ERAP2 functional knockout in humans does not alter surface heavy chains or HLA-B27, inflammatory cytokines or endoplasmic reticulum stress markers

Robinson, Philip C., Lau, Eugene, Keith, Patricia, Lau, Max C., Thomas, Gethin P., Bradbury, Linda A., Brown, Matthew. A., & Kenna, Tony J. (2015) ERAP2 functional knockout in humans does not alter surface heavy chains or HLA-B27, inflammatory cytokines or endoplasmic reticulum stress markers. Annals of the Rheumatic Diseases, 74(11), pp. 2092-2095.

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Abstract

Introduction

Single nucleotide polymorphisms in ERAP2 are strongly associated with ankylosing spondylitis (AS). One AS-associated single nucleotide polymorphism, rs2248374, causes a truncated ERAP2 protein that is degraded by nonsense-mediated decay. Approximately 25% of the populations of European ancestry are therefore natural ERAP2 knockouts. We investigated the effect of this associated variant on HLA class I allele presentation, surface heavy chains, endoplasmic reticulum (ER) stress markers and cytokine gene transcription in AS.

Methods

Patients with AS and healthy controls with either AA or GG homozygous status for rs2248374 were studied. Antibodies to CD14, CD19-ECD, HLA-A-B-C, Valpha7.2, CD161, anti-HC10 and anti-HLA-B27 were used to analyse peripheral blood mononuclear cells. Expression levels of ER stress markers (GRP78 and CHOP) and proinflammatory genes (tumour necrosis factor (TNF), IL6, IL17 and IL22) were assessed by qPCR.

Results

There was no significant difference in HLAclass I allele presentation or major histocompatibility class I heavy chains or ER stress markers GRP78 and CHOP or proinflammatory gene expression between genotypes for rs2248374 either between cases, between cases and controls, and between controls.

Discussion

Large differences were not seen in HLAB27 expression or cytokine levels between subjects with and without ERAP2 in AS cases and controls. This suggests that ERAP2 is more likely to influence AS risk through other mechanisms.

Impact and interest:

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ID Code: 94070
Item Type: Journal Article
Refereed: Yes
Keywords: aminopeptidase, CD14 antigen, CD161 antigen, CD19 antigen, glucose regulated protein 78, growth arrest and DNA damage inducible protein 153, HLA A antigen, HLA B antigen, HLA B27 antigen, HLA C antigen, interleukin 17, interleukin 22, interleukin 6, major histocompatibility antigen class 1, protein ERAP2, tumor necrosis factor, unclassified drug, cytokine, DDIT3 protein, human, ERAP2 protein, human, heat shock protein, IL6 protein, human, immunoglobulin heavy chain, interleukin derivative, interleukin-22, lymphocyte antigen receptor, messenger RNA, molecular chaperone GRP78, tumor necrosis factor alpha, allele, ankylosing spondylitis, Article, CHOP gene, clinical article, controlled study, endoplasmic reticulum stress, ERAP2 gene, flow cytometry, gene, gene expression, gene silencing, genetic risk, genetic variability, GRP78 gene, homozygosity, human, human cell, IL17 gene, IL22 gene, IL6 gene, peripheral blood mononuclear cell, polymerase chain reaction, priority journal, quantitative analysis, risk factor, single nucleotide polymorphism, TNF gene, case control study, genetics, immunology, metabolism, mononuclear cell, Aminopeptidases, Case-Control Studies, Cytokines, Heat-Shock Proteins, HLA-B27 Antigen, Humans, Immunoglobulin Heavy Chains, Interleukin-17, Interleukin-6, Interleukins, Leukocytes, Mononuclear, Polymorphism, Single Nucleotide, Receptors, Antigen, B-Cell, RNA, Messenger, Spondylitis, Ankylosing, Transcription Factor CHOP, Tumor Necrosis Factor-alpha
DOI: 10.1136/annrheumdis-2015-207467
ISSN: 1468-2060
Divisions: Current > QUT Faculties and Divisions > Faculty of Health
Current > Institutes > Institute of Health and Biomedical Innovation
Funding:
Copyright Owner: Copyright 2016 BMJ Publishing Group Ltd & European League Against Rheumatism
Deposited On: 21 Mar 2016 07:17
Last Modified: 22 Mar 2016 06:02

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