title: Primary biliary cirrhosis is characterized by IgG3 antibodies cross-reactive with the major mitochondrial autoepitope and its Lactobacillus mimic.
abstract: The serological hallmark of primary biliary cirrhosis (PBC) is the presence of pyruvate dehydrogenase complex E2 subunit (PDC-E2) antimitochondrial antibodies (AMAs). Anti-PDC-E2 antibodies cross-react specifically with mycobacterial hsp65, and we have demonstrated that the motif SxGDL[ILV]AE shared by PDC-E2(212-226) and hsp's is a cross-reactive target. Having found that this same motif is present only in beta-galactosidase of Lactobacillus delbrueckii (BGAL LACDE), we hypothesized that this homology would also lead to cross-reactivity. The mimics were tested via ELISA for reactivity and competitive cross-reactivity using sera from 100 AMA-positive and 23 AMA-negative PBC patients and 190 controls. An Escherichia coli (ECOLI) PDC-E2 mimic that has been pathogenetically linked to PBC but lacks this motif has been also tested. Anti-BGAL(266-280) LACDE antibodies were restricted to AMA-positive patients (54 of 95, 57%) and belonged to immunoglobulin (Ig) G3. Of the 190 controls, 22 (12%; P < .001) had anti-BGAL(266-280) antibodies, mainly of the IgG4 subclass. ECOLI PDC-E2 reactivity was virtually absent. BGAL(266-280)/PDC-E2(212-226) reactivity of the IgG3 isotype was found in 52 (52%) AMA-positive PBC patients but in only 1 of the controls (P < .001). LACDE BGAL(266-280)/PDC-E2(212-226) reactivity was due to cross-reactivity as confirmed via competition ELISA. Antibody affinity for BGAL(266-280) was greater than for PDC-E2 mimics. Preincubation of a multireactive serum with BGAL(266-280) reduced the inhibition of enzymatic activity by 40%, while marginal effect (12%) or no effect (2%) was observed in human or ECOLI PDC-E2 mimics. In conclusion, IgG3 antibodies to BGAL LACDE cross-react with the major mitochondrial autoepitope and are characteristic of PBC.
authors: Institute of Liver Studies, King's College Hospital, Denmark Hill, London SE5 9RS, UK.
authors: Dimitrios-Petrou
authors: DP
authors: Bogdanos
authors: Harold
authors: H
authors: Baum
authors: Manabu
authors: M
authors: Okamoto
authors: Paolo
authors: P
authors: Montalto
authors: Umesh C
authors: UC
authors: Sharma
authors: Eirini I
authors: EI
authors: Rigopoulou
authors: John
authors: J
authors: Vlachogiannakos
authors: Yun
authors: Y
authors: Ma
authors: Andrew K
authors: AK
authors: Burroughs
authors: Diego
authors: D
authors: Vergani
mesh_terms: D000328:Adult; D000368:Aged; D000595:Amino Acid Sequence; D015551:Autoimmunity; D003429:Cross Reactions; D051047:Dihydrolipoyllysine-Residue Acetyltransferase; D000939:Epitopes; D005260:Female; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology*; D007778:Lactobacillus / Q000276:immunology*; D008105:Liver Cirrhosis, Biliary / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D008928:Mitochondria / Q000276:immunology*; D008969:Molecular Sequence Data; D011768:Pyruvate Dehydrogenase Complex / Q000276:immunology*; D001616:beta-Galactosidase / Q000276:immunology*
chemical_list: D000939:Epitopes; D007074:Immunoglobulin G; D011768:Pyruvate Dehydrogenase Complex; D051047:Dihydrolipoyllysine-Residue Acetyltransferase; D001616:beta-Galactosidase