A murine model of acute liver injury induced by human monoclonal autoantibody

Abstract

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 A utoimmune hepatitis (AIH) is a chronic disorder of hepatocytes that is accompanied by immunological abnormality as determined by serological examination. 1,2 Based on the observation of alterations in several T cell functions, AIH is generally thought to be a disorder mediated by T cells. [3][4][5][6] However, various types of hepatocyte-specific autoantibodies frequently found in AIH patients are also suspected of being involved in immune-mediated liver injury in this disease. This was supported by the following results: (1) Serum autoantibodies obtained from AIH patients were able to kill human hepatocytes, 7-12 (2) the titer of hepatocyte-specific autoantibody was tightly correlated with liver damage in AIH patients. 13,14 However, despite these important observations, because of the lack of an adequate in vivo system, the precise role of such autoantibodies in immunomediated liver injury has remained obscure.We have previously reported the hepatocyte-specific human monoclonal autoantibody (MoAb) produced by human clone established by peripheral blood mononuclear cells of patients with AIH. 15 This MoAb recognized a 190-kd molecule on the hepatocyte membrane and was able to kill human hepatocyte cell lines in a complementdependent manner. In addition, a similar 190-kd molecule-recognizing immunoglobulin M (IgM) autoantibody was also found in AIH patients, and its titer was Abbreviations: Ig, immunoglobulin; AIH, autoimmune hepatitis; MoAb, monoclonal autoantibody; MP, myeloma protein; TBS, C3, complement component 3; AST, asparate aminotransferase; ALT, alanine aminotransferase. From the

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“…On the other hand, hyperferritinemia accompanied by liver dysfunction occurs in AIH, which is also char- acterized by hepatocellular destruction. Regarding the pathogenesis of AIH, candidate target molecules for autologous hepatocytes have been identified and the participation of humoral immunity has been suggested (13). However, since very high ferritin levels are not common in AIH, the present case suggests the coexistence of different pathological conditions, namely AIH and AOSD.…”

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“…In the present study, the authors show that the MoAb also reacts with a 190 kDa molecule on mouse hepatocytes, indicating that this target antigen is both liver-specific and species cross-reactive. 29 Importantly, they further show that injection of the MoAb into mice rapidly induced massive, predominantly perivenular, complement-mediated hepatocellular necrosis. The authors conclude that the data from these two studies suggest that the IgM anti-190 kDa antibody detected in patients may have an important role in the immunopathogenesis of AIH.…”

“…28 In this issue of HEPATOLOGY, Yamauchi et al describe yet another putative animal model of AIH. 29 The work is an extension of their recent studies on the generation of a human IgM ( -type) monoclonal antibody (MoAb) by Epstein-Barr virus (EBV) transformation of peripheral blood mononuclear cells from a Japanese patient with type 1 AIH. 30 The MoAb recognises a liver-specific 190 kDa molecule expressed on the surfaces of hepatocytes and could induce complement-dependent lysis of a hepatocyte-derived (HuH2) cell line.…”

“…[35][36][37] Yamauchi et al point out, however, that this evidence comes from studies in caucasoids and that such complement gene deletions are not common in Japanese AIH patients. 29 Again, this has some merit, because there is no reason to suppose that what we see as the clinical expression of AIH necessarily arises through the same pathogenetic mechanisms in all individuals with the disease.…”

“…29,30 It will be interesting to know the identity of this 190 kDa molecule, why it is preferentially expressed on perivenular hepatocytes, why there does not appear to be a class switch from an IgM to an IgG response to it in AIH patients, and whether mice injected with their MoAb develop chronic hepatitis over a longer period of observation. …”