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

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

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.

MeSH terms

  • Adult
  • Aged
  • Cells, Cultured
  • DEAD Box Protein 58 / analysis
  • DEAD Box Protein 58 / genetics
  • DEAD Box Protein 58 / metabolism
  • Dendritic Cells
  • Female
  • Humans
  • Interferon Regulatory Factor-7 / analysis
  • Interferon Regulatory Factor-7 / genetics
  • Interferon Regulatory Factor-7 / metabolism
  • Interferon Type I / blood*
  • Interferon-Induced Helicase, IFIH1 / analysis
  • Interferon-Induced Helicase, IFIH1 / genetics
  • Interferon-Induced Helicase, IFIH1 / metabolism
  • Male
  • Middle Aged
  • Monocytes / metabolism
  • Myeloid Differentiation Factor 88 / genetics
  • Oligonucleotide Array Sequence Analysis
  • Phosphorylation
  • Proteins / genetics
  • RNA, Messenger / analysis*
  • Salivary Glands / chemistry
  • Signal Transduction*
  • Sjogren's Syndrome / blood*
  • Sjogren's Syndrome / genetics*
  • Sjogren's Syndrome / metabolism
  • Toll-Like Receptor 7 / analysis
  • Toll-Like Receptor 7 / genetics*
  • Toll-Like Receptor 7 / metabolism
  • Up-Regulation

Substances

  • IRF7 protein, human
  • Interferon Regulatory Factor-7
  • Interferon Type I
  • MYD88 protein, human
  • Myeloid Differentiation Factor 88
  • Proteins
  • RNA, Messenger
  • RSAD2 protein, human
  • TLR7 protein, human
  • Toll-Like Receptor 7
  • DDX58 protein, human
  • IFIH1 protein, human
  • DEAD Box Protein 58
  • Interferon-Induced Helicase, IFIH1