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

部分自身免疫性肝炎(AIH)患者首发时出现肝功能衰竭。然而，目前尚不清楚进展为暴发性肝炎的原因。我们通过诱导Foxp3+调节性T细胞的同时丢失和PD-1介导的信号转导，建立了暴发型AIH小鼠模型。在这些小鼠的AIH进展过程中，T-bet与干扰素-γ和CXCR3在炎症的肝脏中高表达，而T细胞在脾和炎症的肝脏中主要表达CXCR3。CXCR3配体CXCL9在肝脏中的表达增加；体内注射抗CXCL9抑制了AIH的进展。此外，在疾病进展过程中，血清IL-18水平升高，脾和肝脏中的树突状细胞大量产生IL-18。体内应用抗IL-18R可抑制脾CXCR3+T细胞的增多，抑制肝炎的致死性进展。这些数据表明，在我们的模型中，IL-18在发展为重型肝炎中起关键作用。

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.