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World J Gastroenterol. Jan 7, 2016; 22(1): 338-348
Published online Jan 7, 2016. doi: 10.3748/wjg.v22.i1.338
Xenobiotics and loss of tolerance in primary biliary cholangitis
Jinjun Wang, Guoxiang Yang, Alana Mari Dubrovsky, Jinjung Choi, Patrick SC Leung
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
Jinjun Wang, College of Environmental Science and Engineering, Yangzhou University, Yangzhou 225000, Jiangsu Province, China
Author contributions: Wang J, Yang G and Leung PSC contributed to the study design, literature search, manuscript writing and final revision of the manuscript; Dubrovsky AM and Choi J contributed to literature search and manuscript writing.
Supported by National Institutes of Health grants (in part), DK39588, DK090019 and DK067003.
Conflict-of-interest statement: The authors have no conflict of interest to report.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Patrick SC Leung, PhD, Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis, School of Medicine, 451 Health Sciences Drive, Suite 6510, Davis, CA 95616, United States. psleung@ucdavis.edu
Telephone: +1-530-7544943 Fax: +1-530-7546047
Received: April 30, 2015
Peer-review started: May 8, 2015
First decision: July 14, 2015
Revised: August 15, 2015
Accepted: December 1, 2015
Article in press: December 1, 2015
Published online: January 7, 2016
Processing time: 244 Days and 18.3 Hours
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.

Keywords: Antimitochondrial autoantibodies; Primary biliary cholangitis; Pyruvate dehydrogenase E2; Breaking of tolerance; Xenobiotics

Core tip: Environment influences immune functions. In this paper, we examine how environmental chemicals can trigger autoimmunity in an organ specific autoimmune disease, primary biliary cholangitis (PBC). PBC is liver specific autoimmune disease characterized by high titer of anti-mitochondrial autoantibodies directed against the E2 subunit of pyruvate dehydrogenase (PDC-E2) lipoyl domain. Here, we present experimental evidence from quantitative structure-activity relationship and animal models that xenobiotic modification of the PDC-E2 lipoyl domain could lead to loss of self-tolerance and is a pivotal event in the initial etiology of PBC in genetically susceptible hosts.