Identification of 2-nonynoic acid, a cosmetic component, as a potential trigger of primary biliary cirrhosis.
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 2,324th 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.
Rieger
Roman
R
Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis, GBSF 6510, 95616, USA.
Leung
Patrick S C
PS
Jeddeloh
Melissa R
MR
Kurth
Mark J
MJ
Nantz
Michael H
MH
Lam
Kit S
KS
Barsky
Daniel
D
Ansari
Aftab A
AA
Coppel
Ross L
RL
Mackay
Ian R
IR
Gershwin
M Eric
ME
D001323:Autoantibodies / Q000096:biosynthesis / Q000187:drug effects*; D003358:Cosmetics / Q000009:adverse effects / Q000737:chemistry*; D005231:Fatty Acids, Unsaturated / Q000009:adverse effects* / Q000737:chemistry / Q000276:immunology*; D005260:Female; D006801:Humans; D008105:Liver Cirrhosis, Biliary / Q000139:chemically induced* / Q000276:immunology; D008297:Male; D024101:Mitochondrial Proteins / Q000276:immunology; D018716:Molecular Mimicry / Q000276:immunology; D016273:Occupational Exposure; D013329:Structure-Activity Relationship
D001323:Autoantibodies; D003358:Cosmetics; D005231:Fatty Acids, Unsaturated; D024101:Mitochondrial Proteins; C055802:2-nonynoic acid methyl ester