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.
Highlights
The type I interferon (IFN) signature in rheumatoid arthritis (RA) has shown clinical relevance in relation to disease onset and therapeutic response
Induction of these interferon response gene (IRG) is triggered via activation of the type I interferon α/β receptors IFNAR1 and IFNAR2, which dimerize and subsequently activate the Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling pathway, JAK1, TYK2, STAT1, and STAT2, eventually resulting in recruitment of IRF9 and formation of the ISGF3 transcription factor complex [2]
The presence of the IFN signature in RA is not found to be associated with disease parameters such as disease activity or presence of rheumatoid factor and/or anticitrullinated protein antibodies (ACPA) [3], several studies have demonstrated that the IFN signature in RA does have potential clinical relevance
Summary
The type I interferon (IFN) signature in rheumatoid arthritis (RA) has shown clinical relevance in relation to disease onset and therapeutic response. Some of the patients with RA display a so-called IFN signature, which is characterized by relatively high expression of type I IFN response genes (IRGs). Induction of these IRGs is triggered via activation of the type I interferon α/β receptors IFNAR1 and IFNAR2, which dimerize and subsequently activate the Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling pathway, JAK1, TYK2, STAT1, and STAT2, eventually resulting in recruitment of IRF9 and formation of the ISGF3 transcription factor complex [2]. The presence of the IFN signature in RA is not found to be associated with disease parameters such as disease activity or presence of rheumatoid factor and/or anticitrullinated protein antibodies (ACPA) [3], several studies have demonstrated that the IFN signature in RA does have potential clinical relevance
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