Immunopathogenic mechanisms of dry eye disease

描述(申请人提供)：干眼病(DED)是一种发病机制不明的免疫性疾病，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，在严重的情况下，可导致因角膜溃疡和疤痕而致盲。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，其患病率在未来几十年将翻一番。目前用于治疗DED的费用每年超过10亿美元，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。虽然免疫和炎症与DED的发病机制有关，但对DED的确切免疫致病机制知之甚少，除了CD11b+单核细胞和CD4+T细胞持续激活和渗透到眼表维持疾病活动。我们最近已经证明DED的致病T细胞是在引流的淋巴结中产生的，但(I)介导免疫细胞从眼睛到淋巴组织到原始T细胞的运输，(Ii)促进T细胞刺激和(Iii)T细胞归巢到眼表的细胞和分子机制尚不清楚。此外，(Iv)虽然角膜神经丢失和功能障碍是DED的重要方面，但对DED中影响神经变性的机制了解很少。该项目的目标是(I)准确确定DED的分子和细胞致病机制，以及(Ii)确定治疗DED的可能靶点。我们假设DED的发病机制与成熟的角膜抗原提呈细胞(APC)动员到淋巴间隔室有关，在那里它们可以激活T细胞，而T细胞又可以回到眼表，导致上皮性疾病和神经病变。我们提出了四个特定的目标来验证这一假设，在一个经过验证的和特征良好的DED小鼠模型中。其具体目标集中于确定(1)诱导角膜APC成熟，(2)促进APC转运至淋巴室，(3)导致不同(Th1和Th17)致病的CD4+T细胞亚群的产生和周围化，以及(4)导致角膜神经退化的机制。考虑到DED的高患病率以及对其免疫发病机制的普遍缺乏，预计这项研究的总体影响将是显著的。 公共卫生相关性：干眼病是一种眼表面炎症性疾病，与视觉功能障碍和角膜瘢痕形成和感染的风险增加有关，目前尚不清楚其免疫发病机制。我们建议在此确定干眼病的特定免疫细胞和分子致病因素。人们希望，对不同致病机制的准确理解将产生重要的治疗目标，这些目标可能有助于管理数百万患有严重干眼的美国人，以及其他数千万症状不那么严重的人。

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.