Journal article
Silencing or inhibition of endoplasmic reticulum aminopeptidase 1 (ERAP1) suppresses free heavy chain expression and Th17 responses in ankylosing spondylitis.
- Abstract:
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Objective
Human leucocyte antigen (HLA)-B27 and endoplasmic reticulum aminopeptidase 1 (ERAP1) are strongly associated with ankylosing spondylitis (AS). ERAP1 is a key aminopeptidase in HLA class I presentation and can potentially alter surface expression of HLA-B27 free heavy chains (FHCs). We studied the effects of ERAP1 silencing/inhibition/variations on HLAB27 FHC expression and Th17 responses in AS.
Methods
Flow cytometry was used to measure surface expression of HLA class I in peripheral blood mononuclear cells (PBMCs) from patients with AS carrying different ERAP1 genotypes (rs2287987, rs30187 and rs27044) and in ERAP1-silenced/inhibited/ mutated HLA-B27-expressing antigen presenting cells (APCs). ERAP1-silenced/inhibited APCs were cocultured with KIR3DL2CD3ε-reporter cells or AS CD4+ T cells. Th17 responses of AS CD4+ T cells were measured by interleukin (IL)-17A ELISA and Th17 intracellular cytokine staining. FHC cell surface expression and Th17 responses were also measured in AS PBMCs following ERAP1 inhibition.
Results
The AS-protective ERAP1 variants, K528R and Q730E, were associated with reduced surface FHC expression by monocytes from patients with AS and HLA-B27-expressing APCs. ERAP1 silencing or inhibition in APCs downregulated HLA-B27 FHC surface expression, reduced IL-2 production by KIR3DL2CD3ε-reporter cells and suppressed the Th17 expansion and IL-17A secretion by AS CD4+ T cells. ERAP1 inhibition of AS PBMCs reduced HLA class I FHC surface expression by monocytes and B cells, and suppressed Th17 expansion.
Conclusions
ERAP1 activity determines surface expression of HLA-B27 FHCs and potentially promotes Th17 responses in AS through binding of HLA-B27 FHCs to KIR3DL2. Our data suggest that ERAP1 inhibition has potential for AS treatment.
- Publication status:
- Published
- Peer review status:
- Peer reviewed
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- Files:
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(Preview, Version of record, pdf, 5.7MB, Terms of use)
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- Publisher copy:
- 10.1136/annrheumdis-2014-206996
Authors
- Funding agency for:
- Ridley, A
- Bowness, P
- Publisher:
- BMJ Publishing Group
- Journal:
- Annals of the Rheumatic Diseases More from this journal
- Volume:
- 75
- Pages:
- 916-923
- Publication date:
- 2015-06-01
- Acceptance date:
- 2015-04-12
- DOI:
- EISSN:
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1468-2060
- ISSN:
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0003-4967
- Language:
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English
- Keywords:
- Pubs id:
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pubs:529378
- UUID:
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uuid:2e07f9cd-e5f6-448e-8b1d-eba856e34774
- Local pid:
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pubs:529378
- Source identifiers:
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529378
- Deposit date:
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2016-04-06
Terms of use
- Copyright holder:
- Bowness et al
- Copyright date:
- 2015
- Notes:
- This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: http://creativecommons.org/licenses/by/4.0/
- Licence:
- CC Attribution (CC BY)
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