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.