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 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.

Note

This manuscript has been previously published: Colbert RA, Delay ML, Layh-Schmitt G, Sowders DP. HLA-B27 misfolding and spondyloarthropathies. In: Molecular Mechanisms of Spondyloarathropathies. López-Larrea, C and Díaz-Peña, R ed. Austin and New York: Landes Bioscience and Springer Science and Business Media, 2009 In Press.

Figures and Tables

Figure 1 Consequences of protein misfolding. Proper folding of newly synthesized proteins is critical for normal function. Protein misfolding has been linked to a number of diseases that can be broadly categorized as loss-of-function or gain-of-function. Loss-of-function phenotypes result from destruction of partially folded or misfolded proteins by elaborate quality control processes. Gain-of-function phenotypes can result from toxicity if the gene product accumulates and/or activation of cellular stress response pathways such as the UPR. HLA-B27 misfolding is hypothesized to result in gain-of-function abnormalities through sensitization of immune response cells such as macrophages to other exogenous stimuli as reviewed in this chapter.

Figure 2 Proposed paradigm linking HLA-B27 misfolding to innate immune activation. The tendency of HLA-B27 to misfold and activate the UPR when upregulated sensitizes cells to certain pathogen-associated molecular patterns and possibly damage-associated molecular patterns, many of which signal through pattern recognition receptors such as the Toll-like receptors (TLR Agonists). Enhanced upregulation of IL-23 promotes IL-17 production from CD4 T-cells of the Th17 lineage. Th17 cells can produce TNFα and IL-6 and IL-17 is also a potent pro-inflammatory cytokine that acts on many tissue cell types and further induces TNFα, IL-6 and IL-1 as well as chemokines and metalloproteinases. IL-17 is hypothesized to be a key pro-inflammatory cytokine in the immunopathology that develops in the colon of HLA-B27 transgenic rats.