Extensive homology between the major immunodominant mitochondrial antigen in primary biliary cirrhosis and Helicobacter pylori does not lead to immunological cross-reactivity.
BACKGROUND
Primary biliary cirrhosis (PBC) is an immune-mediated chronic cholestatic disease characterized by the presence of antibodies directed predominantly against the E2 subunit of the pyruvate dehydrogenase complex (PDC-E2). What provokes tolerance breakdown in PBC remains to be established, though there is evidence to indicate that microbes may induce anti-mitochondrial antibodies (AMA) through a mechanism of molecular mimicry.


METHODS
Having found that urease beta (UREB)(22-36) antigen of Helicobacter pylori (HELPY) shares extensive (87%) similarity with PDC-E2(212-226), the major mitochondrial autoepitope, it was hypothesized that this would also lead to cross-reactivity. The UREB/PDC-E2 mimics were thus constructed and tested by ELISA in 112 PBC patients and 114 controls.


RESULTS
Reactivity to PDC-E2(212-226) was found in 104 patients but to UREB(22-36) in only 2. In these two patients, the double reactivity was not cross-reactive. The lack of surface antibody accessibility to UREB(22-36), as demonstrated through three-dimensional model prediction analysis, may explain this unexpected finding. There was some speculation on whether HELPY UREB(22-36) might act as a cross-reactive CD4 T-cell epitope. All seven PBC patients, tested in a standard proliferation assay against PDC-E2(212-226), gave a positive response. All seven were unresponsive to HELPY UREB(22-36). The pattern of reactivity to HELPY antigens by immunoblot was similar between anti-PDC-E2-positive and negative PBC cases, as well as between PBC patients and controls.


CONCLUSIONS
Contrary to common belief, extensive sequence homology (molecular mimicry) between self and microbe does not necessarily result in cross-reactivity. It is therefore likely that, when present, cross-reactivity between self and microbes is of biological importance.
Bogdanos
D-P
DP
Institute of Liver Studies, King's College Hospital, London, UK.
Baum
H
H
Gunsar
F
F
Arioli
D
D
Polymeros
D
D
Ma
Y
Y
Burroughs
A K
AK
Vergani
D
D
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001324:Autoantigens / Q000276:immunology; D001426:Bacterial Proteins / Q000276:immunology; D015331:Cohort Studies; D003429:Cross Reactions; D051047:Dihydrolipoyllysine-Residue Acetyltransferase; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D016480:Helicobacter pylori / Q000276:immunology*; D006801:Humans; D016056:Immunodominant Epitopes / Q000276:immunology*; D008105:Liver Cirrhosis, Biliary / Q000097:blood / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D008928:Mitochondria / Q000276:immunology*; D018716:Molecular Mimicry; D011768:Pyruvate Dehydrogenase Complex / Q000032:analysis / Q000276:immunology*; D012494:Sampling Studies; D012680:Sensitivity and Specificity; D014510:Urease / Q000276:immunology*; D018909:src Homology Domains / Q000276:immunology
D001324:Autoantigens; D001426:Bacterial Proteins; D016056:Immunodominant Epitopes; D011768:Pyruvate Dehydrogenase Complex; D051047:Dihydrolipoyllysine-Residue Acetyltransferase; D014510:Urease