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Ann Rheum Dis. 2017 Apr;76(4):721-730. doi: 10.1136/annrheumdis-2016-209589. Epub 2016 Sep 26.

Contrasting expression pattern of RNA-sensing receptors TLR7, RIG-I and MDA5 in interferon-positive and interferon-negative patients with primary Sjögren's syndrome.

Author information

1
Department of Immunology, Erasmus MC, Rotterdam, The Netherlands.
2
Department of Bioinformatics, Erasmus MC, Rotterdam, The Netherlands.
3
Department of Clinical Science, Broegelmann Research Laboratory, University of Bergen, Bergen, Norway.
4
Department of Immunology and Transfusion Medicine, Haukeland University Hospital, Bergen, Norway.
5
Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands.

Abstract

OBJECTIVE:

The interferon (IFN) type I signature is present in over half of patients with primary Sjögren's syndrome (pSS) and associated with higher disease-activity and autoantibody presence. Plasmacytoid dendritic cells (pDCs) are considered as the main source of enhanced IFN type I expression. The objective of this study was to unravel the molecular pathways underlying IFN type I bioactivity in pDCs of patients with pSS.

METHODS:

Blood samples from 42 healthy controls (HC) and 115 patients with pSS were stratified according to their IFN type I signature. CD123+BDCA4+ pDCs and CD14+ monocytes were isolated from peripheral blood mononuclear cells (PBMCs). Genome-wide microarray analysis was conducted on sorted pDCs in a small sample set, followed by validation of differentially expressed genes of interest in pDCs and monocytes.

RESULTS:

We found an upregulation of endosomal toll-like receptor (TLR) 7, but not TLR9, in IFN-positive (IFNpos) pDCs (p<0.05) and monocytes (p=0.024). Additionally, the downstream signalling molecules MyD88, RSAD2 and IRF7 were upregulated, as were the cytoplasmic RNA-sensing receptors DDX58/retinoic acid inducible gene-I (RIG-I) and IFIH1/melanoma differentiation associated gene-5 (MDA5). In vitro triggering of the TLR7-pathway in HC PBMCs induced upregulation of DDX58/RIG-I and IFIH1/MDA5, and downregulated TLR9. The upregulation of TLR7, its downstream signalling pathway, DDX58/RIG-I and IFIH1/MDA5 were confined to patients with IFN-positive pSS. IFN-negative patients had a contrasting expression pattern-TLR7 normal, and decreased TLR9, RIG-I and MDA5.

CONCLUSIONS:

Here we conclude a contrasting expression pattern of the RNA-sensing receptors TLR7, RIG-I and MDA5 in pDCs and monocytes of patients with IFNpos pSS. This profile could explain the pathogenic IFN production and might reveal novel therapeutic targets in these patients.

KEYWORDS:

Autoimmunity; Cytokines; Sjøgren's Syndrome

PMID:
27672125
DOI:
10.1136/annrheumdis-2016-209589
[Indexed for MEDLINE]

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