Innate Immunity and its integration in Autoimmune Disease of the Eye

先天免疫及其在眼自身免疫性疾病中的整合

• 批准号: 9041596
• 负责人: HOLLY Lallman ROSENZWEIG
• 金额: $ 28.35万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9041596
• 关键词: Address; Antibodies; Antibody Formation; Antigen-Antibody Complex; Antigens; Arthritis; Autoimmune Diseases; Autoimmune Responses; Autoimmunity; Bone Marrow; Cells; Chimera organism; Chronic; Complement; Complex; Cues; Data; Deposition; Dermatitis; Development; Disease; Disease model; Effector Cell; Evaluation; Event; Eye; Family; Gene Expression; Genes; Genetic; Genetic Predisposition to Disease; Goals; Grant; Granulomatous; Health; Homeostasis; Host Defense; Human; Hypersensitivity; ITGAM gene; IgG Receptors; Immune; Immune System Diseases; Immune response; Immunoglobulin G; Immunologic Receptors; Infiltration; Inflammation; Inflammatory; Innovative Therapy; Interleukin-17; Invaded; Knockout Mice; Lead; Light; Link; Mediating; Medical; Microglia; Mus; Mutation; Natural Immunity; Outcome; Pathogenesis; Pathogenicity; Pathology; Pathway interactions; Patients; Penetrance; Physiological; Point Mutation; Population; Production; Reaction; Receptor Activation; Receptor Gene; Recruitment Activity; Regulation; Repression; Retina; Retinal; Role; Syndrome; System; T cell regulation; T-Lymphocyte; Testing; Therapeutic; Therapeutic Intervention; Tissues; Toll-like receptors; Update; Uveitis; Vasculitis; Vision; adaptive immunity; autoimmune uveitis; autoinflammatory; autoreactive T cell; base; behavior influence; complement system; gene discovery; in vivo; insight; interstitial retinol-binding protein; macrophage; microbial; molecular pathology; novel; novel strategies; novel therapeutics; pathogen; prevent; programs; receptor; research study; response; sensor; therapy design

 DESCRIPTION (provided by applicant): Innate immunity, as the first line of defense against microbial pathogens, is a response that must be tightly regulated or excessive inflammation will ensue, causing disease. For an optimal therapeutic approach, we need to not only understand basic mechanisms of initiation and early events that lead to disease but importantly, how the body protects itself from aberrant immune responses that can trigger autoimmunity. Uveitis (intraocular inflammation), which occurs in association with a number of systemic immunological diseases, presents a considerable medical challenge due to incomplete understanding of its pathogenesis. The gene NOD2 may provide an important clue into uveitis because a single point mutation results in a rare, inflammatory disease called Blau syndrome, which manifests as granulomatous uveitis. NOD2 belongs to a family of innate immune receptors termed NOD-like receptors (NLRs), which are intracellular sensors involved in host defense against invading pathogens. Since no other single gene has been identified as a singular cause of uveitis, analysis of NOD2-pathways could offer important insight into the underlying mechanisms controlling ocular inflammation. To understand how the endogenous, innate immune receptor NOD2 participates in orchestration of autoimmune responses, we undertook studies using experimental autoimmune uveitis (EAU), a prototypical T cell-mediated autoimmune disease model of the eye. Our preliminary studies led us to the unanticipated discovery that NOD2 deficiency renders mice susceptible to EAU; thereby identifying NOD2 as a major genetic susceptibility factor in autoimmune uveitis. Objectives outlined in this grant will test the centra hypothesis of this proposal that NOD2 is important for maintaining ocular immunological homeostasis by preventing aberrant responses that predispose to autoimmune disease of the eye by: (1) Maintaining proper regulation of T cell effector responses and diverting a pathogenic Th17-effector response; (2) Interpreting microenvironment cues within the eye by controlling the physiological state of microglia; and (3) Minimizing tissue damage caused by hypersensitivity responses involving the Fc-gamma receptor (FcgR) and complement systems that occur in the context of antibody-related activation. The goal of this project is to address currently unanswered questions within the field pertaining to the influence of innate immune receptors and orchestration of autoreactive T cell-driven responses. By focusing on aspects of how NOD2 controls early and innate reactions that exist at the interface of innate and adaptive immunity we hope to identify ways to enhance protective innate defenses within the eye while avoiding maladaptive effects of inflammatory pathology, as a potential novel strategy for therapeutic intervention for uveitis and other potentially vision-threatening diseases.

 描述（由申请人提供）：先天免疫是抵抗微生物病原体的第一道防线，是一种必须严格调节的反应，否则会导致过度炎症，从而引起疾病。对于最佳的治疗方法，我们不仅需要了解导致疾病的起始和早期事件的基本机制，而且重要的是，身体如何保护自己免受可能引发自身免疫的异常免疫反应。葡萄膜炎（眼内炎症），其发生与许多全身性免疫性疾病相关，由于对其发病机制的不完全理解而呈现出相当大的医学挑战。基因NOD 2可能为研究葡萄膜炎提供了重要线索，因为单个点突变会导致一种称为Blau综合征的罕见炎症性疾病，表现为肉芽肿性葡萄膜炎。NOD 2属于称为NOD样受体（NLR）的先天免疫受体家族，其是参与宿主防御入侵病原体的细胞内传感器。由于没有其他单一基因被确定为葡萄膜炎的单一原因，NOD 2通路的分析可以提供重要的洞察控制眼部炎症的潜在机制。为了了解内源性先天免疫受体NOD 2如何参与自身免疫反应的协调，我们使用实验性自身免疫性葡萄膜炎（EAU）进行了研究，EAU是一种典型的T细胞介导的自身免疫性疾病模型。我们的初步研究使我们意外地发现，NOD 2缺乏使小鼠易受EAU的影响，从而确定NOD 2作为自身免疫性葡萄膜炎的主要遗传易感性因子。本授权中概述的目标将测试该提议的中心假设，即NOD 2通过以下方式防止易患眼自身免疫性疾病的异常应答，对维持眼免疫稳态很重要：（1）维持T细胞效应应答的适当调节并转移致病性Th 17效应应答;（2）通过控制小胶质细胞的生理状态来解释眼睛内的微环境线索;和（3）使由涉及Fc-γ受体（FcgR）的超敏反应引起的组织损伤最小化以及在抗体相关活化的情况下发生的补体系统。该项目的目标是解决该领域目前尚未回答的问题，涉及先天免疫受体的影响和自身反应性T细胞驱动的反应的编排。通过关注NOD 2如何控制先天和适应性免疫界面处存在的早期和先天反应，我们希望确定增强眼睛内保护性先天防御的方法，同时避免炎症病理学的适应不良效应，作为葡萄膜炎和其他潜在视力威胁疾病的治疗干预的潜在新策略。