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Downregulation of exhausted cytotoxic T cells in gene expression networks of multisystem inflammatory syndrome in children.

ABSTRACT: Multisystem inflammatory syndrome in children (MIS-C) presents with fever, inflammation and pathology of multiple organs in individuals under 21 years of age in the weeks following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Although an autoimmune pathogenesis has been proposed, the genes, pathways and cell types causal to this new disease remain unknown. Here we perform RNA sequencing of blood from patients with MIS-C and controls to find disease-associated genes clustered in a co-expression module annotated to CD56^dimCD57⁺ natural killer (NK) cells and exhausted CD8⁺ T cells. A similar transcriptome signature is replicated in an independent cohort of Kawasaki disease (KD), the related condition after which MIS-C was initially named. Probing a probabilistic causal network previously constructed from over 1,000 blood transcriptomes both validates the structure of this module and reveals nine key regulators, including TBX21, a central coordinator of exhausted CD8⁺ T cell differentiation. Together, this unbiased, transcriptome-wide survey implicates downregulation of NK cells and cytotoxic T cell exhaustion in the pathogenesis of MIS-C.

SUBMITTER: Beckmann ND

PROVIDER: S-EPMC8357784 | biostudies-literature | 2021 Aug

REPOSITORIES: biostudies-literature

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Downregulation of exhausted cytotoxic T cells in gene expression networks of multisystem inflammatory syndrome in children.

Beckmann Noam D ND Comella Phillip H PH Cheng Esther E Lepow Lauren L Beckmann Aviva G AG Tyler Scott R SR Mouskas Konstantinos K Simons Nicole W NW Hoffman Gabriel E GE Francoeur Nancy J NJ Del Valle Diane Marie DM Kang Gurpawan G Do Anh A Moya Emily E Wilkins Lillian L Le Berichel Jessica J Chang Christie C Marvin Robert R Calorossi Sharlene S Lansky Alona A Walker Laura L Yi Nancy N Yu Alex A Chung Jonathan J Hartnett Matthew M Eaton Melody M Hatem Sandra S Jamal Hajra H Akyatan Alara A Tabachnikova Alexandra A Liharska Lora E LE Cotter Liam L Fennessy Brian B Vaid Akhil A Barturen Guillermo G Shah Hardik H Wang Ying-Chih YC Sridhar Shwetha Hara SH Soto Juan J Bose Swaroop S Madrid Kent K Ellis Ethan E Merzier Elyze E Vlachos Konstantinos K Fishman Nataly N Tin Manying M Smith Melissa M Xie Hui H Patel Manishkumar M Nie Kai K Argueta Kimberly K Harris Jocelyn J Karekar Neha N Batchelor Craig C Lacunza Jose J Yishak Mahlet M Tuballes Kevin K Scott Ieisha I Kumar Arvind A Jaladanki Suraj S Agashe Charuta C Thompson Ryan R Clark Evan E Losic Bojan B Peters Lauren L Roussos Panagiotis P Zhu Jun J Wang Wenhui W Kasarskis Andrew A Glicksberg Benjamin S BS Nadkarni Girish G Bogunovic Dusan D Elaiho Cordelia C Gangadharan Sandeep S Ofori-Amanfo George G Alesso-Carra Kasey K Onel Kenan K Wilson Karen M KM Argmann Carmen C Bunyavanich Supinda S Alarcón-Riquelme Marta E ME Marron Thomas U TU Rahman Adeeb A Kim-Schulze Seunghee S Gnjatic Sacha S Gelb Bruce D BD Merad Miriam M Sebra Robert R Schadt Eric E EE Charney Alexander W AW

Nature communications 20210811 1

Multisystem inflammatory syndrome in children (MIS-C) presents with fever, inflammation and pathology of multiple organs in individuals under 21 years of age in the weeks following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Although an autoimmune pathogenesis has been proposed, the genes, pathways and cell types causal to this new disease remain unknown. Here we perform RNA sequencing of blood from patients with MIS-C and controls to find disease-associated genes clu ...[more]

PMID: 34381049

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Project description:BackgroundEvidence is urgently needed to support treatment decisions for children with multisystem inflammatory syndrome (MIS-C) associated with severe acute respiratory syndrome coronavirus 2.MethodsWe performed an international observational cohort study of clinical and outcome data regarding suspected MIS-C that had been uploaded by physicians onto a Web-based database. We used inverse-probability weighting and generalized linear models to evaluate intravenous immune globulin (IVIG) as a reference, as compared with IVIG plus glucocorticoids and glucocorticoids alone. There were two primary outcomes: the first was a composite of inotropic support or mechanical ventilation by day 2 or later or death; the second was a reduction in disease severity on an ordinal scale by day 2. Secondary outcomes included treatment escalation and the time until a reduction in organ failure and inflammation.ResultsData were available regarding the course of treatment for 614 children from 32 countries from June 2020 through February 2021; 490 met the World Health Organization criteria for MIS-C. Of the 614 children with suspected MIS-C, 246 received primary treatment with IVIG alone, 208 with IVIG plus glucocorticoids, and 99 with glucocorticoids alone; 22 children received other treatment combinations, including biologic agents, and 39 received no immunomodulatory therapy. Receipt of inotropic or ventilatory support or death occurred in 56 patients who received IVIG plus glucocorticoids (adjusted odds ratio for the comparison with IVIG alone, 0.77; 95% confidence interval [CI], 0.33 to 1.82) and in 17 patients who received glucocorticoids alone (adjusted odds ratio, 0.54; 95% CI, 0.22 to 1.33). The adjusted odds ratios for a reduction in disease severity were similar in the two groups, as compared with IVIG alone (0.90 for IVIG plus glucocorticoids and 0.93 for glucocorticoids alone). The time until a reduction in disease severity was similar in the three groups.ConclusionsWe found no evidence that recovery from MIS-C differed after primary treatment with IVIG alone, IVIG plus glucocorticoids, or glucocorticoids alone, although significant differences may emerge as more data accrue. (Funded by the European Union's Horizon 2020 Program and others; BATS ISRCTN number, ISRCTN69546370.).

Dataset Information

Downregulation of exhausted cytotoxic T cells in gene expression networks of multisystem inflammatory syndrome in children.

Publications

Downregulation of exhausted cytotoxic T cells in gene expression networks of multisystem inflammatory syndrome in children.

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