Induction of hepatic fibrosis by an adenovirus encoding the human liver autoantigen cytochrome P450 2D6

Autoimmune hepatitis is an autoimmune liver disease whose cause is currently unknown. We recently developed an animal model which resembles AIH in that antigen-specific B – and T cell responses were observed. To trigger the disease an adenovirus (Ad) encoding the human Cytochrome P450IID6 (hCYP2D6), the major autoantigen in AIH type 2, was used. Importantly, infection with Ad-2D6 initiated autoimmune processes which caused chronic inflammation and fibrogenesis in the liver. Fibrosis was characterized by increased extracellular matrix deposition in and underneath the capsule whereas the liver parenchyma was less affected. Concurrently, we observed at the same locations elevated expression of α-smooth muscle actin, a marker for fibrogenic cell subpopulations, such as capsular fibroblasts or hepatic stellate cells (HSCs). Cell isolation experiments revealed an increased frequency of activated HSCs. Interestingly, intraperitoneal – but not intravenous injection of Ad-2D6 resulted in subcapsular fibrosis, suggesting that the infection route determines fibrosis location. We observed that intraperitoneal infection caused the accumulation of CD11b+ Ly6C+ F4/80+ inflammatory monocytes in the peritoneum. Since these cells expressed collagen I and TGFβ, they may play a central role in the specific location of Ad-2D6-induced fibrosis.

Conclusion: Infection of wildtype FVB mice with Ad-2D6 triggers an autoimmune liver disease which results in permanent hepatic fibrosis. This model should shed light on autoimmune processes triggering fibrogenesis in the liver.