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

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疾病

项目成果

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MEREDITH GREGORY-KSANDER其他文献

MEREDITH GREGORY-KSANDER的其他文献

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{{ truncateString('MEREDITH GREGORY-KSANDER', 18)}}的其他基金

Fas Ligand Cleavage regulates ocular homeostasis and glaucoma
Fas 配体裂解调节眼稳态和青光眼
  • 批准号:
    10374484
  • 财政年份:
    2022
  • 资助金额:
    $ 42.5万
  • 项目类别:
Fas Ligand Cleavage regulates ocular homeostasis and glaucoma
Fas 配体裂解调节眼稳态和青光眼
  • 批准号:
    10867990
  • 财政年份:
    2022
  • 资助金额:
    $ 42.5万
  • 项目类别:
Fas Ligand Cleavage regulates ocular homeostasis and glaucoma
Fas 配体裂解调节眼稳态和青光眼
  • 批准号:
    10550147
  • 财政年份:
    2022
  • 资助金额:
    $ 42.5万
  • 项目类别:
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
  • 财政年份:
    2021
  • 资助金额:
    $ 42.5万
  • 项目类别:
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:
    10527371
  • 财政年份:
    2021
  • 资助金额:
    $ 42.5万
  • 项目类别:
Uncoupling caspase 8-mediated-apotosis from caspase 8-mediated-inflammation in glaucoma.
将青光眼中 caspase 8 介导的细胞凋亡与 caspase 8 介导的炎症解偶联。
  • 批准号:
    9919567
  • 财政年份:
    2019
  • 资助金额:
    $ 42.5万
  • 项目类别:
Regulation of vascular leakage in age related macular degeneration
年龄相关性黄斑变性中血管渗漏的调节
  • 批准号:
    8385057
  • 财政年份:
    2012
  • 资助金额:
    $ 42.5万
  • 项目类别:
Regulation of vascular leakage in age related macular degeneration
年龄相关性黄斑变性中血管渗漏的调节
  • 批准号:
    8534134
  • 财政年份:
    2012
  • 资助金额:
    $ 42.5万
  • 项目类别:
Neurotoxicity and neuroprotection in the DBA/2J spontaneous model of glaucoma
DBA/2J 自发性青光眼模型的神经毒性和神经保护
  • 批准号:
    8237645
  • 财政年份:
    2011
  • 资助金额:
    $ 42.5万
  • 项目类别:
Neurotoxicity and neuroprotection in the DBA/2J spontaneous model of glaucoma
DBA/2J 自发性青光眼模型的神经毒性和神经保护
  • 批准号:
    8389866
  • 财政年份:
    2011
  • 资助金额:
    $ 42.5万
  • 项目类别:

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