Chapter

Molecular Mechanisms of Spondyloarthropathies

Volume 649 of the series Advances in Experimental Medicine and Biology pp 217-234

HLA-B27 Misfolding and Spondyloarthropathies

  • Robert A. ColbertAffiliated withDivision of Rheumatology, Cincinnati Children’s Hospital Medical Center
  • , Monica L. DeLayAffiliated withDivision of Rheumatology, Cincinnati Children’s Hospital Medical Center
  • , Gerlinde Layh-SchmittAffiliated withDivision of Rheumatology, Cincinnati Children’s Hospital Medical Center
  • , Dawn P. SowdersAffiliated withDivision of Rheumatology, Cincinnati Children’s Hospital Medical Center

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Abstract

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 β2 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.