Identification of 2-nonynoic acid, a cosmetic component, as a potential trigger of primary biliary cirrhosis

Roman Rieger, Patrick S Leung, Melissa R. Jeddeloh, Mark J. Kurth, Michael H. Nantz, Kit Lam, Daniel Barsky, Aftab A. Ansari, Ross L. Coppel, Ian R. Mackay, M. Eric Gershwin

Research output: Contribution to journalArticle

130 Citations (Scopus)

Abstract

Antimitochondrial antibodies (AMA) are unique among autoimmune serologic reactants because of their extremely high association with the index disease primary biliary cirrhosis (PBC). This autoantibody response is specifically directed only to the lipoyl domain of the mitochondrial 2-oxo-acid dehydrogenase complexes, which prompted us to search for environmental mimotopes in the form of xenobiotics and led to our identification of 2-octynoic acid as a high-affinity reactant for AMA. To focus on the chemical characteristics requisite for binding of AMA to the xenobiotic-modified self-peptide, quantitative structure-activity relationship (QSAR) studies were performed using a panel of alkynoic compounds, including examination of the length of the carbon chain and the location of the triple bond in the identified mimotope. Analyses of octynamides that varied in the position of the triple bond demonstrated that only the 2-octynamide reacted strongly with PBC sera. Furthermore, among 2-alkynamides with varying carbon chain length, 2-octyn-, 2-nonyn- (particularly) and 2-decynamide exhibited the highest reactivity. Thus, an optimal chemical structure of the xenobiotically modified epitope recognized by AMA-positive PBC sera is provided by 2-nonynoic acid. The methyl ester of this compound is ranked 2324th out of 12,945 compounds to which there is occupational exposure, with an 80% female prevalence due to its use in cosmetic products. Our findings illustrate an unusual polyreactivity of anti-PDC-E2 and support the idea of epitope mimicry in the genesis of this autoantibody and perhaps of PBC itself.

Original languageEnglish (US)
Pages (from-to)7-16
Number of pages10
JournalJournal of Autoimmunity
Volume27
Issue number1
DOIs
StatePublished - Aug 2006

Fingerprint

Biliary Liver Cirrhosis
Cosmetics
Acids
Antibodies
Xenobiotics
Autoantibodies
Epitopes
Carbon
Keto Acids
Quantitative Structure-Activity Relationship
Occupational Exposure
Serum
Oxidoreductases
Esters
Peptides

Keywords

  • Autoepitope
  • Microarray platform
  • Primary biliary cirrhosis
  • Xenobiotics

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy

Cite this

Identification of 2-nonynoic acid, a cosmetic component, as a potential trigger of primary biliary cirrhosis. / Rieger, Roman; Leung, Patrick S; Jeddeloh, Melissa R.; Kurth, Mark J.; Nantz, Michael H.; Lam, Kit; Barsky, Daniel; Ansari, Aftab A.; Coppel, Ross L.; Mackay, Ian R.; Gershwin, M. Eric.

In: Journal of Autoimmunity, Vol. 27, No. 1, 08.2006, p. 7-16.

Research output: Contribution to journalArticle

Rieger, Roman ; Leung, Patrick S ; Jeddeloh, Melissa R. ; Kurth, Mark J. ; Nantz, Michael H. ; Lam, Kit ; Barsky, Daniel ; Ansari, Aftab A. ; Coppel, Ross L. ; Mackay, Ian R. ; Gershwin, M. Eric. / Identification of 2-nonynoic acid, a cosmetic component, as a potential trigger of primary biliary cirrhosis. In: Journal of Autoimmunity. 2006 ; Vol. 27, No. 1. pp. 7-16.
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abstract = "Antimitochondrial antibodies (AMA) are unique among autoimmune serologic reactants because of their extremely high association with the index disease primary biliary cirrhosis (PBC). This autoantibody response is specifically directed only to the lipoyl domain of the mitochondrial 2-oxo-acid dehydrogenase complexes, which prompted us to search for environmental mimotopes in the form of xenobiotics and led to our identification of 2-octynoic acid as a high-affinity reactant for AMA. To focus on the chemical characteristics requisite for binding of AMA to the xenobiotic-modified self-peptide, quantitative structure-activity relationship (QSAR) studies were performed using a panel of alkynoic compounds, including examination of the length of the carbon chain and the location of the triple bond in the identified mimotope. Analyses of octynamides that varied in the position of the triple bond demonstrated that only the 2-octynamide reacted strongly with PBC sera. Furthermore, among 2-alkynamides with varying carbon chain length, 2-octyn-, 2-nonyn- (particularly) and 2-decynamide exhibited the highest reactivity. Thus, an optimal chemical structure of the xenobiotically modified epitope recognized by AMA-positive PBC sera is provided by 2-nonynoic acid. The methyl ester of this compound is ranked 2324th out of 12,945 compounds to which there is occupational exposure, with an 80{\%} female prevalence due to its use in cosmetic products. Our findings illustrate an unusual polyreactivity of anti-PDC-E2 and support the idea of epitope mimicry in the genesis of this autoantibody and perhaps of PBC itself.",
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AB - Antimitochondrial antibodies (AMA) are unique among autoimmune serologic reactants because of their extremely high association with the index disease primary biliary cirrhosis (PBC). This autoantibody response is specifically directed only to the lipoyl domain of the mitochondrial 2-oxo-acid dehydrogenase complexes, which prompted us to search for environmental mimotopes in the form of xenobiotics and led to our identification of 2-octynoic acid as a high-affinity reactant for AMA. To focus on the chemical characteristics requisite for binding of AMA to the xenobiotic-modified self-peptide, quantitative structure-activity relationship (QSAR) studies were performed using a panel of alkynoic compounds, including examination of the length of the carbon chain and the location of the triple bond in the identified mimotope. Analyses of octynamides that varied in the position of the triple bond demonstrated that only the 2-octynamide reacted strongly with PBC sera. Furthermore, among 2-alkynamides with varying carbon chain length, 2-octyn-, 2-nonyn- (particularly) and 2-decynamide exhibited the highest reactivity. Thus, an optimal chemical structure of the xenobiotically modified epitope recognized by AMA-positive PBC sera is provided by 2-nonynoic acid. The methyl ester of this compound is ranked 2324th out of 12,945 compounds to which there is occupational exposure, with an 80% female prevalence due to its use in cosmetic products. Our findings illustrate an unusual polyreactivity of anti-PDC-E2 and support the idea of epitope mimicry in the genesis of this autoantibody and perhaps of PBC itself.

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