Binding of peptides naturally presented by HLA-B27 to the differentially disease-associated B*2704 and B*2706 subtypes, and to mutants mimicking their polymorphism.

B2704 and B2706 are closely related HLA-B27 subtypes of which the former but not the latter is associated to ankylosing spondylitis. Their peptide specificity relative to other disease-associated subtypes was analyzed by testing binding of self-peptides naturally presented by B2705 or B2702, and synthetic analogs, to B2704, B2706, and site-specific mutants mimicking their changes. Peptides with basic, aliphatic or aromatic C-terminal residues bound to B2705 with similar affinity. In B2704 C-terminal aliphatic/ aromatic residues were preferred. B2706 discriminated drastically between polar and nonpolar C-terminal residues, showing strong preference for Leu and Phe, and less than B2704 for basic and Tyr residues. Loss of single acidic charges (D > S77, D > Y116) increased preference for C-terminal Leu and Phe, but allowed efficient binding of peptides with basic residues or Tyr. Their gain (V > E152, H > D114) maintained wide C-terminal specificity, but severely impaired binding, presumably by disrupting interactions with internal peptide residues. This was compensated by Y116 in the double D114Y116 mutant. The specificity of B2704 and B2706 was explained only partially by the separate effects of single mutations, indicating that novel properties arise from concomitant changes at various positions. For instance, specificity of B2706 for nonpolar C-terminal residues required simultaneous removal of Asp77 and Asp116. B2706 differed from B2705, B2702, and B*2704 in its lower suitability for C-terminal Tyr, suggesting that this feature might be relevant for HLA-B27 association to spondyloarthropathy.