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Review
. 2014 Jan;57(1):44-51.
doi: 10.1016/j.molimm.2013.07.013. Epub 2013 Aug 30.

HLA-B27 misfolding and ankylosing spondylitis

Robert A Colbert  1 , Tri M Tran, Gerlinde Layh-Schmitt
Affiliations
Review

HLA-B27 misfolding and ankylosing spondylitis

Robert A Colbert et al. Mol Immunol. 2014 Jan.

Abstract

Understanding how HLA-B27 contributes to the pathogenesis of spondyloarthritis continues to be an important goal. Current efforts are aimed largely on three areas of investigation; peptide presentation to CD8T cells, abnormal forms of the HLA-B27 heavy chain and their recognition by leukocyte immunoglobulin-like receptors on immune effector cells, and HLA-B27 heavy chain misfolding and intrinsic biological effects on affected cells. In this chapter we review our current understanding of the causes and consequences of HLA-B27 misfolding, which can be defined biochemically as a propensity to oligomerize and form complexes in the endoplasmic reticulum (ER) with the chaperone BiP (HSPA5/GRP78). HLA-B27 misfolding is linked to an unusual combination of polymorphisms that identify this allele, and cause the heavy chain to fold and load peptides inefficiently. Misfolding can result in ER-associated degradation (ERAD) of heavy chains, which is mediated in part by the E3 ubiquitin ligase HRD1 (SYVN1), and the ubiquitin conjugating enzyme UBE2JL. Upregulation of HLA-B27 and accumulation of misfolded heavy chains can activate ER stress signaling pathways that orchestrate the unfolded protein response. In transgenic rats where HLA-B27 is overexpressed, UPR activation is prominent. However, it is specific for heavy chain misfolding, since overexpression of HLA-B7, an allele that does not misfold, fails to generate ER stress. UPR activation has been linked to cytokine dysregulation, promoting lL-23, IFNβ, and lL-1α production, and may activate the IL-23/IL-17 axis in these rats. IL-1α and IFNβ are pro- and anti-osteoclastogenic cytokines, respectively, that modulate osteoclast development in HLA-B27-expressing transgenic rat monocytes. Translational studies of patient derived cells expressing HLA-B27 at physiologic levels have provided evidence that ER stress and UPR activation can occur in peripheral blood, but this has not been reported to date in isolated macrophages. Inflamed gastrointestinal tissue reveals evidence for HLA-B27 misfolding, ERAD, and autophagy, without acute UPR activation. A more complete picture of conditions that impact HLA-B27 folding and misfolding, the full spectrum and time course of consequences of ER stress, and critical cell types involved is needed to understand the role of HLA-B27 misfolding in spondyloarthritis pathogenesis.

Keywords: Ankylosing spondylitis; Autophagy; Endoplasmic reticulum stress; MHC class I; Protein misfolding; Spondyloarthritis; Unfolded protein response.

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Figures

Figure 1
Figure 1
Current hypotheses linking HLA-B27 to spondyloarthritis pathogenesis. (1) Arthritogenic Peptides: Self peptides selected and presented by properly folded forms of HLA-B27 complexed with β2m have been hypothesized to be the target of autoreactive CD8+ T cells, and serve as an upstream initiator of inflammation. (2) Recognition of Non-Canonical HLA-B27: Naturally occurring cell surface HLA-B27 dimers are hypothesized to be recognized by killer immunoglobulin receptors (such as KIR3DL2) in the leukocyte immunoglobulin-like receptor family (LILR), and trigger inflammation. (3) HLA-B27 Misfolding: The formation of misfolded oligomers and BiP binding by newly synthesized HLA-B27 heavy chains causes ER stress, which has intrinsic effects on cellular function that are hypothesized to promote development of spondyloarthritis. HLA-B27 can exhibit all three of these behaviors in the same cell, and these concepts are not mutually exclusive.
Figure 2
Figure 2
Consequences of ER protein misfolding. Misfolded ER proteins may be eliminated by ERAD, which involves dislocation from the ER to the cytosol, ubiquitination, and proteasomal degradation. Autophagy contributes to the elimination of aberrant proteins, particularly when ERAD is insufficient or when cytosolic proteins aggregate. ER protein aggregates that do not activate stress response pathways can contribute to cellular dysfunction. An acute ER stress response may be signaled when misfolded or unfolded proteins sequester BiP, thus allowing activation of IRE1, PERK and ATF6. XBP1s and ATF6p50 are active transcription factors, and eIF2α phosphorylation (P) results in translational induction of ATF4 and CHOP, two additional UPR transcription factors, that together orchestrate transcriptional changes that enhance the cell’s ability to fold and secrete proteins, thus reducing ER stress. Transcriptional changes subside after a successful UPR, resulting in adaptation, which may alter the threshold for a subsequent ER stress response.
Figure 3
Figure 3
Comparison of the principle phenotypic features of rat and human spondyloarthritis. Rats with 20–40 or more copies of the HLA-B27 transgene in the presence of 15–30 copies of hβ2m develop spondyloarthritis-like inflammatory disease spontaneously, beginning shortly after weaning. IBD develops in virtually 100% of HLA-B27 transgenic rats, while peripheral and axial arthritis occur with significantly reduced frequency, and generally after several months of age (Rat SpA-1). Human spondyloarthritis (undifferentiated spondyloarthritis classified various ways) exhibits a more equal mix of IBD (Crohn’s disease and ulcerative colitis), and peripheral and axial arthritis. Psoriatic arthritis and psoriatic spondylitis are not represented here. Nevertheless, development of skin and nail changes have been reported in HLA-B27 transgenic rats and psoriatic skin lesions occur in IL-23 overexpressing mice. Human AS represents the other end of the spectrum where axial arthritis in the form of radiographic sacroiliitis occurs in 100% of affected individuals (by definition), and peripheral arthritis and overt IBD are significantly less frequent. However, sub-clinical IBD occurs in close to 70% of individuals with AS, with overt IBD in ~6%. A second rat spondyloarthritis model (SpA-2; not shown) occurs with forced overexpression of additional hβ2m (35 transgene copies) in rats with 20 or more copies of HLA-B27 and at least 50 copies of hβ2m. Rat SpA-2 does not require IBD, although this phenotypic feature still occurs in high copy HLA-B27 transgenic rats with additional hβ2m. Both peripheral and axial arthritis occur at much higher frequency and severity with additional hβ2m, but arthritis is primarily restricted to male rats and requires epididymoorchitis.
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