title: Does a betaretrovirus infection trigger primary biliary cirrhosis?
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.
authors.affiliation: Section of Gastroenterology and Hepatology, Ochsner Clinic Foundation, New Orleans, LA 70121, USA.
authors.forename: Lizhe
authors.initials: L
authors.lastname: Xu
authors.forename: Zhiwei
authors.initials: Z
authors.lastname: Shen
authors.forename: Linsheng
authors.initials: L
authors.lastname: Guo
authors.forename: Brent
authors.initials: B
authors.lastname: Fodera
authors.forename: Adrian
authors.initials: A
authors.lastname: Keogh
authors.forename: Ruth
authors.initials: R
authors.lastname: Joplin
authors.forename: Barbara
authors.initials: B
authors.lastname: O'Donnell
authors.forename: James
authors.initials: J
authors.lastname: Aitken
authors.forename: William
authors.initials: W
authors.lastname: Carman
authors.forename: James
authors.initials: J
authors.lastname: Neuberger
authors.forename: Andrew
authors.initials: A
authors.lastname: Mason
mesh_terms: D001324:Autoantigens / Q000096:biosynthesis / Q000276:immunology; D001327:Autoimmune Diseases / Q000276:immunology / Q000821:virology*; D030121:Betaretrovirus / Q000235:genetics / Q000302:isolation & purification / Q000472:pathogenicity*; D001653:Bile Ducts, Intrahepatic / Q000648:ultrastructure / Q000821:virology; D003001:Cloning, Molecular; D018920:Coculture Techniques; D004279:DNA, Viral / Q000235:genetics / Q000302:isolation & purification; D051047:Dihydrolipoyllysine-Residue Acetyltransferase; D004847:Epithelial Cells / Q000648:ultrastructure / Q000821:virology; D019084:Fluorescent Antibody Technique, Indirect; D006801:Humans; D008105:Liver Cirrhosis, Biliary / Q000276:immunology / Q000821:virology*; D008198:Lymph Nodes / Q000737:chemistry / Q000821:virology; D008324:Mammary Tumor Virus, Mouse / Q000235:genetics; D008854:Microscopy, Electron; D008969:Molecular Sequence Data; D010641:Phenotype; D011533:Proviruses / Q000235:genetics / Q000302:isolation & purification*; D011768:Pyruvate Dehydrogenase Complex / Q000096:biosynthesis / Q000276:immunology; D012192:Retroviridae Infections / Q000276:immunology / Q000473:pathology / Q000821:virology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017385:Sequence Homology; D014020:Tissue Extracts / Q000494:pharmacology
chemical_list: D001324:Autoantigens; D004279:DNA, Viral; D011768:Pyruvate Dehydrogenase Complex; D014020:Tissue Extracts; D051047:Dihydrolipoyllysine-Residue Acetyltransferase