Autoimmune hepatitis-like disease in C57BL/6 mice infected with mouse hepatitis virus A59

Abstract

Mouse hepatitis virus A59 (MHV A59) induces autoantibodies (autoAb) to fumarylacetoacetate hydrolase (FAH), a soluble cytosolic enzyme present in the liver and kidneys, in various mouse strains. The aim of this work was to amplify and diversify the autoimmune response restricted to FAH through the use of the exogenous adjuvant called PADRE. Accordingly, C57BL/6 mice were chosen, because these animals respond to PADRE better than other mouse strains. Results presented herein indicate that, surprisingly, C57BL/6 mice developed signs of autoimmune hepatitis-like disease (AIH), including transient hypergammaglobulinemia, elevated transaminases, autoAb directed against different liver proteins and hepatic cellular infiltrates, indicating that a new model of experimental AIH could be generated by a viral inoculation. Furthermore, PADRE administration amplified the MHV effect, extending the duration of hypergammaglobulinemia and increasing the binding of autoAb as well as the degree of hepatic infiltrates. However, the adjuvant did not expand the time of the symptoms. Additionally, since plasmatic uric acid and high-mobility group box protein 1 (HGMB1) concentrations augmented in MHV- and/or PADRE-treated mice, it is suggested that both alarmins were probably involved in the spreading of the immune response induced by the viral infection and the adjuvant administration.

Complementary serum proteomic analysis of autoimmune hepatitis in mice and patients

“…Similarly, Kuo et al found a marked elevation of serum alpha-fetoprotein with severe jaundice as an initial manifestation of AIH [21]. The fumarylacetoacetase, which was also identified to be upregulated in our AIH mice, was also verified by its autoantibody in sera of a mouse hepatitis model [22]. The findings brought into correspondence with our experimental result which showed an increase in AIH model compared to the control group.…”

Crosstalk of liver immune cells and cell death mechanisms in different murine models of liver injury and its clinical relevance

“…[88][89][90] Another pathogenic strain, MHV-A59 (derived from normal mouse liver cell line-NCTC-1469 or from L2 cells) induced fulminant hepatitis as well as autoimmunity in susceptible C57BL/6 mice with formation of autoantibodies (autoAb) to fumarylacetoacetate hydrolase (FAH), a soluble cytosolic enzyme present in the liver and kidneys. [91] The acute liver injury (after 3-5 days infection) induced by MHV-A59 is associated with an increase level of IL-6, TNF-α and IL-17 in mice. [89] In contrast, the non-pathogenic strain isolated from persistently infected YAC lymphoid cell line (YAC-MHV3) does not induce an acute lethal disease but only subclinical infection in mice.…”

Pathogen Infection as a Possible Cause for Autoimmune Hepatitis

“…HLA-DR binding epitope) [111] applified the MHV-induced AIH [110]. These data indicate that virus-infections can promote autoimmunity in the liver and that additional exogenous stimuli can accelerate this process.…”

“…Recently, Aparicio et al generated a further model by infecting wild-type C57BL/6 mice with the mouse hepatitis virus A59 (MHV) and thereby generating autoantibodies to fumarylacetoacetat hydrolase (FAH), which is expressed in the liver and kidney [110]. The mice displayed features of AIH, including hypergammaglobulinemia, elevated serum aminotransferases, hepatic cellular infiltrations, and antibodies to liver autoantigens.…”