辅助T细胞介导的肠-视网膜对话调节视网膜神经损伤的免疫机制研究

视网膜神经损伤是世界范围内难可逆盲的首位病因，视网膜节细胞结构功能异常是视觉损伤的重要原因之一。节细胞损伤的机制复杂，而免疫因素不可忽视。近年发现T细胞介导中枢神经变性疾病，但在视网膜损伤中的免疫调控作用不清。前期研究发现肠源性系统免疫活化参与节细胞损伤，伴随视网膜Th1/Th17细胞浸润及MAdCAM-1、ALCAM等粘附分子表达上调，故推测肠黏膜活化的Th细胞在粘附分子-配体介导下定向迁移至视网膜，藉由直接损伤以及与固有免疫的级联放大共同参与节细胞-视神经损伤。本项目拟构建“局部诱导+外周免疫活化”节细胞损伤模型，研究视网膜浸润Th细胞的功能表型，并通过基因敲除、分子靶向干预Th细胞迁移及节细胞损伤过程中的关键分子信号通路，阐明“肠-视网膜”对话参与视网膜神经损伤的免疫共性机制，为临床干预提供新的靶点和思路。

Retinal neurodegeneration is the first cause of irreversible blindness worldwide. Retinal ganglion cell (RGC) structural dysfunction is one of the important causes of visual impairment. Various factors have been reported to be involved in the pathogenesis of RGC injury, especially the immune responses, which remains mostly unknown. Emerging evidences have suggested that T helper (Th) cells play an important role in the pathogenesis of RGC injury. However, the potential mechanism of how T cells regulate in the induction and development of retinal neurodegeneration is still unclear. We found that aberrant intestinal mucosal immune responses led to RGC injury, accompanied by infiltration of Th1/Th17 cells and up-regulation of MAdCAM-1 and ALCAM. Based on these findings, we speculated that the abnormal expression of adhesion molecules might contribute to mediating the migration of Th cells into the retina and facilitating the differentiation of these T cells toward Th1/Th17 lineages, thus participating in the modulation of retinal innate immune responses, leading to ganglion cell injury. In this study, we will establish a model of RGC injury using the combination of “local stress + peripheral immune responses”, and examine the phenotype of infiltrated Th cells. By generating knockout mice, we aim to investigate the mechanisms of how adhesion molecules regulate Th cell migration and RGC injury. This study may provide new insights into the pathogenesis of neuro-immune crosstalk in the gut-retina axis.