Related Experiment Video
Updated: May 12, 2026
Single-cell Analysis of Immunophenotype and Cytokine Production in Peripheral Whole Blood via Mass Cytometry
Published on: June 26, 2018
Cell-free DNA reveals distinct pathology of multisystem inflammatory syndrome in children
Temesgen E Andargie1,2, Katerina Roznik3, Neelam Redekar4
1Genomic Research Alliance for Transplantation (GRAfT) and Laboratory of Applied Precision Omics, National Heart, Lung, and Blood Institute (NHLBI), NIH, Bethesda, Maryland, USA. GFAfT is detailed in Supplemental Acknowledgments.
Insights
Multisystem inflammatory syndrome in children (MIS-C) involves significant tissue injury, primarily driven by innate immune responses. Cell-free DNA (cfDNA) analysis reveals damage in various tissues, offering insights into MIS-C pathogenesis.
Area of Science:
- Immunology
- Molecular Biology
- Pediatrics
Background:
- Multisystem inflammatory syndrome in children (MIS-C) is a severe hyperinflammatory condition linked to SARS-CoV-2 infection.
- The precise mechanisms of systemic tissue injury in MIS-C remain poorly understood.
- Understanding MIS-C pathophysiology is crucial for developing effective treatments.
Purpose of the Study:
- To investigate the spectrum of tissue injury in MIS-C using epigenomics and cytokine profiling.
- To elucidate the role of innate immunity in MIS-C pathogenesis.
- To evaluate cell-free DNA (cfDNA) as a biomarker for tissue damage in MIS-C.
Main Methods:
- Analysis of plasma cell-free DNA (cfDNA) epigenomics in MIS-C patients, pediatric COVID-19 (pCOVID-19) patients, and pediatric healthy controls (pHCs).
- Measurement of plasma cytokine levels.
- Correlation analysis between cfDNA origins, cytokine levels, and clinical presentation.
Main Results:
- MIS-C patients exhibited elevated cfDNA levels originating from innate immune cells, megakaryocyte-erythroid precursors, and non-hematopoietic tissues (liver, heart, kidney).
- cfDNA profiles in MIS-C showed significant interindividual variability, reflecting heterogeneous clinical symptoms.
- Innate immune cell cfDNA levels correlated with inflammatory cytokines and non-hematopoietic tissue cfDNA, suggesting innate immunity drives multisystem pathology.
Conclusions:
- MIS-C pathogenesis is predominantly mediated by innate immunity, leading to widespread tissue injury.
- cfDNA analysis is a sensitive tool for mapping tissue damage in MIS-C.
- cfDNA holds potential as a biomarker for various multiorgan inflammatory conditions.
Abstract:
Multisystem inflammatory syndrome in children (MIS-C) is a rare but life-threatening hyperinflammatory condition induced by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that causes pediatric COVID-19 (pCOVID-19). The relationship of the systemic tissue injury to the pathophysiology of MIS-C is poorly defined. We leveraged the high sensitivity of epigenomics analyses of plasma cell-free DNA (cfDNA) and plasma cytokine measurements to identify the spectrum of tissue injury and glean mechanistic insights. Compared with pediatric healthy controls (pHCs) and patients with pCOVID-19, patients with MIS-C had higher levels of cfDNA primarily derived from innate immune cells, megakaryocyte-erythroid precursor cells, and nonhematopoietic tissues such as hepatocytes, cardiac myocytes, and kidney cells. Nonhematopoietic tissue cfDNA levels demonstrated significant interindividual variability, consistent with the heterogenous clinical presentation of MIS-C. In contrast, adaptive immune cell-derived cfDNA levels were comparable in MIS-C and pCOVID-19 patients. Indeed, the cfDNA of innate immune cells in patients with MIS-C correlated with the levels of innate immune inflammatory cytokines and nonhematopoietic tissue-derived cfDNA, suggesting a primarily innate immunity-mediated response to account for the multisystem pathology. These data provide insight into the pathogenesis of MIS-C and support the value of cfDNA as a sensitive biomarker to map tissue injury in MIS-C and likely other multiorgan inflammatory conditions.
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