Jr. Lamas et al., Modulation at multiple anchor positions of the peptide specificity of HLA-B27 subtypes differentially associated with ankylosing spondylitis, ARTH RHEUM, 42(9), 1999, pp. 1975-1985
Objective, To investigate the rules governing peptide binding to HLA-B*2705
, and to B*2704 and B*2706, which are 2 subtypes differentially associated
with ankylosing spondylitis.
Methods. Poly-Ala analogs carrying the HLA-B27 motif Arg-2, and substitutio
ns at anchor positions P1, P3, or P Omega, were used to determine a binding
score for each residue at each position. Binding was assessed in a quantit
ative epitope stabilization assay, where the cell surface expression of HLA
-B27 was measured by flow cytometry as a function of peptide concentration.
Results. Peptide anchor residues contributed additively to B*2705 binding.
About 15% of the natural B*2705 ligands used a deficient P3 or P Omega anch
or, but never both, indicating that detrimental anchoring at one of these p
ositions is always compensated by a good anchor at the other one. About 50%
of the B*2705 ligands used suboptimal P1 residues. However, this was compe
nsated with optimal P3 and/or P Omega anchoring. Peptides that were longer
than decamers used good anchor residues at the 3 positions, suggesting more
stringent binding requirements. B*2704 and B*2706 differed in their residu
e specificity at P1, P3, and P Omega, The rules derived for B*2705 also app
lied to the known ligands of these 2 subtypes,
Conclusion. The B*2705, B*2704, and B*2706 peptide repertoires are limited
by the allowed residue combinations described in this study. The differenti
al association of B*2704 and B*2706 with spondylarthropathy correlates with
differences in their peptide specificity at multiple anchor positions. How
ever, it is now possible to predict the peptide features that determine thi
s differential binding to both subtypes.