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

• 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
• 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

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(申请人提供)：在系统性红斑狼疮(SLE)中，CD4T细胞通过提供共刺激信号和细胞因子，是B细胞依赖性自身抗体反应的关键驱动因素。快速清除凋亡细胞(ACS)被认为是消解炎症和预防自身免疫性疾病的核心。目前的学说认为，吞噬细胞摄取ACS，通过识别AC特异性分子，诱导免疫调节细胞因子转化生长因子-β(转化生长因子-β)的合成，导致免疫抑制状态的产生和预防。来源于急性冠脉综合征的持久性自身抗原是系统性红斑狼疮发病机制中的一个重要致病事件。实验研究表明，在系统性红斑狼疮患者中，树突状细胞(DC)能够处理和递呈自身抗原。相反，我们观察到，在没有微生物刺激的情况下，吞噬ACS的人和小鼠髓系树突状细胞和巨噬细胞产生大量的IL-23、IL-6和转化生长因子-β，这些细胞因子对Th17细胞的发育至关重要，这些细胞因子与SLE的器官特异性发病机制密切相关。我们进一步确定了两个新的转录因子，LRRC16B和FLJ44967，它们在ACS暴露的吞噬细胞中诱导IL-23起关键作用和直接作用。我们推测，在SLE易感个体/宿主中，在吞噬细胞清除ACS的过程中，存在IL-23/Th17生成途径的过度激活，这种激活依赖于LRRC16B和FLJ44967的表达和活性。我们建议：(1)阐明LRRC16B和FLJ44967在专业吞噬细胞/APC中表达的细胞和分子机制；(2)研究LRRC16B和FLJ44967在狼疮和非自身免疫性DWF1小鼠BWF1模型中吞噬ACS的髓系树突状细胞在Th17发育和SLE发病中的作用。这项研究将有助于更深入地了解Th17在稳态生理学中的发育和活动基础，以及自身免疫性疾病的病理生理学。