Th17趋化重症肌无力小鼠B细胞形成生发中心产生自身抗体的分子机制

Currently,there is not any effective immuno-therapy for myasthenia gravis (MG).The Th17 cells that producing IL-17 is the newly defined subset of helper T cells.Our previous studies have demonstrated that Th17 cells, rather than Th1 cells, play a pivotal role in the pathogenesis of autoimmune disease models, including experimental autoimmune myasthenia gravis (EAMG）. However, the intaeraction and signal transduction between autoreactive Th17 cells and B cells in secondary lymphoid organs (spleen and lymph nodes) have not been investigated as yet. .In this study, we plan to use DNA microarray, FACS analysis and shRNA to research on B6, IL-6-/-, IFNγ-/-, IL-17-/- and RAG1-/- mice. We hypothesis that Th17 cells not Th1 cells expressing B cell chemoattractant CXCL13 to active CXCR5 on B cells migrating to T cell zone in spleen and lymph nodes, and IL-17 forming GCs stimulate the "IL-17 receptor inducing the adaptor Act1 depending"NF-κB signaling on B cells to induce EAMG, then B cells differentiate to plasma cells and release pathogenic acetylcholine receptor antibody..This project overlap immunity molecular biology，molecular biology and neurology to find new pathogenesis of MG and provide new therapeutic strategy for MG treatment.

目前重症肌无力（MG）尚无特异性治疗方法。Th17是新定义产生IL-17的辅助T细胞。我们的前期研究已证实在实验性自身免疫性重症肌无力（EAMG）形成中Th17而非Th1细胞起主要作用，但Th17在周围淋巴器官与B细胞的相互作用及T-B细胞间信号转导机制尚不清楚。拟用基因芯片、流式细胞仪和shRNA等技术以B6、IL-6-/-、IFNγ-/-、IL-17-/-和RAG1-/-小鼠为研究对象，从组织、细胞及分子层面证实Th17在小鼠EAMG形成中产生CXCL13趋化表达CXCR5的B细胞归巢于T细胞区再迁移至B细胞区；Th17分泌IL-17促进生发中心形成，与B细胞IL-17R结合，激活Act1活化NF-κB信号途径，使B细胞增殖分化成浆细胞产生乙酰胆碱受体抗体的假说。本课题是免疫分子生物学、分子生物学及神经病学等学科的交叉研究，旨在探索MG发病机制上产生新突破，为其治疗提供理论依据

目前初步研究证实新定义产生IL-17的辅助T细胞Th17在实验性自身免疫性重症肌无力（EAMG）形成中起主要作用，但Th17在周围淋巴器官与B细胞的相互作用及T-B细胞间信号转导机制尚不清楚。本课题EAMG动物模型为研究对象，研究Th17在EAMG形成中产生CXCL13趋化表达CXCR5的B细胞归巢于T细胞区再迁移至B细胞区；Th17分泌IL-17促进生发中心形成，与B细胞IL-17R结合，激活Act1活化NF-κB信号途径，使B细胞增殖分化成浆细胞产生乙酰胆碱受体抗体。上述结果可能在在探索MG发病机制上产生新突破，为其治疗提供理论依据。