免疫细胞和淋巴管生成调控多发性硬化症的病理机制研究

多发性性硬化（MS）是一类中枢神经系统（CNS）炎性脱髓鞘疾病。尚不完全清楚在MS病理条件下，巨噬细胞和小胶质细胞调控T细胞增殖、分化、定向迁入CNS诱发脱髓鞘病变的分子机制。根据临床样本分析我们发现在CD4+T细胞中一种鸟苷交换因子Dock8的表达水平与MS密切相关，并且丧失活化Cdc42的Dock8突变体显著抑制CD4+T细胞浸润到CNS和实验性自身脑脊髓炎（EAE）的发生。Dock8新型结合蛋白LRCH被筛选，转基因表达LRCH抑制EAE的发生，提示LRCH可能抑制Dock8活化Cdc42。我们拟研究Dock8和LRCH调控T细胞在CNS结合抗原呈递细胞的能力、T细胞增殖分化及迁移的分子机制。将利用VEGFR-3突变小鼠模型，探索T细胞和巨噬细胞是否通过VEGFR-3信号介导CNS炎症反应，进而调控脑部淋巴管生成及其对EAE进程的影响。期望本项目为深入了解MS发病机理提出新的见解。

Multiple sclerosis (MS) is an inflammation associated demyelinating disease in which the insulating covers of nerve cells in the brain and spinal cord are damaged. The key pathogenesis of MS is related to the infiltration of macrophages and T lymphocytes that can adhere together and form cell conjugates to recognize autoantigens in central nervous system (CNS).Currently it remains unclear how CD4+ T cells migrate into CNS, proliferate and differentiate into TH1, TH17 or regulatory T cells to control neuroinflammation associated lesion. Our preliminary investigation identified that the expression level of Dock8, a guanine exchange factor, in CD4+T cells was associated with the pathogenesis of MS. Dock8 mutation in its DHR2 domain failed to activate Cdc42 and the mice carrying this mutation suppressed the development of experimental autoimmune encephalomyelitis (EAE) with fewer CD4+T cell infiltration in CNS. Interestingly, LRCH was identified as a novel binding partner of Dock8 with Mass spectrometry as well as yeast two- hybrid assay. We noted that LRCH transgenic mice did ameliorate the severity of EAE. In this application, we aim to explore how Dock8/LRCH regulates CD4+T cell adherent to autoantigen-presenting macrophages or microglia in CNS, resulting T cell activation, migration, proliferation and differentiation. We will continue to investigate how VEGFR-3/VEGF-C signaling in macrophages and T cells regulates the CNS inflammation and lymphangiogenesis, and whether lymphangiogenesis will affect the development of EAE. These investigations will help us to deepen our understanding of the pathogenetic roles of immune cells and neuro-inflammation to control the development of MS.