Over the past 5 years, advances in high-throughput techniques and studies involving large cohorts of patients have led to considerable advances in the identification of novel genetic associations and immune pathways involved in ankylosing spondylitis (AS). These discoveries include genes encoding cytokine receptors, transcription factors, signalling molecules and transport proteins. Although progress has been made in understanding the functions and potential pathogenic roles of some of these molecules, much work remains to be done to comprehend their complex interactions and therapeutic potential in AS. In this Review, we outline the current knowledge of AS pathogenesis, including genetic risk associations, HLA-B27-mediated pathology, perturbations in antigen-presentation pathways and the contribution of the type 3 immune response.

Pathogenesis of ankylosing spondylitis — recent advances and future directions

This article presents the concept that Behcet disease and several spondyloarthropathies might have a common immunopathogenetic basis. The authors propose that barrier dysfunction in environmentally exposed organs, and aberrant innate immune reactions at sites of mechanical stress, trigger secondary adaptive immune CD8+T-cell responses characterized by prominent neutrophilic inflammation. The differential immunopathology of these 'MHC-I-opathies' could reflect antigenic differences in target tissues. The spondyloarthropathies comprise ankylosing spondylitis (AS), reactive arthritis, psoriatic arthritis (PsA) and arthritis associated with inflammatory bowel disease. In this Perspectives article, we describe how Behcet disease and several clinically distinct spondyloarthropathies—all associated with MHC class I (MHC-I) alleles such as HLA-B*51, HLA-C*0602 and HLA-B*27 and epistatic ERAP-1 interactions—have a shared immunopathogenetic basis. As a unifying concept, we propose that barrier dysfunction in environmentally exposed organs such as the skin, and aberrant innate immune reactions at sites of mechanical stress, can often trigger secondary adaptive immune CD8+ T-cell responses with prominent neutrophilic inflammation that culminate in exacerbation and recurrence of these diseases. Of note, these 'MHC-I-opathies' show a differential immunopathology, probably reflecting antigenic differences within target tissues: HLA-B*51 is linked to ocular and mucocutaneous disease but not gut involvement, and HLA-C*0602 is linked to type I psoriasis but not scalp or nail disease.

'MHC-I-opathy'-unified concept for spondyloarthritis and Behcet disease

Ankylosing spondyloarthritis (AS) is a chronic inflammatory disease that involves the axial joints and entheses. Extra-spinal manifestations such as anterior uveitis, psoriasis, and colitis also occur frequently. This review on the pathogenesis of AS includes an update on the recent discoveries within the field. HLA-B*27 is still considered of major importance in the pathogenesis, and it has recently been shown to profoundly affect the gut microbiome and its metabolites and the handling of bacteria during infection. Biochemical and biophysical properties of HLA-B*27 influence its ability to misfold, to induce an endoplasmic reticulum stress response, and to promote autophagy/unfolded protein responses (UPR). HLA-B*27 free heavy chains may induce inflammation through T cells, NK cells, and myeloid cells. Induction of UPR genes results in release of tumor necrosis factor-α (TNF-α), interleukin-17 (IL-17), IL-23, and interferon-γ and increase in T helper (Th) 17 cells. Several other HLA-B and non-B molecules have been associated with AS, although their role in the pathogenesis is unknown. Genotypes of endoplasmic reticulum aminopeptidases (ERAP) 1 and 2 have been associated with alterations in the antigenic pool expressed by HLA-B*27 molecules. In the gut, innate immune cells type 3 (ILC3) influence T cell expression of IL-17 and IL-22. Gamma-delta (γ/δ) T cells are induced by IL-23 to produce IL-17. IL-7 induces mucosa-associated invariant T (MAIT) cells to produce IL-17. Besides the microbiome, zonulin may be important through its effects on the permeability of tight junctions in the intestinal epithelial barrier.

The Pathogenesis of Ankylosing Spondylitis: an Update

The human leukocyte antigen class I gene HLA-B27 is the strongest risk factor for ankylosing spondylitis (AS), a chronic inflammatory arthritic disorder. More recently, the Endoplasmic Reticulum Aminopeptidase (ERAP) 1 and 2 genes have been identified by genome wide association studies (GWAS) as additional susceptibility factors. In the ER, these aminopeptidases trim the peptides to a length suitable to fit into the groove of the major histocompatibility complex (MHC) class I molecules. It is noteworthy that an epistatic interaction between HLA-B27 and ERAP1, but not between HLA-B27 and ERAP2, has been highlighted. However, these observations suggest a paramount centrality for the HLA-B27 peptide repertoire that determines the natural B27 immunological function, i.e. the T cell antigen presentation and, as a by-product, elicits HLA-B27 aberrant behaviours: (i) the misfolding leading to ER stress responses and autophagy and (ii) the surface expression of homodimers acting as ligands for innate immune receptors. In this context, it has been observed that the HLA-B27 carriers, besides being prone to autoimmunity, display a far better surveillance to some viral infections. This review focuses on the ambivalent role of HLA-B27 in autoimmunity and viral protection correlating its functions to the quantitative and qualitative effects of ERAP1 and ERAP2 polymorphisms on their enzymatic activity.

https://www.onlinelibrary.wiley.com/doi/pdf/10.1111/cei.13020

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

The roles of ERAP1 and ERAP2 in autoimmunity and cancer immunity: New insights and perspective.

The role of Endoplasmic Reticulum Aminopeptidase 1(ERAP1) in Ankylosing Spondylitis

Objectives:

The basic mechanisms underlying ankylosing spondylitis (AS) pathogenesis remain unresolved. We previously reported an association of the single nucleotide polymorphisms (SNP) rs2549782 in Endoplasmic Reticulum Aminopeptidase 2 (ERAP2) with AS. It is known that patients homozygous for the G allele (GG) of another ERAP2 SNP rs2248374 have no ERAP2 expression (ERAP2-null). We utilized this information to study the impact of ERAP2 deficiency on HLA-B27 expression in AS patients. We studied the functional interaction of ERAP2 and HLA-B27 in peripheral blood mononuclear cells (PBMC) from AS patients and in vitro using cell lines.

Methods:

The expression of intact peptide-HLA-B27 (pB27) or the MHC-I free heavy chains (FHC) was assessed in PBMCs isolated from HLA-B27 positive AS patients. ERAP2 suppressed stable B27-expressing C1R (C1R-B27) cells were tested for pB27 and FHC as well as markers for unfolded protein response (UPR). Distribution of the single nucleotide polymorphisms (SNPs) in ERAP2, rs2549782 and rs2248374 in AS and Crohn's Disease patients was assessed.

Results:

PBMCs from AS patients lacking ERAP2 expressed higher FHC expression than those with ERAP2. This finding was replicated in C1R-B27 cells after ERAP2 suppression. In addition ERAP2 suppression led to increased UPR markers BiP, CHOP and XBP1-splicing compared to control-shRNA treated cells. There was strong linkage disequilibrium in the ERAP2 locus. All patients with the rs2549782 T allele (increased function) were homozygous for the G allele of rs2248374 (leads to the absence of ERAP2 protein).

Conclusions: ERAP2 deficiency causes increased FHC expression and upregulation of the UPR pathway. This article is protected by copyright. All rights reserved.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/art.40033

Brief Report: Functional Interaction of Endoplasmic Reticulum Aminopeptidase 2 and HLA-B27 Activates the Unfolded Protein Response.

Ankylosing spondylitis (AS) is a chronic, inflammatory arthritis of the spine and peripheral joints linked to the antigen presenting molecule HLA-B27 The risk of AS is increased in patients possessing endoplasmic reticulum aminopeptidase-1 (ERAP1) polymorphisms rs30187 and rs27044 encoding amino acid changes K528R and Q730E, respectively Dysfunction of ERAP1 is hypothesized to cause changes in expression of HLA-B27 classical (pHLA) and non-classical (FHC) conformers on antigen presenting cells (APCs), which interact with the natural killer (NK) cell receptor KIR3DL1 Dysregulation of this pathway may be pathogenic in AS APC cell lines expressing HLA-B27 were found to inhibit cytokine production in KIR3DL1+ NK cells due to decreased APC-NK cell adhesion, and possibly activation of receptor down-regulation Blocking pHLA and FHC reveals that both conformers inhibit cytokine production through KIR3DL1 KIR3DL1 affinity and HLA-B27 surface expression studies suggest that ERAP1 R528 and E730 expression protects from AS by generating sub-optimal pHLA, causing reduced KIR3DL1 affinity and weaker cytokine inhibition Secondarily we observed that KIR3DL1 binding to C1R-B27 APCs is enhanced by blocking pHLA, but not FHC, raising the possibility that antibody mediated HLA-B27 cross-linking may be important in enhancing KIR3DL1+ NK cell function This study establishes the role of both FHC and pHLA in modulating NK cell cytokine secretion and adhesion functions by interacting with KIR3DL1 This interaction varies depending on the AS association status of the ERAP1 variant expressed in APCs Additionally antibody cross-linking of HLA-B27 enhances KIR3DL1 binding and as such could be an important pathogenic mechanism in AS

KIR3DL1 interaction with HLA-B27 is altered by ankylosing spondylitis associated ERAP1 and enhanced by MHC class I cross-linking.

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The role of Endoplasmic Reticulum Aminopeptidase 1(ERAP1) in Ankylosing Spondylitis

Brief Report: Functional Interaction of Endoplasmic Reticulum Aminopeptidase 2 and HLA-B27 Activates the Unfolded Protein Response.

KIR3DL1 interaction with HLA-B27 is altered by ankylosing spondylitis associated ERAP1 and enhanced by MHC class I cross-linking.