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，由自身反应性葡萄膜炎 对视网膜和葡萄膜组织的免疫反应。自身免疫性葡萄膜炎的视网膜和葡萄膜组织 成为自身反应性免疫细胞的目标，这会导致不可逆转的神经损伤，并可进展为 严重的视力障碍。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，以及什么抗原提呈细胞(APC)群体 是否参与局部抗原递呈一直是一个很长的讨论。该提案描述了以下目标 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新机制 视网膜。小胶质细胞是包括视网膜在内的中枢神经系统的常驻免疫细胞，其功能 在维持神经视网膜微环境的动态平衡方面。小胶质细胞在脑出血中的作用和功能 由于其多种表型和/或不同阶段的疾病进展尚不清楚。 在疾病发病机制中与有害或有益的影响相关的激活。 我们最近的工作表明，小胶质细胞的枯竭抑制了EAU的发展，并且小胶质细胞 对疾病的诱发是必不可少的。有趣的是，视网膜小胶质细胞对eau的反应显著激活。 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 在疾病的发生中不起到APC的作用，但实际上起到促进各种循环的渗透作用 免疫细胞进入神经视网膜。我们的数据高度表明，小胶质细胞是启动 血-视网膜屏障被破坏，循环中的APC和T细胞进入视网膜引发 随后的视力改变了自体炎症反应。然而，发生这种情况的机制 仍然不为人知。 在这个提案中，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如何在疾病进展过程中在小鼠模型中发展 实验性自身免疫性葡萄膜炎(EAU)。我们将首先定义EAU和EAU中的启动APC种群 小胶质细胞表达MHC-II在EAU疾病进展中的作用。此外，我们将确定 视网膜小胶质细胞和浸润性免疫细胞在EAU诱导过程中的激活和动力学 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 在EAU中调节，并在吞噬启动和免疫细胞反应性中起作用。了解 小胶质细胞启动自身免疫性葡萄膜炎的机制可能为其开辟新的治疗途径 眼科疾病以及其他致盲的新生血管眼科疾病。