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

• 批准号: 10320063
• 负责人: MEREDITH GREGORY-KSANDER
• 金额: $ 41.23万
• 依托单位: MASSACHUSETTS EYE AND EAR INFIRMARY
• 依托单位国家: 美国
• 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/10320063
• 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; CD47-SIRPα; 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' 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

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威胁视力的疾病，其定义为自身反应性葡萄膜炎。 针对视网膜和葡萄膜组织的免疫反应 在自身免疫性葡萄膜炎中，视网膜和葡萄膜组织。 成为自身反应性免疫细胞的目标，导致不可逆的神经损伤，并可能进展为 由于视网膜是一种受血液保护的所谓“免疫特权”组织。 视网膜屏障、免疫细胞如何进入视网膜以及抗原呈递细胞 (APC) 群体 涉及局部抗原呈递已经进行了长时间的讨论，该提案描述的目的是。 阐明视网膜小胶质细胞介导自身反应性免疫细胞进入视网膜的创新机制 小胶质细胞是中枢神经系统（包括视网膜）的常驻免疫细胞，具有功能。 小胶质细胞在神经视网膜微环境的稳态维持中的作用和功能。 由于其多种表型和/或不同阶段的疾病进展尚不清楚 与疾病发病机制中的有害或有益作用相关的激活。 我们最近的工作表明，小胶质细胞耗竭会抑制 EAU 的发育，并且小胶质细胞是 视网膜小胶质细胞对 EAU 的反应显着激活，这对疾病诱导至关重要。 疾病诱导，迅速定位于视网膜血管系统然而，我们的数据表明小胶质细胞确实如此。 在疾病起始中不发挥 APC 的作用，但事实上其功能是促进多种循环系统的浸润 我们的数据强烈表明，小胶质细胞是启动免疫细胞的关键群体。 血-视网膜屏障被破坏，进入视网膜的循环 APC 和 T 细胞会触发 随后的视力改变自身炎症反应然而，这种情况发生的机制。 仍然未知。 在本提案中，我们将阐明自身反应性免疫细胞进入视网膜的机制 以及随后的自身免疫反应在小鼠模型的疾病进展过程中如何发展 我们首先定义 EAU 和实验性自身免疫性葡萄膜炎 (EAU) 中的起始 APC 群体。 此外，我们将确定 MHC-II 小胶质细胞表达在 EAU 疾病进展过程中的贡献。 视网膜小胶质细胞和浸润免疫细胞在 EAU 诱导中的激活和动力学 最后，我们将定义 SIRPalpha/CD47（一个高度相关的免疫轴）的作用。 在 EAU 中受到调节，并在吞噬作用启动和免疫细胞反应中发挥作用。 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辟新的治疗途径 疾病以及其他致盲的新生血管性眼科疾病。