Novel Pathogenic Roles for Interferon and Autoantibodies in Human SLE

干扰素和自身抗体在人类 SLE 中的新致病作用

• 批准号: 8732913
• 负责人: Maria Virginia Pascual
• 金额: $ 36万
• 依托单位: BAYLOR RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-01 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8732913
• 关键词: Antibodies; Antigen-Antibody Complex; Antinuclear Antibodies; Autoantibodies; Autoimmune Diseases; Autoimmunity; B-Lymphocytes; Blood Platelets; Cells; Complex; DNA; Data; Dendritic Cells; Dendritic cell activation; Development; Drug Metabolic Detoxication; Endothelial Cells; Endothelium; Event; Genomics; Goals; Human; Immune; Inflammation; Interferons; Lead; Ligands; Link; Lupus; Mediating; Mediator of activation protein; Mitochondria; Mitochondrial DNA; Molecular; Natural Immunity; Neutrophil Activation; Nucleic Acids; Organ; Pathogenesis; Pathway interactions; Pattern; Process; Production; Protein Binding; Proteins; Reporting; Role; Stimulus; Systemic Lupus Erythematosus; TLR7 gene; Therapeutic Intervention; Work; adaptive immunity; early onset; insight; neutrophil; new therapeutic target; novel; oxidation; protein complex; receptor; response

Systemic Lupus Erythematosus (SLE) is an autoimmune disease characterized by widespread inflammation and development of autoantibodies against nucleic acids (NAs). SLE pathogenesis is not fully understood but genomic studies support an interplay between innate and adaptive immunity. Pathogenic loops involving immune complex(IC)-containing NAs that activate innate immune cells such as dendritic cells (DCs), platelets and neutrophils through the endosomal TLR pathway result in plasmacytoid DC (pDC) activation and release of type I IFN. Excessive production and/or sensing of NAs is emerging as a fundamental and upstream event in SLE, and over-expression of IFN-inducible transcriptional signatures is a universal finding, especially in early onset SLE. We and others recently reported that neutrophils release DNA-protein complexes that activate pDCs, thus acting as Danger-Associated Molecular Patterns (DAMPs). DAMPS are extruded upon neutrophil activation with SLE immune complexes (ICs) and directly activate pDCs in an FcR-independent and TLR9-dependent manner. Our preliminary data now show that these DAMPs are composed of damaged (oxidized) mitochondrial DNA-protein complexes (mtDAMPs) released upon type I IFN and anti-Sm/RNP mediated endosomal TLR7 activation of neutrophils. This combination of stimuli impairs the detoxification of oxidized mtDNA through lysosomal degradation, which is a fundamental step leading to the extrusion of interferogenic mtDAMPs. Here, we propose 1) to characterize the basic mechanisms that lead to neutrophil mitochondrial damage and release of mtDAMPs in SLE, 2) to identify the interferogenic components of mtDAMPs and the mechanisms responsible for their internalization in pDCs, and 3) to characterize the effects of SLE mtDAMPs on non-hemopoietic cells that become the target of inflammation in SLE, especially endothelial cells. Overall, these studies will provide a better understanding of how breakdown of tolerance to NAs and dysregulation of the IFN pathway are interconnected and amplify each other. These studies will bring novel insight into SLE autoantibody pathogenic roles and perpetuation of IFN-amplification loops

系统性红斑狼疮（SLE）是一种自身免疫性疾病，其特征在于广泛的 炎症和针对核酸（NAs）的自身抗体的发展。SLE发病机制不完全 理解，但基因组研究支持先天免疫和适应性免疫之间的相互作用。致病 涉及含有免疫复合物（IC）的NA的环，其激活先天性免疫细胞，如树突状细胞， 细胞（DC）、血小板和中性粒细胞通过内体TLR途径产生浆细胞样DC（pDC） I型IFN的激活和释放。NAs的过度产生和/或感测正在成为一种新的威胁。 SLE的基础和上游事件，以及IFN诱导的转录标签的过度表达， 这是一个普遍的发现，尤其是在早发性SLE中。我们和其他人最近报道，中性粒细胞释放 激活pDC的DNA-蛋白质复合物，从而充当危险相关分子模式（DAMP）。 DAMPS在中性粒细胞活化时被SLE免疫复合物（IC）挤出，并直接活化 pDC以FcR非依赖性和TLR9依赖性的方式表达。初步数据显示， DAMPs由受损（氧化）的线粒体DNA-蛋白质复合物（mtDAMPs）释放组成。 在I型IFN和抗Sm/RNP介导的中性粒细胞的内体TLR7活化后。的这种组合 刺激通过溶酶体降解损害氧化mtDNA的解毒，这是一个基本的 导致干扰原性mtDAMP挤出的步骤。在这里，我们建议1）描述基本的 机制，导致中性粒细胞线粒体损伤和释放的mtDAMPs在SLE，2）以确定 mtDAMPs的干扰素成分及其内化机制， pDC，以及3）表征SLE mtDAMP对成为靶的非造血细胞的作用 SLE中的炎症，尤其是内皮细胞。总体而言，这些研究将提供更好的 了解对NAs耐受性的破坏和IFN途径的失调是如何 相互连接，相互放大。这些研究将为SLE自身抗体的研究提供新的视角 IFN-放大环的致病作用和永久化