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

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Basic and translational research
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Contrasting expression pattern of RNA-sensing receptors TLR7, RIG-I and MDA5 in interferon-positive and interferon-negative patients with primary Sjögren's syndrome
  1. Naomi I Maria1,
  2. Eline C Steenwijk1,
  3. Arne S IJpma2,
  4. Cornelia G van Helden-Meeuwsen1,
  5. Petra Vogelsang3,4,
  6. Wouter Beumer1,
  7. Zana Brkic1,5,
  8. Paul L A van Daele1,5,
  9. P Martin van Hagen1,5,
  10. Peter J van der Spek2,
  11. Hemmo A Drexhage1,
  12. Marjan A Versnel1
  1. 1Department of Immunology, Erasmus MC, Rotterdam, The Netherlands
  2. 2Department of Bioinformatics, Erasmus MC, Rotterdam, The Netherlands
  3. 3Department of Clinical Science, Broegelmann Research Laboratory, University of Bergen, Bergen, Norway
  4. 4Department of Immunology and Transfusion Medicine, Haukeland University Hospital, Bergen, Norway
  5. 5Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands
  1. Correspondence to Dr Naomi I Maria, Department of Immunology, Erasmus MC, Wytemaweg 80, 3015 CN Rotterdam, The Netherlands n.maria@erasmusmc.nl; nmaria{at}northwell.edu

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.

  • Sjøgren's Syndrome
  • Autoimmunity
  • Cytokines

https://doi.org/10.1136/annrheumdis-2016-209589

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    Footnotes

    • Handling editor Tore K Kvien

    • NIM's current address is Autoimmunity and Musculoskeletal Diseases, The Feinstein Institute for Medical Research, 350 Community drive, Manhasset, New York, USA

    • Correction notice This article has been corrected since it was published Online First. Details of the corresponding author have been corrected.

    • Contributors NIM (guarantor) was involved in conception and study design, overall data acquisition and monitoring, analysis and interpretation of data, drafting and revising the article. ECS, ASIJ, PV and WB were involved in laboratory data acquisition, analysis and interpretation and revising the article. CGvH-M was involved in laboratory data acquisition and analysis and revising the article. ZB, PLAvD and PMvH were involved in clinical data acquisition and interpretation and revising the article. HAD and PJvdS were involved in conception and study design, interpretation of data and revising the article. MAV (guarantor) was involved in conception and study design, data monitoring and interpretation and revising the article. All authors approved the final version.

    • Funding This study was supported by a grant from the Dutch Arthritis Foundation (Reumafonds) (grant number 10-1-401).

    • Competing interests None declared.

    • Patient consent Obtained.

    • Ethics approval The Medical Ethical Review Board of the Erasmus MC Rotterdam.

    • Provenance and peer review Not commissioned; externally peer reviewed.