Transcription factor A mitochondria in SLE pathogenesis

SLE 发病机制中的转录因子 A 线粒体

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要系统性红斑狼疮（SLE）是一种自身免疫性疾病，其特征是无菌性炎症和高尽管 SLE 的病因尚不清楚，但累积的证据表明。干扰素 (IFN) 可能在疾病发病机制中发挥关键作用，可能以 I 型干扰素 (IFN-I) 为代表虽然不同的机制可能会失调 SLE 中 IFN-I 的产生，但针对过去 20 年一直专注于含有基因组 DNA 和 RNA 蛋白 (RNP) 的免疫复合物 (IC) 复合物在 TLR 激活和浆细胞样树突状细胞 (pDC) 诱导 IFN-I 中发挥着关键作用。然而，最近的范式转变数据表明线粒体是干扰原的重要来源特别是，在用 TLR7 激动剂自身抗体激活后，SLE 中性粒细胞释放氧化的信号。 (Ox) 线粒体 DNA (mtDNA) 与转录因子 A 线粒体 (TFAM) 形成复合物，它们一起具有通过 TLR9 激活激活 pDC 产生 IFN-I 的特殊能力。在 SLE 中调节 Ox-mtDNA/TFAM 复合物递送至 TLR9 内体的机制尚不完全清楚。暗示，我们的初步研究首次证明 SLE 患者具有自身抗体基于这个前提，我们认为抗 TFAM 抗体可能会促进内化和 pDC 对 Ox-mtDNA/TFAM 复合物的干扰反应，可能影响 SLE 的疾病活动。该提案的主要目标是进一步了解这些新颖假设的潜在意义在目标 1 中，我们将确定 SLE 发病机制的患病率和初步发现。前瞻性研究 TFAM 抗体的临床关联及其与 IFN 特征的关系 SLE 患者观察队列，可获得广泛的临床和血清学数据，以及在目标 2 中，我们将从单个抗体中产生抗 TFAM 单克隆抗体。 SLE 抗 TFAM 记忆 B 细胞定义其自身反应起源 [例如 V(D)J 使用、体细胞超突变和抗原识别的决定因素]，以及它们在复合物中激活 pDC 的能力和机制与 Ox-mtDNA/TFAM 一起，这些研究旨在增强我们对自身免疫原性的理解。 SLE 中无菌炎症和干扰素产生的潜在途径这项工作的最终目标是获得新的结果。深入了解疾病机制，从而为探索新疗法奠定基础。