title: Novel detection of in vivo HLA-B27 conformations correlates with ankylosing spondylitis association.
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.
  
  
  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.
authors.affiliation: National Health Service Blood and Transplant, Colindale Blood Centre, London, UK.
authors.forename: Helen
authors.initials: H
authors.lastname: Fussell
authors.forename: Darren
authors.initials: D
authors.lastname: Nesbeth
authors.forename: Izabela
authors.initials: I
authors.lastname: Lenart
authors.forename: Elaine C
authors.initials: EC
authors.lastname: Campbell
authors.forename: Sarah
authors.initials: S
authors.lastname: Lynch
authors.forename: Susana
authors.initials: S
authors.lastname: Santos
authors.forename: Keith
authors.initials: K
authors.lastname: Gould
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Powis
authors.forename: Antony N
authors.initials: AN
authors.lastname: Antoniou
mesh_terms: 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*
chemical_list: D015796:HLA-B27 Antigen