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 infection-associated autoimmune cytopenias.

中文翻译：

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SOCS1单倍剂量不足的儿童的免疫失调和多系统炎症综合征（MIS-C）。

背景

我们在急性感染的情况下研究了2名无关的免疫性血小板减少症和自身免疫性溶血性贫血患者。在严重急性呼吸系统综合症冠状病毒2感染的情况下，一名儿童在儿童中发展了多系统炎症综合症。

目标

我们试图确定潜在机制的感染驱动自身免疫性血细胞减少症的发展。

方法

全-是两个病人进行基因组测序，并确定变异的影响，通过使用患者的外周血单个核细胞功能试验验证。

结果

发现每位患者在细胞因子信号传导1（SOCS1）抑制剂中都有独特的杂合截短变异体。SOCS1是I型和II型IFN信号传导的基本负调节剂。患者的PBMC显示出信号转导和转录激活因子1磷酸化水平的提高，以及以I型和II型IFN刺激基因和促凋亡基因的表达增加为特征的转录特征。患者未刺激的PBMC表现出的增强的IFN信号与儿童多系统炎症综合症相关的高炎症状态相平行，这表明SOCS1在调节儿童多系统炎症综合症的炎症反应特征中的贡献。

结论

杂合功能丧失的SOCS1突变与增强的IFN信号传导和增强的免疫细胞活化有关，从而易患感染相关的自身免疫性血细胞减少症。