title: Xenobiotics and loss of tolerance in primary biliary cholangitis.
abstract: Data from genome wide association studies and geoepidemiological studies established that a combination of genetic predisposition and environmental stimulation is required for the loss of tolerance in primary biliary cholangitis (PBC). The serologic hallmark of PBC are the presence of high titer anti-mitochondrial autoantibodies (AMA) that recognize the lipoyl domain of the mitochondrial pyruvate dehydrogenase E2 (PDC-E2) subunit. Extensive efforts have been directed to investigate the molecular basis of AMA. Recently, experimental data has pointed to the thesis that the breaking of tolerance to PDC-E2 is a pivotal event in the initial etiology of PBC, including environmental xenobiotics including those commonly found in cosmetics and food additives, suggesting that chemical modification of the PDC-E2 epitope may render its vulnerable to become a neo-antigen and trigger an immune response in genetically susceptible hosts. Here, we will discuss the natural history, genetics and immunobiology of PBC and structural constraints of PDC-E2 in AMA recognition which makes it vulnerable to chemical modification.
authors.affiliation: Jinjun Wang, Guoxiang Yang, Alana Mari Dubrovsky, Jinjung Choi, Patrick SC Leung, Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis, School of Medicine, Davis, CA 95616, United States.
authors.forename: Jinjun
authors.initials: J
authors.lastname: Wang
authors.affiliation: Jinjun Wang, Guoxiang Yang, Alana Mari Dubrovsky, Jinjung Choi, Patrick SC Leung, Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis, School of Medicine, Davis, CA 95616, United States.
authors.forename: Guoxiang
authors.initials: G
authors.lastname: Yang
authors.affiliation: Jinjun Wang, Guoxiang Yang, Alana Mari Dubrovsky, Jinjung Choi, Patrick SC Leung, Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis, School of Medicine, Davis, CA 95616, United States.
authors.forename: Alana Mari
authors.initials: AM
authors.lastname: Dubrovsky
authors.affiliation: Jinjun Wang, Guoxiang Yang, Alana Mari Dubrovsky, Jinjung Choi, Patrick SC Leung, Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis, School of Medicine, Davis, CA 95616, United States.
authors.forename: Jinjung
authors.initials: J
authors.lastname: Choi
authors.affiliation: Jinjun Wang, Guoxiang Yang, Alana Mari Dubrovsky, Jinjung Choi, Patrick SC Leung, Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis, School of Medicine, Davis, CA 95616, United States.
authors.forename: Patrick S C
authors.initials: PS
authors.lastname: Leung
mesh_terms: D000082:Acetaminophen / Q000009:adverse effects; D000818:Animals; D001323:Autoantibodies / Q000378:metabolism; D001324:Autoantigens / Q000276:immunology; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology; D002761:Cholangitis / Q000209:etiology* / Q000276:immunology; D051047:Dihydrolipoyllysine-Residue Acetyltransferase / Q000276:immunology; D004195:Disease Models, Animal; D006801:Humans; D007108:Immune Tolerance; D051379:Mice; D008928:Mitochondria / Q000276:immunology; D024101:Mitochondrial Proteins / Q000276:immunology; D018716:Molecular Mimicry; D008063:Thioctic Acid / Q000276:immunology; D015262:Xenobiotics / Q000009:adverse effects*
chemical_list: D001323:Autoantibodies; D001324:Autoantigens; D024101:Mitochondrial Proteins; D015262:Xenobiotics; D000082:Acetaminophen; D008063:Thioctic Acid; C052359:DLAT protein, human; D051047:Dihydrolipoyllysine-Residue Acetyltransferase
keywords: Antimitochondrial autoantibodies; Breaking of tolerance; Primary biliary cholangitis; Pyruvate dehydrogenase E2; Xenobiotics