Resistin基于PI3k-Akt和MAPK通路参与重症肌无力CD4+辅助性T细胞亚群失衡的研究

An imbalance in the CD4+ helper T cell-cytokine network, principally induced by two pathways, the PI3k-Akt and MAPK pathways, plays a key role in the pathogenesis of myasthenia gravis (MG). Increased levels of resistin, a proinflammatory cytokine, can induce secretion of various cytokines via different inflammatory signaling pathways such as NF-κB, PI3K, and MAPK pathways. Potential interactions among cytokines underlying the imbalance of CD4+ helper T cell have been identified; however, the role of resistin in MG has not been reported. Previously, we demonstrated that levels of resistin were significantly elevated in patients with acetylcholine receptor antibody-positive MG (AChR-MG). We also observed correlations between serum resistin and MG-ADL scores in patients with AChR-generalized MG; and the resistin levels declined after immunosuppressive therapy. In addition, our preliminary studies showed that resistin can induce an increase in the Th1/Th2 subsets. In the present study, we will investigate the role and molecular mechanisms of resistin with respect to the PI3k-Akt and MAPK pathways in patients with MG and in experimental autoimmune myasthenia gravis (EAMG) mouse model, and investigate whether resistin may be a potential target for MG treatment.

CD4+辅助性T细胞-细胞因子网络失衡在重症肌无力（MG）致病中起重要的作用，而PI3k-Akt和MAPK通路是细胞因子诱导其失衡的重要信号通路。Resistin作为前炎症因子，可启动多个炎症信号通路，诱导大量的细胞因子表达，进而通过相互间的协同作用引起CD4+辅助性T细胞亚群失衡，促进炎症的发展。我们前期已发表的研究发现，乙酰胆碱受体抗体阳性的全身型MG患者Resistin水平明显升高，且Resistin与疾病严重程度呈正相关，免疫治疗后水平显著下降，提示Resitin可能参与了MG的致病过程。此外，细胞水平的预实验发现Resistin可诱导Th1/Th2亚群比例升高。本课题拟在前期基础上，以MG病人及实验性自身免疫性重症肌无力小鼠为媒介，进一步阐明Resistin基于PI3k-Akt和MAPK通路参与MG CD4+辅助T细胞亚群失衡，并探索以Resistin为靶点的分子治疗。

Resistin是一种新近被证实的促炎因子，参与了许多自身免疫疾病的免疫病理过程，但其在重症肌无力(MG)中的作用及机制尚不完全清楚。本研究发现乙酰胆碱受体抗体(AChR)抗体阳性的全身型MG患者血清Resistin水平明显升高，其水平与疾病严重程度呈正相关，且AChR-MG患者经免疫抑制剂治疗后血清Resistin水平明显降低。我们进一步利用流式检测了Resistin处理组CD4+辅助性T细胞比例，发现Resistin使得MG患者T细胞中Th2细胞占比降低，且与Th2细胞成负相关。我们进一步检测了PI3K信号通路，发现Resistin引起PI3K和AKT表达升高。我们还发现，Resistin处理THP1巨噬细胞后， IL-1β和IL-6分泌明显增高，TLR4受体表达增加，且NF-κB和MAPK信号通路被激活。同时我们构建了EAMG模型，我们发现Resistin可加重MG肌无力症状。我们还利用流式检测经Resistin注射EAMG小鼠后T细胞亚群，结果发现Th1/Th2比例升高，PI3K和AKT表达升高。以上结果提示Resistin可通过TLR4受体，激活NF-κB和MAPK信号通路，促进炎性因子的分泌和表达，最终促进了MG炎症的发展。这一研究将有助于对MG致病机制的深入认识，有利于对MG疾病诊疗和预后的评估，并有希望成为MG新的治疗靶点。.本项目已在国际学术刊物上发表SCI期刊论文5篇，有中文综述1篇。协助培养博士和硕士各2名。

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