Disease-associated polymorphisms in ERAP1 do not alter endoplasmic reticulum stress in patients with ankylosing spondylitis

Kenna, Tony J.; Lau, Melanie; Keith, Patricia; Ciccia, Francesco; Costello, Mary-Ellen; Bradbury, L.; Low, P-L.; Agrawal, Nitish; Triolo, G; Alessandro, Riccardo; Robinson, Philip C; Thomas, Gethin; Brown, Matthew A.

doi:10.1038/gene.2014.62

Cited by 30 publications

(22 citation statements)

References 29 publications

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“…77 If this were the case, then ASassociated ERAP1 or ERAP2 variants would be expected to influence endoplasmic reticulum stress, and endoplasmic reticulum stress measures would be higher in patients with AS than controls, as well as in HLA-B27 positive compared with HLA-B*27negative individuals. Studies of protective ERAP1 and ERAP2 variants have not confirmed such changes in peripheral blood mono nuclear cells (PBMCs), 78 nor have previous studies shown any difference in endoplasmic reticulum stress in periph eral blood mononuclear cells or ileal biopsy samples from patients with AS or controls. 79,80 It is possible that in other cell types, or in other diseases, different effects might be seen, or, as has been suggested previously, that phenotypes might vary by HLA-B*27 subtype.…”

Section: Aminopeptidases In Asmentioning

confidence: 97%

Genetics of ankylosing spondylitis—insights into pathogenesis

2015

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Ankylosing spondylitis (AS), an immune-mediated arthritis, is the prototypic member of a group of conditions known as spondyloarthropathies that also includes reactive arthritis, psoriatic arthritis and enteropathic arthritis. Patients with these conditions share a clinical predisposition for spinal and pelvic joint dysfunction, as well as genetic associations, notably with HLA-B(*)27. Spondyloarthropathies are characterized by histopathological inflammation in entheses (regions of high mechanical stress where tendons and ligaments insert into bone) and in the subchondral bone marrow, and by abnormal osteoproliferation at involved sites. The association of AS with HLA-B(*)27, first described >40 years ago, led to hope that the cause of the disease would be rapidly established. However, even though many theories have been advanced to explain how HLA-B(*)27 is involved in AS, no consensus about the answers to this question has been reached, and no successful treatments have yet been developed that target HLA-B27 or its functional pathways. Over the past decade, rapid progress has been made in discovering further genetic associations with AS that have shed new light on the aetiopathogenesis of the disease. Some of these discoveries have driven translational ideas, such as the repurposing of therapeutics targeting the cytokines IL-12 and IL-23 and other factors downstream of this pathway. AS provides an excellent example of how hypothesis-free research can lead to major advances in understanding pathogenesis and to the development of innovative therapeutic strategies.

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Section: Aminopeptidases In Asmentioning

confidence: 97%

Genetics of ankylosing spondylitis—insights into pathogenesis

2015

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“…Dendritic cells derived from HLA-B27 patients with AS exhibited ERAP1 overexpression in comparison with healthy controls, but this did not parallel with an altered amount of overall HLA class I dimers [95]. Another study performed in HLA-B27-positive and HLA-B27-negative AS patients, in the presence of risk or protective ERAP1 variants, did not show significant differences in the expression of ER stress markers nor of proinflammatory cytokines, ruling out the ER stress as cause of disease [96].…”

Section: Hla-b27 and Erap1/2 As Players In Ankylosing Spondylitismentioning

confidence: 99%

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

Vitulano

Tedeschi

Paladini

et al. 2017

Clinical and Experimental Immunology

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1These authors contributed equally to this study. SummaryThe 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.

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“…We have previously shown that ER stress is not changed by AS associated ERAP1 genetic variation, or HLA-B27 status 13. In this study we used the naturally occurring human ERAP2 functional knockout model (homozygous for the G allele at rs2248374) to determine the effect of changes in ERAP2 on cell surface MHC class I presentation, cell surface and ER heavy chain formation.…”

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confidence: 99%