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

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-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.

Is lipstick associated with the development of systemic lupus erythematosus (SLE)?

“…Phthalate, another common ingredient in lipsticks, can induce anti-DNA antibody responses and SLE-like syndromes in lupus-prone mice [6][7][8]. 2-Octynoic acid is a xenobiotic that can modify the immunodominant E2 component of pyruvate dehydrogenase complexes (PDC-E2) and induce the antimitochondrial antibody response in primary biliary cirrhosis [4]. Furthermore, the application of products to the lips confers a unique potential to increase the amount of chemical exposure through oral ingestion and proximity to the buccal mucosa, a site of privileged absorption that evades "first-pass" hepatic metabolism.…”

“…Lipsticks, in particular, contain a variety of chemical agents whose properties might increase the risk for SLE. These include eosin, 2-octynoic acid (a xenobiotic), and phthalate isomers that have been linked to lupus and other autoimmune disorders in vitro and in animals [4][5][6][7][8]. The privileged absorption of the lipstick through the buccal mucosa and oral ingestion may further aggravate the negative effects of these chemicals.…”

Induction of Primary Biliary Cirrhosis in Guinea Pigs following Chemical Xenobiotic Immunization

“…At present, etiology is conceived only in general terms of genetic and environmental factors that predispose to a breakdown in tolerance characterized by autoimmune responses of great specificity. Primary biliary cirrhosis (PBC) 3 illustrates this enigma because of its high degree of concordance in identical twins, clinical uniformity, and the presence of a highly directed, specific serologic marker consisting of antimitochondrial Abs (AMA) directed at the E2 subunits of the 2-oxo-acid dehydrogenase complexes (2-OADC-E2) (1,2). This signature of PBC, the AMA, is a useful probe to enable dissection of potential environmental triggers and has led to the proposition that the inciting event of PBC is a modification of the major autoantigen, the E2 subunit of pyruvate dehydrogenase (PDC-E2), by a xenobiotic via chemical conjugation.…”

“…This signature of PBC, the AMA, is a useful probe to enable dissection of potential environmental triggers and has led to the proposition that the inciting event of PBC is a modification of the major autoantigen, the E2 subunit of pyruvate dehydrogenase (PDC-E2), by a xenobiotic via chemical conjugation. This theory is based on our demonstration that, when the lipoyl domain of PDC-E2 was modified with specific small molecule mimics, the ensuing structures displayed highly specific reactivity to PBC sera, at levels often higher than the native molecule (3,4). Interestingly, the autoimmune response in terms of not only the CD4 ϩ and CD8 ϩ epitopes but also the autoantibodies in PBC all map within the lipoyl domain of the 2-OADC-E2 enzymes (5)(6)(7).…”

“…Screening of these compounds for reactivity with AMA-positive PBC sera led to the identification of a number of organic chemicals that were recognized by AMA with higher relative affinity than that for parent lipoylated-PDC-E2 (3,4,8). Furthermore, immunization of rabbits with one of these xenobiotics, 6-bromohexanoate, conjugated to BSA (6BH-BSA) led to the induction of AMA with the same antigenic specificities and capacity to inhibit the activity of PDC enzymes that is displayed by sera from patients with PBC (9).…”