Immunopathogenic mechanisms of dry eye disease

描述（由申请人提供）：干眼病（DED）是一种很大程度上未知发病机制的免疫疾病，其特征是持续的眼表，特别是角膜炎症，以及眼表上皮屏障的破坏，严重情况下可导致角膜溃疡和疤痕导致失明。DED的患病率非常高，几乎是年龄相关性黄斑变性的三倍，仅在美国就影响了数百万人，并且随着人口老龄化，其患病率将在未来几十年翻一番。目前每年用于治疗DED的费用超过10亿美元，由于它经常影响工作成年人的视觉功能，它会影响工作表现，从而导致生产力下降。虽然免疫和炎症与DED的发病机制有关，但除了CD11b+单核细胞和CD4+ T细胞持续激活和浸润眼表以维持疾病活性外，对DED的确切免疫致病机制知之甚少。我们最近已经证明，DED中的致病性T细胞是在引流淋巴结中产生的，但细胞和分子机制(i)介导免疫细胞从眼睛运输到淋巴组织到原始T细胞，（ii）促进T细胞刺激，（iii） T细胞归巢到眼表仍不清楚。此外，（iv）虽然角膜神经丧失和功能障碍是DED的重要方面，但对DED中影响神经变性的机制知之甚少。该项目的目标是：(i)精确定义DED的分子和细胞致病机制，以及（ii）确定DED的可能治疗靶点。我们假设DED的发病机制与成熟的角膜抗原呈递细胞（APC）动员到淋巴样室，在那里它们可以启动T细胞，T细胞反过来可以回到眼表诱导上皮疾病和神经病变有关。我们提出了四个具体的目标来验证这一假设，在一个有效的和特征良好的小鼠模型的DED。具体目标侧重于确定(1)诱导角膜APC成熟的机制，(2)促进APC转运到淋巴样室，(3)导致不同（Th1和Th17）致病性CD4+ T细胞亚群的产生和外周化，以及(4)导致角膜神经变性的机制。鉴于DED的高患病率和对其免疫发病机制的普遍缺乏，预计本研究的总体影响将是显著的。

DESCRIPTION (provided by applicant): Dry eye disease (DED), an immune disorder of largely unknown pathogenesis, is characterized by sustained ocular surface and in particular corneal inflammation, and disruption of the ocular surface epithelial barrier, which in severe cases can lead to blindness from corneal ulceration and scarring. DED has a very high prevalence, almost triple that of age-related macular degeneration, affecting many millions of individuals in the US alone, and its prevalence is set to double in the coming decades with the aging of the population. Current expenditures for treating DED surpass $1 billion dollars annually, and because it often affects visual function in working adults, it leads to lost productivity by impacting job performance. While immunity and inflammation have been implicated in its pathogenesis, very little is known about the precise immunopathogenic mechanisms of DED except that disease activity is sustained by ongoing activation and infiltration of the ocular surface by CD11b+ monocytes and CD4+ T cells. We have recently demonstrated that pathogenic T cells in DED are generated in the draining lymph nodes, but the cellular and molecular mechanisms that (i) mediate trafficking of immune cells from the eye to the lymphoid tissues to prime T cells, (ii) promote T cell stimulation and (iii) T cell homing onto the ocular surface remain unknown. In addition, (iv) while corneal nerve loss and dysfunction are important aspects of DED, very little is understood about the mechanisms that effect nerve degeneration in DED. The objectives of this project are to (i) precisely define the molecular and cellular pathogenic mechanisms of DED, and (ii) identify possible targets for treatment of DED. We hypothesize that pathogenesis of DED is associated with mobilization of mature corneal antigen-presenting cells (APC) to the lymphoid compartment where they can prime T cells, which can in turn home to the ocular surface to induce epithelial disease and neuropathy. We propose four specific aims to test this hypothesis in a validated and well-characterized mouse model of DED. The Specific Aims focus on identifying the mechanisms that (1) induce maturation of corneal APC, (2) facilitate APC trafficking to the lymphoid compartment, (3) lead to generation and peripheralization of different (Th1 and Th17) pathogenic CD4+ T cell subsets, and (4) cause corneal nerve degeneration. It is anticipated that the overall impact of this research will be significant given the high prevalence of DED and the general dearth of knowledge regarding its immunopathogenesis. PUBLIC HEALTH RELEVANCE: Dry eye disease is an inflammatory disorder of the ocular surface, associated with visual dysfunction and heightened risk of corneal scarring and infection, with as of yet poorly understood immunopathogenesis. We propose here to determine the specific immune-based cellular and molecular pathogenic elements of dry eye disease. The hope is that precise understanding of distinct pathogenic mechanisms will yield important therapeutic targets which could be useful in the management of the millions of Americans suffering from severe dry eye, and tens of millions of others with less severe symptoms.