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

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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.