Transcription factor A mitochondria in SLE pathogenesis

SLE 发病机制中的转录因子 A 线粒体

• 批准号: 10467330
• 负责人: Felipe Andrade
• 金额: $ 24.56万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-22 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10467330
• 关键词: Address; Agonist; Antibodies; Antibody titer measurement; Antigen-Antibody Complex; Antigens; Area; Autoantibodies; Autoantigens; Autoimmune Diseases; Binding; Blood Platelets; Cells; Chronic; Clinical; Clone Cells; Complex; DNA; Data; Dendritic Cells; Dendritic cell activation; Development; Diagnosis; Disease; Endosomes; Enzyme-Linked Immunosorbent Assay; Etiology; Feeds; Flare; Foundations; Gene Expression Profiling; Genes; Genetic Transcription; Genomic DNA; Goals; High Mobility Group Proteins; Human; Immune response; Immunoglobulin Somatic Hypermutation; Inflammation; Interferon Type I; Interferons; Lead; Link; Maintenance; Measures; Mediator of activation protein; Memory B-Lymphocyte; Mitochondria; Mitochondrial DNA; Modeling; Molecular; Monoclonal Antibodies; Outcome Study; Oxides; Pathogenesis; Pathway interactions; Patients; Pattern; Play; Prevalence; Prevention; Production; Recombinants; Research Project Grants; Role; Sequence Analysis; Serology; Signal Transduction; Source; Specificity; Sterility; Stimulator of Interferon Genes; Systemic Lupus Erythematosus; TLR7 gene; Technology; Time; Western Blotting; Work; autoimmune rheumatologic disease; autoreactivity; base; clinically significant; cohort; design; experimental study; extracellular; genomic RNA; immunogenic; insight; interest; mitochondrial genome; mtTF1 transcription factor; neutrophil; new therapeutic target; novel; novel diagnostics; novel therapeutics; patient subsets; peripheral blood; potential biomarker; prevent; prospective; protein complex; receptor for advanced glycation endproducts; response; sensor; seropositive; targeted treatment; tool

PROJECT SUMMARY/ABSTRACT Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by sterile inflammation and high titer antibodies against self-antigens. Although the etiology of SLE is still unknown, cumulative evidence suggest that interferons (IFNs) might play a critical role in disease pathogenesis, likely with type I IFN (IFN-I) as the dominant mediator. While different mechanisms may dysregulate the production of IFN-I in SLE, studies for the last 20 years have been focused on immune complexes (ICs) containing genomic DNA and RNA–protein (RNP) complexes as critical players in TLR activation and the induction of IFN-I by plasmacytoid dendritic cells (pDCs). Recent paradigm shifting data, however, suggest that the mitochondria is an important source of interferogenic signals in SLE. In particular, upon activation with TLR7-agonist autoantibodies, SLE neutrophils release oxidized (Ox) mitochondrial DNA (mtDNA) in complex with transcription factor A mitochondria (TFAM), which together have an exceptional capacity to activate pDCs to produce IFN-I via TLR9 activation. Yet, mechanisms that modulate the delivery of Ox-mtDNA/TFAM complexes into TLR9 endosomes in SLE are not fully understood. Interestingly, our preliminary studies demonstrate for the first time that patients with SLE have autoantibodies to TFAM. Based on this premise, we hypothesize that anti-TFAM antibodies may facilitate the internalization and interferogenic response to Ox-mtDNA/TFAM complexes by pDCs, which may influence disease activity in SLE. The major goal of this proposal is to gain further insights into the potential significance of these novel hypotheses and preliminary findings in the context of SLE pathogenesis. In Aim 1, we will determine the prevalence and clinical associations of antibodies to TFAM and their relationship to the IFN-signature in a prospective observational cohort of patients with SLE, for which extensive clinical and serologic data is available, as well as IFN-induced gene expression analysis. In Aim 2, we will generate anti-TFAM monoclonal antibodies from single SLE anti-TFAM memory B cells to define their autoreactive origin [e.g. V(D)J usage, somatic hypermutations and determinants of antigen recognition], as well as their capacity and mechanism to activate pDCs in complex with Ox-mtDNA/TFAM. Together, these studies seek to enhance our understanding of self-immunogenic pathways underlying sterile inflammation and IFN production in SLE. The final goal of this work is to gain new insights into disease mechanisms, thus laying the foundation to explore novel therapies.

项目摘要/摘要 全身性红斑狼疮（SLE）是一种自身免疫性疾病，其特征是无菌注射和高 针对自我抗原的滴度抗体。尽管SLE的病因仍然未知，但累积证据表明 该干扰素（IFN）可能在疾病发病机理中起关键作用，可能以I型IFN（IFN-I）为 主要调解人。虽然不同的机制可能会使SLE中的IFN-I产生失调，但研究 最近20年一直集中在含有基因组DNA和RNA - 蛋白质（RNP）的免疫复合物（ICS）上 复合物是TLR激活中的关键参与者，并被静脉细顶树突状细胞（PDC）诱导IFN-I。 然而，最近的范式转移数据表明线粒体是介原性的重要来源 SLE中的信号。特别是，在用TLR7激动剂自身抗体激活后，SLE中性粒细胞释放出氧化 （OX）线粒体DNA（mtDNA）与转录因子A线粒体（TFAM）的复合物中 具有特殊的能力，可以通过TLR9激活激活PDC来产生IFN-I。然而，机制 调节SLE中的OX-MTDNA/TFAM复合物向TLR9内体的递送尚不完全了解。 有趣的是，我们的初步研究首次证明了SLE患者的自身抗体 TFAM。基于这个前提，我们假设抗TFAM抗体可能有助于内在化和 PDC对OX-MTDNA/TFAM复合物对OX-MTDNA/TFAM复合物的反应，这可能会影响SLE的疾病活动。 该提案的主要目标是进一步了解这些新假设的潜在意义 和在SLE发病机理的背景下的初步发现。在AIM 1中，我们将确定患病率和 抗TFAM抗体的临床关联及其与预期的IFN签名的关系 SLE患者的观察队列，可为其提供广泛的临床和血清学数据以及 IFN诱导的基因表达分析。在AIM 2中，我们将产生来自单个的抗TFAM单克隆抗体 SLE抗TFAM记忆B细胞定义其自动反应性的起源[例如v（d）j使用，躯体高压 并确定抗原识别]，以及它们在复合物中激活PDC的能力和机制 与OX-MTDNA/TFAM。这些研究共同寻求增强我们对自我免疫原性的理解 SLE中无菌注射和IFN产生的途径。这项工作的最终目标是获得新 对疾病机制的见解，从而奠定了探索新疗法的基础。