Abstract
The mechanism by which human leukocyte antigen B27 (HLA-B27) contributes to ankylosing spondylitis (AS) remains unclear. Genetic studies demonstrate that association with and interaction between polymorphisms of endoplasmic reticulum aminopeptidase 1 (ERAP1) and HLA-B27 influence the risk of AS. It has been hypothesised that ERAP1-mediated HLA-B27 misfolding increases endoplasmic reticulum (ER) stress, driving an interleukin (IL) 23-dependent, pro-inflammatory immune response. We tested the hypothesis that AS-risk ERAP1 variants increase ER-stress and concomitant pro-inflammatory cytokine production in HLA-B27+ but not HLA-B27− AS patients or controls. Forty-nine AS cases and 22 healthy controls were grouped according to HLA-B27 status and AS-associated ERAP1 rs30187 genotypes: HLA-B27+ERAP1risk, HLA-B27+ERAP1protective, HLA-B27−ERAP1risk and HLA-B27−ERAP1protective. Expression levels of ER-stress markers GRP78 (8 kDa glucose-regulated protein), CHOP (C/EBP-homologous protein) and inflammatory cytokines were determined in peripheral blood mononuclear cell and ileal biopsies. We found no differences in ER-stress gene expression between HLA-B27+ and HLA-B27− cases or healthy controls, or between cases or controls stratified by carriage of ERAP1 risk or protective alleles in the presence or absence of HLA-B27. No differences were observed between expression of IL17A or TNF (tumour necrosis factor) in HLA-B27+ERAP1risk, HLA-B27+ERAP1protective and HLA-B27−ERAP1protective cases. These data demonstrate that aberrant ERAP1 activity and HLA-B27 carriage does not alter ER-stress levels in AS, suggesting that ERAP1 and HLA-B27 may influence disease susceptibility through other mechanisms.
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Acknowledgements
Written informed consent was obtained from patients and controls for publication of this manuscript and accompanying images. We acknowledge the contribution of the subjects who participated in this study. We thank Murray Hargrave for his assistance in the preparation of this manuscript and Dr Helen Benham for helpful discussions. This study was supported by Australian National Health and Medical Research Council (NHMRC) grant #569830. TJK was supported by an AFA-ARA Heald Fellowship, PCR was supported by NHMRC PhD scholarship and MAB was supported by NHMRC Senior Principal Research Fellowship APP1024879.
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Kenna, T., Lau, M., Keith, P. et al. Disease-associated polymorphisms in ERAP1 do not alter endoplasmic reticulum stress in patients with ankylosing spondylitis. Genes Immun 16, 35–42 (2015). https://doi.org/10.1038/gene.2014.62
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DOI: https://doi.org/10.1038/gene.2014.62
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