Electrophile-modified lipoic derivatives of PDC-E2 elicits anti-mitochondrial antibody reactivity

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 Leung

Research output: Contribution to journalArticle

29 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)209-216
Number of pages8
JournalJournal of Autoimmunity
Volume37
Issue number3
DOIs
StatePublished - Nov 2011

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Biliary Liver Cirrhosis
Anti-Idiotypic Antibodies
Xenobiotics
Disulfides
Thioctic Acid
Dihydrolipoyllysine-Residue Acetyltransferase
Serum
Self Tolerance
Protein Array Analysis
Cholangitis
Quantitative Structure-Activity Relationship
Autoantigens
Acetaminophen
Bovine Serum Albumin
Electron Transport
Immunization
Anti-Inflammatory Agents
Pharmaceutical Preparations

Keywords

  • Anti-mitochondrial antibodies
  • Primary biliary cirrhosis
  • Pyruvate dehydrogenase
  • Xenobiotics

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy

Cite this

Electrophile-modified lipoic derivatives of PDC-E2 elicits anti-mitochondrial antibody reactivity. / Naiyanetr, Phornnop; Butler, Jeffrey D.; Meng, Liping; Pfeiff, Janice; Kenny, Thomas P.; Guggenheim, Kathryn G.; Reiger, Roman; Lam, Kit; Kurth, Mark J.; Ansari, Aftab A.; Coppel, Ross L.; López-Hoyos, Marcos; Gershwin, M. Eric; Leung, Patrick S.

In: Journal of Autoimmunity, Vol. 37, No. 3, 11.2011, p. 209-216.

Research output: Contribution to journalArticle

Naiyanetr, P, Butler, JD, Meng, L, Pfeiff, J, Kenny, TP, Guggenheim, KG, Reiger, R, Lam, K, Kurth, MJ, Ansari, AA, Coppel, RL, López-Hoyos, M, Gershwin, ME & Leung, PS 2011, 'Electrophile-modified lipoic derivatives of PDC-E2 elicits anti-mitochondrial antibody reactivity', Journal of Autoimmunity, vol. 37, no. 3, pp. 209-216. https://doi.org/10.1016/j.jaut.2011.06.001
Naiyanetr, Phornnop ; Butler, Jeffrey D. ; Meng, Liping ; Pfeiff, Janice ; Kenny, Thomas P. ; Guggenheim, Kathryn G. ; Reiger, Roman ; Lam, Kit ; Kurth, Mark J. ; Ansari, Aftab A. ; Coppel, Ross L. ; López-Hoyos, Marcos ; Gershwin, M. Eric ; Leung, Patrick S. / Electrophile-modified lipoic derivatives of PDC-E2 elicits anti-mitochondrial antibody reactivity. In: Journal of Autoimmunity. 2011 ; Vol. 37, No. 3. pp. 209-216.
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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.",
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