Contrasting expression pattern of RNA-sensing receptors TLR7, RIG-I and MDA5 in interferon-positive and interferon-negative patients with primary Sjögren's syndrome.
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.
Department of Immunology, Erasmus MC, Rotterdam, The Netherlands.
Naomi I
NI
Maria
Department of Immunology, Erasmus MC, Rotterdam, The Netherlands.
Eline C
EC
Steenwijk
Department of Bioinformatics, Erasmus MC, Rotterdam, The Netherlands.
Arne S
AS
IJpma
Department of Immunology, Erasmus MC, Rotterdam, The Netherlands.
Cornelia G
CG
van Helden-Meeuwsen
Department of Clinical Science, Broegelmann Research Laboratory, University of Bergen, Bergen, Norway.|Department of Immunology and Transfusion Medicine, Haukeland University Hospital, Bergen, Norway.
Petra
P
Vogelsang
Department of Immunology, Erasmus MC, Rotterdam, The Netherlands.
Wouter
W
Beumer
Department of Immunology, Erasmus MC, Rotterdam, The Netherlands.|Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands.
Zana
Z
Brkic
Department of Immunology, Erasmus MC, Rotterdam, The Netherlands.|Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands.
Paul L A
PL
van Daele
Department of Immunology, Erasmus MC, Rotterdam, The Netherlands.|Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands.
P Martin
PM
van Hagen
Department of Bioinformatics, Erasmus MC, Rotterdam, The Netherlands.
Peter J
PJ
van der Spek
Department of Immunology, Erasmus MC, Rotterdam, The Netherlands.
Hemmo A
HA
Drexhage
Department of Immunology, Erasmus MC, Rotterdam, The Netherlands.
Marjan A
MA
Versnel
D000328:Adult; D000368:Aged; D002478:Cells, Cultured; D000071457:DEAD Box Protein 58 / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D003713:Dendritic Cells; D005260:Female; D006801:Humans; D050839:Interferon Regulatory Factor-7 / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D007370:Interferon Type I / Q000097:blood*; D000072640:Interferon-Induced Helicase, IFIH1 / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000378:metabolism; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D044925:Oxidoreductases Acting on CH-CH Group Donors; D010766:Phosphorylation; D011506:Proteins / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis*; D011971:Receptors, Immunologic; D012469:Salivary Glands / Q000737:chemistry; D015398:Signal Transduction; D012859:Sjogren's Syndrome / Q000097:blood* / Q000235:genetics* / Q000378:metabolism; D051199:Toll-Like Receptor 7 / Q000032:analysis / Q000235:genetics* / Q000378:metabolism; D015854:Up-Regulation; D000090123:Viperin Protein
D000071457:DEAD Box Protein 58; D050839:Interferon Regulatory Factor-7; D007370:Interferon Type I; D000072640:Interferon-Induced Helicase, IFIH1; D053594:Myeloid Differentiation Factor 88; D044925:Oxidoreductases Acting on CH-CH Group Donors; D011506:Proteins; D012333:RNA, Messenger; D011971:Receptors, Immunologic; D051199:Toll-Like Receptor 7; C494234:IRF7 protein, human; C507779:MYD88 protein, human; C495348:TLR7 protein, human; C444427:RSAD2 protein, human; D000090123:Viperin Protein; C452820:RIGI protein, human; C452815:IFIH1 protein, human
Autoimmunity; Cytokines; Sjøgren's Syndrome