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

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.Ankylosing spondylitis (AS) 6 is an immune-mediated inflammatory disease, which affects primarily the spine and belongs to the family of rheumatoid diseases called spondyloarthropathies (1, 2). For more than 40 years, the human leukocyte antigen (HLA)-B27 gene has been known to be linked with AS pathology (3,4). This is one of the strongest genetic associations that has ever been described between an autoimmune disease and an HLA gene, with an odds ratio greater than 100. HLA-B27 is expressed by 90 -95% of all AS patients, and studies on HLA-B27 ϩ twins showed a concordance rate for developing AS of 63 and 23% for monozygotic and dizygotic twin pairs, respectively (5, 6). Moreover, HLA-B27 ϩ individuals have a 6 -16 times greater risk of developing AS if they have a firstdegree relative with AS (3). Although recent genome-and phenome-wide association studies suggested that additional loci are associated with AS, such as ERAP1 (endoplasmic reticulum aminopeptidase 1), HLA-B27 has been repeatedly confirmed as the most relevant genetic predisposition for the development and onset of AS (7-10).Despite extensive studies during the last few decades, the exact role of HLA-B27 in disease initiation and progression remains unknown, but several theories have been suggested to

Lessons on SpA pathogenesis from animal models

“…These non-canonical conformers could bind to innate immune receptors that include KIRs on human cells and paired immunoglobulin receptors expressed by rodent APCs, with putative pro-inflammatory consequences, including TNF production [16,60]. However, the relevance of this phenomenon to HLA-B27 pathogenicity has recently been challenged, given its lack of correlation with disease susceptibility among HLA-B27 subtypes [62].…”

Understanding the Pathogenesis of Spondyloarthritis

“…The ability to form homodimers of eight common HLA-B*27 alleles (HLA-B*2702 to HLA-B*2709) was analyzed and no major differences were found between disease-associated and non-associated HLA-B*27 allotypes. In particular, HLA-B*27:03, an arthritis-associated HLA-B*27 subtype, had a reduced ability to form cell-surface homodimers [ 70 ]. These findings challenge the role of HLA-B*27 homodimer formation in SpA pathogenesis and suggest that other features of HLA-B*27 play a more central role in the disease mechanism.…”

Understanding the Pathogenesis of Spondyloarthritis

“…In particular, HLA-B*27:03, an arthritis-associated HLA-B27 subtype, has a reduced ability to form cell-surface homodimers. These findings challenge the role of HLA-B27 homodimer formation in SpA pathogenesis and suggest that other features of HLA-B27 play a more central role in disease mechanism [66].…”