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The autoimmune signature of hyperinflammatory multisystem inflammatory syndrome in children.
- Source :
-
The Journal of clinical investigation [J Clin Invest] 2021 Oct 15; Vol. 131 (20). - Publication Year :
- 2021
-
Abstract
- Multisystem inflammatory syndrome in children (MIS-C) manifests as a severe and uncontrolled inflammatory response with multiorgan involvement, occurring weeks after SARS-CoV-2 infection. Here, we utilized proteomics, RNA sequencing, autoantibody arrays, and B cell receptor (BCR) repertoire analysis to characterize MIS-C immunopathogenesis and identify factors contributing to severe manifestations and intensive care unit admission. Inflammation markers, humoral immune responses, neutrophil activation, and complement and coagulation pathways were highly enriched in MIS-C patient serum, with a more hyperinflammatory profile in severe than in mild MIS-C cases. We identified a strong autoimmune signature in MIS-C, with autoantibodies targeted to both ubiquitously expressed and tissue-specific antigens, suggesting autoantigen release and excessive antigenic drive may result from systemic tissue damage. We further identified a cluster of patients with enhanced neutrophil responses as well as high anti-Spike IgG and autoantibody titers. BCR sequencing of these patients identified a strong imprint of antigenic drive with substantial BCR sequence connectivity and usage of autoimmunity-associated immunoglobulin heavy chain variable region (IGHV) genes. This cluster was linked to a TRBV11-2 expanded T cell receptor (TCR) repertoire, consistent with previous studies indicating a superantigen-driven pathogenic process. Overall, we identify a combination of pathogenic pathways that culminate in MIS-C and may inform treatment.
- Subjects :
- Adaptive Immunity
Adolescent
Biomarkers metabolism
COVID-19 genetics
COVID-19 immunology
COVID-19 metabolism
Case-Control Studies
Child
Child, Preschool
Cohort Studies
Cytokine Release Syndrome immunology
Female
Humans
Infant
Inflammation immunology
Male
Mucocutaneous Lymph Node Syndrome genetics
Mucocutaneous Lymph Node Syndrome immunology
Mucocutaneous Lymph Node Syndrome metabolism
Neutrophil Activation
Proteomics
RNA-Seq
Receptors, Antigen, B-Cell genetics
Severity of Illness Index
Systemic Inflammatory Response Syndrome genetics
Systemic Inflammatory Response Syndrome metabolism
Autoimmunity
COVID-19 complications
Systemic Inflammatory Response Syndrome immunology
Subjects
Details
- Language :
- English
- ISSN :
- 1558-8238
- Volume :
- 131
- Issue :
- 20
- Database :
- MEDLINE
- Journal :
- The Journal of clinical investigation
- Publication Type :
- Academic Journal
- Accession number :
- 34437303
- Full Text :
- https://doi.org/10.1172/JCI151520