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01.12.2018 | Research article | Ausgabe 1/2018 Open Access

Arthritis Research & Therapy 1/2018

Type I IFN signature in childhood-onset systemic lupus erythematosus: a conspiracy of DNA- and RNA-sensing receptors?

Zeitschrift:
Arthritis Research & Therapy > Ausgabe 1/2018
Autoren:
M. Javad Wahadat, Iris L. A. Bodewes, Naomi I. Maria, Cornelia G. van Helden-Meeuwsen, Annette van Dijk-Hummelman, Eline C. Steenwijk, Sylvia Kamphuis, Marjan A. Versnel
Wichtige Hinweise

Electronic supplementary material

The online version of this article (doi:https://​doi.​org/​10.​1186/​s13075-017-1501-z) contains supplementary material, which is available to authorized users.

Abstract

Background

Childhood-onset systemic lupus erythematosus (cSLE) is an incurable multi-systemic autoimmune disease. Interferon type I (IFN-I) plays a pivotal role in the pathogenesis of SLE. The objective of this study was to assess the prevalence of the IFN-I signature and the contribution of cytosolic nucleic acid receptors to IFN-I activation in a cohort of primarily white cSLE patients.

Methods

The IFN-I score (positive or negative), as a measure of IFN-I activation, was assessed using real-time quantitative PCR (RT-PCR) expression values of IFN-I signature genes (IFI44, IFI44L, IFIT1, Ly6e, MxA, IFITM1) in CD14+ monocytes of cSLE patients and healthy controls (HCs). Innate immune receptor expression was determined by RT-PCR and flow cytometry. To clarify the contribution of RNA-binding RIG-like receptors (RLRs) and DNA-binding receptors (DBRs) to IFN-I activation, peripheral blood mononuclear cells (PBMCs) from patients were treated with BX795, a TANK-binding kinase 1 (TBK1) inhibitor blocking RLR and DBR pathways.

Results

The IFN-I signature was positive in 57% of cSLE patients and 15% of the HCs. Upregulated gene expression of TLR7, RLRs (IFIH1, DDX58, DDX60, DHX58) and DBRs (ZBP-1, IFI16) was observed in CD14+ monocytes of the IFN-I-positive cSLE patients. Additionally, RIG-I and ZBP-1 protein expression was upregulated in these cells. Spontaneous IFN-I stimulated gene (ISG) expression in PBMCs from cSLE patients was inhibited by a TBK1-blocker.

Conclusions

IFN-I activation, assessed as ISG expression, in cSLE is associated with increased expression of TLR7, and RNA and DNA binding receptors, and these receptors contribute to IFN-I activation via TBK1 signaling. TBK1-blockers may therefore be a promising treatment target for SLE.
Zusatzmaterial
Additional file 1: Correlation between RLR or DBR expression levels and IFN scores. (PDF 345 kb)
13075_2017_1501_MOESM1_ESM.pdf
Additional file 2: Gating strategy and representative histogram. (PDF 281 kb)
13075_2017_1501_MOESM2_ESM.pdf
Additional file 3: RLR and DBR protein expression in pDCs from patients with cSLE. (PDF 204 kb)
13075_2017_1501_MOESM3_ESM.pdf
Additional file 4: Titration curve for BX795. (PDF 178 kb)
13075_2017_1501_MOESM4_ESM.pdf
Additional file 5: Effectivity of inhibitors of TBK1, TLR7 and TLR7 + TLR9 to downregulate imiquimod-induced MxA expression. (PDF 248 kb)
13075_2017_1501_MOESM5_ESM.pdf
Literatur
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