Regulation of the neuroinflammatory response in autoimmune uveitis

自身免疫性葡萄膜炎神经炎症反应的调节

基本信息

批准号：
10115860
负责人：
MEREDITH GREGORY-KSANDER
金额：
$ 42.5万
依托单位：
MASSACHUSETTS EYE AND EAR INFIRMARY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-01-01 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10115860
关键词：
Ablation Accounting Adoptive Transfer Anti-CD47 Antibodies Antigen Presentation Antigen Targeting Antigen-Presenting Cells Antigens Astrocytes Autoantigens Autoimmune Autoimmune Responses Blindness Blood-Retinal Barrier CD47 gene Cells Chronic Data Development Disease Disease Progression Endothelial Cells Etiology Experimental Models Eye Goals Immune Immune response Immune system Immunization Immunosuppression Infiltration Inflammation Inflammatory Inflammatory Response Injury Kinetics Lead Leukocytes MHC Class II Genes Maintenance Mediating Microglia Modeling Muller&apos s cell Mus Neuraxis Optic Nerve Pathogenesis Patients Phagocytosis Pharmacology Phenotype Photoreceptors Population Prevalence Production RNA Sequences Regulation Reporting Research Retina Role Sarcoidosis Secondary to Syndrome Systemic disease T-Lymphocyte Testing Time Tissues Transgenic Mice Transgenic Organisms Tumor-infiltrating immune cells Uveitis Uveomeningoencephalitic Syndrome Vision Visual impairment Work autoimmune uveitis autoinflammatory autoreactivity cell type cytokine innovation mouse model neovascular neuroinflammation prevent receptor recruit relating to nervous system response single-cell RNA sequencing

Ablation Accounting Adoptive Transfer Anti-CD47 Antibodies Antigen Presentation Antigen Targeting Antigen-Presenting Cells Antigens Astrocytes Autoantigens Autoimmune Autoimmune Responses Blindness Blood-Retinal Barrier CD47 gene Cells Chronic Data Development Disease Disease Progression Endothelial Cells Etiology Experimental Models Eye Goals Immune Immune response Immune system Immunization Immunosuppression Infiltration Inflammation Inflammatory Inflammatory Response Injury Kinetics Lead Leukocytes MHC Class II Genes Maintenance Mediating Microglia Modeling Muller&apos s cell Mus Neuraxis Optic Nerve Pathogenesis Patients Phagocytosis Pharmacology Phenotype Photoreceptors Population Prevalence Production RNA Sequences Regulation Reporting Research Retina Role Sarcoidosis Secondary to Syndrome Systemic disease T-Lymphocyte Testing Time Tissues Transgenic Mice Transgenic Organisms Tumor-infiltrating immune cells Uveitis Uveomeningoencephalitic Syndrome Vision Visual impairment Work autoimmune uveitis autoinflammatory autoreactivity cell type cytokine innovation mouse model neovascular neuroinflammation prevent receptor recruit relating to nervous system response single-cell RNA sequencing

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项目摘要

Research Abstract: Autoimmune uveitis is a serious sight-threatening condition defined by an autoreactive immune response against the retina and uveal tissues. In autoimmune uveitis, the retina and uveal tissues become a target of autoreactive immune cells, which leads to irreversible neural damages and can progress to significant visual impairment. Since the retina is a so-called “immune privileged” tissue protected by blood- retinal barrier, how immune cells gain entry into the retina and what antigen presenting cell (APC) populations are involved in local antigen presentation have been a long discussion. This proposal describes aims to elucidate an innovative mechanism whereby retinal microglia mediate autoreactive immune cell entry into the retina. Microglia are the resident immune cells of the central nervous system, including the retina, and function in the homeostatic maintenance of the neuro-retinal microenvironment. The role and function of microglia in disease progression is not well understood due to their multiple phenotypes and/or different stages of activation that are associated with either harmful or beneficial effects in disease pathogenesis. Our recent work demonstrated that microglial depletion inhibits development of EAU and that microglia are essential to disease induction. Interestingly, retinal microglia are significantly activated in response to EAU disease induction, quickly localizing to the retinal vasculature. However, our data indicated that microglia do not function as APCs in disease initiation, but in fact function to facilitate infiltration of a variety of circulating immune cells into the neuroretina. Our data highly suggested that microglia are key population that initiates blood-retinal barrier breakdown and that the circulating APCs and T cells that enter the retina trigger the subsequent vision altering auto-inflammatory response. However, the mechanisms by which this occurs remains unknown. In this proposal, we will elucidate the mechanism by which autoreactive immune cells gain entry into the retina and how the subsequent autoimmune response develops during disease progression in a mouse model of experimental autoimmune uveitis (EAU). We will begin by defining the initiating APC populations in EAU and the contribution of microglial expression of MHC-II during EAU disease progression. Moreover, we will identify the activation and kinetics of retinal microglia and infiltrating immune cells in EAU induction by using a single cell RNA sequence profiling. Lastly, we will define the role of SIRPalpha/CD47, an immune axis that is highly regulated in EAU and that functions in phagocytosis initiation and immune cell reactivity. Understanding the mechanism by which microglia initiate autoimmune uveitis will likely open new avenues of therapy for this disease as well as other blinding neovascular ophthalmic diseases.

研究摘要：自身免疫性葡萄膜炎是一种严重的视力威胁性疾病对视网膜和紫veal组织的免疫反应。在自身免疫性葡萄膜炎中，视网膜和卵子组织成为自动反应性免疫电池的目标，这会导致不可逆的神经损害，并可以发展为重大视觉障碍。由于视网膜是一种由血液保护的所谓“免疫特权”组织视网膜屏障，免疫细胞如何进入视网膜以及什么抗原呈现细胞（APC）种群参与局部抗原表现一直是一个漫长的讨论。该提议描述的目的是阐明一种创新机制，视网膜小胶质细胞介导自动反应性免疫细胞进入视网膜。小胶质细胞是中枢神经系统的居民，包括视网膜，功能在神经视网膜微环境的稳态维护中。小胶质细胞在由于其多种表型和/或不同的阶段，疾病进展尚未得到很好的了解与疾病发病机理中有害或有益作用相关的激活。我们最近的工作表明，小胶质部署抑制了EAU的发展，而小胶质细胞是疾病诱导至关重要。有趣的是，视网膜小胶质细胞可显着激活EAU 疾病诱导，迅速将其定位到视网膜脉管系统中。但是，我们的数据表明小胶质细胞做在疾病开始中不充当APC，但实际上功能可以促进各种循环的渗透免疫细胞进入神经素。我们的数据强烈建议小胶质细胞是启动的关键人群血液 - 视网膜屏障的分解以及进入视网膜的循环APC和T细胞触发随后的视力改变自动炎症反应。但是，发生这种情况的机制仍然未知。在此提案中，我们将阐明自动反应性免疫球进入视网膜的机制以及如何在疾病进展过程中随后的自身免疫反应发生在小鼠模型中实验性自身免疫性葡萄膜炎（EAU）。我们将首先定义EAU的启动APC群体和 MHC-II在EAU疾病进展过程中的小胶质表达的贡献。而且，我们将确定通过使用单个单一细胞RNA序列分析。最后，我们将定义sirpalpha/cd47的作用，这是一种高度的免疫轴在EAU中调节，并在吞噬作用和免疫细胞反应性中起作用。了解小胶质细胞引发自身免疫性葡萄膜炎的机制可能会为此开放新的治疗途径疾病以及其他盲目的新生血管眼科疾病。