The autoimmune signature of hyperinflammatory multisystem inflammatory syndrome in children

• Published in: The Journal of clinical investigation Vol. 131; no. 20; pp. 1 - 17
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 15.10.2021
• Subjects: 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
• DOI: 10.1172/JCI151520
• ISSN: 1558-8238; 0021-9738

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.