Common and distinct pathogenic mechanisms in autoimmune hepatitis and lupus related to anti-DNA antibodies

系统性红斑狼疮（SLE）和1型自身免疫性肝炎（AIH）的血清学标志是产生针对核抗原（ANA）的抗体（Abs）。在ANA中，对双链DNA（dsDNA）的高亲和力IgG Ab被认为在SLE中具有高度特异性和致病性。此外，抗dsDNA抗体用于SLE的疾病监测和亚分类。然而，抗dsDNA抗体的产生不仅限于SLE，在1型AIH中也很常见。事实上，SLE和AIH似乎代表了唯一已知的与dsDNA具有这种反应性的自身免疫性疾病，但与SLE相反，抗dsDNA抗体的出现及其在AIH发病机制中的潜在相关性被广泛忽视。另一方面，这些抗体的出现似乎在两种疾病中具有不同的后果。最值得注意的是，抗dsDNA抗体可以刺激SLE的全身性自身免疫以及形成抗DNA免疫复合物，导致肾炎，这似乎不属于AIH。因此，本提案的总体目标是更深入地了解AIH和SLE中与抗DNA抗体相关的共同和不同的致病机制。我们将对AIH患者的外周血和肝脏样本进行彻底的分析，与没有抗DNA抗体的患者以及对照组的SLE患者进行比较。因此，我们将探索的整体假设，即抗dsDNA抗体的出现是直接相关的AIH的发病机制，因此，定义一个临床和免疫学上独特的表型AIH.In目的1，我们将调查抗DNA抗体在AIH的临床意义。我们的初步数据表明，三分之一的AIH患者显示抗DNA抗体，与AIH中的其他自身抗体相比，抗DNA抗体似乎与疾病活动和治疗反应相关。 在目标2中，我们将探讨SLE和AIH都具有特异性B辅助性T细胞亚群的异常活性的假说，该亚群驱动抗DNA抗体的产生。此外，我们的目标是确定形式的免疫原性DNA驱动抗体生产在AIH（目的3）。在我以前的工作中，我们建立了与循环微粒（MP）相关的游离DNA作为散发性SLE中抗原性自身DNA的基本来源，以及分泌的DNA酶DNASE1L3作为限制其抗原性的关键因素。基于这些结果，我们将研究AIH中与凋亡MP相关的DNA的丰度和免疫原性。值得注意的是，我们期望该提议不仅阐明AIH的发病机制，而且还鉴定与AIH的发病机制直接相关的新型生物标志物，如T细胞亚群、细胞因子和自身抗体模式，因此，将允许用于免疫监测、新型治疗方法以及新型诊断标志物。

The serological hallmark of both systemic lupus erythematosus (SLE) and type 1 autoimmune hepatitis (AIH) is the production of antibodies (Abs) to nuclear antigens (ANA). Among ANAs, high-affinity IgG Abs to double-stranded DNA (dsDNA) are considered highly specific and pathogenic in SLE. Also, anti-dsDNA Abs are used for disease monitoring and sub-classification in SLE. However, the production of anti-dsDNA Abs is not limited to SLE but is also common in type 1 AIH. In fact, SLE and AIH seem to represent the only known autoimmune disorders with this reactivity to dsDNA, but in contrast to SLE, the appearance of anti-dsDNA Abs and its potential relevance in the pathogenesis of AIH has been widely neglected. On the other hand, the appearance of these Abs seems to have different consequences in both disorders. Most notably, anti-dsDNA Abs can stimulate systemic autoimmunity in SLE as well as the formation of anti-DNA immune complexes leading to nephritis, which seems not to pertain in AIH. Therefore, this proposal pursues the overall goal to develop deeper understanding of the common and distinct pathogenic mechanisms in AIH and SLE related to anti-DNA Abs. We will perform a thorough analysis of peripheral blood and liver samples of AIH patients with anti-DNA Abs compared to those with without as well as to a control group of SLE patients. Thereby, we will explore the overall hypothesis that the appearance of anti-dsDNA Abs is directly related to the pathogenesis of AIH, and therefore, defines a clinically and immunologically distinct phenotype of AIH.In Aim 1, we will investigate the clinical significance of anti-DNA Abs in AIH. Our preliminary data indicate that one third of AIH patients displays anti-DNA Abs, and that in contrast to other auto-Abs in AIH, anti-DNA Abs seem to correlate with disease activity and treatment response. In Aim 2, we will explore the hypothesis that both, SLE and AIH, share an aberrant activity of specific B helper T cell subsets that drive the production of anti-DNA Abs. Moreover, we aim to identify the form of immunogenic DNA driving Abs-production in AIH (Aim 3). In my previous work, we established cell-free DNA associated with circulating microparticles (MP) as a fundamental source of antigenic self-DNA in sporadic SLE, and the secreted DNase DNASE1L3 as the crucial factor restricting its antigenicity. Based on these results, we will study the abundance and immunogenicity of DNA associated with apoptotic MP in AIH. Of note, we expect this proposal not only to elucidate the pathogenesis of AIH, but also to identify novel biomarkers such as T-cell subpopulations, cytokine and auto-Abs patterns that are directly related to the pathogenesis of AIH, and therefore, would allow to be used for immunomonitoring, novel therapeutic approaches as well as novel diagnostic markers.