Hepatitis mouse models: from acute-to-chronic autoimmune hepatitis

Abstract

Autoimmune hepatitis (AIH) is a chronic inflammatory liver disease associated with interface hepatitis, raised plasma liver enzymes, the presence of autoantibodies and regulatory T-cell (Tregs) dysfunction. The clinical course is heterogeneous, manifested by a fulminant or indolent course. Although genetic predisposition is well accepted, the combination with currently undefined environmental factors is crucial for the development of the disease. Progress in the development of reliable animal models provides added understanding of the pathophysiology of AIH, and these will be very useful in evaluating potential therapeutics. It appears that artificially breaking tolerance in the liver is easy. However, maintaining this state of tolerance breakdown, to get chronic hepatitis, is difficult because liver immune homeostasis is strongly regulated by several immune response inhibitory mechanisms. For example, Tregs are crucial regulators in acute and chronic hepatitis, and C57BL/6 mice are most prone to experimental AIH. Immunization of C57BL/6 mice with liver (AIH) autoantigens (CYP2D6/FTCD or IL-4R) and the disturbance of liver regulatory mechanism(s), leading to experimental AIH, are likely to be most representative of human AIH pathology.

Keywords: CYP2D6; Th17; formiminotransferase cyclodeaminase; liver tolerance; mouse models; tregs.

Figure 1

Schematic overview of the different features of autoimmune hepatitis (AIH). Liver-specific enzymes such as cytochrome P 450 (CYP2D6) and formiminotransferase cyclodeaminase (FTCD) are the best-defined immunogenic antigens for AIH. Recently, a type I AIH liver autoantigen antigen, IL-4R, was identified in adult AIH. Furthermore, autoantibodies to soluble liver antigen (SLA) can be present in both types. IL-17 and IL-21 cytokines were increased, whereas IL-4 and IL-10 cytokine production was lower compared with healthy controls. Genetic susceptibility plays a role as was shown by the increased frequency of human leucocyte antigen (HLA) class II – polymorphisms in patients with AIH that is associated with the presence of autoreactive CD4⁺/CD8⁺ T cells. Liver sinusoidal endothelial cells (LSEC) dysfunction and/or cross-presentation are responsible for the survival of autoreactive lymphocytes. A decrease of regulatory T cells (Tregs), B cells (Bregs) and natural killing T cells (NKT cells) number (#) and/or function (φ) was documented (Czaja ; Limmer et al. ; Lapierre et al. ; Mizutani et al. ; Longhi et al. ; Oo et al. ; Zingaretti et al. ; Ma et al. 2013).