Hospital for Special Surgery and Weill Cornell Medical College, New York, New York.
Arthritis Rheumatol. 2015 Apr;67(4):977-87. doi: 10.1002/art.39029.
To investigate whether an elevated interferon-α (IFNα) level early in pregnancy is associated with poor pregnancy outcomes and to examine the relationship of an elevated IFNα level to angiogenic imbalance.
Women were enrolled in a longitudinal case-control study of pregnant patients with lupus. Serum samples obtained monthly throughout pregnancy were assayed for IFNα and for the antiangiogenic factor soluble Flt-1 and the proangiogenic factor placenta growth factor (PlGF). Each of 28 patients with systemic lupus erythematosus (SLE) with a poor pregnancy outcome was matched to an SLE patient with an uncomplicated pregnancy and to a pregnant healthy control. The effects of IFNα and/or soluble Flt-1 on human endothelial cells and endothelial cell-trophoblast interactions were assessed.
Compared to SLE patients with uncomplicated pregnancies, patients with preeclampsia had increased IFNα levels before clinical symptoms. Patients without autoimmune disease who developed preeclampsia did not have increased IFNα levels. In SLE patients with low IFNα levels, marked angiogenic imbalance (higher soluble Flt-1, lower PlGF, and higher soluble Flt-1:PlGF ratios) preceded maternal manifestations of preeclampsia, whereas in SLE patients with high IFNα levels, preeclampsia occurred without evidence of systemic angiogenic imbalance. Treatment of human endothelial cells with soluble Flt-1 induced expression of sFLT1 messenger RNA, and IFNα dramatically amplified responses to soluble Flt-1. In a model of spiral artery transformation, only the combination of IFNα and soluble Flt-1 disrupted the ability of trophoblast cells to remodel endothelial tube structures.
Our findings identify a new mechanism by which IFNα induces an antiangiogenic milieu and increases the sensitivity of endothelial cells to soluble Flt-1, and suggest that elevated IFNα levels may contribute to the pathogenesis of preeclampsia in some pregnant patients with SLE.
探讨妊娠早期干扰素-α（IFNα）水平升高是否与不良妊娠结局相关，并研究其与血管生成失衡的关系。
对患有狼疮的妊娠患者进行了一项纵向病例对照研究，入组了这些患者。在整个妊娠期间每月采集血清样本，检测 IFNα、抗血管生成因子可溶性 Flt-1 和促血管生成因子胎盘生长因子（PlGF）的水平。将 28 例系统性红斑狼疮（SLE）不良妊娠结局患者与 SLE 无并发症妊娠患者和健康妊娠对照患者进行匹配。评估了 IFNα 和/或可溶性 Flt-1 对人内皮细胞和内皮细胞-滋养层相互作用的影响。
与无并发症妊娠的 SLE 患者相比，发生子痫前期的患者在出现临床症状前 IFNα 水平升高。无自身免疫性疾病但发生子痫前期的患者 IFNα 水平未升高。在 IFNα 水平较低的 SLE 患者中，明显的血管生成失衡（可溶性 Flt-1 升高、PlGF 降低、可溶性 Flt-1/PlGF 比值升高）先于子痫前期的母体表现，而在 IFNα 水平较高的 SLE 患者中，子痫前期发生而无系统性血管生成失衡的证据。可溶性 Flt-1 处理人内皮细胞可诱导 sFLT1 信使 RNA 的表达，IFNα 可显著放大对可溶性 Flt-1 的反应。在螺旋动脉转化模型中，只有 IFNα 和可溶性 Flt-1 的组合才会破坏滋养细胞重塑内皮管结构的能力。
我们的研究结果确定了一种新的机制，即 IFNα 诱导抗血管生成环境，并增加内皮细胞对可溶性 Flt-1 的敏感性，并提示在某些患有 SLE 的妊娠患者中，升高的 IFNα 水平可能导致子痫前期的发病机制。
