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

Abstract

BackgroundChildhood-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.MethodsThe 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.ResultsThe 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.ConclusionsIFN-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.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-017-1501-z) contains supplementary material, which is available to authorized users.

Inverse correlation between serum complement component C1q levels and whole blood type‐1 interferon signature in active tuberculosis and QuantiFERON‐positive uveitis: implications for diagnosis

“…Positive blood type-1 IFN gene signatures also occur in substantial numbers of patients with systemic autoimmune disease, including pSS, SLE or SSc. [28][29][30][31] We did not observe a correlation between the disease-specific type-1 IFN gene signature score and serum C1q level in systemic autoimmune disease (pSS, SLE or SLE). Several studies did identify transcriptional differences, as well as similarities, in type-1 IFN-inducible gene signatures between various autoimmune diseases, TB, and normal immune responses, supporting the use of disease-specific IFN gene signatures.…”

“…Substantial subsets of patients with pSS, SLE and SSc also display a positive type-1 IFN signature. [28][29][30][31] represents a more general phenomenon, we also determined the relation between serum C1q levels and peripheral blood type-1 IFN signature scores in pSS, SLE and SSc patients. Serum C1q did not show any correlation with the peripheral blood type-1 IFN signature scores in any of these systemic autoimmune diseases (Supplementary figure 1).…”

“…Sera from three previously collected cohorts, two TB cohorts from Indonesia (from now on designated as cohort 1 47 and 2 48 ) and one cohort consisting of systemic autoimmune patients from mainly Caucasian origin (from now on designated as cohort 3 [28][29][30] ), were included in this study. All individuals from cohorts 1 and 3 and all TB patients from cohort 2 were HIV negative, and healthy controls from cohort 2 were largely untested.…”

“…22 In addition, from cohort 3, the systemic autoimmune disease-related peripheral blood type-1 IFN signature scores were available and determined as previously described. [28][29][30] Genes comprising the diseaserelated type-1 IFN signatures, as well as the formula used to calculate the type-1 IFN signature score, are provided in Supplementary table 1.…”

Study on the differentially expressed genes and signaling pathways in dermatomyositis using integrated bioinformatics method

“…[ 59 ] DDX58 gene plays an important role in activating NF-κ B pathway and plays an important role in the pathogenesis of dermatomyositis. [ 60 ] It has been found that DDX58 gene is significantly up regulated in psoriasis patients and psoriasis like mice. [ 61 ]…”