The type I interferon signature in leukocyte subsets from peripheral blood of patients with early arthritis: a major contribution by granulocytes

Abstract

BackgroundThe type I interferon (IFN) signature in rheumatoid arthritis (RA) has shown clinical relevance in relation to disease onset and therapeutic response. Identification of the cell type(s) contributing to this IFN signature could provide insight into the signature’s functional consequences. The aim of this study was to investigate the contribution of peripheral leukocyte subsets to the IFN signature in early arthritis.MethodsBlood was collected from 26 patients with early arthritis and lysed directly or separated into peripheral blood mononuclear cells (PBMCs) and polymorphonuclear granulocytes (PMNs). PBMCs were sorted into CD4+ T cells, CD8+ T cells, CD19+ B cells, and CD14+ monocytes by flow cytometry. Messenger RNA expression of three interferon response genes (IRGs RSAD2, IFI44L, and MX1) and type I interferon receptors (IFNAR1 and IFNAR2) was determined in whole blood and blood cell subsets by quantitative polymerase chain reaction. IRG expression was averaged to calculate an IFN score for each sample.ResultsPatients were designated “IFNhigh” (n = 8) or “IFNlow” (n = 18) on the basis of an IFN score cutoff in whole peripheral blood from healthy control subjects. The difference in IFN score between IFNhigh and IFNlow patients was remarkably large for the PMN fraction (mean 25-fold) compared with the other subsets (mean 6- to 9-fold), indicating that PMNs are the main inducers of IRGs. Moreover, the relative contribution of the PMN fraction to the whole-blood IFN score was threefold higher than expected from its abundance in blood (p = 0.008), whereas it was three- to sixfold lower for the other subsets (p ≤ 0.063), implying that the PMNs are most sensitive to IFN signaling. Concordantly, IFNAR1 and IFNAR2 were upregulated compared with healthy controls selectively in patient PMNs (p ≤ 0.0077) but not in PBMCs.ConclusionsPMNs are the main contributors to the whole-blood type I IFN signature in patients with early arthritis, which seems due to increased sensitivity of these cells to type I IFN signaling. Considering the well-established role of neutrophils in the pathology of arthritis, this suggests a role of type I IFN activity in the disease as well.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-016-1065-3) contains supplementary material, which is available to authorized users.

Differential CpG DNA methylation in peripheral naïve CD4+ T-cells in early rheumatoid arthritis patients

“…Dysregulation of type-I INFs are often observed in autoimmunity and chronic inflammatory diseases [34][35][36][37]. In a study of at-risk individual for RA, IFN signalling genes were indicative of progression to the inflammatory stage [38][39][40]; however, IFN signatures were no longer reported predictive later in the disease course [35,41,42]. As supported by our data, this suggests that IFN signalling is associated with early pathogenesis, independently of whether this can be exploited clinically later in the disease.…”

Type I interferon response gene expression in established rheumatoid arthritis is not associated with clinical parameters

“…It has been shown that SSZ reduces the levels of RA-related cytokines, such as interleukin-1β and tumor necrosis factor-α [16], suggesting that SSZ might function through overall suppression of inflammatory cytokines, including type I IFNs. Furthermore, it was demonstrated that SSZ is able to accelerate apoptosis of neutrophils [17], which we have recently shown to be major inducers of the type I IFN response in RA [18]. Consequently, suppression of the type I IFN response by SSZ might be mediated via an increase in neutrophil apoptosis.…”

Chromosome conformation signatures define predictive markers of inadequate response to methotrexate in early rheumatoid arthritis

“…It is now clear that the developing immune response is influenced by genetic and epigenetic factors [ 41 ]. IFNAR1, IL-21R and IL-23 loci have been reported to play a key role in the pathogenesis of RA [ 83 – 85 ] and Th17 cells are implicated in pathogenesis especially in the pre-RA phase [ 68 , 72 , 73 ]. Whether the CCS differences we observed represent changes impacting the pre-RA phase or are acquired during the early phase of RA is at present unclear.…”