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Please use this identifier to cite or link to this item: http://repository.li.mahidol.ac.th/dspace/handle/123456789/11972
Title: Electrophile-modified lipoic derivatives of PDC-E2 elicits anti-mitochondrial antibody reactivity
Authors: Phornnop Naiyanetr
Jeffrey D. Butler
Liping Meng
Janice Pfeiff
Thomas P. Kenny
Kathryn G. Guggenheim
Roman Reiger
Kit Lam
Mark J. Kurth
Aftab A. Ansari
Ross L. Coppel
Marcos López-Hoyos
M. Eric Gershwin
Patrick S.C. Leung
University of California, Davis
Emory University
Monash University
Hospital Universitario Marques de Valdecilla
Mahidol University
Keywords: Immunology and Microbiology;Medicine
Issue Date: 1-Nov-2011
Citation: Journal of Autoimmunity. Vol.37, No.3 (2011), 209-216
Abstract: Our laboratory has hypothesized that xenobiotic modification of the native lipoyl moiety of the major mitochondrial autoantigen, the E2 subunit of the pyruvate dehydrogenase complex (PDC-E2), may lead to loss of self-tolerance in primary biliary cirrhosis (PBC). This thesis is based on the finding of readily detectable levels of immunoreactivity of PBC sera against extensive panels of protein microarrays containing mimics of the inner lipoyl domain of PDC-E2 and subsequent quantitative structure-activity relationships (QSARs). Importantly, we have demonstrated that murine immunization with one such mimic, 2-octynoic acid coupled to bovine serum albumin (BSA), induces anti-mitochondrial antibodies (AMAs) and cholangitis. Based upon these data, we have focused on covalent modifications of the lipoic acid disulfide ring and subsequent analysis of such xenobiotics coupled to a 15mer of PDC-E2 for immunoreactivity against a broad panel of sera from patients with PBC and controls. Our results demonstrate that AMA-positive PBC sera demonstrate marked reactivity against 6,8-bis(acetylthio)octanoic acid, implying that chemical modification of the lipoyl ring, i.e. disruption of the S-S disulfide, renders lipoic acid to its reduced form that will promote xenobiotic modification. This observation is particularly significant in light of the function of the lipoyl moiety in electron transport of which the catalytic disulfide constantly opens and closes and, thus, raises the intriguing thesis that common electrophilic agents, i.e. acetaminophen or non-steroidal anti-inflammatory drugs (NSAIDs), may lead to xenobiotic modification in genetically susceptible individuals that results in the generation of AMAs and ultimately clinical PBC. © 2011 Elsevier Ltd.
URI: https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=80755133531&origin=inward
http://repository.li.mahidol.ac.th/dspace/handle/123456789/11972
ISSN: 10959157
08968411
Appears in Collections:Scopus 2011-2015

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