Immune dysregulation and multisystem inflammatory syndrome in children (MIS-C) in individuals with haploinsufficiency of SOCS1
Immune dysregulation and multisystem inflammatory syndrome in children (MIS-C) in individuals with haploinsufficiency of SOCS1
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DOI：
10.1016/j.jaci.2020.07.033
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发表时间：
2020-11-01
影响因子：
14.2
通讯作者：
Chou, Janet
中科院分区：
文献类型：
--
作者：
Lee, Pui Y.;Platt, Craig D.;Chou, Janet
背景：我们研究了 2 名在急性感染情况下患有免疫性血小板减少症和自身免疫性溶血性贫血的无关患者。一名儿童在严重急性呼吸综合征冠状病毒 2 感染的情况下出现多系统炎症综合征。目的：我们试图确定感染驱动的自身免疫性血细胞减少症发生的潜在机制。方法：对两名患者进行全外显子组测序，并通过使用患者的 PBMC 进行功能测定来验证已识别变异的影响。结果：发现每位患者的细胞因子信号传导抑制因子 1 (SOCS1) 均具有独特的杂合截短变异。 SOCS1 是 I 型和 II 型 IFN 信号传导的重要负调节因子。患者的 PBMC 显示信号转导子和转录 1 磷酸化激活剂水平增加，以及以 I 型和 II 型 IFN 刺激基因和促凋亡基因表达增加为特征的转录特征。患者未受刺激的PBMC表现出增强的IFN信号，与儿童多系统炎症综合征相关的高炎症状态相似，表明SOCS1在调节儿童多系统炎症综合征的炎症反应特征中的贡献。结论：杂合性功能丧失的SOCS1突变与IFN信号增强和免疫细胞激活增加有关，从而易患感染相关的自身免疫性血细胞减少症。
Background: We studied 2 unrelated patients with immune thrombocytopenia and autoimmune hemolytic anemia in the setting of acute infections. One patient developed multisystem inflammatory syndrome in children in the setting of a severe acute respiratory syndrome coronavirus 2 infection. Objectives: We sought to identify the mechanisms underlying the development of infection-driven autoimmune cytopenias.Methods: Whole-exome sequencing was performed on both patients, and the impact of the identified variants was validated by functional assays using the patients' PBMCs.Results: Each patient was found to have a unique heterozygous truncation variant in suppressor of cytokine signaling 1 (SOCS1). SOCS1 is an essential negative regulator of type I and type II IFN signaling. The patients' PBMCs showed increased levels of signal transducer and activator of transcription 1 phosphorylation and a transcriptional signature characterized by increased expression of type I and type II IFN-stimulated genes and proapoptotic genes. The enhanced IFN signature exhibited by the patients' unstimulated PBMCs parallels the hyperinflammatory state associated with multisystem inflammatory syndrome in children, suggesting the contributions of SOCS1 in regulating the inflammatory response characteristic of multisystem inflammatory syndrome in children.Conclusions: Heterozygous loss-of-function SOCS1 mutations are associated with enhanced IFN signaling and increased immune cell activation, thereby predisposing to infectionassociated autoimmune cytopenias.