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

This article has been Reviewed by the following groups

Read the full article See related articles

Listed in

Log in to save this article

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 dim CD57 + 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.

Article activity feed

  1. SciScore for 10.1101/2020.08.29.20182899: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    Institutional Review Board StatementIRB: Bayesian Network analysis: In the context of a large independent IBD study, whole blood RNA-seq data was obtained via a protocol approved by the Icahn School of Medicine at Mount Sinai Institutional Review Board.
    Consent: Informed consent was obtained from all participants recruited into this independent study.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Sex as a biological variablenot detected.

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    The quality-filtered raw data was then converted into FASTQ files using bcl2fastq Conversion tool (Illumina).
    bcl2fastq
    suggested: (bcl2fastq , RRID:SCR_015058)
    RNA-seq reads were …
  2. Strength of evidence

    Reviewers: Moshe Arditi, Magali Noval Rivas, Rebecca A. Porritt (Cedars-Sinai Medical Center) | 📒📒📒◻️◻️
    Ashraf Harahsheh, Vanessa Bundy (Children's National Hospital) | 📙📙 ◻️◻️◻️
    Paolo Palma (Bambino Gesù Children's Hospital) | 📕 ◻️◻️◻️◻️

  3. Paolo Palma

    Review 3: "Cytotoxic lymphocytes are dysregulated in multisystem inflammatory syndrome in children"

    This study compares transcriptomes from patients afflicted with MIS-C, a condition resulting from COVID-19, with other pediatric disorders and finds MIS-C shares a similar molecular etiology to Kawasaki Disease. Reviewers found the claims unsubstantiated and greatly misleading.

  4. Ashraf Harahsheh, Vanessa Bundy

    Review 2: "Cytotoxic lymphocytes are dysregulated in multisystem inflammatory syndrome in children"

    This study compares transcriptomes from patients afflicted with MIS-C, a condition resulting from COVID-19, with other pediatric disorders and finds MIS-C shares a similar molecular etiology to Kawasaki Disease. Reviewers found the claims unsubstantiated and greatly misleading.

  5. Moshe Arditi, Magali Noval Rivas, Rebecca A. Porritt

    Review 1: "Cytotoxic lymphocytes are dysregulated in multisystem inflammatory syndrome in children"

    This study compares transcriptomes from patients afflicted with MIS-C, a condition resulting from COVID-19, with other pediatric disorders and finds MIS-C shares a similar molecular etiology to Kawasaki Disease. Reviewers found the claims unsubstantiated and greatly misleading.