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Please use this identifier to cite or link to this item: http://repository.li.mahidol.ac.th/dspace/handle/123456789/32422
Title: Antimitochondrial antibody heterogeneity and the xenobiotic etiology of primary biliary cirrhosis
Authors: Richy C.Y. Chen
Phornnop Naiyanetr
Shang An Shu
Jinjun Wang
Guo Xiang Yang
Thomas P. Kenny
Kathryn C. Guggenheim
Jeffrey D. Butler
Christopher Bowlus
Mi Hua Tao
Mark J. Kurth
Aftab A. Ansari
Marshall Kaplan
Ross L. Coppel
Ana Lleo
M. Eric Gershwin
Patrick S.C. Leung
University of California, Davis
Mahidol University
Institute of Biomedical Sciences Academia Sinica Taiwan
Emory University School of Medicine
Tufts University School of Medicine
Monash University
Humanitas University
Keywords: Medicine
Issue Date: 1-Apr-2013
Citation: Hepatology. Vol.57, No.4 (2013), 1498-1508
Abstract: Antimitochondrial antibodies (AMAs) directed against the lipoyl domain of the E2 subunit of pyruvate dehydrogenase (PDC-E2) are detected in 95% of patients with primary biliary cirrhosis (PBC) and are present before the onset of clinical disease. The recent demonstration that AMAs recognize xenobiotic modified PDC-E2 with higher titers than native PDC-E2 raises the possibility that the earliest events involved in loss of tolerance are related to xenobiotic modification. We hypothesized that reactivity to such xenobiotics would be predominantly immunoglobulin M (IgM) and using sera from a large cohort of PBC patients and controls (n = 516), we examined in detail sera reactivity against either 6,8-bis(acetylthio) octanoic acid (SAc)-conjugated bovine serum albumin (BSA), recombinant PDC-E2 (rPDC-E2) or BSA alone. Further, we also defined the relative specificity to the SAc moiety using inhibition enzyme-linked immunosorbent assay (ELISA); SAc conjugate and rPDC-E2-specific affinity-purified antibodies were also examined for antigen specificity, isotype, and crossreactivity. Reactivity to SAc conjugates is predominantly IgM; such reactivity reflects a footprint of previous xenobiotic exposure. Indeed, this observation is supported by both direct binding, crossreactivity, and inhibition studies. In both early and late-stage PBC, the predominant Ig isotype to SAc is IgM, with titers higher with advanced stage disease. We also note that there was a higher level of IgM reactivity to SAc than to rPDC-E2 in early-stage versus late-stage PBC. Interestingly, this finding is particularly significant in light of the structural similarity between SAc and the reduced form of lipoic acid, a step which is similar to the normal physiological oxidation of lipoic acid. Conclusion: Specific modifications of the disulfide bond within the lipoic-acid-conjugated PDC-E2 moiety, i.e., by an electrophilic agent renders PDC-E2 immunogenic in a genetically susceptible host. © 2012 American Association for the Study of Liver Diseases.
URI: https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=84876121192&origin=inward
http://repository.li.mahidol.ac.th/dspace/handle/123456789/32422
ISSN: 15273350
02709139
Appears in Collections:Scopus 2011-2015

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