1. Development of a New Murine Model of Type 2 Autoimmune Hepatitis Using a Human Liver Protein
- Author
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Elvis Efraín Sánchez-Marce, A.D. Cano-Contreras, I.Y. Izaguirre-Hernández, Karina Guadalupe Hernández-Flores, Héctor Vivanco-Cid, Pablo Thomas-Dupont, Peter Grube-Pagola, and José María Remes-Troche
- Subjects
Necrosis ,Autoimmune hepatitis ,Pathology and Forensic Medicine ,Pathogenesis ,Interferon ,Animals ,Humans ,Medicine ,Autoantibodies ,B-Lymphocytes ,Mice, Inbred BALB C ,Kidney ,business.industry ,Hypergammaglobulinemia ,Proteins ,Alanine Transaminase ,medicine.disease ,Adoptive Transfer ,Cellular infiltration ,Disease Models, Animal ,Hepatitis, Autoimmune ,medicine.anatomical_structure ,Liver ,Immunology ,Female ,medicine.symptom ,business ,Hepatic fibrosis ,medicine.drug - Abstract
Autoimmune hepatitis (AIH) is a chronic inflammatory condition of the liver characterized by parenchymal destruction, hypergammaglobulinemia, specific autoantibody production, and hepatic fibrosis and necrosis. Murine models of AIH have been described; however, little is known about the immunologic mechanisms of tissue destruction. In this study, a new murine model of type 2 AIH was developed using recombinant human cytochrome P450 (CYP) 2D6 emulsified with complete Freund's adjuvant (CFA). BALB/c mice were immunized with 2 μg/mL i.p. of CYP2D6 in CFA. The control group received CFA or phosphate-buffered saline alone. Alanine aminotransferase activity, autoantibody production, IgG concentrations, histologic damage, and specific T-cell response were evaluated. Persistent AIH, characterized by cellular infiltration, hepatic fibrosis, elevated alanine aminotransferase, and the production of anti-liver kidney microsomal antibody type 1 developed in CFA/CYP2D6-immunized mice. This group presented high levels of IgG and its subclasses IgG1, IgG2a, and IgG2b against liver self-proteins. Interestingly, IL-2+ and interferon γ-positive Cyp2d6-specific T cells were present in greater concentrations in mice immunized with CFA/CYP2D6 compared with controls. Immunization with CFA, in combination with a natural human autoantigen like CYP2D6, was demonstrated to break tolerance, resulting in a chronic form of autoimmune-related liver damage. This murine model of type 2 AIH is expected to be instrumental in understanding the immunologic mechanisms of the pathogenesis of this autoimmune liver disease.
- Published
- 2022
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