. Autoimmune hepatitis (AIH) is an inflammatory liver disease of unknown etiology. The inflammatory response is thought to be orchestrated by CD4+ T lymphocytes recognizing liver self- antigens. The identification of susceptibility HLA-DRB1 (*0401 and *0301) alleles within the human leukocyte antigen (HLA) region suggested that faulty antigen presentation by these alleles and ensuing T cell activation may play a role in the pathogenesis of AIH. We recently generated a mouse model, Traf6?TEC, displaying impaired antigen presentation in the thymus due to depletion of medullary thymic epithelial cells (mTECs). Expression of tissue restricted antigens (TRAs) by mTECs and presentation of these self-antigens to developing thymocytes leads to elimination of autoreactive T cells and suppression of autoimmunity. Conditional depletion of mTECs in Traf6?TEC mice associated with spontaneous development of autoimmune hepatitis (AIH) that recapitulated the known histopathological and immunological hallmarks of human AIH. More recently we found that antibiotic treatment reduced AIH histopathology in Traf6?TEC mice implicating the gut microbiota in AIH development. We also found increased production of regulatory T cells and T cells expressing the gut-homing receptors ?4?7 and CCR9 in the gut and liver of Traf6?TEC mice accompanied by increased expression of endothelial-cell adhesion molecules and chemokines in the liver. These results establish a connection between the gut microbiota and development of AIH in this mouse model and additionally recapitulate similar evidence observed in the clinical setting of other liver autoimmune diseases. Based on our results to date, we propose the following hypothesis: mTEC depletion leads to production of autoreactive T cells that home to the liver and initiate inflammation through aberrant recognition of liver self-antigens. Changes in the microbiota of knockout animals lead to increased production of mucosal T cells that circulate to the liver and exacerbate AIH. To examine this hypothesis we will: 1) Determine the contributions of autoreactive T cells vs. the gut microbiota in AIH development/maintenance and identify liver self-antigens targeted by autoreactive T cells; 2) Elucidate the mechanism of gut-mediated induction and/or exacerbation of AIH; and 3) Define the microbiota profile of Traf6?TEC and how it differs from normal microbiota and identify a signature/bacterial species that associate with AIH pathology. Elucidation of the mechanisms that regulate of AIH development may lead to much-needed novel therapeutic strategies to better manage and perhaps treat this disease. These experiments may also define a common mechanism underling the development of other liver autoimmune diseases irrespective of their ultimate cellular targets.
. In this application, we aim to use a novel mouse model of autoimmune hepatitis (AIH) we generated to elucidate the pathophysiology of the disease. This mouse model recapitulates the known histological and immunological parameters of AIH and differs from existing models in that disease development is the result of impaired antigen presentation which may mimic the cause of human AIH.
