Chemical xenobiotics and mitochondrial autoantigens in primary biliary cirrhosis

Identification of antibodies against a common environmental, cosmetic, and food additive, 2-octynoic acid

Katsushi Amano, Patrick S Leung, Roman Rieger, Chao Quan, Xiaobing Wang, Jan Marik, Yat Fan Suen, Mark J. Kurth, Michael H. Nantz, Aftab A. Ansari, Kit Lam, Mikio Zeniya, Eiji Matsuura, Ross L. Coppel, M. Eric Gershwin

Research output: Contribution to journalArticle

132 Citations (Scopus)

Abstract

Emerging evidence has suggested environmental factors as causative agents in the pathogenesis of primary biliary cirrhosis (PBC), We have hypothesized that in PBC the lipoyl domain of the immunodominant E2 component of pyruvate dehydrogenase (PDC-E2) is replaced by a chemical xenobiotic mimic, which is sufficient to break self-tolerance. To address this hypothesis, based upon our quantitative structure-activity relationship data, a total of 107 potential xenobiotic mimics were coupled to the lysine residue of the immunodominant 15 amino acid peptide of the PDC-E2 inner lipoyl domain and spotted on microarray slides. Sera from patients with PBC (n = 47), primary sclerosing cholangitis (n = 15), and healthy volunteers (n = 20) were assayed for Ig reactivity. PBC sera were subsequently absorbed with native lipoylated PDC-E2 peptide or a xenobiotically modified PDC-E2 peptide, and the remaining reactivity analyzed. Of the 107 xenobiotics, 33 had a significantly higher IgG reactivity against PBC sera compared with control sera. In addition, 9 of those 33 compounds were more reactive than the native lipoylated peptide. Following absorption, 8 of the 9 compounds demonstrated cross-reactivity with lipoic acid. One compound, 2-octynoic acid, was unique in both its quantitative structure-activity relationship analysis and reactivity. PBC patient sera demonstrated high Ig reactivity against 2-octynoic acid-PBC-E2 peptide. Not only does 2-octynoic acid have the potential to modify PDC-E2 in vivo but importantly it was/is widely used in the environment including perfumes, lipstick, and many common food flavorings.

Original languageEnglish (US)
Pages (from-to)5874-5883
Number of pages10
JournalJournal of Immunology
Volume174
Issue number9
StatePublished - May 1 2005

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Food Additives
Biliary Liver Cirrhosis
Autoantigens
Xenobiotics
Cosmetics
Antibodies
Peptides
Serum
Quantitative Structure-Activity Relationship
Perfume
Self Tolerance
Thioctic Acid
Immunodominant Epitopes
Sclerosing Cholangitis
2-octynoic acid
Pyruvic Acid
Lysine
Healthy Volunteers
Oxidoreductases
Immunoglobulin G

ASJC Scopus subject areas

  • Immunology

Cite this

Chemical xenobiotics and mitochondrial autoantigens in primary biliary cirrhosis : Identification of antibodies against a common environmental, cosmetic, and food additive, 2-octynoic acid. / Amano, Katsushi; Leung, Patrick S; Rieger, Roman; Quan, Chao; Wang, Xiaobing; Marik, Jan; Suen, Yat Fan; Kurth, Mark J.; Nantz, Michael H.; Ansari, Aftab A.; Lam, Kit; Zeniya, Mikio; Matsuura, Eiji; Coppel, Ross L.; Gershwin, M. Eric.

In: Journal of Immunology, Vol. 174, No. 9, 01.05.2005, p. 5874-5883.

Research output: Contribution to journalArticle

Amano, K, Leung, PS, Rieger, R, Quan, C, Wang, X, Marik, J, Suen, YF, Kurth, MJ, Nantz, MH, Ansari, AA, Lam, K, Zeniya, M, Matsuura, E, Coppel, RL & Gershwin, ME 2005, 'Chemical xenobiotics and mitochondrial autoantigens in primary biliary cirrhosis: Identification of antibodies against a common environmental, cosmetic, and food additive, 2-octynoic acid', Journal of Immunology, vol. 174, no. 9, pp. 5874-5883.
Amano, Katsushi ; Leung, Patrick S ; Rieger, Roman ; Quan, Chao ; Wang, Xiaobing ; Marik, Jan ; Suen, Yat Fan ; Kurth, Mark J. ; Nantz, Michael H. ; Ansari, Aftab A. ; Lam, Kit ; Zeniya, Mikio ; Matsuura, Eiji ; Coppel, Ross L. ; Gershwin, M. Eric. / Chemical xenobiotics and mitochondrial autoantigens in primary biliary cirrhosis : Identification of antibodies against a common environmental, cosmetic, and food additive, 2-octynoic acid. In: Journal of Immunology. 2005 ; Vol. 174, No. 9. pp. 5874-5883.
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abstract = "Emerging evidence has suggested environmental factors as causative agents in the pathogenesis of primary biliary cirrhosis (PBC), We have hypothesized that in PBC the lipoyl domain of the immunodominant E2 component of pyruvate dehydrogenase (PDC-E2) is replaced by a chemical xenobiotic mimic, which is sufficient to break self-tolerance. To address this hypothesis, based upon our quantitative structure-activity relationship data, a total of 107 potential xenobiotic mimics were coupled to the lysine residue of the immunodominant 15 amino acid peptide of the PDC-E2 inner lipoyl domain and spotted on microarray slides. Sera from patients with PBC (n = 47), primary sclerosing cholangitis (n = 15), and healthy volunteers (n = 20) were assayed for Ig reactivity. PBC sera were subsequently absorbed with native lipoylated PDC-E2 peptide or a xenobiotically modified PDC-E2 peptide, and the remaining reactivity analyzed. Of the 107 xenobiotics, 33 had a significantly higher IgG reactivity against PBC sera compared with control sera. In addition, 9 of those 33 compounds were more reactive than the native lipoylated peptide. Following absorption, 8 of the 9 compounds demonstrated cross-reactivity with lipoic acid. One compound, 2-octynoic acid, was unique in both its quantitative structure-activity relationship analysis and reactivity. PBC patient sera demonstrated high Ig reactivity against 2-octynoic acid-PBC-E2 peptide. Not only does 2-octynoic acid have the potential to modify PDC-E2 in vivo but importantly it was/is widely used in the environment including perfumes, lipstick, and many common food flavorings.",
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AU - Rieger, Roman

AU - Quan, Chao

AU - Wang, Xiaobing

AU - Marik, Jan

AU - Suen, Yat Fan

AU - Kurth, Mark J.

AU - Nantz, Michael H.

AU - Ansari, Aftab A.

AU - Lam, Kit

AU - Zeniya, Mikio

AU - Matsuura, Eiji

AU - Coppel, Ross L.

AU - Gershwin, M. Eric

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