美国西奈山伊坎医学院Dusan Bogunovic团队近期取得重要工作进展，他们研究发现I型干扰素的过度负调控破坏了唐氏综合症患者的病毒控制。该项研究成果2022年10月14日在线发表于《免疫学》杂志上。

唐氏综合征（DS）通常由21号染色体的三倍引起的。从表型上看，DS表现为发育、神经认知和免疫方面的特征。从流行病学角度看，DS患者的病毒感染较少，但一旦出现，这些感染会导致更严重的疾病。有效的抗病毒细胞因子I型干扰素（IFN-I）受体亚单位IFNAR1和IFNAR2位于21号染色体上。虽然IFNAR1/2表达增加最初导致对IFN-I过敏，但它触发了过多的负反馈，导致DS患者随后IFN-I刺激的低反应和对病毒敏感性的增加。IFNAR2表达的上调与DS IFN-I动力学和21三体性无关。

来自DS患者的CD14⁺单核细胞表现出先前IFN-I暴露的标记物，对体外IFN-I刺激的反应减弱。他们的发现揭示唐氏综合征中对IFN-I的过度和低反应的振荡，使个体更易降低病毒性疾病的发病率和增加感染相关的发病率和死亡率。

附：英文原文

Title: Excessive negative regulation of type I interferon disrupts viral control in individuals with Down syndrome

Author: Louise Malle, Marta Martin-Fernandez, Sofija Buta, Ashley Richardson, Douglas Bush, Dusan Bogunovic

Issue&Volume: 2022-10-14

Abstract: Down syndrome (DS) is typically caused by triplication of chromosome 21. Phenotypically,DS presents with developmental, neurocognitive, and immune features. Epidemiologically,individuals with DS have less frequent viral infection, but when present, these infectionslead to more severe disease. The potent antiviral cytokine type I Interferon (IFN-I)receptor subunits IFNAR1 and IFNAR2 are located on chromosome 21. While increasedIFNAR1/2 expression initially caused hypersensitivity to IFN-I, it triggered excessivenegative feedback. This led to a hypo-response to subsequent IFN-I stimuli and anensuing viral susceptibility in DS compared to control cells. Upregulation of IFNAR2expression phenocopied the DS IFN-I dynamics independent of trisomy 21. CD14+ monocytes from individuals with DS exhibited markers of prior IFN-I exposure andhad muted responsiveness to ex vivo IFN-I stimulation. Our findings unveil oscillations of hyper- and hypo-response toIFN-I in DS, predisposing individuals to both lower incidence of viral disease andincreased infection-related morbidity and mortality.

DOI: 10.1016/j.immuni.2022.09.007

Source: https://www.cell.com/immunity/fulltext/S1074-7613(22)00501-5