Cellular and Molecular Mechanisms that Contribute to Ocular Surface Disease during Severe Allergic Inflammation

严重过敏性炎症期间导致眼表疾病的细胞和分子机制

• 批准号: 9919560
• 负责人: Daniel Raphael Saban
• 金额: $ 39.75万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-02-01 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9919560
• 关键词: Address; Affect; Allergic; Allergic inflammation; American; Animal Model; Anterior; Antigen-Presenting Cells; Area; Blepharitis; Blindness; Bone Marrow; Bullous Pemphigoid; Cell Degranulation; Cells; Cellular biology; Chimera organism; Chronic; Clinical; Collaborations; Cornea; Cre-LoxP; Data; Defect; Dendritic Cells; Development; Disease; Disease model; Duct (organ) structure; Eosinophilia; Etiology; Event; Eye; Eye diseases; Fibrosis; Film; Flow Cytometry; Genetic Techniques; Gland; Glean; Grant; Health; Histologic; Homeostasis; Human; Hypersensitivity; Immune; Immune System Diseases; Immune response; Immune system; Immunologics; Impairment; Individual; Infiltration; Inflammation; Inflammatory; Keratoconjunctivitis; Lead; Lung; Lymphocyte; Lymphocyte Activation; Mediating; Mediator of activation protein; Medical; Medicine; Microscopy; Modeling; Molecular; Mucous Membrane; Mus; Ocular Rosacea; Oils; Pathogenesis; Pathogenicity; Pathologic; Pathology; Pathway interactions; Patients; Pharmacology; Play; Plug-in; Process; Production; Psoriasis; Quality of life; Role; Secondary to; Series; Site; Stevens-Johnson Syndrome; System; T cell response; Technology; Thinking; Time; Transgenic Mice; Tumor-infiltrating immune cells; Work; adaptive immune response; adaptive immunity; base; bulbar conjunctiva; chronic graft versus host disease; clinical examination; conjunctiva; experimental study; in vivo; mast cell; meibomian gland; meibomian gland dysfunction; mouse model; neutrophil; novel; novel therapeutics; ocular surface; response; tool

ABSTRACT Inflammatory lid margin disease, which arises in chronic ocular surface inflammation, constitutes a major health problem in the U.S. and abroad. This type of inflammation, also referred to as blepharitis, can affect both the anterior and posterior aspects of the lid margin, and may include meibomian gland dysfunction (MGD). Long-term defects of the tear film and secondary impairments to the conjunctiva and cornea often develop due to MGD, as the meibomian gland is responsible for the oil (or meibum) production required for tear film homeostasis. Such debilitating blepharitis occurs regularly in patients with chronic forms of allergic eye disease, such as in atopic keratoconjunctivitis (AKC). Likewise, blepharitis occurs in ocular rosacea, chronic graft versus host disease, Stevens-Johnson Syndrome, and other chronic inflammatory ocular surface diseases. Our lab has previously established and validated a severe allergic eye disease (AED) mouse model. This AED model reproducibly develops various clinical sequelae consistent with AKC in humans, including corneal involvement, subepithelial fibrosis of the bulbar conjunctiva, and blepharitis (anterior and posterior). The utility of this model has proven to permit identification of unknown pathogenic events that mediate severe eye allergy, which is a disease with an unmet medical need. Along these lines, the aim of this grant is to elucidate the immunologic mechanisms that specifically cause blepharitis in the AED model. Experiments proposed go beyond the examination of classical allergic inflammation, such as mast cell degranulation, T helper 2 responses and eosinophilia. Instead, our preliminary data has led us to focus our efforts on the central role of the T helper 17 pathway. Experiments herein also seek to elucidate upstream mediators, including identification of the bona fide dendritic cell subsets, and their mediators, responsible for eliciting the T helper 17 pathway in this disease model. Our approach involves a myriad of in vivo genetic techniques to enable conditional/inducible depletion of specific dendritic cell subsets in a site specific manner. These strategies and others will empower us to pinpoint the mediators and their mechanisms that cause lid margin disease in the AED model. This timely and novel proposal is poised to catalyze our understanding of eye mucosal dendritic cells in disease and lymphocyte activation in blepharitis. Furthermore, information gleaned from these experiments could be relevant in the broader context of ocular surface inflammatory disease.

摘要 炎症性睑缘疾病，它出现在慢性眼表炎症，构成了一个主要的 健康问题在美国和国外。这种类型的炎症，也称为睑缘炎，可以影响 眼睑边缘的前部和后部，并且可能包括睑板腺功能障碍（MGD）。 泪膜的长期缺陷以及结膜和角膜的继发性损伤通常由于 MGD，因为睑板腺负责泪膜所需的油（或睑脂）的产生 体内平衡这种使人衰弱的睑缘炎经常发生在患有慢性形式的过敏性眼病的患者中， 例如特应性角膜结膜炎（AKC）。同样，睑缘炎发生在眼部酒渣鼻，慢性移植物与 宿主疾病、Stevens-Johnson综合征和其他慢性炎性眼表疾病。我们实验室 之前已经建立并验证了严重过敏性眼病（AED）小鼠模型。这个AED模型 可重复地发展与人类AKC一致的各种临床后遗症，包括角膜受累， 球结膜上皮下纤维化和睑炎（前部和后部）。该模型的实用性 已证明允许鉴定介导严重眼过敏的未知致病事件，这是一种 一种未满足医疗需求的疾病。沿着这些路线，这项资助的目的是阐明免疫学 在AED模型中特异性引起睑缘炎的机制。建议的实验超越了 检查经典的过敏性炎症，如肥大细胞脱粒，T辅助细胞2反应和 嗜酸性粒细胞增多症相反，我们的初步数据使我们把精力集中在T辅助细胞的核心作用上。 通路本文的实验还试图阐明上游介质，包括识别Bona 真正的树突状细胞亚群及其介体，负责引发这种疾病中的T辅助细胞17通路 模型我们的方法涉及无数的体内遗传技术，以实现条件性/诱导性耗竭 以位点特异性方式表达特定的树突状细胞亚群。这些战略和其他战略将使我们能够 在AED模型中查明引起眼睑边缘疾病的介质及其机制。这次及时和 一项新的提议有望促进我们对疾病中眼粘膜树突状细胞的理解， 睑缘炎中的淋巴细胞活化。此外，从这些实验中收集到的信息可能是 与眼表面炎性疾病的更广泛背景相关。