TGF-β/Smad促进Th9细胞分化及其IL-9分泌加剧MOGAD自身免疫炎症的机制研究

抗髓鞘少突胶质细胞糖蛋白（MOG）抗体（MOG-IgG）相关疾病（MOGAD）是新确定的神经免疫疾病。既往研究证实MOGAD患者脑脊液Th9标志性细胞因子IL-9升高。但Th9细胞是否参与MOGAD的自身免疫炎症及其具体作用机制不明。我们的流式细胞术研究发现MOGAD患者外周血Th9细胞水平升高。既往研究也观察到TGF-β激活其下游Smad信号分子，促进Th9细胞分化；Th9细胞分化过程中其IL-9分泌增加，加剧炎症反应。据此我们提出假设：在MOGAD中TGF-β/Smad信号介导Th9细胞分化，后者触发促炎症细胞因子IL-9分泌，最终加剧MOGAD的自身免疫炎症。本项目拟应用流式细胞术、单细胞mRNA测序技术、基因工程小鼠、中和抗体、细胞因子抑制剂等进行临床、动物模型和细胞模型研究，阐明Th9细胞上下游信号通路在MOGAD发病机制中的作用，将为MOGAD的免疫调节治疗提供干预靶点。

Myelin oligodendrocyte glycoprotein (MOG) immunoglobulin-G (MOG-IgG) associated disease (MOGAD) is a newly identified neuroimmune disease. Previous studies have confirmed that IL-9, the marker cytokine of Th9 cells , is elevated in cerebrospinal fluid of patients with MOGAD. However, whether Th9 cells are involved in autoimmune inflammation of MOGAD and its specific mechanism have not been clarified. Our flow cytometry study found that the proportion of Th9 cells went up in peripheral blood of MOGAD patients. Previous studies also observed that TGF-β activated its downstream signaling molecules Smad and promoted Th9 cells differentiation; and Th9 cells differentiation can increase its IL-9 secretion, exacerbating inflammation. Based on this, we propose the hypothesis that TGF-β/Smad signaling mediates Th9 cells differentiation in MOGAD, which triggers the secretion of pro-inflammatory cytokine IL-9, ultimately exacerbating autoimmune inflammation of MOGAD. This project intends to apply flow cytometry, single-cell mRNA sequencing, genetically engineered mice, neutralizing antibodies, cytokine inhibitors and so on, to conduct clinical, animal model and cell model studies to elucidate the upstream and downstream signaling pathways of Th9 cells in pathogenesis of MOGAD. It will provide intervention targets for immunomodulatory therapy for MOGAD.