Abstract
Abstract The etiology of autoimmune hepatitis (AIH) is poorly understood although the major autoantigen, cytochrome P450 2D6 (CYP2D6), has been identified. We generated an animal model for human AIH using the natural autoantigen CYP2D6. We infected transgenic mice expressing human CYP2D6 in the liver with an Adenovirus-CYP2D6 vector (Ad-2D6) to break self-tolerance. Upon infection with Ad-2D6 not only transgenic CYP2D6 mice but also wildtype FVB mice showed persistent features of severe liver damage associated with AIH (hepatic fibrosis, fused liver lobules, cellular infiltrations, elevated serum ALT levels, confluent necrosis). Ad-2D6-infected mice (CYP2D6 and FVB) generated high titers of anti-CYP2D6 antibodies. Epitope mapping revealed that anti-CYP2D6 antibodies predominantly recognized the same immunodominant linear epitope recognized by sera of AIH patients (AQPPRD aa265-270). In contrast, mice infected with a control Adenovirus expressing green fluorescence protein did neither develop liver damage nor generated anti-CYP2D6 antibodies. The severity of liver damage as well as antibody formation was enhanced in FVB mice compared to transgenic CYP2D6 mice indicating a stronger tolerance to human CYP2D6 in CYP2D6 mice. In FVB mice, due to the homology of the mouse isoenzymes of the CYP superfamily to human CYP2D6, autoimmune liver damage by Ad-2D6-infection was possibly induced via true molecular mimicry.
Published Version
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