Immunopathogenic mechanisms of dry eye disease

干眼病的免疫致病机制

• 批准号: 10524044
• 负责人: Reza Dana
• 金额: $ 49.25万
• 依托单位: SCHEPENS EYE RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-30 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10524044
• 关键词: Adult; Age; Age related macular degeneration; Aging; American; Antigen-Presenting Cells; Blindness; Caring; Cell physiology; Cells; Chronic; Corneal Ulcer; Data; Desiccation; Development; Diagnosis; Direct Costs; Disease; Dose; Dry Eye Syndromes; Elements; Epithelium; Exposure to; Eye; Financial Hardship; Functional disorder; GFI1 gene; Generations; Healthcare Systems; High Prevalence; Homeostasis; Homing; IL17 gene; IL7 gene; Immune; Immunity; Immunologic Memory; Impairment; In Vitro; Inflammation; Inflammatory; Interferon Type II; Interleukin-2; Knockout Mice; Knowledge; Laboratories; Maintenance; Mediating; Memory; Molecular; Mus; Pathogenicity; Patients; Phenotype; Predisposition; Prevalence; Principal Investigator; Process; Regulation; Regulatory T-Lymphocyte; Research; Risk; Series; Severities; Severity of illness; Source; Stress; Substance P; Visit; Work; aged; corneal scar; cytokine; effective therapy; experimental study; functional restoration; improved; in vivo; insight; interleukin-23; novel; ocular surface; ocular surface disease; productivity loss; promoter; response; restoration; therapeutic target; trafficking; transcription factor; translational impact; visual dysfunction

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.

干眼症（DED）是一种慢性免疫介导的眼表，其特征是 上皮屏障和持续的眼表炎症的破坏，在严重的情况下，这会导致 在角膜溃疡和疤痕的失明中。 DED可以说是最常见的眼科 患者访问眼保健专业人员的状况，据估计有超过1600万美国成年人 已被诊断出患有DED（高于年龄相关的黄斑变性）。值得注意的是 DED的患病率随着年龄的增长而增加。美国医疗保健系统的财务负担很大， 由于生产力损失的直接成本和费用估计每年超过35亿美元。 包括主要研究人员在内的几个实验室的工作揭示了关键的见解 关于DED的免疫病变。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启动子。 PI的实验室已显示 记忆Th17（MTH17）细胞保持疾病的慢性，导致眼表面上皮病， 暴露于干燥压力后的多个月持续存在。此外，PI实验室的数据表明 调节性T细胞（Tregs）在抑制DED中的Th17响应方面有缺陷。此外，Pi的实验室 已经确定了控制抗原呈递细胞（APC）激活和运输中的关键机制 DED以及效应子Th17启动，扩展和归巢。尽管取得了长足的进步 潜在的免疫病机制，重要的问题仍未得到解答。 我们假设（1）慢性DED的特征是长期障碍 通常维持免疫静止的调节性T细胞（Tregs），（2）年龄更多 由于较大的记忆池Th17易受DED的影响，其功能不充分受老化的调节 Tregs。该项目的主要目标是（i）精确定义表型变化 表征了DED中促进长期Treg功能障碍的机制； （ii）确定 MTH17细胞的细胞前体以及影响产生的细胞因子机制 免疫记忆； （iii）定义了扩增衰老中MTH17免疫力的因素。实现这些 目标，已经定义了三个特定目标以回答以下问题：目标1：什么是什么 DED中持续treg功能障碍的致病机制？目标2：哪个效应子Th17子集是 容易进入内存池（因此允许DED慢性），以及哪些因素对此进行调节 过程？最终目标3：增强Th17介导的细胞和分子机制是什么 衰老？预计，鉴于高 DED的患病率，我们仍然对其免疫发育的知识仍然有限，相对 有效治疗的稀缺。