Related Experiment Video
Updated: Oct 3, 2025
Detection of Polyfunctional T Cells in Children Vaccinated with Japanese Encephalitis Vaccine via the Flow Cytometry Technique
Published on: September 23, 2022
Immunopathological signatures in multisystem inflammatory syndrome in children and pediatric COVID-19
Keith Sacco1, Riccardo Castagnoli1,2, Svetlana Vakkilainen1
1Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
Insights
Children with multisystem inflammatory syndrome (MIS-C) show distinct immune responses compared to pediatric COVID-19. These findings reveal key differences in inflammation and genetic susceptibility, aiding in understanding MIS-C pathophysiology.
Area of Science:
- Immunology
- Pediatric Infectious Diseases
- Genetics
Background:
- Pediatric Coronavirus Disease 2019 (pCOVID-19) is typically mild, but some children develop severe multisystem inflammatory syndrome (MIS-C).
- Understanding the distinct immunopathological mechanisms of pCOVID-19 and MIS-C is crucial for effective therapeutic strategies.
Purpose of the Study:
- To comprehensively profile the multi-omic signatures of children with pCOVID-19 and MIS-C.
- To identify distinct immunological and genetic factors differentiating pCOVID-19 from MIS-C.
Main Methods:
- Longitudinal multi-institutional study utilizing multi-omics: soluble biomarkers, proteomics, single-cell gene expression, and immune repertoire analysis.
- Comparison of 110 children with pCOVID-19, 76 with MIS-C, and 76 pediatric healthy controls (pHCs).
- Analysis included interferon responses, NF-κB activation, matrisome, circulating spike protein, T cell clonotypes, HLA alleles, and B cell mutation load.
Main Results:
- pCOVID-19 exhibited robust type I interferon responses.
- MIS-C showed prominent type II interferon and NF-κB-dependent signatures, matrisome activation, and elevated spike protein, independent of PCR status.
- MIS-C was associated with transient TRBV11-2 T cell expansion, specific HLA alleles (A*02, B*35, C*04), and increased B cell mutation load.
Conclusions:
- Distinct immunopathological signatures differentiate pCOVID-19 and MIS-C.
- Findings suggest genetic susceptibility and specific immune dysregulation in MIS-C.
- These results provide insights into MIS-C pathophysiology and may guide future therapies.
Abstract:
Pediatric Coronavirus Disease 2019 (pCOVID-19) is rarely severe; however, a minority of children infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) might develop multisystem inflammatory syndrome in children (MIS-C), with substantial morbidity. In this longitudinal multi-institutional study, we applied multi-omics (analysis of soluble biomarkers, proteomics, single-cell gene expression and immune repertoire analysis) to profile children with COVID-19 (n = 110) and MIS-C (n = 76), along with pediatric healthy controls (pHCs; n = 76). pCOVID-19 was characterized by robust type I interferon (IFN) responses, whereas prominent type II IFN-dependent and NF-κB-dependent signatures, matrisome activation and increased levels of circulating spike protein were detected in MIS-C, with no correlation with SARS-CoV-2 PCR status around the time of admission. Transient expansion of TRBV11-2 T cell clonotypes in MIS-C was associated with signatures of inflammation and T cell activation. The association of MIS-C with the combination of HLA A*02, B*35 and C*04 alleles suggests genetic susceptibility. MIS-C B cells showed higher mutation load than pCOVID-19 and pHC. These results identify distinct immunopathological signatures in pCOVID-19 and MIS-C that might help better define the pathophysiology of these disorders and guide therapy.
