The role of androgens in autoimmune liver diseases

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Women are more prone to develop the autoimmune liver diseases autoimmune hepatitis (AIH) and primary biliary cholangitis (PBC). Affected men, on the other hand, show a more severe course of disease. Indeed, sex differences in autoimmune liver diseases are among the strongest of all autoimmune diseases. Autoimmune liver diseases are rare diseases which are difficult to treat and thus often lead to liver cirrhosis and death. Due to the lack of understanding disease pathogenesis causal treatment is not available. Understanding mechanisms leading to autoimmunity in the liver is crucial in order to develop targeted treatment strategies. Mechanisms behind sex differences in autoimmune liver diseases are still unknown and their elucidation will enhance our knowledge of disease pathogenesis. Suitable animal models to study sex differences in AIH or PBC had been lacking. We have developed an inducible mouse model of autoimmune cholangitis, which shows female predominance similar to PBC. In castration and hormone replacement studies we demonstrated, that male resistance to liver inflammation was attributed to the protective effects of testosterone and that testosterone was effective in suppressing liver inflammation in female mice. Indeed, evidence accumulates that androgens modulate immune responses. Based on our previous and preliminary data from mouse models and human studies we here hypothesize that androgens play a critical role in the development and progression of autoimmune liver diseases by modulating T cells directly or indirectly via antigen presenting cells.In order to investigate the mechanisms underlying the direct and indirect effects of androgens on T cells we will use in vitro T cell conversion and co-culturing assays with blood and liver derived antigen presenting cells, multi-colour flow cytometry based immunophenotyping, using over 70 phenotypic markers and the technique of single cell sequencing and CITE-seq. Biosamples from unique clinical cohorts of male and female patients with PBC and AIH and from women undergoing high-dose testosterone treatment during sex change together with mouse models of T cell driven liver inflammation will enable to decipher the cellular and molecular mechanisms leading to sex differences in autoimmune liver disease.