Novel detection of in vivo HLA-B27 conformations correlates with ankylosing spondylitis association

Helen Fussell, Darren Nesbeth, Izabela Lenart, Elaine C Campbell, Sarah Lynch, Susana Santos, Keith Gould, Simon J Powis, Antony N Antoniou

Research output: Contribution to journalArticlepeer-review

24 Citations (Scopus)

Abstract

OBJECTIVE: The class I major histocompatibility complex (MHC) molecule HLA-B27 exhibits a strong association with the autoimmune inflammatory arthritis disorder ankylosing spondylitis (AS) and with other related spondylarthropathies. In the absence of both a defined autoimmune response and a target autoantigen(s), the propensity of HLA-B27 to misfold has been hypothesized to be a major parameter in disease pathogenesis. We undertook this study to test the hypothesis that HLA-B27 misfolding is due to exposure of cysteine residues within the heavy chain to the oxidizing environment of the endoplasmic reticulum.

METHODS: A rapid acidification and alkylation modification method was used to examine cysteine residue exposure and accessibility within AS-associated and non-AS-associated HLA-B27 subtypes.

RESULTS: This novel approach to probing in vivo class I MHC structure revealed that the HLA-B27 heavy chain adopts conformations not previously described. Furthermore, amino acid residues specific to subtypes HLA-B*2706, B*2709, and B*2704 can have an impact on these novel conformations and on cysteine residue exposure.

CONCLUSION: HLA-B27 can adopt novel conformations, resulting in differential accessibility of cysteine residues, which can explain the propensity to misfold. Cysteine exposure in the HLA-B27 heavy chain is also affected by residues within the 114 and 116 regions, thereby providing a potential biochemical basis for the association of HLA-B27 subtypes with AS.

Original languageEnglish
Pages (from-to)3419-24
Number of pages6
JournalArthritis and Rheumatism
Volume58
Issue number11
DOIs
Publication statusPublished - Nov 2008

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