HLA-B27 misfolding and ankylosing spondylitis

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 CD8 T 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.

The interplay between HLA-B27 and ERAP1/ERAP2 aminopeptidases: from anti-viral protection to spondyloarthritis

“…First, the HLA-B27 displays an altered folding rate during the assembly into the ER [9,21,22]. This misfolding is a consequence of the particularly slow HLA-B27 maturation rate that triggers the endoplasmic reticulum (ER)-associated degradation (ERAD) of the heavy chains [22].…”

“…First, the HLA-B27 displays an altered folding rate during the assembly into the ER [9,21,22]. This misfolding is a consequence of the particularly slow HLA-B27 maturation rate that triggers the endoplasmic reticulum (ER)-associated degradation (ERAD) of the heavy chains [22]. However, the accumulation of misfolded heavy chains, aggregates or even dimeric structures, which do not transit further along the secretory pathway, generates ER stress and the unfolded protein response (UPR) [22][23][24].…”

“…This misfolding is a consequence of the particularly slow HLA-B27 maturation rate that triggers the endoplasmic reticulum (ER)-associated degradation (ERAD) of the heavy chains [22]. However, the accumulation of misfolded heavy chains, aggregates or even dimeric structures, which do not transit further along the secretory pathway, generates ER stress and the unfolded protein response (UPR) [22][23][24]. In turn, the UPR promotes cytokine dysregulation and activates the interleukin (IL)-23/IL-17 axis [25].…”

“…The formation of B27 dimers and oligomers is a complex process in which a series of unpaired Cys residues HLA-B27 and ERAP1/2 aminopeptidases (positions 67, 308 and 325) appear to play important roles, but the conserved Cys residues at 101 and 164 could also be relevant [22,30,41,42]. These Cys residues are shared by all B27 alleles; therefore, other residues must influence their reactivity and accessibility to the oxidizing environment of the ER for a time sufficient to allow the formation of aberrant disulphide bonds.…”

The relation between ER stress and HLA-B27 misfolding

“…Familiarly, in ER, increased level of transcription of genes that facilitates misfolded protein to refold involved in retrotranslocation and protein degradation in the cytosol [1]. The studies about protein quality process have been dealt with its increased complexity but the importance of relation between protein misfolding pathogenesis of a number of diseases [47]. Even in a full MHC class I assembly induction event, disulfide-linked homodimers and multimers can be formed as a result of accumulation of misfolded HLA-B27 heavy chains in the ER.…”