[6] Most of these findings usually followed reports of genetic predispositions in other autoimmune diseases and the contribution to liver-related autoimmunity remained unclear. Regarding the involvement of environmental triggers, several infections[7-9] and drug exposures were reported to precede the development of AIH, but so far no single causative agent has been identified. In addition, most patients are discovered late in the disease course and therefore infections preceding the diagnosis might not to be causative for the initiation of autoimmunity. It

rather seems as if there is a long lag-period between initiation of autoimmunity and diagnosis of symptomatic disease, as almost 40% present with liver cirrhosis at time of diagnosis. Therefore, the role of environmental triggers also remains unclear. However, the HER2 inhibitor search for causative agents was supported by the idea of molecular

LY294002 cost mimicry between environmental agents and self-antigens, usually searching for molecular identity.[10] Animal models of AIH are usually restricted to short liver-specific immune responses usually ending in liver-specific tolerance rather than chronic autoimmunity. Although these models were very helpful in studying determinants of liver-specific immune responses, they were insufficient to explain AIH or to develop new therapeutic interventions. We developed a model of chronic AIH by infecting NOD mice with replication deficient adenoviruses expressing the human liver autoantigen formiminotransferase learn more cyclodeaminase (FTCD), formally known as anti-liver cytosol type 1 (LC-1), which is one of the key antigens in AIH Type 2. The mice were developing a chronic hepatitis that closely resembled the human AIH for the first time. Using this model we could demonstrate that experimental murine AIH (emAIH) is just initiated by a strong inflammatory danger signal. This is just occurring in genetically predisposed individuals, explaining the low prevalence

of AIH in the general population. In addition, we could show that molecular similarity of the autoantigen is as efficient as molecular identity to lose tolerance against endogenous self-antigens. We could demonstrate that a break of humoral and cellular tolerance is required for the development of liver-specific autoimmunity and that CD4+ T cells act as drivers of the disease. Finally, classic immunosuppressive intervention with prednisolone and budesonide were successful in treating the disease. Taken together, we identified several key elements in the initiation of AIH. The model will be helpful to develop and test new therapeutic interventions in the future. Animal care and experiments were done in accordance with institutional and national guidelines.