重症肌无力(MG)是主要由自身抗体介导的、T细胞和补体参与的自身免疫病。我们的的研究发现MG患者肌肉中碳酸酐酶III(CAR3)的表达特异性降低；Car3缺陷(Car3-/-)小鼠重症肌无力动物模型的肌无力症状比野生型明显加重，血清中的自身抗体水平显著升高，且骨骼肌细胞胞内补体成分C3a明显增多，骨骼肌中滤泡样辅助T细胞(Tfh)比例显著上升。因此我们认为CAR3通过调控骨骼肌细胞胞内补体C3a的产生，抑制Tfh的分化和抗体的产生，对肌无力有保护作用。本项目拟利用细胞和动物模型研究：CAR3在调控骨骼肌细胞胞内补体C3a产生中的作用和分子基础；胞内补体C3a调控Tfh分化的作用模式和机制；靶向调控CAR3和骨骼肌细胞胞内C3a的产生在治疗MG中的可行性。本项目有助于明确CAR3调控骨骼肌细胞胞内补体C3/C3a在MG中的作用和分子机制，为干预MG提供新的作用靶点和治疗策略。

Myasthenia gravis is an autoimmune disease mediated mainly by autoantibodies with participation of T cells and complements. Our previous study showed that carbonic anhydrase III (CAR3) is insufficient in the skeletal muscles from myasthenia gravis patients. Compared with wildtype mice, the myasthenia symptoms are more severe in myasthenia gravis animal model based on Car3-/- mice, and so is the serum autoantibody against acetylcholine receptor. In addition, intracellular C3a in skeletal muscle cells is much higher in Car3-/- myasthenia mice, with an enhanced follicular helper T cell (Tfh) percentage in CD4+ T cells in skeletal muscle. So, we assume that CAR3 regulates production of intracellular C3a, and inhibits Tfh differentiation, B cell activation and antibody production, thus is protective from myasthenia. Based on that, we would like to use cell and mice animal model of myasthenia gravis to explore the role of CAR3 in regulating the production of intracellular C3a in skeletal muscle cells and how, the role and the mechanism of C3a to modulate Tfh differentiation and antibody production, and the feasibility to treat myasthenia gravis by interfering production of intracellular C3a and the downstream signaling. Our project will shed light on the insight of how CAR3 regulates intracellular C3a during the pathogenesis of myasthenia gravis, and potentially provides new therapeutic targets and strategy.