Modulation at multiple anchor positions of the peptide specificity of HLA-B27 subtypes differentially associated with ankylosing spondylitis.
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 substitutions at anchor positions P1, P3, or Pomega, were used to determine a binding score for each residue at each position. Binding was assessed in a quantitative 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 Pomega anchor, but never both, indicating that detrimental anchoring at one of these positions 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 compensated with optimal P3 and/or Pomega 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 residue specificity at P1, P3, and Pomega. The rules derived for B*2705 also applied to the known ligands of these 2 subtypes.


CONCLUSIONS
The B*2705, B*2704, and B*2706 peptide repertoires are limited by the allowed residue combinations described in this study. The differential association of B*2704 and B*2706 with spondylarthropathy correlates with differences in their peptide specificity at multiple anchor positions. However, it is now possible to predict the peptide features that determine this differential binding to both subtypes.
Lamas
J R
JR
Consejo Superior de Investigaciones Científicas, Madrid, Spain.
Paradela
A
A
Roncal
F
F
López de Castro
J A
JA
D000595:Amino Acid Sequence; D000939:Epitopes / Q000737:chemistry; D015796:HLA-B27 Antigen / Q000737:chemistry* / Q000235:genetics; D006801:Humans; D008024:Ligands; D010455:Peptides / Q000276:immunology*; D011110:Polymorphism, Genetic; D013167:Spondylitis, Ankylosing / Q000276:immunology*
D000939:Epitopes; D015796:HLA-B27 Antigen; D008024:Ligands; D010455:Peptides