T cell responses to the putative dominant autoepitope in primary biliary cirrhosis (PBC).
PBC is characterized by T cell-mediated destruction of the biliary epithelial cells lining the small intrahepatic bile ducts. The E2 and E3 binding protein (E3BP (protein X)) components of pyruvate dehydrogenase complex (PDC) are disease-specific autoantigens in PBC. Attempts to localize the T cell autoepitopes within PDC-E2 have, however, generated contradictory results. One study has suggested the presence of T cell epitopes throughout PDC-E2, whilst another has identified a single dominant 14 amino acid T cell epitope (p163) spanning the lipoic acid binding lysine residue in the inner lipoyl domain (ILD) of PDC-E2. The aim of the current study was to determine the prevalence of T cell responses to p163 and PDC-E2 ILD, and the role played by lipoylation of these antigens in their immunogenicity, in a UK PBC population. We found that the majority of the PBC patients showing a 6-day peripheral blood T cell proliferative response to native human PDC also responded, in a MHC class II-restricted fashion, to biochemically purified PDC-E2 and E3BP (which co-purify) (9/10 positive (SI > 2.76), mean SI 5.74 +/- 5.04 (PDC-E2/E3BP) versus 6.67 +/- 3.84 (PDC), P = NS), implying that the important PBC-specific T cell epitopes are contained within the PDC-E2 or E3BP components of PDC. Only a minority of patients responsive to PDC, however, responded to either lipoylated recombinant PDC-E2 ILD (4/10 positive, mean SI 1.98 +/- 1.24, P < 0.005 versus PDC response) or lipoylated p163 (4/12 positive, mean SI 1.90 +/- 1.58, P < 0.001). The lipoylation state did not affect the T cell response to either ILD or p163. Our findings suggest that in some UK patients with PBC there are immunodominant T cell autoepitopes within PDC-E2/E3BP which are outside the ILD of PDC-E2.
Palmer
J M
JM
Centre for Liver Research, Medical School, University of Newcastle, Newcastle-upon-Tyne, UK.
Diamond
A G
AG
Yeaman
S J
SJ
Bassendine
M F
MF
Jones
D E
DE
D001324:Autoantigens; D015551:Autoimmunity; D051047:Dihydrolipoyllysine-Residue Acetyltransferase; D000939:Epitopes; D006801:Humans; D016056:Immunodominant Epitopes; D008105:Liver Cirrhosis, Biliary / Q000276:immunology*; D008239:Lysine / Q000276:immunology; D010446:Peptide Fragments / Q000276:immunology; D011768:Pyruvate Dehydrogenase Complex / Q000276:immunology*; D011994:Recombinant Proteins / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D008063:Thioctic Acid / Q000276:immunology
D001324:Autoantigens; D000939:Epitopes; D016056:Immunodominant Epitopes; D010446:Peptide Fragments; D011768:Pyruvate Dehydrogenase Complex; D011994:Recombinant Proteins; D008063:Thioctic Acid; D051047:Dihydrolipoyllysine-Residue Acetyltransferase; D008239:Lysine