Rheumatology Division, Faculdade de Medicina da Universidade de São Paulo (USP), Brazil.
Laboratory of Genomics and Molecular Biology, AC Camargo Cancer Center, São Paulo, Brazil.
Autoimmun Rev. 2019 Apr;18(4):393-398. doi: 10.1016/j.autrev.2018.11.004. Epub 2019 Feb 14.
Recently, two studies demonstrated that a relevant percentage of primary antiphospholipid syndrome (PAPS) patients had an upregulation of interferon (IFN) genes. However, 20%-28% of these patients had anti-dsDNA, a highly specific systemic lupus erythematosus (SLE) autoantibody. This study aimed to determine the prevalence of the type I IFN signature in the peripheral blood mononuclear cells of PAPS patients without specific SLE autoantibodies and search for its clinical associations.
Fifty-three PAPS patients (Sydney's criteria) were consecutively selected and age-matched with 50 healthy controls. A third group of nonimmune-mediated thrombophilia patients was also included. The expression of 41 IFN-induced genes was analyzed using real time quantitative PCR. A principal component analysis determined which genes composed the IFN signature, and the z-score was calculated. An ROC curve defined the signature cut-off.
Six genes remained in the IFN signature DNAJA1, IFIT5, IFI27, MX1, IFI6, and TYK2. The ROC cutoff was 3.9-fold (AUC = 0.706, S = 0.49, E = 0.86, PPV = 0.79, NPV = 0.61). The type I IFN signature was present in 49% of the patients with PAPS compared with 14.0% of the healthy controls and 17% of the nonimmune-mediated thrombophilia patients (p < .0001). The IFN signature was associated with a younger age at the first antiphospholipid syndrome event (p = .023) and with preeclampsia (p = .032).
Our results indicate that PAPS patients without lupus-specific antibodies have an enhanced type I IFN gene signature that is not observed in nonimmune-mediated thrombophilia. Also, this overexpression of type I IFN-regulated genes associated with an earlier onset of antiphospholipid syndrome event and preeclampsia.
最近，两项研究表明，相当一部分原发性抗磷脂综合征（PAPS）患者存在干扰素（IFN）基因的上调。然而，这些患者中有 20%-28%存在抗双链 DNA，这是一种高度特异性的系统性红斑狼疮（SLE）自身抗体。本研究旨在确定无特异性 SLE 自身抗体的 PAPS 患者外周血单个核细胞中 I 型 IFN 特征的流行情况，并寻找其临床相关性。
连续选择 53 名 PAPS 患者（悉尼标准），并与 50 名健康对照者年龄匹配。还纳入了一组非免疫介导的血栓形成倾向患者。使用实时定量 PCR 分析 41 个 IFN 诱导基因的表达。主成分分析确定了构成 IFN 特征的基因，计算了 z 分数。ROC 曲线定义了特征截止值。
有 6 个基因保留在 IFN 特征 DNAJA1、IFIT5、IFI27、MX1、IFI6 和 TYK2 中。ROC 截止值为 3.9 倍（AUC=0.706，S=0.49，E=0.86，PPV=0.79，NPV=0.61）。与 14.0%的健康对照组和 17%的非免疫介导的血栓形成倾向患者相比，PAPS 患者中有 49%存在 I 型 IFN 特征（p<0.0001）。IFN 特征与抗磷脂综合征首次发生时的年龄较小（p=0.023）和子痫前期（p=0.032）相关。
我们的结果表明，无狼疮特异性抗体的 PAPS 患者存在增强的 I 型 IFN 基因特征，而在非免疫介导的血栓形成倾向中则没有观察到。此外，I 型 IFN 调节基因的过度表达与抗磷脂综合征事件的更早发作和子痫前期相关。
