Mechanisms of immune homeostasis and regulation of intraocular inflammation

免疫稳态机制和眼内炎症调节

基本信息

批准号：
10019987
负责人：
Charles E Egwuagu
金额：
$ 50.4万
依托单位：
NATIONAL EYE INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10019987
关键词：
Autoimmune Diseases Autoimmune Process B-Lymphocytes Binding CD8-Positive T-Lymphocytes CISH gene CNS autoimmune disease Cell Death Cell Proliferation Cells Communicable Diseases Disease Elements Embryonic Development Etiology Goals Homeostasis Immune Immune system Inflammation Inflammatory Innate Immune System Insecta Instruction Interferons Interleukin-10 Lymphocyte Mammals Mediating Multiple Sclerosis Neurodegenerative Disorders PTPN6 gene Pathologic Pathway interactions Physarum polycephalum Physiological Physiological Processes Platelet Factor 4 Play Production Proteins Regulation Regulatory T-Lymphocyte Research Role STAT3 gene Signal Pathway Signal Transduction Signal Transduction Pathway T-Lymphocyte T-Lymphocyte Subsets Therapeutic Transcription Factor AP-1 Uveitis adaptive immune response base cell type cytokine effector T cell in vivo monocyte recruit transcription factor

项目摘要

Innate lymphocytes, monocytes, regulatory T cells (Tregs) and regulatory B cells (Bregs) suppress CNS autoimmune diseases such as Uveitis or Multiple Sclerosis by secreting IL-10 and IL-35. The activities of these immune suppressive cytokines are mediated through activation of JAK/STAT signaling pathway and are under stringent regulation. In this study, we sought to identify major cell types that produce both cytokines in-vivo and to characterize mechanisms that regulate their production. Compared to innate or Tregs we found that Bregs are the major producers of IL-35 and IL-10 in vivo during ocular inflammatory diseases. We also found that BATF, IFN regulatory factor (IRF)-4, and IRF-8 transcription factors are recruited and bind to AP1-IRF-composite elements (AICEs) of il12a, ebi3, and/or il10 loci, suggesting that these transcription factors regulate IL-10 and IL-35 expression by activated B cells. We also found that STAT3-dependent and independent pathways control ocular inflammation. These studies suggest that targeting STAT3 pathways and the BATF/IRF-4/IRF-8 axis can be exploited therapeutically to regulate physiological levels of IL-10/IL-35-Bregs and ocular inflammation.

先天淋巴细胞，单核细胞，调节性T细胞（TREG）和调节B细胞（Bregs）通过分泌IL-10和IL-35来抑制CNS自身免疫性疾病，例如葡萄膜炎或多发性硬化症。这些免疫抑制性细胞因子的活性是通过激活JAK/STAT信号通路介导的，并且受到严格的调节。在这项研究中，我们试图确定产生细胞因子体内细胞因子的主要细胞类型，并表征调节其生产的机制。与先天或Treg相比，我们发现Bregs是眼部炎症性疾病期间体内IL-35和IL-10的主要生产者。我们还发现，募集BATF，IFN调节因子（IRF）-4和IRF-8转录因子并与IL12A，EBI3和/或IL10基因座的AP1-IRF复合元件（AICS）结合，这表明这些转录因子调节IL-100和IL-35表达由活性B细胞调节IL-10和IL-35表达。我们还发现STAT3依赖性和独立途径控制眼部炎症。这些研究表明，可以对STAT3途径和BATF/IRF-4/IRF-8轴进行治疗利用以调节IL-10/IL-35-BREG和眼部炎症的生理水平。