HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Amano, K. Articles by Gershwin, M. E. Search for Related Content PubMed PubMed Citation Articles by Amano, K. Articles by Gershwin, M. E.

Chemical Xenobiotics and Mitochondrial Autoantigens in Primary Biliary Cirrhosis: Identification of Antibodies against a Common Environmental, Cosmetic, and Food Additive, 2-Octynoic Acid ¹

Katsushi Amano^*,, Patrick S. C. Leung^*, Roman Rieger^*, Chao Quan, Xiaobing Wang, Jan Marik, Yat Fan Suen, Mark J. Kurth, Michael H. Nantz, Aftab A. Ansari^¶, Kit S. Lam, Mikio Zeniya, Eiji Matsuura^||, Ross L. Coppel# and M. Eric Gershwin^2,*

^* Division of Rheumatology, Allergy and Clinical Immunology, Genomic and Biomedical Sciences Facility, University of California, Davis, CA 95616; Division of Gastroenterology and Hepatology, Department of Internal Medicine, Jikei University School of Medicine, Tokyo, Japan; University of California Cancer Center, Division of Hematology and Oncology, Department of Internal Medicine, University of California at Davis, Sacramento, CA 95817; Department of Chemistry, University of California, Davis, CA 95616; ^¶ Department of Pathology, Emory University, Atlanta, GA 30322; Department of Cell Chemistry, Okayama University, Okayama, Japan; and ^|| Department of Microbiology, Monash University, Clayton, Victoria, Australia

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-PDC-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.

This article has been cited by other articles:

				A. Kawano, S. Shimoda, T. Kamihira, F. Ishikawa, H. Niiro, Y. Soejima, A. Taketomi, Y. Maehara, M. Nakamura, A. Komori, et al. Peripheral Tolerance and the Qualitative Characteristics of Autoreactive T Cell Clones in Primary Biliary Cirrhosis J. Immunol., September 1, 2007; 179(5): 3315 - 3324. [Abstract] [Full Text] [PDF]