儿童新型冠状病毒相关多系统炎症综合征中Notch1-CD22依赖性免疫失调

Notch1-CD22-Dependent Immune Dysregulation in the SARS-CoV2-Associated Multisystem Inflammatory Syndrome in Children.

作者信息

Chatila Talal A, Benamar Mehdi, Chen Qian, Chou Janet, Julé Amelie, Boudra Rafik, Contini Paola, Crestani Elena, Wang Muyun, Fong Jason, Lai Peggy, Rockwitz Shira, Lee Pui, Chan Tsz Man Fion, Altun Ekin Zeynep, Kepenekli Eda, Karakoc-Aydiner Elif, Ozen Ahmet, Boran Perran, Aygun Fatih, Onal Pinar, Sakalli Ayse Ayzit Kilinc, Cokugras Haluk, Gelmez Metin, Öktelik Fatma, Cetin Esin Aktaş, Zhong Yuelin, Taylor Maria, Irby Katherine, Halasa Natasha, Signa Sara, Prigione Ignazia, Gattorno Marco, Cotugno Nicola, Amodio Donato, Geha Raif, Son Mary Beth, Newburger Jane, Agrawal Pankaj, Volpi Stefano, Palma Paolo, Kiykim Ayca, Randolph Adrienne, Deniz Gunnur, Baris Safa, De Palma Raffaele, Schmitz-Abe Klaus, Charbonnier Louis-Marie, Henderson Lauren

机构信息

Boston Children's Hospital - Harvard Medical School.

INSERM.

出版信息

Res Sq. 2022 Apr 11:rs.3.rs-1054453. doi: 10.21203/rs.3.rs-1054453/v1.

DOI:10.21203/rs.3.rs-1054453/v1

PMID:35441180

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9016654/

Abstract

Multisystem inflammatory syndrome in children (MIS-C) evolves in some pediatric patients following acute infection with SARS-CoV-2 by hitherto unknown mechanisms. Whereas acute-COVID-19 severity and outcome were previously correlated with Notch4 expression on regulatory T (Treg) cells, here we show that the Treg cells in MIS-C are destabilized in association with increased Notch1 expression. Genetic analysis revealed that MIS-C patients were enriched in rare deleterious variant impacting inflammation and autoimmunity pathways, including dominant negative mutations in the Notch1 regulators and . Notch1 signaling in Treg cells induced CD22, leading to their destabilization in an mTORC1 dependent manner and to the promotion of systemic inflammation. These results establish a Notch1-CD22 signaling axis that disrupts Treg cell function in MIS-C and point to distinct immune checkpoints controlled by individual Treg cell Notch receptors that shape the inflammatory outcome in SARS-CoV-2 infection.

摘要

儿童多系统炎症综合征（MIS-C）在一些儿科患者中，由迄今未知的机制在感染SARS-CoV-2后演变而来。虽然急性COVID-19的严重程度和结局以前与调节性T（Treg）细胞上的Notch4表达相关，但在这里我们表明，MIS-C中的Treg细胞因Notch1表达增加而不稳定。基因分析显示，MIS-C患者中影响炎症和自身免疫途径的罕见有害变异富集，包括Notch1调节因子和中的显性负性突变。Treg细胞中的Notch1信号诱导CD22，导致其以mTORC1依赖的方式不稳定，并促进全身炎症。这些结果建立了一个Notch1-CD22信号轴，该轴破坏了MIS-C中Treg细胞的功能，并指出了由个体Treg细胞Notch受体控制的不同免疫检查点，这些受体塑造了SARS-CoV-2感染中的炎症结局。