Mechanisms of Ocular Immune Privilege in the Posterior Eye

描述（由申请人提供）：作为一种为器官和组织提供免疫保护的机制，免疫特权在所有物种中都是保守的。免疫特权允许在没有炎症的情况下进行免疫保护。当免疫特权受损时，眼睛就会面临免疫炎症和自身免疫性疾病（如葡萄膜炎）的风险。免疫特权是一个多层次的过程，即使在自身免疫性葡萄膜炎实验中，免疫特权也只是暂时丧失，并会恢复以防止疾病的再次发生(1)。然而，我们的研究表明，一只眼睛的视网膜激光烧伤（RLB）在激光治疗和未治疗的眼睛中都会导致眼部免疫特权的长期丧失(2)。在这个R21项目中，我们想利用这些观察结果并分析导致废除免疫特权的机制。我们认为RLB通过诱导视网膜色素上皮（RPE）及其抑制功能的改变而取消免疫特权，从而导致实验性自身免疫性葡萄膜炎（EAU）的易感性增加。我们的研究计划将会。分析RPE抑制功能是如何丢失的以及丢失了什么；2.） 比较RLB期间和RLB后候选RPE调控分子的表达变化；3)。确定RLB后小鼠对自身免疫性葡萄膜炎的易感性是否增加。

DESCRIPTION (provided by applicant): Immune privilege is conserved in all species as a mechanism to provide immunoprotection for organs and tissues. Immune privilege allows for immune protection in the absence of inflammation. When immune privilege is compromised, the eye is at risk for immune inflammatory and autoimmune diseases such as uveitis. Immune privilege is a multi-layered process and even during experiment autoimmune uveitis, immune privilege is only transiently lost, and returns to prevent a reoccurrence of the disease (1). However, our studies show that retinal laser burn (RLB) in one eye caused an extended loss of ocular immune privilege in both the laser treated and non-treated eye (2). In this R21 project we would like to exploit these observations and analyze the mechanisms that led to the abrogation of immune privilege. We propose that RLB abrogates immune privilege by inducing changes to the retinal- pigmented epithelium (RPE) and its suppressor function which in turn leads to increased susceptibility to experimental autoimmune uveitis (EAU). Our research plan will 1.) Analyze how and what RPE suppression function is lost; 2.) Compare changes in the expression of candidate regulatory molecules on RPE that might change during or after RLB; 3.) Determine if there is increased susceptibility to autoimmune uveitis in mice after RLB. PUBLIC HEALTH RELEVANCE: This R21 application will determine (using state of the art cellular, molecular approaches) how experimental retinal laser burn abrogates immune privilege in the posterior eye. The knowledge gained from these studies will enhance our understanding of ocular immune homeostasis and may aid in the development of new therapies for restoration of the immune privileged status in eyes that suffer from trauma or inflammatory diseases such as autoimmune uveitis.