IL-37通路在多发性硬化发病机制中的保护性作用研究

Multiple sclerosis (MS) is one of the most common auto-immune diseases in central nervous system (CNS). The demyelination found in MS is thought to be caused by an autoimmune process, in which activating CD4+T cell and releasing inflammatory cytokines will lead to glial damage. MS is one of most important reasons for youth population lost their ability to work. The pathogenesis of MS is still unclear. There is no effective way to cure MS. MS place heavy burdens on the patients, the families, and the society. IL-37 is a new member of the interleukin 1 family. In Recent studies，IL-37 is shown can inhibit the release of inflammatory cytokines in the inflammatory process and regulate CD4+T cell immunity through Samd3 pathway. Based on the applicant's research about the immunological mechanisms of MS, in this project, we use animal experiments and vitro cell culture to prove the protective effect of IL-37 pathway in MS model though regulate the differentiation of Th1, Th17 and Treg cells, and reduce the production of inflammatory cytokines. We also statistics IL-37 levels in serum and cerebrospinal fluid during relapse and remission.To provide the theoretical basis for the clinical application of IL-37, we explore the correlation among IL-37 levels, expanded disability status scale，EDSS) scales, CD4+T cell subsets and the levels of inflammatory cytokines.

多发性硬化是一种常见的中枢神经系统自身免疫性疾病，以CD4+T细胞激活和炎症因子释放，损伤胶质细胞，导致神经纤维髓鞘脱失为主要病理过程，是造成青年人群丧失劳动能力的重要原因。MS的发病机制至今未明，目前无特效的治疗方法，给社会和家庭带来沉重的负担。IL-37是白细胞介素1家族的新成员，在最近的研究中显示有IL-37可以显著减少各种炎症因子的释放，还可能通过Smad3途径可以影响CD4+T细胞亚群的激活、分化。本课题旨在依据申请者多年对MS的免疫学机制研究基础上，通过动物实验和体外细胞培养验证IL-37对Th1、Th17、Treg细胞的分化调节及其对炎症因子的释放的影响，直观的展示IL-37通路对MS模型的保护性作用，通过临床研究统计MS患者复发期和缓解期血清、脑脊液IL-37水平变化和扩展残疾状况评分、CD4+T细胞亚群以及炎症因子的相关性，为IL-37的临床应用提供理论依据。

多发性硬化是最常见CD4+T细胞激活为主的自身免疫性中枢神经系统脱髓鞘疾病，青壮年发病，严重影响青年人群的劳动能力，给社会和家庭带来沉重的负担。多发性硬化目前缺乏有效的治疗手段。前期的研究成果表明CD4+Th1和CD4+Th17细胞激活，而同时伴随CD4+Th2细胞和CD4+Treg细胞的功能抑制是MS的核心免疫学机制。IL-37是一种新型的细胞因子，具有调节CD4+T细胞分化的功能。本研究证实在多发性硬化患者的复发期期有多种急性期蛋白的激活，尤以CD4+Th1和CD4+Th17相关炎症因子为主，和血浆IL-37的水平呈负相关。动物实验也证明，IL-37可明显减轻实验自身免疫性脑脊髓炎（多发性硬化的动物模型）的髓鞘脱失及中枢神经系统炎症反应，减少脾脏Th1和Th17细胞的激活，增加Terg细胞的激活，更是可以减少多发性硬化动物模型病灶周围小静脉血管套样结构，减轻血管周围炎症细胞的聚集，降低血管内皮损伤，最终抑制神经元凋亡，降低神经元损伤。体外实验也证实IL-37可以在体外环境中调节Th1/Th2轴和Th17/Treg轴的分化，使Th1、Th17细胞分化减少，而Th2、Treg细胞分化增多，证明IL-37对MS的潜在治疗作用，是一种有效的治疗MS的药物。