1. Primary biliary cirrhosis is characterized by IgG3 antibodies cross-reactive with the major mitochondrial autoepitope and its Lactobacillus mimic
- Author
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Eirini I. Rigopoulou, M. Okamoto, Yun Ma, Dimitrios-Petrou Bogdanos, Andrew K. Burroughs, Harold Baum, John Vlachogiannakos, Umesh C. Sharma, Diego Vergani, and P. Montalto
- Subjects
Adult ,Male ,Molecular Sequence Data ,Autoimmunity ,Pyruvate Dehydrogenase Complex ,Cross Reactions ,Biology ,Dihydrolipoyllysine-Residue Acetyltransferase ,Immunoglobulin G ,Subclass ,Epitope ,Microbiology ,Serology ,Epitopes ,Primary biliary cirrhosis ,medicine ,Humans ,Amino Acid Sequence ,Aged ,Hepatology ,Liver Cirrhosis, Biliary ,Middle Aged ,beta-Galactosidase ,Pyruvate dehydrogenase complex ,medicine.disease ,Isotype ,Mitochondria ,Lactobacillus ,biology.protein ,Female ,Antibody - 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.
- Published
- 2005
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