Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 131, Issue 20, Pages -Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI151520
Keywords
-
Categories
Funding
- Cedars-Sinai Precision Health award
- NIH [R01 AI072726, 3RO1AI072726-10S1, R01HL11136]
- Advanced Clinical Biosystems Research Institute
- Erika Glazer Covid Fund
Ask authors/readers for more resources
This study characterized the immunopathogenesis of MIS-C using proteomics, RNA sequencing, autoantibody arrays, and BCR repertoire analysis. The findings revealed a strong autoimmune signature with autoantibodies targeting ubiquitously expressed and tissue-specific antigens, as well as a cluster of patients with enhanced neutrophil responses and high levels of anti-Spike IgG and autoantibodies. The research also identified pathogenic pathways that lead to MIS-C, potentially informing treatment strategies.
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 TRBV112 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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available