title: Antimitochondrial antibody heterogeneity and the xenobiotic etiology of primary biliary cirrhosis.
abstract: Antimitochondrial antibodies (AMAs) directed against the lipoyl domain of the E2 subunit of pyruvate dehydrogenase (PDC-E2) are detected in 95% of patients with primary biliary cirrhosis (PBC) and are present before the onset of clinical disease. The recent demonstration that AMAs recognize xenobiotic modified PDC-E2 with higher titers than native PDC-E2 raises the possibility that the earliest events involved in loss of tolerance are related to xenobiotic modification. We hypothesized that reactivity to such xenobiotics would be predominantly immunoglobulin M (IgM) and using sera from a large cohort of PBC patients and controls (n = 516), we examined in detail sera reactivity against either 6,8-bis(acetylthio) octanoic acid (SAc)-conjugated bovine serum albumin (BSA), recombinant PDC-E2 (rPDC-E2) or BSA alone. Further, we also defined the relative specificity to the SAc moiety using inhibition enzyme-linked immunosorbent assay (ELISA); SAc conjugate and rPDC-E2-specific affinity-purified antibodies were also examined for antigen specificity, isotype, and crossreactivity. Reactivity to SAc conjugates is predominantly IgM; such reactivity reflects a footprint of previous xenobiotic exposure. Indeed, this observation is supported by both direct binding, crossreactivity, and inhibition studies. In both early and late-stage PBC, the predominant Ig isotype to SAc is IgM, with titers higher with advanced stage disease. We also note that there was a higher level of IgM reactivity to SAc than to rPDC-E2 in early-stage versus late-stage PBC. Interestingly, this finding is particularly significant in light of the structural similarity between SAc and the reduced form of lipoic acid, a step which is similar to the normal physiological oxidation of lipoic acid.
  
  
  CONCLUSIONS
  Specific modifications of the disulfide bond within the lipoic-acid-conjugated PDC-E2 moiety, i.e., by an electrophilic agent renders PDC-E2 immunogenic in a genetically susceptible host.
authors.affiliation: Division of Rheumatology/Allergy and Clinical Immunology, University of California, Davis, CA 95616, USA.
authors.forename: Richy C Y
authors.initials: RC
authors.lastname: Chen
authors.forename: Phornnop
authors.initials: P
authors.lastname: Naiyanetr
authors.forename: Shang-An
authors.initials: SA
authors.lastname: Shu
authors.forename: Jinjun
authors.initials: J
authors.lastname: Wang
authors.forename: Guo-Xiang
authors.initials: GX
authors.lastname: Yang
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Kenny
authors.forename: Kathryn C
authors.initials: KC
authors.lastname: Guggenheim
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Butler
authors.forename: Christopher
authors.initials: C
authors.lastname: Bowlus
authors.forename: Mi-Hua
authors.initials: MH
authors.lastname: Tao
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Kurth
authors.forename: Aftab A
authors.initials: AA
authors.lastname: Ansari
authors.forename: Marshall
authors.initials: M
authors.lastname: Kaplan
authors.forename: Ross L
authors.initials: RL
authors.lastname: Coppel
authors.forename: Ana
authors.initials: A
authors.lastname: Lleo
authors.forename: M Eric
authors.initials: ME
authors.lastname: Gershwin
authors.forename: Patrick S C
authors.initials: PS
authors.lastname: Leung
mesh_terms: D000888:Antibodies, Anti-Idiotypic / Q000276:immunology*; D000918:Antibody Specificity; D001324:Autoantigens / Q000276:immunology; D016022:Case-Control Studies; D015209:Cholangitis, Sclerosing / Q000097:blood / Q000276:immunology; D051047:Dihydrolipoyllysine-Residue Acetyltransferase / Q000276:immunology; D019693:Hepatitis, Autoimmune / Q000097:blood / Q000276:immunology; D006801:Humans; D007075:Immunoglobulin M / Q000097:blood; D008105:Liver Cirrhosis, Biliary / Q000097:blood / Q000209:etiology* / Q000276:immunology*; D008928:Mitochondria / Q000276:immunology*; D024101:Mitochondrial Proteins / Q000276:immunology; D011994:Recombinant Proteins / Q000276:immunology; D012710:Serum Albumin, Bovine / Q000276:immunology; D015262:Xenobiotics / Q000009:adverse effects*
chemical_list: D000888:Antibodies, Anti-Idiotypic; D001324:Autoantigens; D007075:Immunoglobulin M; D024101:Mitochondrial Proteins; D011994:Recombinant Proteins; D015262:Xenobiotics; D012710:Serum Albumin, Bovine; C052359:DLAT protein, human; D051047:Dihydrolipoyllysine-Residue Acetyltransferase