Microbial mimics are major targets of crossreactivity with human pyruvate dehydrogenase in primary biliary cirrhosis.
OBJECTIVE
Previous studies on patients with primary biliary cirrhosis (PBC) have shown extensive cross-reactivity between the dominant B- and T-cell epitopes of human pyruvate dehydrogenase complex-E2 (PDC-E2), and microbial mimics. Such observations have suggested microbial infection as having a role in the induction of anti-mitochondrial antibodies, through a mechanism of molecular mimicry. However the biological significance of these cross-reactivities is questionable, because PDC-E2 is so highly conserved among various species.


METHODS
Interrogating protein databases, ten non-PDC-E2 microbial sequences with high degree of similarity to PDC-E2(212-226) were found in Escherichia coli (6), Helicobacter pylori, Pseudomonas aeruginosa, Cytomegalovirus, and Haemophilus influenzae. We report on a study testing reactivity and competitive cross-reactivity against these respective peptides, and in some cases the parent protein, using sera from 55 patients with PBC, compared to reactivity of 190 pathological and 28 healthy controls.


RESULTS
Cross-reactivity to E. coli mimics was commonly seen in PBC, and in a subset of pathological controls except where there was no evidence of urinary tract infection and correlated with anti-mitochondrial reactivity.


CONCLUSIONS
E. coli/PDC-E2 cross-reactive immunity characterizes primary biliary cirrhosis; the large number of E. coli immunogenic mimics may account for the dominance of the major PDC-E2 autoepitope.
Bogdanos
Dimitrios-Petrou
DP
Institute of Liver Studies, King's College Hospital, Denmark Hill, London SE5 9RS, UK.
Baum
Harold
H
Grasso
Alessandro
A
Okamoto
Manabu
M
Butler
Patrice
P
Ma
Yun
Y
Rigopoulou
Eirini
E
Montalto
Paolo
P
Davies
Edward T
ET
Burroughs
Andrew K
AK
Vergani
Diego
D
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000595:Amino Acid Sequence; D001426:Bacterial Proteins / Q000235:genetics / Q000276:immunology; D016022:Case-Control Studies; D003429:Cross Reactions; D051047:Dihydrolipoyllysine-Residue Acetyltransferase; D004926:Escherichia coli / Q000201:enzymology*; D005260:Female; D006801:Humans; D008105:Liver Cirrhosis, Biliary / Q000201:enzymology* / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D018716:Molecular Mimicry; D010455:Peptides / Q000235:genetics / Q000276:immunology; D011768:Pyruvate Dehydrogenase Complex / Q000276:immunology* / Q000378:metabolism*; D014764:Viral Proteins / Q000235:genetics / Q000276:immunology
D001426:Bacterial Proteins; D010455:Peptides; D011768:Pyruvate Dehydrogenase Complex; D014764:Viral Proteins; D051047:Dihydrolipoyllysine-Residue Acetyltransferase