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Polymorphisms in the F pocket of HLA-B27 subtypes strongly affect assembly, chaperone interactions and heavy-chain misfolding

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Author(s)

David B. Guiliano, Helen North, Eleni Panayoitou, Elaine C. Campbell, Kirsty McHugh, Fiona G. M. Cooke, Marine Silvestre, Paul Bowness, Simon J. Powis, Antony N. Antoniou

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Abstract

Objective - HLA-B27 is associated with the inflammatory spondyloarthropathies (SpAs). Of significance, subtypes HLA-B*27:06 and HLA-B*27:09 are not associated with the SpAs. These subtypes primarily differ from the HLA-B*27:05 disease associated allele at residues 114 and 116 of the heavy chain, part of the F pocket of the antigen-binding groove. Dimerisation of HLA-B27 during assembly has been implicated in disease onset. This study investigated the factors influencing differences in dimerisation between disease associated and non-associated HLA-B27 alleles.
Methods – HLA-B*27:05 and mutants resembling the HLA-B*27:06 and 09 subtypes were expressed in the rat C58 T cell line, the human CEM T cell line and its calnexin deficient variant CEM.NKR. Immunoprecipitation, pulse chase, flow cytometry and immunoblotting were performed to study the assembly kinetics, heavy chain dimerisation and chaperone associations.
Results - By expressing HLA-B*27:05, 06-like and 09 alleles on a restrictive rat TAP peptide transporter background, we demonstrate that a tyrosine expressed at p116 or together with an aspartic acid residue at p114 inhibited HLA-B27 dimerisation and increased the assembly rate. F pocket residues alter the associations with chaperones of the early MHC class I folding pathway. Calnexin was demonstrated to participate in endoplasmic reticulum (ER) stress mediated degradation of dimers, whereas the oxidoreductase ERp57 does not appear to influence dimerization.
Conclusion - Residues within the F pocket of the peptide-binding groove differing between disease-associated and non-disease-associated HLA-B27 subtypes can influence the assembly process and heavy chain dimerisation, events which have been linked to the initiation of disease pathogenesis.
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Original languageEnglish
Pages (from-to)610-621
Number of pages12
JournalArthritis & Rheumatology
Volume69
Issue number3
Early online date27 Feb 2017
DOIs
Publication statusPublished - Mar 2017

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