HLA-B27 Misfolding and Spondyloarthropathies

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 β 2 m 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 β 2 m 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.

Toll-like receptor-mediated IRE1α activation as a therapeutic target for inflammatory arthritis

“…Recent studies suggest that ER stress is a driving force for, or a consequence of, inflammatory disease (Turner et al , 2005; Colbert et al , 2009; Harama et al , 2009; Nundlall et al , 2010; Yoo et al , 2012). However, a direct connection between IRE1α activation and inflammatory RA had not been established.…”

Old and new HLA associations with ankylosing spondylitis

“…IL‐17 has emerged as a cytokine that links autoimmune or inflammatory reactions. The associations of the IL12B and IL23R loci underscore the pathogenic involvement of the IL‐23/IL‐17 axis in AS . Candidate gene analyses have also implicated genes within IL‐1 cluster on chromosome 2q13 as AS susceptibility locus .…”

“…Although changes in residues 114 and 116 of the heavy chain affect the peptide‐binding cleft (specifically the F pocket), no such ‘arthritogenic peptide’ has so far been identified. It has also been hypothesized that HLA‐B27 contributes to AS through its propensity to form B27 homodimers, forming disulphide bonds involving Cys67, by inducing ER stress caused by inefficient folding of B27 molecules , or by interaction with receptors of innate immunity (Figure B, C). However, it is not known whether formation of B27 dimers is correlated with the presence of AS.…”

HLA-B27 Subtypes Distribution among Moroccan Patients with Ankylosing Spondylitis

“…In 1973, two groups working independently reported a striking association between what we now know as human leukocyte antigen-B27 (HLA-B27) and ankylosing spondylitis [5,6], however the exact role of B27 molecule in the etiology of the disease still remains elusive. To explain its pathogenic role, a number of theories confirmed by transgenic rats, have emerged relating to various aspects of the HLA-B27 molecule, from its classical role in antigen presentation to its propensity to misfold during assembly in the endoplasmic reticulum and to undergo dimerization [7,8].…”