HLA‑B27 misfolding and spondyloarthropathies


HLA‑B27 plays a central role in the pathogenesis of many spondyloarthropathies and in
particular ankylosing spondylitis. The observation that the HLA‑B27 heavy chain has
a tendency to misfold has raised the possibility that associated diseases may belong in a
rapidly expanding category of protein misfolding disorders. The synthesis of the HLA‑B27 heavy
chain, 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 ER
prior to b2m association and peptide optimization and is manifested in the formation of aberrant
inter‑ and intra‑chain disulfide bonds and accumulation of heavy chain bound to the chaperone
BiP. Enhanced accumulation of misfolded heavy chains during the induction of class I expression
by 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 important
missing links between HLA‑B27 misfolding and spondyloarthritis. In this chapter we will
review what has been learned about HLA‑B27 misfolding in human cells and in the transgenic rat
model of spondyloarthritis‑like disease, considering it in the context of other protein misfolding
disorders. These studies provide a framework to support much needed translational work assessing
HLA‑B27 misfolding and UPR activation in patient‑derived material, its consequences for disease
pathogenesis and ultimately how and where to focus intervention strategies.

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HLA‑B27 misfolding and spondyloarthropathies