Expression of HLA-B27 is strongly associated with predisposition towards 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 8 most prevalent HLA-B27 allotypes (HLA-B*27:02 - HLA-B*27:09) to form homodimers. We observed in cellulo that HLA-B*27:03 – a disease-associated HLA-B27 subtype – showed a significantly reduced ability to form homodimers in comparison to all other allotypes, including the non-disease-associated/protective allotypes HLA-B*27:06 and HLA-B*27:09. We used X-ray crystallography in combination with 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 the polymorphism at position-59, which differentiates HLA-B*27:03 from all other HLA-B27 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.
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 challenges the role of HLA-B27 homodimers in AS pathoetiology and rather implicates other features and mechanisms intrinsic to HLA-B27 to be pivotal for disease pathogenesis.