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


CONCLUSIONS
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.
Fussell
Helen
H
National Health Service Blood and Transplant, Colindale Blood Centre, London, UK.
Nesbeth
Darren
D
Lenart
Izabela
I
Campbell
Elaine C
EC
Lynch
Sarah
S
Santos
Susana
S
Gould
Keith
K
Powis
Simon J
SJ
Antoniou
Antony N
AN
D002460:Cell Line; D004721:Endoplasmic Reticulum / Q000378:metabolism; D015796:HLA-B27 Antigen / Q000032:analysis* / Q000737:chemistry; D006801:Humans; D011487:Protein Conformation; D013167:Spondylitis, Ankylosing / Q000276:immunology*
D015796:HLA-B27 Antigen