The X and why of xenobiotics in primary biliary cirrhosis.
Primary biliary cirrhosis (PBC) is a chronic autoimmune liver disease characterized by inflammation and destruction of intrahepatic biliary epithelial cells, ultimately leading to liver failure. The serological hallmark of PBC is the presence of high-titer antimitochondrial antibodies (AMA) against the inner lipoyl domain of E2 subunits of 2-oxo-acid dehydrogenase complexes, in particular the E2 component of the pyruvate dehydrogenase complex (PDC-E2). The initiating events triggering the autoimmune response are not yet identified but the hypothesis of molecular mimicry is a widely proposed mechanism for the development of autoimmunity in PBC. Several candidates, including bacteria and viruses, have been suggested as causative agents, but also environmental factors, such as chemical xenobiotics, have been implicated in the pathogenesis of primary biliary cirrhosis. In this review, we will discuss our current knowledge of the immunoreactivity of xenobiotically modified PDC peptide antigens. In addition, we will provide a working hypothesis how xenobiotic modification of antigens might occur that ultimately leads to the breaking of self-tolerance and the induction of PBC.
Rieger
Roman
R
Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis, School of Medicine, 451 East Health Sciences Drive, Suite 6510, Davis, CA 95616, USA.
Gershwin
M Eric
ME
D000818:Animals; D001323:Autoantibodies / Q000096:biosynthesis / Q000276:immunology*; D001327:Autoimmune Diseases / Q000276:immunology*; D006801:Humans; D008105:Liver Cirrhosis, Biliary / Q000209:etiology / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D024101:Mitochondrial Proteins / Q000276:immunology*; D018716:Molecular Mimicry / Q000187:drug effects / Q000276:immunology*; D011768:Pyruvate Dehydrogenase Complex / Q000276:immunology*; D015262:Xenobiotics / Q000276:immunology / Q000378:metabolism / Q000633:toxicity*
D001323:Autoantibodies; D024101:Mitochondrial Proteins; D011768:Pyruvate Dehydrogenase Complex; D015262:Xenobiotics