{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,29]],"date-time":"2026-05-29T21:09:32Z","timestamp":1780088972679,"version":"3.54.0"},"reference-count":16,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2017,4,26]],"date-time":"2017-04-26T00:00:00Z","timestamp":1493164800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100000142","name":"Arthritis Society","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000142","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Arthritis &amp; Rheumatology"],"published-print":{"date-parts":[[2017,5]]},"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>The basic mechanisms underlying the pathogenesis of ankylosing spondylitis (AS) remain unresolved. We previously reported an association of the single\u2010nucleotide polymorphism (SNP) rs2549782 in the endoplasmic reticulum aminopeptidase 2 gene (<jats:italic>ERAP2<\/jats:italic>) with AS. It is known that patients homozygous for the G allele (GG) of another <jats:italic>ERAP2<\/jats:italic> SNP, rs2248374, lack expression of <jats:italic>ERAP2<\/jats:italic> (<jats:italic>ERAP2<\/jats:italic> null). The present study utilized this information to study the impact of <jats:italic>ERAP2<\/jats:italic> deficiency on HLA\u2013B27 expression in patients with AS, specifically focusing on the functional interaction of <jats:italic>ERAP2<\/jats:italic> and HLA\u2013B27 in peripheral blood mononuclear cells (PBMCs) from patients with AS and assessing the effects in vitro in specific cell lines.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Expression of intact peptide HLA\u2013B27 (pB27) or the major histocompatibility complex class I free heavy chains (FHCs) was assessed in PBMCs isolated from HLA\u2013B27\u2013positive patients with AS. <jats:italic>ERAP2<\/jats:italic>\u2010suppressed, stable B27\u2013expressing C1R cells (C1R\u2010B27) were tested for the expression levels of pB27 and FHCs, as well as for markers of the unfolded protein response (UPR). Distribution of the <jats:italic>ERAP2<\/jats:italic> SNPs rs2549782 and rs2248374 in patients with AS and in patients with Crohn's disease was assessed.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>PBMCs from AS patients lacking <jats:italic>ERAP2<\/jats:italic> expressed higher levels of FHCs than did PBMCs from patients positive for <jats:italic>ERAP2<\/jats:italic>. This finding was replicated in C1R\u2010B27 cells after suppression of <jats:italic>ERAP2<\/jats:italic>. In addition, <jats:italic>ERAP2<\/jats:italic> suppression led to increased levels of the UPR markers BiP, CCAAT\/enhancer binding protein homologous protein 10, and X\u2010box binding protein 1 [spliced] as compared to that in short hairpin RNA\u2013treated control cells. There was strong linkage disequilibrium in the <jats:italic>ERAP2<\/jats:italic> locus. All patients with the rs2549782 T allele (which reportedly increases the function of the ERAP\u20102 protein) were homozygous for the G allele of rs2248374, leading to absence of <jats:italic>ERAP2<\/jats:italic>.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p><jats:italic>ERAP2<\/jats:italic> deficiency causes increased FHC expression and up\u2010regulation of the UPR pathway.<\/jats:p><\/jats:sec>","DOI":"10.1002\/art.40033","type":"journal-article","created":{"date-parts":[[2016,12,28]],"date-time":"2016-12-28T11:53:12Z","timestamp":1482925992000},"page":"1009-1015","source":"Crossref","is-referenced-by-count":18,"title":["Brief Report: Functional Interaction of Endoplasmic Reticulum Aminopeptidase 2 and HLA\u2013B27 Activates the Unfolded Protein Response"],"prefix":"10.1002","volume":"69","author":[{"given":"Zhenbo","family":"Zhang","sequence":"first","affiliation":[{"name":"Toronto Western Research Institute Toronto Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesco","family":"Ciccia","sequence":"additional","affiliation":[{"name":"Universit\u00e0 degli Studi di Palermo Palermo Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fanxing","family":"Zeng","sequence":"additional","affiliation":[{"name":"Toronto Western Research Institute Toronto Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuliana","family":"Guggino","sequence":"additional","affiliation":[{"name":"Universit\u00e0 degli Studi di Palermo Palermo Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kirby","family":"Yee","sequence":"additional","affiliation":[{"name":"Toronto Western Research Institute, Toronto, Ontario, Canada, and McMaster University Hamilton Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hasan","family":"Abdullah","sequence":"additional","affiliation":[{"name":"Toronto Western Research Institute and University of Toronto Toronto Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark S.","family":"Silverberg","sequence":"additional","affiliation":[{"name":"University of Toronto and Mount Sinai Hospital Toronto Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Riccardo","family":"Alessandro","sequence":"additional","affiliation":[{"name":"Universit\u00e0 degli Studi di Palermo Palermo Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giovanni","family":"Triolo","sequence":"additional","affiliation":[{"name":"Universit\u00e0 degli Studi di Palermo Palermo Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nigil","family":"Haroon","sequence":"additional","affiliation":[{"name":"Toronto Western Research Institute, University of Toronto, and University Health Network Toronto Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2017,4,26]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1080\/03009740802213310"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.22295"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2012-202925"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1136\/ard.2008.103804"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2011-200347"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1001157"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1200918"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.1780270401"},{"key":"e_1_2_7_10_1","first-page":"2286","article-title":"A new approach to defining disease status in ankylosing spondylitis: the Bath Ankylosing Spondylitis Disease Activity Index","volume":"21","author":"Garrett S","year":"1994","journal-title":"J Rheumatol"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btn564"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2015-207416"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.3899\/jrheum.101257"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2013-204170"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.4161\/auto.3930"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2667"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2015-207467"}],"container-title":["Arthritis &amp; 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