Area of Immunology, Department of Functional Biology, Faculty of Medicine, University of Oviedo, Oviedo, Spain.
Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Oviedo, Spain.
Front Immunol. 2019 Jan 7;9:3085. doi: 10.3389/fimmu.2018.03085. eCollection 2018.
Overactivation of the type I interferon (IFN) signature has been observed in several systemic autoimmune conditions, such as Systemic Lupus Erythematosus (SLE) or Rheumatoid Arthritis (RA). Impaired control of Interferon-Responding Genes (IRGs) expression by their regulatory mechanisms, including Interferon Regulatory Factors (IRFs), may underlie these findings and it may explain the heterogeneity observed among these conditions. In the present study we aimed to evaluate the associations between IRF4 gene expression and those of IRGs in SLE and RA patients to gain insight about its links with the IFN signature as well as to explore the potential clinical relevance of these associations. The gene expression of IRF4 and IRGs (IFI44, IFI44L, IFI6, and MX1) in peripheral blood was analyzed in 75 SLE patients, 98 RA patients, and 28 healthy controls. A group of 13 biological-naïve RA patients was prospectively followed upon TNFα-blockade. The associations among IRF4 and IRGs were evaluated by principal component analyses (PCA), correlations and network analyses. Publicly available datasets were used for replication. A broad activation of IRGs was observed in autoimmune patients, although certain heterogeneity can be distinguished, whereas IRF4 was only upregulated in RA. The differential expression of IRF4 in RA was then confirmed in publicly available gene expression datasets. PCA revealed different associations among IRF4 and IRGs in each condition, which was later confirmed by correlation and network analyses. Cluster analysis identified 3 gene expression signatures on the basis of IRF4 and IRGs expression which were differentially used by SLE and RA patients. Cluster III was associated with markers of disease severity in SLE patients. Cluster II, hallmarked by IRF4 upregulation, was linked to clinical stage and mild disease course in RA. TNFα-blockade led to changes in the association between IRF4 and IRGs, whereas increasing IRF4 expression was associated with a good clinical outcome in RA. The differential expression of IRF4 and IRGs observed in SLE and RA can delineate gene expression signatures associated with clinical features and treatment outcomes. These results support a clinically-relevant phenomenon of shaping of the IFN signature by IRF4 in autoimmune patients.
I 型干扰素（IFN）信号的过度激活已在多种系统性自身免疫性疾病中观察到，例如红斑狼疮（SLE）或类风湿关节炎（RA）。其调节机制（包括干扰素调节因子（IRFs））对干扰素反应基因（IRGs）表达的控制受损，可能是这些发现的基础，并可以解释这些疾病之间观察到的异质性。在本研究中，我们旨在评估 IRF4 基因表达与 SLE 和 RA 患者中 IRGs 之间的相关性，以深入了解其与 IFN 特征的关系，并探讨这些相关性的潜在临床意义。在 75 例 SLE 患者、98 例 RA 患者和 28 例健康对照者的外周血中分析了 IRF4 和 IRGs（IFI44、IFI44L、IFI6 和 MX1）的基因表达。一组 13 例生物初治的 RA 患者在 TNFα 阻断后进行前瞻性随访。通过主成分分析（PCA）、相关性和网络分析评估了 IRF4 和 IRGs 之间的相关性。使用公开的数据集进行复制。在自身免疫性疾病患者中观察到 IRGs 的广泛激活，尽管可以区分出某些异质性，而仅在 RA 中观察到 IRF4 的上调。RA 中 IRF4 的差异表达随后在公开的基因表达数据集中得到证实。PCA 显示在每种情况下，IRF4 和 IRGs 之间存在不同的相关性，这随后通过相关性和网络分析得到证实。聚类分析基于 IRF4 和 IRGs 的表达，确定了 SLE 和 RA 患者使用的 3 个基因表达特征。III 类与 SLE 患者疾病严重程度的标志物相关。以 IRF4 上调为标志的 II 类与 RA 的临床分期和轻度病程有关。TNFα 阻断导致 IRF4 和 IRGs 之间的相关性发生变化，而 RA 中 IRF4 表达增加与良好的临床结局相关。SLE 和 RA 中观察到的 IRF4 和 IRGs 的差异表达可以描绘与临床特征和治疗结果相关的基因表达特征。这些结果支持了在自身免疫性疾病患者中，IRF4 塑造 IFN 特征的具有临床意义的现象。
