Abstract
Expression of human leukocyte antigen (HLA)-B27 is strongly associated with predisposition toward ankylosing spondylitis (AS) and other spondyloarthropathies. However, the exact involvement of HLA-B27 in disease initiation and progression remains unclear. The homodimer theory, which proposes that HLA-B27 heavy chains aberrantly form homodimers, is a central hypothesis that attempts to explain the role of HLA-B27 in disease pathogenesis. Here, we examined the ability of the eight most prevalent HLA-B27 allotypes (HLA-B*27:02 to HLA-B*27:09) to form homodimers. We observed that HLA-B*27:03, a disease-associated HLA-B27 subtype, showed a significantly reduced ability to form homodimers compared with all other allotypes, including the non-disease-associated/protective allotypes HLA-B*27:06 and HLA-B*27:09. We used X-ray crystallography and site-directed mutagenesis to unravel the molecular and structural mechanisms in HLA-B*27:03 that are responsible for its compromised ability to form homodimers. We show that polymorphism at position 59, which differentiates HLA-B*27:03 from all other allotypes, is responsible for its compromised ability to form homodimers. Indeed, histidine 59 in HLA-B*27:03 leads to a series of local conformational changes that act in concert to reduce the accessibility of the nearby cysteine 67, an essential amino acid residue for the formation of HLA-B27 homodimers. Considered together, the ability of both protective and disease-associated HLA-B27 allotypes to form homodimers and the failure of HLA-B*27:03 to form homodimers challenge the role of HLA-B27 homodimers in AS pathoetiology. Rather, this work implicates other features, such as peptide binding and antigen presentation, as pivotal mechanisms for disease pathogenesis.
Highlights
Expression of human leukocyte antigen (HLA)-B27 is strongly associated with predisposition toward ankylosing spondylitis (AS) and other spondyloarthropathies
In agreement with previous studies [12, 13, 21], the addition of the reducing reagent DTT resulted in a complete loss of the homodimers, confirming that HLA-B27 homodimers are covalently linked via disulfide bridges
With the exception of HLA-B*27:04, HLA-B*27:05, and HLA-B*27:09, none of these HLA-B27 allotypes have been tested previously for their ability to form homodimers, and, to our knowledge, this is the first report that compared homodimer formation of multiple HLA-B27 allotypes in the one parental cell line
Summary
Expression of human leukocyte antigen (HLA)-B27 is strongly associated with predisposition toward ankylosing spondylitis (AS) and other spondyloarthropathies. One of the central hypotheses is the “HLA-B27 homodimer theory,” which proposes that the formation and subsequent cell-surface presentation of HLA-B27 heavy-chain homodimers triggers an aberrant immune response leading to autoimmunity In support of this theory, HLA-B27 molecules exhibit an atypically high propensity to form homodimers, and stably expressed HLA-B27 homodimers have been observed both in vitro and in vivo [12,13,14,15,16]. A recent report used comparative flow cytometric analyses to show that the arthritis-associated allotype HLA-B*27:05 forms more cell-surface homodimers than the non-disease-associated subtype HLAB*27:09 [18], which suggests that expression levels of HLA-B27 homodimer might correlate with disease pathogenesis. The observation that a disease-associated HLA-B27 subtype is barely able to form homodimers may suggest that HLA-B27 homodimers are not as important in disease initiation and progression as previously anticipated
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