Physiological evidence for diversification of IFNα- and IFNβ-mediated response programs in different autoimmune diseases.
Physiological evidence for diversification of IFNα- and IFNβ-mediated response programs in different autoimmune diseases.
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DOI：
10.1186/s13075-016-0946-9
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发表时间：
2016-02-17
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;Vosslamber S;Mantel E;de Ridder S;Wesseling JG;van der Pouw Kraan TC;Leurs C;Hegen H;Deisenhammer F;Killestein J;Lundberg IE;Vencovsky J;Nurmohamed MT;van Schaardenburg D;Bultink IE;Voskuyl AE;Pegtel DM;van der Laken CJ;Bijlsma JW;Verweij CL
I型干扰素（IFN）应答程序的激活被描述用于几种自身免疫性疾病，包括系统性红斑狼疮（SLE）、多发性硬化（MS）、肌炎（IIM）和类风湿性关节炎（RA）。虽然IFNα有助于SLE病理，但IFNβ治疗通常对MS有益，这意味着这些IFN的免疫调节作用不同。本研究旨在探讨IFNα和IFNβ介导的应答程序在自身免疫性疾病中的潜在多样性。检测了54例健康对照（HC）、69例SLE（47例检测，22例验证）、149例IFNβ治疗的MS（71例检测，78例验证）、160例未治疗的MS、78例IIM和76例RA患者外周血中23个原型I型IFN应答基因（IRGs）的基因表达。选择具有I型IFN特征的患者进行分析。我们在SLE和IFNβ治疗的MS患者中鉴定了IFNα和IFNβ特异性应答程序（分别为GC-A和GC-B）。一致地，所有SLE患者的GC-A/GC-B对数比为阳性，而几乎所有IFNβ治疗的MS患者的GC-A/GC-B对数比为阴性，这在其他队列中得到证实。将此信息应用于其他自身免疫性疾病，IIM患者显示阳性GC-A/GC-B对数比，表明主要的IFNα活性。RA患者GC-A/GC-B的对数比值较低，部分患者接近于零，表明两个聚类的相对重要性。值得注意的是，GC-A/GC-B对数比在未经治疗的MS中表现出最大的异质性;一半的患者显示GC-A优势，而其他患者显示GC-B优势或对数比接近零。我们的研究结果表明，多样化的I型干扰素在自身免疫性疾病的反应，表明不同的致病作用的I型干扰素。本文的在线版本（doi：10.1186/s13075-016-0946-9）包含补充材料，可供授权用户使用。
Activation of the type I interferon (IFN) response program is described for several autoimmune diseases, including systemic lupus erythematosus (SLE), multiple sclerosis (MS), myositis (IIM) and rheumatoid arthritis (RA). While IFNα contributes to SLE pathology, IFNβ therapy is often beneficial in MS, implying different immunoregulatory roles for these IFNs. This study was aimed to investigate potential diversification of IFNα-and IFNβ-mediated response programs in autoimmune diseases. Peripheral blood gene expression of 23 prototypical type I IFN response genes (IRGs) was determined in 54 healthy controls (HCs), 69 SLE (47 test, 22 validation), 149 IFNβ-treated MS (71 test, 78 validation), 160 untreated MS, 78 IIM and 76 RA patients. Patients with a type I IFN signature were selected for analysis. We identified IFNα- and IFNβ-specific response programs (GC-A and GC-B, respectively) in SLE and IFNβ-treated MS patients. Concordantly, the GC-A/GC-B log-ratio was positive for all SLE patients and negative for virtually all IFNβ-treated MS patients, which was confirmed in additional cohorts. Applying this information to other autoimmune diseases, IIM patients displayed positive GC-A/GC-B log-ratios, indicating predominant IFNα activity. The GC-A/GC-B log-ratio in RA was lower and approached zero in part of the patients, implying relative importance of both clusters. Remarkably, GC-A/GC-B log-ratios appeared most heterogeneous in untreated MS; half of the patients displayed GC-A dominance, whereas others showed GC-B dominance or log-ratios near zero. Our findings show diversification of the type I IFN response in autoimmune diseases, suggesting different pathogenic roles of the type I IFNs. The online version of this article (doi:10.1186/s13075-016-0946-9) contains supplementary material, which is available to authorized users.