treatment of RA, and reveal the therapeutic mechanism of the anti-rheumatic Chinese medicine Zaocys.