A murine model of acute liver injury induced by human monoclonal autoantibody.
We have previously reported an immunoglobulin (Ig) M autoantibody to hepatocyte-related 190-kd molecules in patients with type 1 autoimmune hepatitis (AIH). This molecule was first isolated by hepatocyte-specific human monoclonal antibody (MoAb). To elucidate the role of this IgM autoantibody in hepatocyte injury, we examined the reactivity of this MoAb to murine hepatocytes and then questioned whether acute hepatic injury could be induced in mice via injection of this MoAb. The reactivity of MoAb was examined via both FACS analysis using murine hepatocytes and immunostaining of liver tissues. We then identified the murine hepatocyte membrane molecule recognized by this MoAb. The role of this MoAb in the immunopathogenesis of AIH was assessed by testing whether its injection into mice could increase serum aminotransferase levels as well as cause changes in liver histology. The present results demonstrate that this MoAb cross-reacted with murine hepatocytes and recognized a 190-kd molecule on the murine hepatocyte membrane just as in human hepatocytes. One hour after the injection of MoAb, the deposition of both IgM and complement component 3 was found in liver tissues. At 8 hours after the injection, serum aminotransferase levels were significantly increased in MoAb-injected mice compared with controls. Histological study revealed massive hepatocyte necrosis in MoAb-injected mice. In conclusion, human MoAb recognized a 190-kd molecule of both human and murine hepatocytes, and the injection of this MoAb to mice resulted in acute liver injury, indicating that this type of autoantibody may play an important role in the immunopathogenesis of AIH.
Yamauchi
Katsumi
K
Department of Gastroenterology and Medicine, Tokyo Women's Medical University, Japan. yamauchi@ige.twmu.ac.jp
Yamaguchi
Naoko
N
Furukawa
Takaji
T
Takatsu
Kazuko
K
Nakanishi
Toshimi
T
Ishida
Kohji
K
Komatsu
Tatsuji
T
Tokushige
Katsutoshi
K
Nagahara
Hikaru
H
Hashimoto
Etsuko
E
Shiratori
Keiko
K
D000818:Animals; D000911:Antibodies, Monoclonal / Q000009:adverse effects* / Q000276:immunology; D001323:Autoantibodies / Q000009:adverse effects* / Q000276:immunology; D019693:Hepatitis, Autoimmune / Q000276:immunology*; D022781:Hepatocytes / Q000276:immunology / Q000473:pathology*; D006801:Humans; D007075:Immunoglobulin M / Q000009:adverse effects / Q000276:immunology; D017114:Liver Failure, Acute / Q000276:immunology*; D051379:Mice; D023421:Models, Animal; D009336:Necrosis
D000911:Antibodies, Monoclonal; D001323:Autoantibodies; D007075:Immunoglobulin M