Transcription factor A mitochondria in SLE pathogenesis

项目总结/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表达的免疫抑制剂。 抗自身抗原的抗体滴度。虽然SLE的病因仍不清楚，但累积的证据表明， 干扰素（IFN）可能在疾病发病机制中起关键作用，可能与I型IFN（IFN-1）有关。 主导调解人虽然不同的机制可能会失调IFN-Ⅰ的生产在系统性红斑狼疮，研究表明， 近20年来，人们一直关注含有基因组DNA和RNA蛋白（RNP）的免疫复合物（IC）， 在TLR活化和浆细胞样树突状细胞（pDC）诱导IFN-1中，复合物是关键参与者。 然而，最近的范式转变数据表明，线粒体是干扰素的重要来源。 SLE中的信号特别地，在用TLR7激动剂自身抗体活化后，SLE中性粒细胞释放氧化的 (Ox)线粒体DNA（mtDNA）与转录因子A线粒体（TFAM）复合， 具有通过TLR9活化来活化pDC以产生IFN-1的特殊能力。然而， 调节SLE中Ox-mtDNA/TFAM复合物向TLR9内体的递送还不完全清楚。 有趣的是，我们的初步研究首次证明SLE患者有抗 TFAM。基于这一前提，我们假设抗TFAM抗体可以促进细胞的内化， pDC对Ox-mtDNA/TFAM复合物的干扰应答，这可能影响SLE的疾病活动。 本提案的主要目标是进一步深入了解这些新假说的潜在意义 以及SLE发病机制的初步研究结果。在目标1中，我们将确定患病率， TFAM抗体的临床相关性及其与IFN信号的关系 SLE患者的观察性队列，可获得广泛的临床和血清学数据，以及 IFN诱导的基因表达分析。在目标2中，我们将从单个TFAM产生抗TFAM单克隆抗体。 SLE抗TFAM记忆B细胞，以确定其自身反应起源[例如V（D）J使用，体细胞超突变 和抗原识别的决定簇]，以及它们在复合物中激活pDC的能力和机制。 与Ox-mtDNA/TFAM。总之，这些研究旨在加强我们对自我免疫原性的理解。 SLE中无菌性炎症和IFN产生的潜在途径。这项工作的最终目标是获得新的 深入了解疾病机制，从而为探索新的治疗方法奠定基础。

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.