A J Czaja1. 1. Division of Gastroenterology and Hepatology, Mayo Clinic and Mayo Foundation, Rochester, Minnesota, 55905, USA.
Abstract
OBJECTIVES: The aim of this study was to review the pathogenic mechanisms of autoimmune hepatitis, identify gaps in knowledge, and focus future investigative efforts. METHODS: The study was based on a review of all relevant articles on the mechanisms of autoimmunity in autoimmune liver disease from 1980 to 2000, extraction of pertinent concepts from the medical literature; and integration of evolving paradigms of pathogenesis with personal experiences and investigations. RESULTS: Autoimmune hepatitis is a consequence of autoantigen exposure, genetic predisposition, and defective immunoregulatory mechanisms. Autoantigen is optimally presented by class II molecules of the major histocompatibility complex that have lysine residues at position DRbeta71 of the antigen-binding groove. Cytokines and non-disease-specific autoimmune promoters modulate immune reactivity. Cell-mediated and antibody-dependent mechanisms contribute to hepatocyte injury. CONCLUSIONS: Multiple disturbances in the homeostatic mechanisms that preserve self-tolerance are likely in autoimmune hepatitis. Future investigations must focus on individual determinants of autoantigen presentation, immunocyte activation, and liver cell destruction. Findings can then be integrated into a comprehensive knowledge base that may be applicable to other autoimmune diseases.
OBJECTIVES: The aim of this study was to review the pathogenic mechanisms of autoimmune hepatitis, identify gaps in knowledge, and focus future investigative efforts. METHODS: The study was based on a review of all relevant articles on the mechanisms of autoimmunity in autoimmune liver disease from 1980 to 2000, extraction of pertinent concepts from the medical literature; and integration of evolving paradigms of pathogenesis with personal experiences and investigations. RESULTS:Autoimmune hepatitis is a consequence of autoantigen exposure, genetic predisposition, and defective immunoregulatory mechanisms. Autoantigen is optimally presented by class II molecules of the major histocompatibility complex that have lysine residues at position DRbeta71 of the antigen-binding groove. Cytokines and non-disease-specific autoimmune promoters modulate immune reactivity. Cell-mediated and antibody-dependent mechanisms contribute to hepatocyte injury. CONCLUSIONS: Multiple disturbances in the homeostatic mechanisms that preserve self-tolerance are likely in autoimmune hepatitis. Future investigations must focus on individual determinants of autoantigen presentation, immunocyte activation, and liver cell destruction. Findings can then be integrated into a comprehensive knowledge base that may be applicable to other autoimmune diseases.
Authors: S Berardi; F Lodato; A Gramenzi; A D'Errico; M Lenzi; A Bontadini; M C Morelli; M R Tamè; F Piscaglia; M Biselli; C Sama; G Mazzella; A D Pinna; G Grazi; M Bernardi; P Andreone Journal: Gut Date: 2006-06-23 Impact factor: 23.059