Systematic Identification and Comparative Analysis of Human Cartilage-Derived Self-peptides Presented Differently by Ankylosing Spondylitis (AS)-Associated HLA-B*27:05 and Non-AS-associated HLA-B*27:09
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The human leukocyte antigen B27 (HLA-B27) gene has been observed to significantly increase the risk of developing ankylosing spondylitis (AS). The HLA-B27 allele B*27:05, a genetic ancestor of all other HLA-B27 alleles, is strongly associated with AS, whereas its close relative B*27:09 does not predispose for AS, although they differ by only a single residue (D116H substitution). In the present study, an integrative biology strategy that combines in silico calculations with in vitro assays is described to perform quantitative sequence-activity model (QSAM)-based high-throughput virtual screening, molecular dynamics/energetics-based large-scale mutagenesis analysis and FACS-based HLA stabilization assay against 28,244 9-mer self-peptides derived from 17 human cartilage proteins as the antigen candidates of HLA-B27. It is revealed that the D116H mutation, which brings B*27:05 to B*27:09, does not substantially shift the peptide binding profile of HLA-B27, suggesting that the B*27:05 and B*27:09 share a similar peptide repertoire. However, few self-peptides that bind differently to B*27:05 and B*27:09 are identified; their sequences are primarily differed by C-terminus (but basically consistent in N-terminus and middle region). HLA stabilization assays substantiate that three identified self-peptides, 2515KRSSRHPRR2523 (Aggrecan), 200TRSVSHLRK208 (Annexin) and 131EKAFSPLRK139 (Biglycan), exhibit high affinity to B*27:05 (BL50 = 76.3, 28.5 and 8.6 nM, respectively) and strong selectivity for B*27:05 over B*27:09 (8.9-fold, 4.3-fold and 12.7-fold, respectively), which are highly promising as the potential candidates involved in AS elicitation.
KeywordsAnkylosing spondylitis HLA-B27 B*27:0 B*27:09 Cartilage protein Self-peptide
This study was funded by the Anhui Provincial Hospital Affiliated to Anhui Medical University.
Compliance with Ethical Standards
Conflict of interest
The authors declare that they have no conflict of interest.
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