Does a betaretrovirus infection trigger primary biliary cirrhosis?
Does a betaretrovirus infection trigger primary biliary cirrhosis?
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DOI：
10.1073/pnas.1433063100
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发表时间：
2003-07-08
影响因子：
11.1
通讯作者：
Mason, A
中科院分区：
文献类型：
--
作者：
Xu, LZ;Shen, ZW;Mason, A
原发性胆汁性肝硬变患者的进行性胆管减少与产生的抗线粒体抗体有关，该抗体与胆管上皮细胞和肝周淋巴结上异常表达的蛋白质发生反应。虽然还没有确定特定的微生物，但人们认为是一种感染性因素在遗传易感个体中触发了这种自身免疫性肝病。以前的血清学研究已经提供了证据，表明病毒与原发性胆汁性肝硬变有关。在这里，我们描述了用电子显微镜鉴定胆管上皮细胞中的病毒颗粒，并克隆了来自原发性胆汁性肝硬变患者的外源逆转录病毒核苷酸序列。这种推定的病原体被称为人类β病毒，因为它与小鼠乳腺肿瘤病毒和从乳腺癌组织中克隆的人类逆转录病毒有密切的同源性。在活体实验中，我们发现大多数原发性胆汁性肝硬变患者都有人β-病毒在淋巴结中感染的RT-PCR和免疫组织化学证据。此外，病毒蛋白共定位于细胞，表现出异常的自身抗原表达。在体外，我们发现原发性胆汁性肝硬变患者的淋巴组织匀浆可以在共培养的正常胆管上皮细胞中诱导自身抗原的表达。当正常的胆管上皮细胞与含有人β-受体病毒或小鼠乳腺肿瘤病毒的培养上清进行连续传代培养时，也会出现原发性胆汁性肝硬变的表型表现，这为在体外测试Koch假说提供了一个模型。
Patients with primary biliary cirrhosis develop progressive ductopenia associated with the production of antimitochondrial antibodies that react with a protein aberrantly expressed on biliary epithelial cells and peri-hepatic lymph nodes. Although no specific microbe has been identified, it is thought that an infectious agent triggers this autoimmune liver disease in genetically predisposed individuals. Previous serologic studies have provided evidence to suggest a viral association with primary biliary cirrhosis. Here we describe the identification of viral particles in biliary epithelium by electron microscopy and the cloning of exogenous retroviral nucleotide sequences from patients with primary biliary cirrhosis. The putative agent is referred to as the human betaretrovirus because it shares close homology with the murine mammary tumor virus and a human retrovirus cloned from breast cancer tissue. In vivo, we have found that the majority of patients with primary biliary cirrhosis have both RT-PCR and immunohistochemistry evidence of human betaretrovirus infection in lymph nodes. Moreover, the viral proteins colocalize to cells demonstrating aberrant autoantigen expression. In vitro, we have found that lymph node homogenates from patients with primary biliary cirrhosis can induce autoantigen expression in normal biliary epithelial cells in coculture. Normal biliary epithelial cells also develop the phenotypic manifestation of primary biliary cirrhosis when cocultivated in serial passage with supernatants containing the human betaretrovirus or the murine mammary tumor virus, providing a model to test Koch's postulates in vitro.