Does a betaretrovirus infection trigger primary biliary cirrhosis?
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.
Xu
Lizhe
L
Section of Gastroenterology and Hepatology, Ochsner Clinic Foundation, New Orleans, LA 70121, USA.
Shen
Zhiwei
Z
Guo
Linsheng
L
Fodera
Brent
B
Keogh
Adrian
A
Joplin
Ruth
R
O'Donnell
Barbara
B
Aitken
James
J
Carman
William
W
Neuberger
James
J
Mason
Andrew
A
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
D001324:Autoantigens; D004279:DNA, Viral; D011768:Pyruvate Dehydrogenase Complex; D014020:Tissue Extracts; D051047:Dihydrolipoyllysine-Residue Acetyltransferase