Allelic association with ankylosing spondylitis fails to correlate with human leukocyte antigen B27 homodimer formation

Journal article

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.

Authors: Lim Kam Sian, TCC; Indumathy, S; Halim, H; Greule, A; Cryle, MJ

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: American Society for Biochemistry and Molecular Biology
• Journal: Journal of Biological Chemistry
• Volume: 294
• Issue: 52
• Pages: 20185-20195
• Publication date: 2019-11-18
• Acceptance date: 2019-11-18
• DOI: 10.1074/jbc.ra119.010257
• EISSN: 1083-351X
• ISSN: 0021-9258
• Pmid: 31740583
• Language: English
• Keywords: Ankylosing spondylitis; single-nucleotide polymorphism (SNP); HLA-B*27:03; arthritis; HLA-B27; major histocompatibility complex (MHC); HLA heavy chain homodimers; autoimmune disease; X-ray crystallography; FFR; crystallography