Immunopathogenic mechanisms of dry eye disease

干眼病（DED）是一种慢性免疫介导的眼表疾病，其特征在于 上皮屏障的破坏和持续的眼表炎症，在严重的情况下， 因角膜溃疡和疤痕而失明DED可以说是最常见的眼科疾病 据估计，超过1600万美国成年人因这种疾病而就诊于眼科护理专业人员。 被诊断患有DED（比年龄相关性黄斑变性高出几倍）。特别是 DED的患病率随着年龄的增长而增加。DED给美国医疗保健系统带来的经济负担是巨大的， 生产力损失的直接成本和费用估计每年超过35亿美元。 包括首席研究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，辅助性T细胞-17（Th 17） 是免疫介导的眼表损伤的关键启动子。私家侦探的实验室显示 记忆性Th 17（mTh 17）细胞维持疾病慢性，导致眼表上皮病变， 在暴露于干燥胁迫后仍能持续数月。此外，PI实验室的数据显示， 在DED中，调节性T细胞（T细胞）在抑制Th 17应答方面有缺陷。另外，私家侦探的实验室 已经确定了控制抗原呈递细胞（APC）激活和运输的关键机制， DED以及效应子Th 17引发、扩增和归巢。尽管在解开 潜在的免疫病理机制，重要的问题仍然没有答案。 我们假设：（1）慢性DED的特征是长期损害的功能， 调节性T细胞（TCFs）通常维持免疫静止，（2）老年人更多 易受DED的影响，这是由于较大的存储器池Th 17，其功能不受老化的调节 你好该项目的主要目标是（i）精确定义表型变化， 表征，以及促进DED中长期Treg功能障碍的机制;（ii）确定 mTh 17细胞的细胞前体，以及影响mTh 17细胞生成的细胞因子机制。 免疫记忆;和（iii）定义的因素，放大mTh 17免疫老化。实现这些 目标，三个具体的目标已经确定，以回答以下问题：目标1：什么是 DED中持续Treg功能障碍的致病机制？目的2：哪些效应子Th 17亚群是 倾向于进入内存池（从而允许DED长期性），什么因素调节这一点 过程？最后，目标3：什么是增强Th 17介导的细胞和分子机制？ 在老化中？预计这项研究将产生重大的翻译影响， DED的患病率，我们对其免疫发病机制的了解仍然有限， 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.