HLA‑B27 misfolding and spondyloarthropathies

Abstract

HLA‑B27 plays a central role in the pathogenesis of many spondyloarthropathies and inparticular ankylosing spondylitis. The observation that the HLA‑B27 heavy chain hasa tendency to misfold has raised the possibility that associated diseases may belong in arapidly expanding category of protein misfolding disorders. The synthesis of the HLA‑B27 heavychain, assembly with b2m and the loading of peptide cargo, occurs in the endoplasmic reticulum(ER) before transport to the cell surface. The evidence indicates that misfolding occurs in the ERprior to b2m association and peptide optimization and is manifested in the formation of aberrantinter‑ and intra‑chain disulfide bonds and accumulation of heavy chain bound to the chaperoneBiP. Enhanced accumulation of misfolded heavy chains during the induction of class I expressionby cytokines, can cause ER stress resulting in activation of the unfolded protein response (UPR).Effects of UPR activation on cytokine production are beginning to emerge and may provide importantmissing links between HLA‑B27 misfolding and spondyloarthritis. In this chapter we willreview what has been learned about HLA‑B27 misfolding in human cells and in the transgenic ratmodel of spondyloarthritis‑like disease, considering it in the context of other protein misfoldingdisorders. These studies provide a framework to support much needed translational work assessingHLA‑B27 misfolding and UPR activation in patient‑derived material, its consequences for diseasepathogenesis and ultimately how and where to focus intervention strategies.