Immunopathological signatures in multisystem inflammatory syndrome in children and pediatric COVID-19
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-inst...
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Published in | Nature medicine Vol. 28; no. 5; pp. 1050 - 1062 |
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Main Authors | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
New York
Nature Publishing Group US
01.05.2022
Nature Publishing Group |
Subjects | |
Online Access | Get full text |
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Summary: | 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.
Transcriptomic, proteomic and immune repertoire profiling reveals distinct peripheral features of MIS-C and pediatric COVID-19, including elevated soluble spike protein levels, more pronounced type II IFN-dependent gene expression and a higher B cell mutation rate in patients with MIS-C. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Equally contributing co-first authors Author Contributions List of participants and their affiliations appear at the end of the paper KS, RC, SV, CL performed experiments, analyzed data, wrote and reviewed the manuscript and prepared figures and tables; OMD, CO, SA, FB, AADJ, LBR, ES, FP, DLF, DG, VO, JC, BAS, TH, MA, SH, DBK, MSL, and RG-M performed experiments, analyzed results and contributed to the writing of the manuscript; KD, YZ, MB, TK, and JJD coordinated collection, processing and cataloguing of samples; SMH supervised analysis of autoantibodies; JL analyzed HLA typing; ALS and CLD performed DNA extraction and genomic sequencing allowing resolution of HLA alleles; IMK and TMS performed high-throughput sequencing of TCR and BCR repertoire; PDB and JIC performed serology studies; AC analyzed autoantibody data; MSV analyzed data; GAMS, KB, MAS and MM reviewed clinical metadata; ER-J, CV, MCP, AL, DM, GLM, FL, UR, VD, ALV, AG, EME, LI, AS, AB, SM, DG and MT consented patients, provided biological specimens and clinical metadata; HCS coordinated with LDN collection and processing of the samples and the research project overall; JST supervised CITE-Seq experiments and critically reviewed the draft of the manuscript; LDN coordinated and supervised the research project, wrote and revised the manuscript and prepared figures and tables. |
ISSN: | 1078-8956 1546-170X 1546-170X |
DOI: | 10.1038/s41591-022-01724-3 |