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The CYP2D6 Animal Model: How to Induce Autoimmune Hepatitis in Mice
Published on: February 3, 2012
Molecular mimicry rather than identity breaks T-cell tolerance in the CYP2D6 mouse model for human autoimmune
Janine Ehser1, Martin Holdener, Selina Christen
1Pharmazentrum Frankfurt/ZAFES, Klinikum der Johann Wolfgang Goethe Universität, Theodor-Stern Kai 7, 60590 Frankfurt am Main, Germany.
Abstract:
In our novel mouse model for autoimmune hepatitis (AIH), wildtype FVB mice infected with an Adenovirus (Ad) expressing the major AIH autoantigen human cytochrome P450 2D6 (hCYP2D6) show persistent histological and immunological features associated with AIH, including the generation of anti-hCYP2D6 antibodies with an epitope specificity identical to LKM-1 autoantibodies in AIH-patients. Since FVB mice do not express hCYP2D6, the immune response was directed against mouse CYP (mCYP) homologues. Additional expression of hCYP2D6 in transgenic mice resulted in amelioration of the liver disease. In the present study we used the CYP2D6 model to assess why tolerance breakdown and induction of autoimmune liver disease is more efficient if the triggering antigen is similar but not identical to the target autoantigen. We found that in contrast to the specificity and magnitude of anti-hCYP2D6 antibody responses, T-cell responses differ profoundly between wildtype and transgenic mice. Detailed T-cell epitope mapping studies show a robust, antigen-specific T-cell reactivity in FVB mice largely directed against one CD4 and three CD8 epitopes, activating a total of approximately 1% CD4 and 10% CD8 T-cells, respectively, while infected hCYP2D6 mice generated almost no hCYP2D6-specific T-cells. The frequency of hCYP2D6-specific T-cells was approximately 3-fold higher in the liver compared with the spleen. Amino acid sequence comparison revealed that the immunodominant epitopes were located in hCYP2D6-segments of intermediate homology between hCYP2D6 and its mCYP homologues. Our data indicate that self/non-self molecular mimicry, rather than molecular identity, is a prerequisite for breaking T-cell tolerance in the liver.
Insights
Molecular mimicry, not identity, triggers autoimmune hepatitis (AIH) by breaking T-cell tolerance. This study reveals that partial similarity between foreign and self-antigens, like human cytochrome P450 2D6 (hCYP2D6) and its mouse counterpart, is key to initiating AIH in a novel mouse model.
Area of Science:
- Immunology
- Hepatology
- Molecular Biology
Background:
- Autoimmune hepatitis (AIH) involves immune responses against liver autoantigens.
- A novel mouse model using Adenovirus (Ad) expressing human cytochrome P450 2D6 (hCYP2D6) mimics AIH features.
- Tolerance breakdown is more efficient when the triggering antigen is similar but not identical to the self-antigen.
Purpose of the Study:
- To investigate why autoimmune liver disease induction is more efficient with partially similar antigens.
- To compare T-cell responses in wildtype and transgenic mice expressing hCYP2D6.
- To identify key factors in breaking T-cell tolerance in the liver.
Main Methods:
- Adenovirus-mediated expression of hCYP2D6 in wildtype FVB mice and transgenic mice expressing hCYP2D6.
- Analysis of histological and immunological features of AIH.
- T-cell epitope mapping and quantification of antigen-specific T-cells (CD4 and CD8).
- Comparison of T-cell frequencies in liver and spleen.
Main Results:
- Wildtype mice developed AIH features, including anti-hCYP2D6 antibodies.
- T-cell responses differed significantly: FVB mice showed robust reactivity to specific epitopes, while transgenic mice had minimal response.
- Immunodominant epitopes were in regions of intermediate homology between hCYP2D6 and mouse CYP homologues.
- hCYP2D6-specific T-cells were more frequent in the liver than the spleen.
Conclusions:
- Self/non-self molecular mimicry, not molecular identity, is crucial for breaking T-cell tolerance in AIH.
- Partial homology of triggering antigens facilitates the induction of autoimmune liver disease.
- T-cell responses, rather than antibody responses, are profoundly affected by the degree of antigen similarity.
