The autoimmune signature of hyperinflammatory multisystem inflammatory syndrome in children

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...

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Vydáno v:	The Journal of clinical investigation Ročník 131; číslo 20; s. 1 - 17
Hlavní autoři:	Porritt, Rebecca A., Binek, Aleksandra, Paschold, Lisa, Rivas, Magali Noval, McArdle, Angela, Yonker, Lael M., Alter, Galit, Chandnani, Harsha K., Lopez, Merrick, Fasano, Alessio, Van Eyk, Jennifer E., Binder, Mascha, Arditi, Moshe
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	United States American Society for Clinical Investigation 15.10.2021
Témata:	Adaptive Immunity Adolescent Antigens Autoantibodies Autoimmunity B-cell receptor Biomarkers Biomarkers - metabolism Biomedical research Case-Control Studies Cell activation Child Child, Preschool Children Cohort Studies Complement activation Coronaviruses COVID-19 COVID-19 - complications COVID-19 - genetics COVID-19 - immunology COVID-19 - metabolism Cytokine Release Syndrome - immunology Cytokine storm Disease Female Genetic aspects Health aspects Humans Immune response Immune response (humoral) Immunoglobulin G Immunopathogenesis Infant Inflammation Inflammation - immunology Intensive care Leukocytes (neutrophilic) Lymphocytes Lymphocytes T Male Mucocutaneous Lymph Node Syndrome - genetics Mucocutaneous Lymph Node Syndrome - immunology Mucocutaneous Lymph Node Syndrome - metabolism Multisystem inflammatory syndrome in children Neutrophil Activation Neutrophils Pandemics Pathogenesis Patients Pediatric research Pediatrics Peptides Plasma Proteins Proteomics Receptors, Antigen, B-Cell - genetics RNA-Seq Severe acute respiratory syndrome coronavirus 2 Severity of Illness Index Systemic Inflammatory Response Syndrome - genetics Systemic Inflammatory Response Syndrome - immunology Systemic Inflammatory Response Syndrome - metabolism T cell receptors Variable region United States COVID-19 Inflammation Cytokines Autoimmune diseases Cellular immune response
ISSN:	1558-8238, 0021-9738, 1558-8238
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Popis
Shrnutí:	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.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 Authorship note: RAP, AB, and LP contributed equally to this work. JVE, MB, and MA are co–senior authors and contributed equally to this work.
ISSN:	1558-8238 0021-9738 1558-8238
DOI:	10.1172/JCI151520