Immune mechanisms involved in the development of fatal autoimmune hepatitis in mice

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Some of the patients with autoimmune hepatitis (AIH) manifest liver failure at initial presentation. However, it is unknown how the progression to fulminant hepatitis occurs. We developed a mouse model of fulminant AIH by inducing a concurrent loss of Foxp3+ regulatory T cells and PD-1-mediated signaling. During AIH progression in these mice, T-bet together with IFN-gamma and CXCR3 were highly expressed in the inflamed liver, and T cells in the spleen and inflamed liver dominantly expressed CXCR3. Expression of one CXCR3 ligand, CXCL9, was elevated in the liver; in vivo administration of anti-CXCL9 suppressed AIH progression. In addition, serum levels of IL-18 were elevated during progression, and dendritic cells in the spleen and liver highly produced IL-18. In vivo administration of anti-IL-18R suppressed the increase of splenic CXCR3+ T cells and the fatal progression of hepatitis. These data suggest that in our model, IL-18 is critical for the progression to fulminant hepatitis.