Immunopathogenic mechanisms of dry eye disease

描述(申请人提供)：干眼病(DED)是一种慢性免疫调节的眼表疾病，以持续的眼表炎症和眼表上皮细胞破坏为特征，严重时可导致角膜瘢痕形成和失明。DED的患病率非常高，几乎是老年性黄斑变性的三倍，仅在美国就有数百万人受到影响，随着人口老龄化，其患病率将大幅上升。目前用于治疗DED的费用每年超过20亿美元，由于它经常影响在职成年人的视觉功能，因此它会影响工作绩效，从而导致生产力下降。虽然免疫在扩大DED严重程度中的作用已经知道一段时间了，但直到最近我们才对驱动DED的免疫致病机制有了深入的了解。来自几个实验室的证据，包括首席研究员的证据，已经建立了强有力的证据，证明T辅助17(Th17)细胞在驱动免疫介导的DED眼表损伤中发挥关键作用。来自PI实验室的最新证据表明，DED可以通过记忆Th17细胞长期维持数月，即使在眼睛干燥压力终止后也是如此，Th17细胞与急性眼睛干燥压力后介导疾病的效应器T细胞不同。此外，PI实验室的数据表明，在DED中，调节性T细胞(Tregs)通常在抑制T细胞介导的炎症方面非常有效，但在抑制Th17反应方面尤其缺陷。虽然这些数据为DED的免疫发病机制提供了新的见解，但许多重要的问题仍然没有答案。我们假设DED的特征是一个促进Th17免疫产生和维持的微环境，而Th17免疫反过来又导致正常维持免疫静止的Treg功能受到抑制。本项目的主要目的是(I)明确影响免疫记忆产生和维持的因素，并准确地描述DED患者角膜上皮功能障碍和(Iii)Treg在维持免疫平衡中的作用。为了实现这些主要目标，定义了三个具体目标来回答以下问题：目标1：在慢性干眼病中诱导和维持Th17免疫记忆的关键细胞因子机制是什么？目的2：DED角膜上皮损伤如何影响角膜上皮的免疫调节功能？还有，目标3：在Th17相关的细胞因子中，哪些与Tregs直接相互作用，从而抑制其调节功能？考虑到DED的高患病率，我们对其确切的免疫发病机制的了解仍然有限，以及相对缺乏有效的治疗方法，预计这项研究将产生重大的翻译影响。

DESCRIPTION (provided by applicant): Dry eye disease (DED), a chronic immune-mediated disorder of the ocular surface, is characterized by sustained ocular surface inflammation and disruption of the ocular surface epithelium, which in severe cases can lead to corneal scarring and blindness. DED has a very high prevalence, almost triple that of age-related macular degeneration, affecting many millions of individuals in the United States alone, and its prevalence is set to increase considerably with the aging of the population. Current expenditures for treating DED surpass $2 billion dollars annually, and because it often affects visual function in working adults, it leads to lost productivity by impacting job performance. While the role of immunity in amplifying DED severity has been known for some time, it is only recently that we have gained insights into the immunopathogenic mechanisms that drive DED. Evidence from several laboratories, including the Principal Investigator's, has established strong evidence for the critical role of T helper-17 (Th17) cells, in driving immune-mediated damage to the ocular surface in DED. More recent evidence from the PI's lab shows that DED can be maintained chronically for months, even after termination of desiccating stress to the eye, by memory Th17 cells, which are distinct from the effector T cells that mediate disease after acute ocular desiccating stress. In addition, data from the PI's lab demonstrate that in DED the regulatory T cells (Tregs), which are normally highly effective in suppressing T cell-mediated inflammation, are particularly defective in suppressing the Th17 response. While these data provide new insights into DED immunopathogenesis, numerous important questions remain unanswered. We hypothesize that DED is characterized by a microenvironment that promotes the generation and maintenance of Th17 immunity, which in turn leads to suppressed function of Tregs that normally maintain immune quiescence. The principal objectives of this project are to (i) define the factors that influence the generation and maintenance of immunologic memory, and characterize precisely the dysfunction of (ii) the corneal epithelium and (iii) Tregs in maintaining immune homeostasis in DED. To achieve these major objectives, three specific aims have been defined to answer the following questions: Aim 1: What are the critical cytokine mechanisms that lead to induction and maintenance of Th17 immunological memory in chronic dry eye disease? Aim 2: How does epithelial damage affect the immunomodulatory function of the corneal epithelium in DED? And, Aim 3: Which among the Th17- associated cytokines interact directly with Tregs to suppress their regulatory function? 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 precise immunopathogenesis, and the relative dearth of effective treatments.