肠源性效应辅助性T细胞调节炎症性肠病视网膜损伤的机制研究

炎症性肠病（IBD）是一种发生在胃肠道的慢性自身免疫性疾病，除消化道损伤外，还可累及多个肠外器官。报道发现IBD可能并发视网膜神经元损伤，但病理表现及潜在损伤机制等尚无报道。我们前期发现IBD小鼠视网膜电位图（ERG）b波及震荡电位振幅下降，内层神经元显著损伤，肠源性CD4+T细胞浸润内层视网膜，其中分泌IFN-γ的T细胞与损伤的神经元毗邻。基于此，我们推测肠道炎症发生时，产生具有致炎性的肠源性CD4+T细胞效应亚型，其中以Th1或Th1-like为主的效应细胞浸润至视网膜后，通过分泌细胞因子、表达粘附分子等途径导致视网膜损伤。本项目通过检测IBD小鼠视网膜内肠源性CD4+T细胞的功能表型以及对效应分子的筛查及验证，明确神经元损伤的免疫分子机制，并在IBD患者中进行相关验证，为临床管理IBD眼部并发症以及研究全身性疾病累及视网膜的免疫损伤共性机制提供新的思路和基础。

Inflammatory bowel disease (IBD) is known as a chronic, relapse and inflammatory disorder of the gastrointestinal tract. Emerging evidences have demonstrated that IBD frequently leads to extra-intestinal injury, and over a half of IBD patient present extra-intestinal manifestations (EIMs), including the liver, joints, the skin, and the eyes. To varying degrees, retina dysfunction has been observed in patients with IBD and experimental colitic mice. Mice with dextran sodium sulfate (DSS)-induced colitis displayed abnormal electroretinography (ERG). Posterior segment signs were reported in IBD subjects, including retinal pigment epithelium disturbance, serous retinal detachment, and central retinal vein occlusion. However, whether neuroretina injury exists in IBD patients and the exquisite immunological pathogenesis of retinal complications remains largely unclear. We previously found experimental colitis resulted in severe damage of inner retinal neurons (especially bipolar cells), providing an explanation of the abnormal ERG detected in mice with experimental colitis. Importantly, we found significantly increased infiltration of α4β7-expressing CD4+ T cells into the retina during colitis, which were co-localized with inner retinal neurons. Additionally, we identified a subpopulation of these CD4+ T cells were capable of producing IFN-γ, which was considered as a signature cytokine of Th1 or Th1-like responses. Based on these evidences, we speculated that pro-inflammatory retina-targeting CD4+ T cells with a “gut-homing” nature might be generated during intestinal mucosal inflammation, and these cells might display a “Th1 or Th1-like” phenotype. After entering the retina, these Th1 or Th1-like cells might contribute to the degeneration of inner neurons by multiple mechanisms, including secreting cytokines, expressing membrane-associated molecules. In this study, we will analyze the dominant functional effector subset(s) of gut-homing CD4+ T cells in the retina during colitis, and investigate the underlying mechanism whereby CD4+ T cells induce retinal neurodegeneration. We are planning to enroll IBD patients and examine the expression of retinodegeneration-associated proteins in their peripheral blood. This study may provide new insights into the pathogenesis of IBD-associated retinal neurodegeneration and shed new light on the understanding of common immunopathologic mechanisms of retinal injury induced by systemic disease.