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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. 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-kappa B-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.

The antibody profile against autoantigens previously associated with autoimmune diseases and other human proteins in patients with COVID-19 or multisystem inflammatory syndrome in children (MIS-C) remains poorly defined. Here we show that 30% of adults with COVID-19 had autoantibodies against the lung antigen KCNRG, and 34% had antibodies to the SLE-associated Smith-D3 protein. Children with COVID-19 rarely had autoantibodies; one of 59 children had GAD65 autoantibodies associated with acute onset of insulin-dependent diabetes. While autoantibodies associated with SLE/Sjögren's syndrome (Ro52, Ro60, and La) and/or autoimmune gastritis (gastric ATPase) were detected in 74% (40/54) of MIS-C patients, further analysis of these patients and of children with Kawasaki disease (KD), showed that the administration of intravenous immunoglobulin (IVIG) was largely responsible for detection of these autoantibodies in both groups of patients. Monitoring in vivo decay of the autoantibodies in MIS-C children showed that the IVIG-derived Ro52, Ro60, and La autoantibodies declined to undetectable levels by 45-60 days, but gastric ATPase autoantibodies declined more slowly requiring >100 days until undetectable. Further testing of IgG and/or IgA antibodies against a subset of potential targets identified by published autoantigen array studies of MIS-C failed to detect autoantibodies against most (16/18) of these proteins in patients with MIS-C who had not received IVIG. However, Troponin C2 and KLHL12 autoantibodies were detected in 2 of 20 and 1 of 20 patients with MIS-C, respectively. Overall, these results suggest that IVIG therapy may be a confounding factor in autoantibody measurements in MIS-C and that antibodies against antigens associated with autoimmune diseases or other human proteins are uncommon in MIS-C.

This repository contains the CITE-Seq data set used in the manuscript titled "Multiomics approach identifies novel age-, time- and treatment-related immunopathological signatures in MIS-C and pediatric COVID-19". This data set is composed of the expression levels of 188 surface proteins, RNA expression, and BCR/TCR repertoire in single peripheral blood mononuclear cells from 7 multisystem inflammatory syndrome in children (MIS-C) and 8 pediatric COVID-19 patients, in addition to 7 age- and sex-matched pediatric healthy controls. 1. misc_SeuratObj_submission.rds -- Seurat object contains all count data used for the manuscript - raw sequencing data are not provided due to privacy issue - metadata is included in the Seurat object 2. MIS-C_cohort_citeseq.xlsx -- sample meta data 3. immcant_bcr_ighl_filtered.csv -- single cell BCR data 4. TCR_filtered_contig_annotations.csv -- single cell TCR data 5. README.txt -- Descriptions of the individual data files, This work was supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health (grant ZIA AI001270-01 to LDN and ZIA AI001265 to HCS), by Regione Lombardia, Italy (project "Risposta immune in pazienti con COVID-19 e co-morbidità" to RC, AL, DM, GLM for Pavia, Italy and LI and AS for Brescia, Italy), by ANID COVID 0999, Fondecyt nº 11181222 (to MCP, Chile). In addition, this project has been funded in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. 75N91019D00024 (to DBK).