Novel Detection of In Vivo HLA-B27 Conformations Correlates With Ankylosing Spondylitis Association

作者：Fussell Helen; Ne**eth Darren; Lenart Izabela; Campbell Elaine C; Lynch Sarah; Santos Susana; Gould Keith; Powis Simon J; Antoniou Antony N^*

来源：Arthritis and Rheumatism, 2008, 58(11): 3419-3424.

DOI：10.1002/art.23990

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.

• 出版日期2008-11
• 单位河北医科大学