Molecular mimicry rather than identity breaks T cell tolerance in a mouse model for autoimmune hepatitis

The etiology of autoimmune hepatitis (AIH) is poorly understood although the major autoantigen, cytochrome P450 2D6 (CYP2D6), has been identified and immunodominant epitopes mapped. We generated a mouse model for AIH using the natural human autoantigen CYP2D6 as a triggering molecule. Wildtype FVB mice infected with an adenovirus expressing the human CYP2D6 (Ad-2D6) to break self-tolerance to the mouse CYP2D6 homologues (molecular mimicry) showed persistent features characteristic for liver damage associated with AIH (fibrosis, ‘fused’ lobules, cellular infiltrations and necrosis). Ad-2D6-infected mice generated anti-CYP2D6 antibodies recognizing the identical immunodominant epitope as LKM-1 antibodies from AIH patients. In contrast, Ad-2D6-infection of transgenic mice expressing the human CYP2D6 in the liver (CYP2D6 mice) (molecular identity) resulted in a delayed kinetics and a reduced severity of liver damage. We analyzed the T cell mediated immune response by stimulating lymphocytes with 61 overlapping 20-mer peptides covering the entire human CYP2D6. The frequency of CYP2D6-specific CD4 and CD8 cells was dramatically decreased in CYP2D6 mice indicating the presence of a strong T cell tolerance to human CYP2D6 established in CYP2D6 mice expressing the identical target antigen compared to wildtype FVB mice expressing the mouse homologues only. T cell epitope mapping revealed that CYP2D6-specific T cells reacted to human CYP2D6 peptides with intermediate homology to the mouse homologues but not to those with high homology or identity. Our data indicate that molecular mimicry rather than molecular identity efficiently breaks tolerance in the CYP2D6 model and causes persistent autoimmune liver damage. The CYP2D6 model provides a platform to investigate mechanisms involved in the immunopathogenesis of autoimmune mediated chronic hepatic injury as seen in human AIH and to evaluate possible ways of therapeutic interference.

CYP2D6 - epitope mapping