The role of androgens in autoimmune liver diseases

女性更容易患上自身免疫性肝病，如自身免疫性肝炎（AIH）和原发性胆管炎（PBC）。另一方面，受影响的男性表现出更严重的病程。事实上，自身免疫性肝病的性别差异是所有自身免疫性疾病中最强的。自身免疫性肝病是一种罕见的疾病，难以治疗，因此经常导致肝硬化和死亡。由于缺乏对疾病发病机制的了解，无法进行因果治疗。了解导致肝脏自身免疫的机制对于制定有针对性的治疗策略至关重要。自身免疫性肝病性别差异背后的机制仍然是未知的，他们的阐明将提高我们对疾病发病机制的认识。研究AIH或PBC性别差异的动物模型一直缺乏。我们已经开发了一种诱导型自身免疫性胆管炎小鼠模型，该模型显示出与PBC相似的女性优势。在去势和激素替代研究中，我们证明，雄性对肝脏炎症的抵抗力归因于睾酮的保护作用，睾酮在抑制雌性小鼠肝脏炎症方面是有效的。事实上，越来越多的证据表明雄激素调节免疫反应。基于我们先前的小鼠模型和人类研究的初步数据，我们在这里假设雄激素通过直接或间接地通过抗原呈递细胞调节T细胞在自身免疫性肝病的发生和发展中起关键作用。为了研究雄激素对T细胞的直接和间接作用的机制，我们将使用体外T细胞转化和共刺激技术。使用血液和肝脏来源的抗原呈递细胞进行培养测定，基于多色流式细胞术的免疫表型分析，使用70多种表型标记物以及单细胞测序和CITE-seq技术。来自PBC和AIH的男性和女性患者的独特临床队列以及来自在性别改变期间接受高剂量睾酮治疗的女性的生物样品以及T细胞驱动的肝脏炎症的小鼠模型将能够破译导致自身免疫性肝病性别差异的细胞和分子机制。

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.