Extrahepatic manifestations in transgenic mice of osteopontin in hepatocytes - A clue to advent of pathological state in various organs of chronic hepatitis C patients
Extrahepatic manifestations in transgenic mice of osteopontin in hepatocytes - A clue to advent of pathological state in various organs of chronic hepatitis C patients
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DOI：
10.1016/j.hepres.2005.01.010
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发表时间：
2005-04-01
影响因子：
4.2
通讯作者：
Fujiwara, K
中科院分区：
文献类型：
--
作者：
Saitoh, E;Matsui, A;Fujiwara, K
骨桥蛋白是Th1免疫反应启动所必需的细胞因子。我们建立了在肝细胞中表达骨桥蛋白的转基因小鼠，其中从12周龄起逐渐出现肝脏坏死伴淋巴细胞浸润，循环中骨桥蛋白水平上调，这表明过度的Th 1免疫反应也可能导致肝外表现。我们检查了这些小鼠的各种器官的组织学和免疫组织化学特征。脾肿大和肝、肠周围淋巴结肿大在转基因小鼠24周龄以后变得明显，并伴有明显的小淋巴细胞浸润。免疫组化显示脾和淋巴结中的淋巴细胞为CD 3或CD 20阳性，表明浸润的淋巴细胞为B和T细胞。在肺、肾和下颌下腺中发现了类似的淋巴细胞浸润。肺泡隔肥大伴淋巴细胞浸润，肺表现为间质性肺炎。这些病变与慢性丙型肝炎患者的肝外表现相似，提示对丙型肝炎病毒（HCV）蛋白或具有HCV分子模拟物的蛋白的Th1免疫反应增强可能是丙型肝炎病毒慢性感染下不仅在肝脏而且在各种器官中形成病理状态的促成因素。(c)2005 Elsevier B.V.保留所有权利。
Osteopontin is a cytokine essential for initiation of Th1 immune reaction. We established transgenic mice expressing osteopontin in hepatocyte, in which liver necrosis with lymphocyte infiltration developed gradually from 12 weeks of age with up-regulated osteopontin levels in the circulation, suggesting that extrahepatic manifestations might also occur as a result of excessive Th1 immune reaction. We examined histological and immunohistochemical features of various organs in these mice. Splenomegaly and enlargement of lymph nodes around the liver and intestine became apparent with marked infiltration of small lymphocytes in the transgenic mice later than 24 weeks of age. Immunostaining revealed that lymphocytes in the spleen and lymph nodes were positive for either CD3 or CD20, suggesting that the infiltrating lymphocytes were both B and T cells. Similar lymphocyte infiltration was found in the lung, kidney and submandibular gland. Alveolar septa became hypertrophic with lymphocyte infiltration, and the lung showed the appearance of interstitial pneumonia. These lesions are similar to extrahepatic manifestations in chronic hepatitis C patients, suggesting that augmented Th1 immune reaction to hepatitis C virus (HCV) proteins or the proteins with molecular mimicry of HCV may be a contributing factor for the formation of the pathological state not only in the liver but also in various organs under chronic infection of hepatitis C virus. (c) 2005 Elsevier B.V. All rights reserved.