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. 2016 Jul 13:18:165.
doi: 10.1186/s13075-016-1065-3.

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

Tamarah D de Jong  1   2 , Joyce Lübbers  3 , Samina Turk  4 , Saskia Vosslamber  3 , Elise Mantel  3   5 , Hetty J Bontkes  3   6 , Conny J van der Laken  5 , Johannes W Bijlsma  5   4   7 , Dirkjan van Schaardenburg  4   7 , Cornelis L Verweij  3
Affiliations

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

Tamarah D de Jong et al. Arthritis Res Ther. .

Abstract

Background: The 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.

Methods: Blood 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.

Results: Patients were designated "IFN(high)" (n = 8) or "IFN(low)" (n = 18) on the basis of an IFN score cutoff in whole peripheral blood from healthy control subjects. The difference in IFN score between IFN(high) and IFN(low) 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.

Conclusions: PMNs 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.

Keywords: Granulocytes; Rheumatoid arthritis; Type I interferon.

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Figures

Fig. 1
Fig. 1
Whole-blood interferon (IFN) scores in all 26 patients with early arthritis. Eight patients were designated patients with an interferon signature (IFNhigh) on the basis of the mean + 2 SD cutoff in healthy control subjects. Patients within the 95 % limits of healthy control subjects (indicated between the dashed lines) were considered IFNlow
Fig. 2
Fig. 2
Interferon (IFN) scores per leukocyte subset of patients within the 95 % limits of healthy control subjects (IFNlow) and patients with an interferon signature (IFNhigh). Fold differences between the two groups, as well as p values of the statistical comparisons, are indicated below the graph. PMN polymorphonuclear granulocyte
Fig. 3
Fig. 3
Selective upregulation of interferon α/β receptor (IFNAR) mRNA expression in polymorphonuclear granulocytes (PMNs) from patients with early arthritis. IFNAR1 (a) and IFNAR2 (b) expression in peripheral blood mononuclear cells (PBMCs) and PMNs from healthy control subjects (HC) and patients with early arthritis. *p = 0.05–0.01 **p = 0.01–0.001; ***p ≤ 0.001. IFN high patients with an interferon signature, IFN low patients within the 95 % limits of healthy control subjects, ns not significant
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