A murine model of acute liver injury induced by human monoclonal autoantibody
A murine model of acute liver injury induced by human monoclonal autoantibody
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DOI：
10.1002/hep.20726
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发表时间：
2005-07-01
期刊：
影响因子：
13.5
通讯作者：
Shiratori, K
中科院分区：
文献类型：
--
作者：
Yamauchi, K;Yamaguchi, N;Shiratori, K
我们之前曾报道过 1 型自身免疫性肝炎 (AIH) 患者体内存在针对肝细胞相关 190-kd 分子的免疫球蛋白 (Ig) M 自身抗体。该分子首先通过肝细胞特异性人单克隆抗体（MoAb）分离出来。为了阐明这种 IgM 自身抗体在肝细胞损伤中的作用，我们检查了这种 MoAb 与小鼠肝细胞的反应性，然后质疑是否可以通过注射这种 MoAb 在小鼠中诱导急性肝损伤。通过使用鼠肝细胞的 FACS 分析和肝组织的免疫染色检查 MoAb 的反应性。然后我们鉴定了该 MoAb 识别的小鼠肝细胞膜分子。通过测试将这种 MoAb 注射到小鼠体内是否会增加血清转氨酶水平以及引起肝脏组织学的变化，评估了这种 MoAb 在 AIH 免疫发病机制中的作用。目前的结果表明，该 MoAb 与鼠肝细胞发生交叉反应，并像在人肝细胞中一样识别鼠肝细胞膜上的 190-kd 分子。注射MoAb 1小时后，在肝组织中发现IgM和补体成分3沉积。注射后 8 小时，与对照组相比，注射 MoAb 的小鼠血清转氨酶水平显着升高。组织学研究显示注射 MoAb 的小鼠出现大量肝细胞坏死。总之，人MoAb可识别人和小鼠肝细胞的190-kd分子，并将该MoAb注射到小鼠体内导致急性肝损伤，表明此类自身抗体可能在AIH的免疫发病机制中发挥重要作用。
We have previously reported an immunoglobulin (Ig) M autoantibody to hepatocy-te-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.