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.
Keywords: Autoimmune diseases; COVID-19; Cellular immune response; Cytokines; Inflammation.
【저자키워드】 COVID-19, Inflammation, Cytokines, Cellular immune response, Autoimmune diseases, 【초록키워드】 Treatment, IgG, Autoimmunity, proteomics, Cytokines, intensive care, Cellular immune response, SARS-COV-2 infection, children, Sequencing, neutrophil, complement, immune, MIS-C, Coagulation, B cell, serum, T cell, Immunoglobulin, anti-Spike IgG, autoantibodies, immune responses, Immunopathogenesis, RNA sequencing, Patient, pathway, Cluster, Mild, antigens, Autoimmune, receptor, Autoimmune diseases, humoral immune responses, TCR, T cell receptor, Admission, autoantigen, inflammation markers, BCR, Multiorgan, intensive care unit admission, Combination, Inflammatory response, Analysis, Inflammatory, superantigen, manifestation, neutrophil activation, autoantibody, TRBV11-2, heavy chain, variable region, Factor, coagulation pathways, tissue damage, Previous studies, Usage, antigenic, sequence, syndrome, pathogenic, previous study, Hyperinflammatory, Genes, neutrophil response, identify, expressed, contributing to, IGHV, 【제목키워드】 children, Autoimmune, Inflammatory, syndrome, Hyperinflammatory,