Molecular mechanism and regulation in Sjogren's syndrome

干燥综合征（SS）是一种自身免疫性疾病。本研究旨在阐明SS发病的分子机制，并针对靶分子建立新的治疗策略。在这项研究中，我们专注于毒蕈碱乙酰胆碱受体3（M3 R），因为这种受体是一种功能分子，从唾液腺产生唾液。我们的结果如下。1)约50%的SS患者存在抗M3 R自身抗体和M3 R反应性T细胞。2)B细胞表位位于M3 R分子的N区、第一、第二和第三胞外区。3)针对M3 R第二胞外区的抗体是抑制唾液产生的致病性自身抗体。4)本研究采用M3 RKO小鼠和Rag-1 KO小鼠建立了M3 R免疫的小鼠涎腺炎（sialadenitis，MIS）模型。5)产生IFN-γ和/或IL-17的M3 R反应性T细胞是产生MIS所必需的。6)M3 R的优势T细胞表位是诱导MIS的第一个胞外结构域。目前，我们正在选择APL的T细胞表位，并在不久的将来尝试通过抗原特异性治疗策略来控制MIS和SS。

Sjogren's syndrome (SS) is one of autoimmune diseases. The purpose of this study is to clarify the molecular mechanism in the pathogenesis of SS and establish the new therapeutic strategy against target molecule. In this research, we focused on Muscarinic acetylcholine receptor 3 (M3R), because this receptor is a functional molecule to produce saliva from salivary glands. Our results are followings. 1) There were anti-M3R autoantibodies and M3R reactive T cells in about 50% of patients with SS. 2) The B cell epitopes were on N region, the first, the second, and the third extra-cellular domains of M3R molecules. 3) Antibodies against the second extracellular domain of M3R were the pathogenic autoantibody to suppress the saliva production. 4) We established M3R immunized sialadenitis (MIS) mouse model using M3RKO mouse and Rag-1KO mouse. 5) IFN-γand/or IL-17 producing M3R reactive T cells were necessary to generate MIS. 6) The dominant T cell epitope of M3R was the first extracellular domain to induce MIS. Now we are selecting APL of T cell epitope and near future try to control MIS and SS via antigen-specific therapeutic strategy.