Chemical xenobiotics and mitochondrial autoantigens in primary biliary cirrhosis: identification of antibodies against a common environmental, cosmetic, and food additive, 2-octynoic acid.
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.
Amano
Katsushi
K
Division of Rheumatology, Allergy and Clinical Immunology, Genomic and Biomedical Sciences Facility, University of California, Davis, CA 95616, USA.
Leung
Patrick S C
PS
Rieger
Roman
R
Quan
Chao
C
Wang
Xiaobing
X
Marik
Jan
J
Suen
Yat Fan
YF
Kurth
Mark J
MJ
Nantz
Michael H
MH
Ansari
Aftab A
AA
Lam
Kit S
KS
Zeniya
Mikio
M
Matsuura
Eiji
E
Coppel
Ross L
RL
Gershwin
M Eric
ME
D000595:Amino Acid Sequence; D000918:Antibody Specificity; D000937:Antigen-Antibody Reactions; D001323:Autoantibodies / Q000096:biosynthesis / Q000097:blood / Q000378:metabolism*; D001324:Autoantigens / Q000276:immunology* / Q000378:metabolism; D003358:Cosmetics / Q000009:adverse effects; D003429:Cross Reactions; D051047:Dihydrolipoyllysine-Residue Acetyltransferase; D004781:Environmental Exposure / Q000009:adverse effects; D004797:Enzyme-Linked Immunosorbent Assay; D005229:Fatty Acids, Monounsaturated / Q000276:immunology* / Q000378:metabolism; D005503:Food Additives / Q000009:adverse effects; D006801:Humans; D008105:Liver Cirrhosis, Biliary / Q000097:blood / Q000276:immunology*; D008928:Mitochondria / Q000276:immunology* / Q000378:metabolism; D018716:Molecular Mimicry / Q000276:immunology; D008969:Molecular Sequence Data; D021122:Protein Subunits / Q000276:immunology / Q000378:metabolism; D011768:Pyruvate Dehydrogenase Complex / Q000097:blood / Q000276:immunology / Q000378:metabolism; D015262:Xenobiotics / Q000276:immunology* / Q000378:metabolism
D001323:Autoantibodies; D001324:Autoantigens; D003358:Cosmetics; D005229:Fatty Acids, Monounsaturated; D005503:Food Additives; D021122:Protein Subunits; D011768:Pyruvate Dehydrogenase Complex; D015262:Xenobiotics; C060855:2-octynoic acid; D051047:Dihydrolipoyllysine-Residue Acetyltransferase