Immunopathogenic mechanisms of dry eye disease

干眼病(DED)是一种慢性免疫介导的眼表疾病，其特征是 上皮屏障的破坏和持续的眼表炎症，在严重的情况下会导致 因角膜溃疡和疤痕而失明。DED可以说是最常见的眼科疾病 患者就诊于眼科护理专业人员的情况，据估计，超过1600万美国成年人 被诊断出患有DED(比老年性黄斑变性高几倍)。值得注意的是， DED的患病率随着年龄的增长而增加。DED给美国医疗体系带来的财政负担是巨大的， 据估计，每年由生产力损失造成的直接成本和支出超过35亿美元。 包括首席调查员在内的几个实验室的工作揭示了关键的见解 关于DED的免疫发病机制。现在有强有力的证据表明，T辅助17(Th17)细胞 是免疫介导的眼表损伤的关键促进剂。私家侦探的实验室显示 记忆Th17(MTh17)细胞维持疾病的慢性化，导致眼表上皮病 在暴露于干燥的压力下后会持续数月。此外，公安局实验室的数据显示， 调节性T细胞(Tregs)在抑制DED的Th17反应方面存在缺陷。此外，私家侦探的实验室 已经确定了控制抗原提呈细胞(APC)激活和贩运的关键机制 DED，以及效应器TH17的引爆、扩张和寻的。尽管在解体方面取得了实质性进展 在潜在的免疫致病机制中，重要的问题仍然没有答案。 我们假设：(1)慢性DED的特征是脑功能长期受损。 正常维持免疫静止的调节性T细胞(Treg)，以及(2)老年人更多 由于Th17的内存池较大，易患DED，其功能不受老年人的充分调节 特雷格斯。该项目的主要目标是：(I)准确定义 确定DED患者长期Treg功能障碍的特征和机制；(Ii)确定 MTh17细胞的细胞前体以及影响mTh17细胞生成的细胞因子机制 免疫记忆；以及(Iii)确定在衰老过程中放大mTh17免疫的因素。要实现这些目标 目标，定义了三个具体目标，以回答以下问题：目标1：什么是 DED患者耐受性Treg功能障碍的发病机制？目标2：哪些效应器Th17子集 倾向于进入内存池(从而允许DED慢性化)，以及哪些因素调节这一点 流程呢？最后目标3：增强Th17介导的细胞和分子机制是什么 衰老中的死亡？预计这项研究将产生重大的翻译影响，因为 DED的流行，我们对其免疫发病机制的了解仍然有限，以及相对的 缺乏有效的治疗方法。

Dry eye disease (DED) is a chronic immune-mediated disorder of the ocular surface, characterized by disruption of the epithelial barrier and sustained ocular surface inflammation, which in severe cases results in blindness from corneal ulceration and scarring. DED is arguably the most common ophthalmologic condition for which patients visit eye care professionals, with more than 16 million US adults estimated to have been diagnosed with DED (several folds higher than age-related macular degeneration). Notably, the prevalence of DED increases with age. The financial burden of DED to the US healthcare system is vast, with direct costs and expenses from productivity losses estimated to exceed $3.5 billion annually. The work of several laboratories, including the Principal Investigator's, has revealed key insights concerning the immunopathogenesis of DED. There is now strong evidence that T helper-17 (Th17) cells are critical promoters of immune-mediated damage to the ocular surface. The PI's laboratory has shown that memory Th17 (mTh17) cells maintain disease chronicity, resulting in ocular surface epitheliopathy that persists for many months after exposure to desiccating stress. Moreover, data from the PI's lab show that regulatory T cells (Tregs) are defective in suppressing the Th17 response in DED. In addition, the PI's lab has identified critical mechanisms controlling antigen-presenting cell (APC) activation and trafficking in DED, as well as effector Th17 priming, expansion and homing. Despite substantial progress in unraveling underlying immunopathogenic mechanisms, important questions remain unanswered. We hypothesize that (1) chronic DED is characterized by long-term impairment in the function of regulatory T cells (Tregs) that normally maintain immune quiescence, and that (2) the aged are more susceptible to DED due to a larger pool of memory Th17, whose function is inadequately regulated by aged Tregs. The principal objectives of this project are to (i) precisely define the phenotypic changes that characterize, and the mechanisms that promote long-term Treg dysfunction in DED; (ii) determine the cellular precursors of mTh17 cells, as well as the cytokine mechanisms that influence the generation of immunologic memory; and (iii) define the factors that amplify mTh17 immunity in aging. To achieve these objectives, three specific aims have been defined to answer the following questions: Aim 1: What are the causative mechanisms of enduring Treg dysfunction in DED? Aim 2: Which effector Th17 subsets are predisposed to enter the memory pool (thus permitting DED chronicity), and what factors regulate this process? And finally Aim 3: What are the cellular and molecular mechanisms that augment Th17-mediated DED in aging? It is anticipated that this research will have significant translational impact given the high prevalence of DED, the still limited knowledge we have regarding its immunopathogenesis, and the relative scarcity of effective treatments.