Copyright ©The Author(s) 2019. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Dec 7, 2019; 25(45): 6579-6606
Published online Dec 7, 2019. doi: 10.3748/wjg.v25.i45.6579
Examining pathogenic concepts of autoimmune hepatitis for cues to future investigations and interventions
Albert J Czaja
Albert J Czaja, Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, MN 55905, United States
Author contributions: Czaja AJ researched, designed, and wrote this article; The 4 tables and 2 color figures are original, constructed by Czaja AJ, and developed solely for this review; The review article is original, current, and comprehensive, and it has not been published previously.
Conflict-of-interest statement: Albert J Czaja has no conflict of interests to declare.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
Corresponding author: Albert J Czaja, FAASLD, AGAF, FACG, FACP, MD, Professor Emeritus of Medicine, Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, 200 First Street S.W., Rochester, MN 55905, United States.
Telephone: +1-507-2842691 Fax: +1-507-2840538
Received: November 1, 2019
Peer-review started: November 1, 2019
First decision: November 22, 2019
Revised: November 25, 2019
Accepted: November 29, 2019
Article in press: November 29, 2019
Published online: December 7, 2019

Multiple pathogenic mechanisms have been implicated in autoimmune hepatitis, but they have not fully explained susceptibility, triggering events, and maintenance or escalation of the disease. Furthermore, they have not identified a critical defect that can be targeted. The goals of this review are to examine the diverse pathogenic mechanisms that have been considered in autoimmune hepatitis, indicate investigational opportunities to validate their contribution, and suggest interventions that might evolve to modify their impact. English abstracts were identified in PubMed by multiple search terms. Full length articles were selected for review, and secondary and tertiary bibliographies were developed. Genetic and epigenetic factors can affect susceptibility by influencing the expression of immune regulatory genes. Thymic dysfunction, possibly related to deficient production of programmed cell death protein-1, can allow autoreactive T cells to escape deletion, and alterations in the intestinal microbiome may help overcome immune tolerance and affect gender bias. Environmental factors may trigger the disease or induce epigenetic changes in gene function. Molecular mimicry, epitope spread, bystander activation, neo-antigen production, lymphocytic polyspecificity, and disturbances in immune inhibitory mechanisms may maintain or escalate the disease. Interventions that modify epigenetic effects on gene expression, alter intestinal dysbiosis, eliminate deleterious environmental factors, and target critical pathogenic mechanisms are therapeutic possibilities that might reduce risk, individualize management, and improve outcome. In conclusion, diverse pathogenic mechanisms have been implicated in autoimmune hepatitis, and they may identify a critical factor or sequence that can be validated and used to direct future management and preventive strategies.

Keywords: Autoimmune hepatitis, Pathogenesis, Epigenetics, Molecular mimicry, Epitope spread, Intestinal microbiome

Core tip: The next generation of management of autoimmune hepatitis will depend on clarification of the pathogenic sequence from susceptibility to triggering events to disease maintenance or escalation. Studies that move the pathogenesis of autoimmune hepatitis closer to its cause have the potential to replace blanket immunosuppressive regimens and even suggest strategies for prevention. Investigations that expand concepts of acquired epigenetic change in gene expression, pathogenic molecular mimicries, epitope spread, bystander activation, and intestinal dysbiosis may narrow the knowledge gap between environmental factors and disease occurrence and behavior. Protective as well as site-specific corrective interventions may emerge.