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)的血清学特征都是产生核抗原抗体(ANA)。其中，抗双链DNA(DsDNA)的高亲和力抗体在SLE中被认为具有高度的特异性和致病性。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，而且在1型AIH中也很常见。事实上，SLE和AIH似乎是唯一已知的对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，这些抗体的出现在这两种疾病中似乎有不同的后果。最值得注意的是，抗dsDNA抗体可以刺激SLE患者的系统自身免疫，以及导致肾炎的抗DNA免疫复合体的形成，这似乎与AIH无关。因此，这项建议追求的总体目标是加深对AIH和SLE中与抗DNA抗体相关的共同和不同的致病机制的了解。我们将对有抗DNA抗体的AIH患者和没有抗DNA抗体的AIH患者以及SLE患者的对照组的外周血液和肝脏样本进行彻底的分析。因此，我们将探索抗dsDNA抗体的出现与AIH的发病机制直接相关的假设，从而定义AIH的临床和免疫学不同的表型。我们的初步数据显示，三分之一的AIH患者显示出抗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性和治疗反应有关。在目标2中，我们将探索这样的假设，即SLE和AIH都具有驱动抗DNA抗体产生的特定B辅助T细胞亚群的异常活性。此外，我们的目标是确定在AIH中驱动抗体产生的免疫原性DNA的形式(目标3)。在我之前的工作中，我们建立了与循环微粒(MP)相关的无细胞DNA作为散发性SLE自身抗原性DNA的基本来源，并将分泌的DNase 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MP凋亡相关的DNA的丰度和免疫原性。值得注意的是，我们希望这一建议不仅能阐明AIH的发病机制，而且还能识别与AIH的发病机制直接相关的新的生物标志物，如T细胞亚群、细胞因子和自身抗体模式，因此，将被用于免疫监测、新的治疗方法以及新的诊断标志物。

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.