Role of two novel genes in IL-23 production and Th17-mediated pathogenesis in SLE

两个新基因在 IL-23 产生和 Th17 介导的 SLE 发病机制中的作用

基本信息

批准号：
8831592
负责人：
XIAOJING MA
金额：
$ 21.19万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-04-07 至 2017-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8831592
关键词：
Affect Apoptotic Arthritis Autoantibodies Autoantigens Autoimmune Diseases Autoimmune Process Autoimmunity B-Lymphocytes Binding CD4 Positive T Lymphocytes Cell Differentiation process Cells Complex Cytokine Signaling DNA Binding Dendritic Cells Development Eating Event Excision Functional disorder Generations Genes Genetic Transcription Health Host Defense Human IL9 gene Immune response Immunization Immunosuppressive Agents In Vitro Individual Infection Inflammation Inflammatory Inflammatory Bowel Diseases Interleukin-1 Interleukin-10 Interleukin-6 Intervention Invaded Investigation Kinetics Lead Ligands Lupus Maintenance Mediating Modeling Molecular Mus Myelogenous Nuclear Nuclear Protein Opsonin Organ Outcome Outcomes Research Pathogenesis Pathway interactions Pattern Pattern recognition receptor Phagocytes Phagocytosis Phosphatidylserines Phosphotransferases Physiologic pulse Physiology Prevention Process Production Promoter Regions Proteins Proteomics Regulation Resolution Role Self Tolerance Signal Transduction Staging Stimulus Systemic Lupus Erythematosus Toll-like receptors Transforming Growth Factor beta base cell type cytokine extracellular in vivo innovation insight interleukin-23 macrophage metaplastic cell transformation microbial microorganism novel pathogen prevent receptor research study response transcription factor uptake

项目摘要

DESCRIPTION (provided by applicant): In systemic lupus erythematosus (SLE), CD4 T cells are critical drivers of the B cell- dependent autoantibody responses via provision of co-stimulatory signals and cytokines. Rapid removal of apoptotic cells (ACs) is considered central to the resolution of inflammation and in preventing autoimmune disease. Current dogma states that uptake of ACs by phagocytes induces synthesis of the immunoregulatory cytokine transforming growth factor- beta (TGF-b) through recognition of AC-specific molecules, resulting in the generation of an immunosuppressive state and prevention. Persistent self-antigens derived from ACs is a major causative event in the etiopathogenesis of SLE. Experimental studies have shown that dendritic cells (DCs) can process and present autoantigens from ACs in SLE. In contrast to the dogma, we observed that in the absence of microbial stimuli, human and mouse myeloid DCs and macrophages engulfing ACs produced substantial amounts of IL-23, IL-6, and TGF-b, the essential cytokines for the development of Th17 cells that have been strongly implicated in organ-specific pathogenesis of SLE. We further identified two novel transcription factors, LRRC16B and FLJ44967, as critically important and direct for the induction of IL-23 in phagocytes exposed to ACs. We hypothesize that in SLE-susceptible individuals/hosts, there is an overactivation of the IL-23/Th17-generating pathway in the process of clearance of ACs by phagocytes in a manner dependent on the expression and activities of LRRC16B and FLJ44967. We propose to: (1) Elucidate the cellular and molecular mechanisms whereby expression of LRRC16B and FLJ44967 is induced in professional phagocytes/APCs in response to ACs; (2) Investigate the role of LRRC16B and FLJ44967 in myeloid DCs engulfing ACs in Th17 development and SLE pathogenesis in the BWF1 model of lupus and non-autoimmune DWF1 mice. This investigation will lead to greater insights into the basis of Th17 development and activities in steady state physiology, and in the pathophysiology of autoimmune disorders.

描述（由申请人提供）：在全身性红斑狼疮（SLE）中，CD4 T细胞是通过提供共刺激信号和细胞因子的B细胞依赖性自身抗体反应的关键驱动因素。快速去除凋亡细胞（AC）被认为是炎症解决和预防自身免疫性疾病的核心。当前的教条指出，吞噬细胞吸收ACS会诱导通过识别AC特异性分子的识别的免疫调节细胞因子转化生长因子（TGF-B）的合成，从而导致免疫抑制状态和预防的产生。源自ACS的持续性自我抗原是SLE发生的疗法发生中的主要病因。实验研究表明，树突状细胞（DC）可以处理SLE中ACS的自身抗原。与教条相反，我们观察到，在没有微生物刺激的情况下，人类和小鼠髓样DC和巨噬细胞吞噬AC会产生大量的IL-23，IL-6和TGF-B，这是对TH17细胞发育的必需细胞因子，这些细胞的发育涉及到机器人疗法的Th17细胞的发育。我们进一步确定了两个新型的转录因子LRRC16B和FLJ44967，对于暴露于ACS的吞噬细胞中IL-23的诱导至关重要，并且是直接的。我们假设在遇到SLE敏感的个体/宿主中，在吞噬细胞清除ACS的过程中，IL-23/TH17生成途径过度激活，其方式取决于LRRC16B和FLJ44967的表达和活性。我们建议：（1）阐明细胞和分子机制，通过该机制，在专业的吞噬细胞/APC中诱导LRRC16B和FLJ44967的表达，以响应ACS；（2）研究LRRC16B和FLJ44967在髓样DC中的作用在Th17发育中吞噬ACS和SLE发病机理在狼疮和非自动免疫DWF1小鼠的BWF1模型中的作用。这项研究将导致对稳态生理学的TH17发展和活动的基础以及自身免疫性疾病的病理生理学的基础。