The role of the unfolded protein response in axial spondyloarthritis

Susceptibility to ankylosing spondylitis is highly genetic, with a heritability greater than 90 %. Presence of the HLA-B27 MHC class I allele remains the greatest genetic risk factor identified to date. Beyond its nominal role in antigen presentation, HLA-B27 displays interesting and possibly unique biochemical characteristics which may contribute to disease pathogenesis. During its biosynthesis in the endoplasmic reticulum (ER), HLA-B27 folds very slowly and misfolds, inducing ER stress. Herein, we describe a major outcome of ER stress, the unfolded protein response (UPR), as well as consequences of the UPR for inflammation and autophagy. The ability of the UPR to augment inflammatory cytokine production is particularly intriguing given the centrality of cytokines in spondyloarthritis. Evidence for the relevance of an HLA-B27-related UPR to spondyloarthritis pathogenesis in animal models and human subjects will be reviewed. As greater pharmacologic capacity to modulate ER stress becomes available, improved understanding of the role of the UPR in spondyloarthritis may yield new therapeutic targets.