Immunopathogenic mechanisms of dry eye disease

干眼病的免疫致病机制

• 批准号: 8539627
• 负责人: Reza Dana
• 金额: $ 39.81万
• 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 2014-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8539627
• 关键词: Abbreviations; Adult; Affect; Age related macular degeneration; Aging; American; Antigen-Presenting Cells; Blindness; CCL2 gene; CCL20 gene; CCL3 gene; CCL4 gene; CCR; CCR1 gene; CCR5 gene; CCR6 gene; CD11c Antigens; CD4 Positive T Lymphocytes; CD80 gene; CXCL10 gene; CXCL11 gene; CXCL9 gene; CXCR3 gene; Cell Culture Techniques; Cells; Clinical; Conditioned Culture Media; Confocal Microscopy; Cornea; Corneal Ulcer; Cyclosporine; Development; Disease; Elements; Epithelial; Expenditure; Eye; Eye diseases; Figs - dietary; Flow Cytometry; Frequencies; Functional disorder; Generations; Glossary; Growth; High Prevalence; Histocompatibility Antigens Class II; Home environment; Homing; IL17 gene; IL4 gene; IL6 gene; ITGAM gene; Immune; Immune System Diseases; Immunity; In Situ Nick-End Labeling; Individual; Infection; Infiltration; Inflammation; Inflammatory; Interferon Type II; Interferons; Interleukin-1; Interleukin-10; Interleukin-12; Interleukin-17; Interleukin-6; Interleukins; Kinetics; Knowledge; Langerhans cell; Lead; Length; Ligands; Lymphangiogenesis; Lymphatic; Lymphoid; Lymphoid Tissue; Mediating; Messenger RNA; Molecular; Morphology; Nerve; Nerve Degeneration; Nerve Fibers; Neurites; Neurons; Neuropathy; Pathogenesis; Performance at work; Peripheral; Population; Prevalence; Productivity; Proteins; Purinoceptor; RANTES; Regulatory T-Lymphocyte; Research; Risk; Sensory; Severities; Signal Transduction; Stress; Symptoms; T cell response; T-Cell Activation; T-Lymphocyte; T-Lymphocyte Subsets; TNF gene; TNFRSF5 gene; Testing; Th1 Cells; Transgenic Mice; Trigeminal System; Tumor Necrosis Factor-alpha; Vascular Endothelial Growth Factor C; Vascular Endothelial Growth Factor D; Vascular Endothelial Growth Factor Receptor; Vascular Endothelial Growth Factors; Vision; Visual; Work; base; beta-Chemokines; blink reflexes; chemokine; chemokine receptor; corneal scar; cytokine; extracellular; eye dryness; in vivo; interleukin-23; lymph nodes; lymphatic vessel; monocyte; mouse model; neuron apoptosis; ocular surface; public health relevance; receptor binding; receptor expression; terthienyl; therapeutic target; trafficking

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.

描述（由申请人提供）：干眼病（DED）是一种发病机制基本未知的免疫性疾病，其特征在于持续的眼表面，特别是角膜炎症，以及眼表面上皮屏障的破坏，在严重的情况下，这可能导致角膜溃疡和瘢痕形成导致失明。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，其患病率在未来几十年内将翻一番。目前每年用于治疗DED的支出超过10亿美元，并且由于它经常影响工作成年人的视觉功能，它通过影响工作表现而导致生产力损失。虽然免疫和炎症与其发病机制有关，但对DED的精确免疫致病机制知之甚少，除了疾病活动是通过CD11b+单核细胞和CD4+ T细胞持续激活和浸润眼表来维持。我们最近已经证明，DED中的致病性T细胞在引流淋巴结中产生，但是（i）介导免疫细胞从眼睛运输到淋巴组织以引发T细胞，（ii）促进T细胞刺激和（iii）T细胞归巢到眼表面的细胞和分子机制仍然未知。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）确定治疗DED的可能靶点。我们假设DED的发病机制与成熟角膜抗原呈递细胞（APC）向淋巴区室的动员有关，在淋巴区室中，它们可以引发T细胞，T细胞又可以回到眼表面以诱导上皮疾病和神经病变。我们提出了四个具体的目标来测试这一假设，在一个验证和良好的表征小鼠模型DED。特定目的重点在于确定以下机制：（1）诱导角膜APC成熟，（2）促进APC运输至淋巴区室，（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。鉴于DED的高患病率和关于其免疫发病机制的知识的普遍缺乏，预计这项研究的总体影响将是显著的。 公共卫生关系：干眼病是眼表的炎性疾病，与视觉功能障碍和角膜瘢痕形成和感染的高风险相关，其免疫发病机制尚不清楚。我们建议在这里，以确定特定的免疫为基础的细胞和分子的干眼病的致病因素。希望是，对不同致病机制的精确理解将产生重要的治疗靶点，这可能有助于管理数百万患有严重干眼症的美国人以及数千万症状不太严重的其他人。