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

Abstract

The human major histocompatibility complex class I (HLA-I) gene HLA-B*27 is the main risk factor for the rheumatic disease ankylosing spondylitis (AS) through an unknown mechanism. However, in African populations, where B*27 is rare, the B*14:03 allotype is strongly associated with AS, while B*14:02, which only differs from B*14:03 at one residue (L156R), is not associated with the disease. Here, we have used large-scale mass spectrometry-based peptide sequencing to analyze the peptidomes of HLA-B*14:03, HLA-B*14:02, and HLA-B*27:05, obtaining more than 2000 peptide ligands for each molecule. Remarkably, we found 1011 ligands shared by the AS-associated HLA-B*27:05 and -B*14:03 alleles and 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 show a large overlap of their ligands (64 and 43% respectively), while B*14:03 and B*14:02, which differ by only one residue, show a lower degree of overlap (33-35%). B*14:03 peptide repertoire most resembles that of B*27:05 at the P1, P2, and P5 positions of the peptides, and differs most at the C-terminal position, where B*14:03 is more restrictive than B*27:05. We have modeled how the change at residue 156 of the two B*14 alleles could have a long-range indirect effect on residues P1, P2, and P5 of the peptide ligands, explaining the different amino acid distribution observed between the two B*14 subtypes at those positions. Most of the 1011 specific ligands of B*14:03 and B*27:05 presented R/K/A/G at P1, R at P2, and L/F at the C-terminal position. Of these 1,011 peptides, 10 have been previously identified as presented by the three HLA-B*27 subtypes most strongly associated with AS and are absent in non-associated subtypes, while four peptides from the HLA 169-181 region-previously implicated in the autoimmune pathogenesis of AS-were also identified, suggesting that differential peptide binding may influence disease development. In summary, our results show that the two AS-associated allotypes B*14:03 and B*27:05, but not the non-AS-associated allotype B*14:02, share very 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 ankylosing spondylitis.