Down syndrome (DS) is characterized by the occurrence of three copies of human chromosome 21 (HSA21). HSA21 contains a cluster of four interferon receptor (IFN-R) genes: IFNAR1, IFNAR2, IFNGR2, and IL10RB. DS patients often develop mucocutaneous infections and autoimmune diseases, mimicking patients with heterozygous gain-of-function (GOF) STAT1 mutations, which enhance cellular responses to three types of interferon (IFN). A gene dosage effect at these four loci may contribute to the infectious and autoimmune manifestations observed in individuals with DS. We report high levels of IFN-αR1, IFN-αR2, and IFN-γR2 expression on the surface of monocytes and EBV-transformed-B (EBV-B) cells from studying 45 DS patients. Total and phosphorylated STAT1 (STAT1 and pSTAT1) levels were constitutively high in unstimulated and IFN-α- and IFN-γ-stimulated monocytes from DS patients but lower than those in patients with GOF STAT1 mutations. Following stimulation with IFN-α or -γ, but not with IL-6 or IL-21, pSTAT1 and IFN-γ activation factor (GAF) DNA-binding activities were significantly higher in the EBV-B cells of DS patients than in controls. These responses resemble the dysregulated responses observed in patients with STAT1 GOF mutations. Concentrations of plasma type I IFNs were high in 12% of the DS patients tested (1.8% in the healthy controls). Levels of type I IFNs, IFN-Rs, and STAT1 were similar in DS patients with and without recurrent skin infections. We performed a genome-wide transcriptomic analysis based on principal component analysis and interferon modules on circulating monocytes. We found that DS monocytes had levels of both IFN-α- and IFN-γ-inducible ISGs intermediate to those of monocytes from healthy controls and from patients with GOF STAT1 mutations. Unlike patients with GOF STAT1 mutations, patients with DS had normal circulating Th17 counts and a high proportion of terminally differentiated CD8⁺ T cells with low levels of STAT1 expression. We conclude a mild interferonopathy in Down syndrome leads to an incomplete penetrance at both cellular and clinical level, which is not correlate with recurrent skin bacterial or fungal infections. The constitutive upregulation of type I and type II IFN-R, at least in monocytes of DS patients, may contribute to the autoimmune diseases observed in these individuals.

唐氏综合症 (DS) 的特征是出现人类 21 号染色体 (HSA21) 的三个拷贝。HSA21 包含一组四个干扰素受体 (IFN-R) 基因：IFNAR1、IFNAR2、IFNGR2和IL10RB。DS 患者经常发生皮肤黏膜感染和自身免疫性疾病，类似于杂合性功能获得 (GOF) STAT1患者突变，可增强细胞对三种干扰素 (IFN) 的反应。这四个基因座的基因剂量效应可能导致在 DS 个体中观察到的感染和自身免疫表现。我们报告了对 45 名 DS 患者进行研究后，单核细胞和 EBV 转化的 B (EBV-B) 细胞表面的高水平 IFN-αR1、IFN-αR2 和 IFN-γR2 表达。来自 DS 患者的未刺激和 IFN-α 和 IFN-γ 刺激的单核细胞的总和磷酸化 STAT1（STAT1 和 pSTAT1）水平组成性高，但低于 GOF STAT1患者的水平突变。在用 IFN-α 或 -γ（而非 IL-6 或 IL-21）刺激后，DS 患者的 EBV-B 细胞中的 pSTAT1 和 IFN-γ 激活因子 (GAF) DNA 结合活性显着高于对照组. 这些反应类似于在STAT1患者中观察到的失调反应GOF 突变。12% 的 DS 患者的血浆 I 型干扰素浓度很高（健康对照组为 1.8%）。有和没有复发性皮肤感染的 DS 患者的 I 型 IFN、IFN-R 和 STAT1 的水平相似。我们基于循环单核细胞的主成分分析和干扰素模块进行了全基因组转录组分析。我们发现 DS 单核细胞的 IFN-α 和 IFN-γ 诱导型 ISG 水平介于健康对照和 GOF STAT1突变患者的单核细胞水平之间。与 GOF STAT1突变患者不同，DS 患者具有正常的循环 Th17 计数和高比例的终末分化 CD8 ⁺STAT1 表达水平低的 T 细胞。我们得出结论，唐氏综合征中的轻度干扰素病导致细胞和临床水平的不完全外显，这与复发性皮肤细菌或真菌感染无关。I 型和 II 型 IFN-R 的组成型上调，至少在 DS 患者的单核细胞中，可能导致在这些个体中观察到的自身免疫性疾病。