Closer Peptide Repertoire Similarity of HLA-B∗14:03 and HLA-B∗27:05 Sheds Light on Ankylosing Spondylitis Susceptibility

The human major histocompatibility complex class I gene HLA-B∗27 is the main risk factor for ankylosing spondylitis (AS) through a mechanism that remains unknown. In African populations, where B∗27 is rare, the B∗14:03 allotype is strongly associated with AS, whereas B∗14:02, which differs at only one residue (L156R), is not associated. Using large-scale mass spectrometry-based peptide sequencing, we analyzed the peptidomes of HLA-B∗14:03, HLA-B∗14:02, and HLA-B∗27:05, obtaining more than 2000 ligands for each. Remarkably, we identified 1011 peptides shared by the AS-associated HLA-B∗27:05 and B∗14:03 alleles but not by the non-AS-associated B∗14:02 allele. Surprisingly, although B∗14:03 and B∗27:05 differ by 15 amino acids in their peptide-binding domain, they share a large portion of their ligands (64 and 43%, respectively), while B∗14:03 and B∗14:02, differing by only one residue, show less overlap (33-35%). The B∗14:03 peptide repertoire most closely resembles that of B∗27:05 at the P1, P2, and P5 peptide positions but diverges at the C-terminus, where B∗14:03 is more selective. Structural modeling suggests that the L156R difference between B∗14 alleles may induce long-range effects on peptide binding at P1, P2, and P5 residues, explaining the distinct repertoires. Most of the 1011 shared ligands contained R/K/A/G at P1, R at P2, and L/F at the C-terminus. Of these, ten peptides were previously identified as ligands of the three HLA-B∗27 subtypes most strongly associated with AS and are absent in nonassociated subtypes, while four peptides from the HLA 169 to 181 region-previously implicated in AS pathogenesis-were also identified, suggesting that differential peptide binding may influence disease development. In summary, the AS-associated allotypes B∗14:03 and B∗27:05, but not the non-AS-associated allotype B∗14:02, share similar peptide repertoires and binding characteristics, supporting specific common peptide ligands of HLA-B∗27:05 and B∗14:03 as a mechanism to explain the development of AS.