title: Xenobiotic-induced loss of tolerance in rabbits to the mitochondrial autoantigen of primary biliary cirrhosis is reversible.
abstract: Previous work has demonstrated that immunization of rabbits with the xenobiotic 6-bromohexanoate coupled to BSA breaks tolerance and induces autoantibodies to mitochondria in rabbits. Such immunized rabbits develop high-titer Abs to pyruvate dehydrogenase complex (PDC)-E2, the major autoantigen of primary biliary cirrhosis. In efforts to map the fine specificity of these autoantibodies, rabbits were immunized biweekly with 6-bromohexanoate-BSA and screened for reactivity using a unique xenobiotic-peptide-agarose microarray platform with an emphasis on identifying potential structures that mimic the molecular image formed by the association of lipoic acid with the immunodominant PDC-E2 peptide. Essentially, a total of 23 xenobiotics and lipoic acid were coupled to the 12-mer peptide backbones, PDC, a mutant PDC, and albumin. As expected, we succeeded in breaking tolerance using this small organic molecule coupled to BSA. However, unlike multiple experimental methods of breaking tolerance, we report in this study that, following continued immunization, the rabbits recover tolerance. With repeated immunization, the response to the rPDC-E2 protein increased with a gradual reduction in autoantibodies against the lipoic acid-peptide, i.e., the primary tolerance-breaking autoantigen. Detailed analysis of this system may provide strategies on how to restore tolerance in patients with autoimmune disease.
authors.affiliation: Division of Rheumatology, Allergy, and Clinical Immunology, University of California, Davis, CA 95616, USA.
authors.forename: Katsushi
authors.initials: K
authors.lastname: Amano
authors.forename: Patrick S C
authors.initials: PS
authors.lastname: Leung
authors.forename: Qingchai
authors.initials: Q
authors.lastname: Xu
authors.forename: Jan
authors.initials: J
authors.lastname: Marik
authors.forename: Chao
authors.initials: C
authors.lastname: Quan
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Kurth
authors.forename: Michael H
authors.initials: MH
authors.lastname: Nantz
authors.forename: Aftab A
authors.initials: AA
authors.lastname: Ansari
authors.forename: Kit S
authors.initials: KS
authors.lastname: Lam
authors.forename: Mikio
authors.initials: M
authors.lastname: Zeniya
authors.forename: Ross L
authors.initials: RL
authors.lastname: Coppel
authors.forename: M Eric
authors.initials: ME
authors.lastname: Gershwin
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000096:biosynthesis / Q000378:metabolism; D001324:Autoantigens / Q000276:immunology*; D001666:Binding Sites, Antibody; D001667:Binding, Competitive / Q000276:immunology; D051047:Dihydrolipoyllysine-Residue Acetyltransferase; D005260:Female; D006801:Humans; D006842:Hydrocarbons, Brominated / Q000008:administration & dosage / Q000276:immunology* / Q000378:metabolism; D007074:Immunoglobulin G / Q000378:metabolism; D008105:Liver Cirrhosis, Biliary / Q000201:enzymology / Q000276:immunology*; D008930:Mitochondria, Liver / Q000201:enzymology / Q000276:immunology*; D020411:Oligonucleotide Array Sequence Analysis; D009842:Oligopeptides / Q000008:administration & dosage / Q000276:immunology; D011768:Pyruvate Dehydrogenase Complex / Q000276:immunology*; D011817:Rabbits; D017634:Self Tolerance; D012710:Serum Albumin, Bovine / Q000008:administration & dosage / Q000276:immunology; D008063:Thioctic Acid / Q000276:immunology / Q000378:metabolism; D015262:Xenobiotics / Q000008:administration & dosage / Q000276:immunology* / Q000378:metabolism
chemical_list: D001323:Autoantibodies; D001324:Autoantigens; D006842:Hydrocarbons, Brominated; D007074:Immunoglobulin G; D009842:Oligopeptides; D011768:Pyruvate Dehydrogenase Complex; D015262:Xenobiotics; D012710:Serum Albumin, Bovine; D008063:Thioctic Acid; D051047:Dihydrolipoyllysine-Residue Acetyltransferase