可溶性BTLA通过激活STAT3通路促进Th17细胞分化在重症肌无力发病中的机制研究

重症肌无力(MG)是自身抗体介导、T细胞依赖和补体参与的自身免疫病，以T细胞为切入点对MG发病机制进行研究具有重要意义。我们前期研究发现免疫检查点分子BTLA的可溶性剪接体(sBTLA)在MG血浆中明显升高，且与临床严重度及IL-17水平呈正相关。基于对HVEM/BTLA的基本认识，提出本研究假：sBTLA是否可通过激活STAT3通路促进Th17细胞分化，进而参与MG的发病。本课题拟通过MG和实验性自身免疫性MG(EAMG)模型大鼠单核细胞与CD4+T细胞共培养，明确sBTLA在MG中可促进Th17分化；其次在共培养体系中上调STAT3上游抑制分子SHP-1、下调STAT3上游活化分子NIK和STAT3，明确sBTLA激活STAT3促Th17分化的具体信号通路；然后在EAMG模型中过表达和RNA干扰特异性沉默sBTLA，探索靶向sBTLA的治疗潜能，为MG的发病机制和临床治疗提供新的思路。

Myasthenia gravis(MG), characterized by T cell involving and complement dependence, is a group of autoimmune diseases with antibodies targeting neuromuscular junctions. Exploring the pathogenesis of MG targeting T cells will contribute to find new target-specific immunotherapies. In previous work, we found the plasma level of soluble checkpoint B and T lymphocyte attenuator (sBTLA) was elevated in MG and it correlated with clinical severity and plasma level of IL-17. Based on this，we hypothesize that soluble BTLA could promote Th17 cell differentiation through STAT3 activation in the pathogenesis of MG. In this study, we will first observe the influence of sBTLA on the differentiation of Th17 cells in MG with coculture of CD4+T and monocytes from MG patients and experimental autoimmune myasthenia gravis(EAMG) rats. Then we will interfere the system with SHP-1 agonists, NIK inhibitors and STAT3 inhibitors respectively to find out the pathway involving sBTLA promoting Th17 cell differentiation via STAT3. Last, we will overexpress and silence sBTLA with lentivirus in EAMG rat to investigate the potential of sBTLA in the treatment of MG. This study will provide a new perspective in the pathogenesis and treatment of MG.