Increased Conformational Flexibility of HLA–B*27 Subtypes Associated With Ankylosing Spondylitis

Abstract

Objective Dissimilarities in antigen processing and presentation are known to contribute to the differential association of HLA–B*27 subtypes with the inflammatory rheumatic disease ankylosing spondylitis (AS). In support of this notion, previous x‐ray crystallographic data showed that peptides can be displayed by almost identical HLA–B*27 molecules in a subtype‐dependent manner, allowing cytotoxic T lymphocytes to distinguish between these subtypes. For example, a human self‐peptide derived from vasoactive intestinal peptide receptor type 1 (pVIPR; sequence RRKWRRWHL) is displayed in a single conformation by B*27:09 (which is not associated with AS), while B*27:05 (which is associated with AS) presents the peptide in a dual binding mode. In addition, differences in conformational flexibility between these subtypes might affect their stability or antigen presentation capability. This study was undertaken to investigate B*27:04 and B*27:06, another pair of minimally distinct HLA–B*27 subtypes, to assess whether dual peptide conformations or structural dynamics play a role in the initiation of AS. Methods Using x‐ray crystallography, we determined the structures of the pVIPR–B*27:04 and pVIPR–B*27:06 complexes and used isotope‐edited infrared (IR) spectroscopy to probe the dynamics of these HLA–B*27 subtypes. Results As opposed to B*27:05 and B*27:09, B*27:04 (which is associated with AS) displays pVIPR conventionally and B*27:06 (which is not associated with AS) presents the peptide in a dual conformation. Comparison of the 4 HLA–B*27 subtypes using IR spectroscopy revealed that B*27:04 and B*27:05 possess elevated molecular dynamics compared to the nonassociated subtypes B*27:06 and B*27:09. Conclusion Our results demonstrate that an increase in conformational flexibility characterizes the disease‐associated subtypes B*27:04 and B*27:05.

Ankylosing Spondylitis and Axial Spondyloarthritis

“…These substitutions affect the repertoire of bound peptides, biochemical and intracellular behaviors, and the conformational flexibility of the HLA-B27 heavy chain, and these features correlate with susceptibility to disease. [47][48][49] A recent study of single-nucleotide polymorphisms (SNPs) in the HLA region identified a small number of other statistically significant but weakly associated HLA class I and class II alleles (odds ratio for the alleles, 1.06 to 2.35). 50 The basis for the association between HLA-B27 and axial spondyloarthritis and ankylosing spondylitis remains unexplained.…”

The interplay between HLA-B27 and ERAP1/ERAP2 aminopeptidases: from anti-viral protection to spondyloarthritis

“…These data can also be interpreted on the basis of recent biophysical and computational analyses. Indeed, several studies have described an enhanced degree of flexibility and disorder of B*2705 and B*2704 peptide-binding cleft in comparison to that of B*2706 and B*2709 alleles [45][46][47]. This would influence the tapasin dependence, the folding dynamics and the stability of HLA-peptide complexes overall [46].…”

Implications of the diversity of class I HLA associations in psoriatic arthritis

“…Further support for the role of the TCR-peptide-MHC complex in the genesis of ankylosing spondylitis is based on x-ray crystal structures and IR spectroscopy studies of the manner in which a self-peptide from the vasoactive intestinal peptide type 1 receptor binds to each of the B*27 subtypes (22). When bound by B*27:05, this peptide was displayed in two different conformations, and additionally when studied by IR spectroscopy all of the disease-associated B*27 molecules exhibited greater conformational flexibility in peptide binding than the non–disease-associated molecules, suggesting this flexibility in binding is implicated in disease development.…”

“…When bound by B*27:05, this peptide was displayed in two different conformations, and additionally when studied by IR spectroscopy all of the disease-associated B*27 molecules exhibited greater conformational flexibility in peptide binding than the non–disease-associated molecules, suggesting this flexibility in binding is implicated in disease development. (22)…”