Differences in peptide-binding specificity of two ankylosing spondylitis-associated HLA-B27 subtypes

Area of Science:

• Immunology
• Molecular Biology
• Genetics

Background:

• Ankylosing spondylitis (AS) is a chronic inflammatory disease strongly associated with the HLA-B27 gene.
• Two specific subtypes, HLA-B*2702 and HLA-B*2705, are linked to AS, suggesting differential roles in disease pathogenesis.
• Understanding peptide binding specificities of these subtypes is crucial for identifying potential arthritogenic peptides.

Purpose of the Study:

• To investigate the peptide binding affinities of HLA-B*2702 and HLA-B*2705 subtypes.
• To compare the binding preferences of these subtypes for nonapeptides with varying amino acids at position 9 (P9).
• To identify characteristics of potential arthritogenic peptides presented by HLA-B27.

Main Methods:

• Utilized HLA alpha chain refolding assays to measure peptide binding.
• Tested binding affinity of polyalanine model nonapeptides with specific amino acid substitutions at P9.
• Isolated alpha chains from B*2705 and two B*2702 cell lines (BTB and NW) with distinct peptide presentation behaviors.

Main Results:

• HLA-B*2705 exhibited high binding affinity for peptides with basic (Arg, Lys), aliphatic (Leu), and aromatic (Phe, Tyr) residues at P9.
• HLA-B*2702 demonstrated strong binding to P9 aliphatic and aromatic peptides but weak binding to P9 basic peptides.
• Differential binding patterns were observed between the two HLA-B27 subtypes.

Conclusions:

• The arthritogenic peptide presumed to cause ankylosing spondylitis likely possesses an aromatic or aliphatic residue at P9.
• Peptides with basic residues at P9 are less likely candidates for causing AS due to poor binding with HLA-B*2702.
• These findings highlight the importance of HLA-B27 subtype-specific peptide binding in AS pathogenesis.