Anti-neutrophil cytoplasmic antibodies in a rat model of trinitrobenzenesulphonic acid-induced liver injury

Background In sera from patients with autoimmune liver diseases, e.g. prima ry sclerosing cholangitis (PSC) and autoimmune hepatitis, anti-neutrophil c ytoplasmic antibodies (ANCAs) can be found. Until now, no animal model of A NCA induction in liver disease has been described. In this study, we descri be a novel rat model of acute liver injury and subsequent ANCA production. Materials and methods The hapten reagent 2,4,6-trinitrobenzenesulphonic aci d (TNBS) was injected into the portal vein of female Lewis rats. Two experi mental groups were studied: group A (TNBS/ethanol) received different TNBS concentrations; control animals of group B (ethanol) were injected with 10% (v/v)ethanol/0.9% (w/v) NaCl. Results A dose-dependent acute necrotizing liver injury occurred after inje ction of TNBS. Histopathological examination revealed acute hepatic injury with confluent parenchymal necrosis, mild bile duct proliferation and perip ortal infiltration. The periportal infiltration consisted mainly of macroph ages and T lymphocytes. ANCAs were found in an allogenic test system betwee n 1 and 8 weeks after TNBS injection in 11 out of 28 (39%) TNBS-treated rat s (group A) and did not correlate with the extent of liver injury or TNBS d ose. Autoantibody specificities of IgG type were directed against catalase (29%), myeloperoxidase (14%) and actin (7%), as detected by enzyme-linked i mmunosorbent assay and Western blotting. Moreover, autoantibodies against t he asialoglycoprotein receptor were observed. Peripheral blood mononuclear cells and spleen lymphocytes from TNBS-treated rats were shown to produce A NCAs. Conclusion In summary, we were able to show that intraportal administration of the hapten reagent TNBS induces an acute necrotizing liver injury with subsequent ANCA production in Lewis rats. ANCA specificities were mainly di rected against catalase, an autoantigen that has recently been identified i n sera from patients with primary sclerosing cholangitis and autoimmune hep atitis. This animal model offers the opportunity to study the pathomechanis ms of ANCA production in necrotizing liver injury.