Does a betaretrovirus infection trigger primary biliary cirrhosis?

Lizhe Xu, Zhiwei Shen, Linsheng Guo, Brent Fodera, Adrian Keogh, Ruth Joplin, Barbara O'Donnell, James Aitken, William Carman, James Neuberger, Andrew Mason

Research output: Contribution to journalArticle

186 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)8454-8459
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume100
Issue number14
DOIs
StatePublished - Jul 8 2003
Externally publishedYes

ASJC Scopus subject areas

  • General

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    Xu, L., Shen, Z., Guo, L., Fodera, B., Keogh, A., Joplin, R., O'Donnell, B., Aitken, J., Carman, W., Neuberger, J., & Mason, A. (2003). Does a betaretrovirus infection trigger primary biliary cirrhosis? Proceedings of the National Academy of Sciences of the United States of America, 100(14), 8454-8459. https://doi.org/10.1073/pnas.1433063100