The type I interferon signature in leukocyte subsets from peripheral blood of patients with early arthritis: a major contribution by granulocytes.
The type I interferon signature in leukocyte subsets from peripheral blood of patients with early arthritis: a major contribution by granulocytes.
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DOI：
10.1186/s13075-016-1065-3
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发表时间：
2016-07-13
影响因子：
4.9
通讯作者：
Verweij CL
中科院分区：
文献类型：
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作者：
de Jong TD;Lübbers J;Turk S;Vosslamber S;Mantel E;Bontkes HJ;van der Laken CJ;Bijlsma JW;van Schaardenburg D;Verweij CL
类风湿性关节炎（RA）中的I型干扰素（IFN）特征已显示出与疾病发作和治疗反应相关的临床相关性。鉴定促成该IFN特征的细胞类型可以提供对该特征的功能后果的了解。本研究的目的是探讨外周血白细胞亚群的贡献，在早期关节炎的干扰素签名。收集26例早期关节炎患者的血液，直接裂解或分离成外周血单个核细胞（PBMC）和多形核粒细胞（PMN）。通过流式细胞术将PBMC分选为CD 4 + T细胞、CD 8 + T细胞、CD 19 + B细胞和CD 14+单核细胞。通过定量聚合酶链反应测定全血和血细胞亚群中三种干扰素应答基因（IRGs RSAD 2、IFI 44 L和MX 1）和I型干扰素受体（IFNAR 1和IFNAR 2）的信使RNA表达。对IRG表达取平均值以计算每个样品的IFN评分。基于来自健康对照受试者的全外周血中的IFN分数截止值，将患者指定为“IFN高”（n = 8）或“IFN低”（n = 18）。IFN高和IFN低患者之间的IFN评分的差异对于PMN分数（平均25倍）与其他子集（平均6- 9倍）相比是显著大的，表明PMN是IRG的主要诱导物。此外，PMN组分对全血IFN评分的相对贡献比其在血液中丰度的预期高3倍（p = 0.008），而其他子集的相对贡献低3 - 6倍（p ≤ 0.063），这意味着PMN对IFN信号传导最敏感。与健康对照组相比，IFNAR 1和IFNAR 2在患者PMN中选择性上调（p ≤ 0.0077），但在PBMC中未上调。中性粒细胞是早期关节炎患者全血I型IFN信号的主要贡献者，这似乎是由于这些细胞对I型IFN信号的敏感性增加。考虑到中性粒细胞在关节炎病理学中的既定作用，这表明I型IFN活性在疾病中也起作用。本文的在线版本（doi：10.1186/s13075-016-1065-3）包含补充材料，可供授权用户使用。
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. 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. Patients 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. 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. The online version of this article (doi:10.1186/s13075-016-1065-3) contains supplementary material, which is available to authorized users.