tetano
Editor, Senior Moderator
J Clin Invest
. 2023 Aug 31;e171729.
doi: 10.1172/JCI171729. Online ahead of print. Cell-free DNA reveals distinct pathology of multisystem inflammatory syndrome in children (MIS-C)
Temesgen E Andargie[SUP] 1 [/SUP], Katerina Roznik[SUP] 2 [/SUP], Neelam R Redekar[SUP] 3 [/SUP], Tom Hill[SUP] 3 [/SUP], Weiqiang Zhou[SUP] 4 [/SUP], Zainab Apalara[SUP] 5 [/SUP], Hyesik Kong[SUP] 1 [/SUP], Oren Gordon[SUP] 6 [/SUP], Rohan Meda[SUP] 1 [/SUP], Woojin Park[SUP] 1 [/SUP], Trevor S Johnston[SUP] 2 [/SUP], Yi Wang[SUP] 4 [/SUP], Sheila Brady[SUP] 7 [/SUP], Hongkai Ji[SUP] 4 [/SUP], Jack A Yanovski[SUP] 7 [/SUP], Moon Kyoo Jang[SUP] 1 [/SUP], Clarence M Lee[SUP] 8 [/SUP], Andrew H Karaba[SUP] 2 [/SUP], Andrea L Cox[SUP] 9 [/SUP], Sean Agbor-Enoh[SUP] 1 [/SUP]
Affiliations
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 epigenomic analyses of plasma cell-free DNA (cfDNA) and plasma cytokine measurements to identify the spectrum of tissue injury and glean mechanistic insights. Compared to pediatric healthy controls (pHC) and pCOVID-19, MIS-C patients had higher levels of cfDNA primarily derived from innate immune cells, megakaryocyte-erythroid precursor cells, and non-hematopoietic tissues such as hepatocytes, cardiac myocytes, and kidney cells. Non-hematopoietic tissue cfDNA levels demonstrated significant inter-individual 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 innate immune cells cfDNA in MIS-C correlated with levels of innate immune inflammatory cytokines and non-hematopoietic tissue-derived cfDNA, suggesting a primarily innate immunity-mediated response to account for multi-system 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 multi-organ inflammatory conditions.
Keywords: Cytokines; Epigenetics; Infectious disease; Inflammation; Molecular diagnosis.
. 2023 Aug 31;e171729.
doi: 10.1172/JCI171729. Online ahead of print. Cell-free DNA reveals distinct pathology of multisystem inflammatory syndrome in children (MIS-C)
Temesgen E Andargie[SUP] 1 [/SUP], Katerina Roznik[SUP] 2 [/SUP], Neelam R Redekar[SUP] 3 [/SUP], Tom Hill[SUP] 3 [/SUP], Weiqiang Zhou[SUP] 4 [/SUP], Zainab Apalara[SUP] 5 [/SUP], Hyesik Kong[SUP] 1 [/SUP], Oren Gordon[SUP] 6 [/SUP], Rohan Meda[SUP] 1 [/SUP], Woojin Park[SUP] 1 [/SUP], Trevor S Johnston[SUP] 2 [/SUP], Yi Wang[SUP] 4 [/SUP], Sheila Brady[SUP] 7 [/SUP], Hongkai Ji[SUP] 4 [/SUP], Jack A Yanovski[SUP] 7 [/SUP], Moon Kyoo Jang[SUP] 1 [/SUP], Clarence M Lee[SUP] 8 [/SUP], Andrew H Karaba[SUP] 2 [/SUP], Andrea L Cox[SUP] 9 [/SUP], Sean Agbor-Enoh[SUP] 1 [/SUP]
Affiliations
- PMID: 37651206
- DOI: 10.1172/JCI171729
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 epigenomic analyses of plasma cell-free DNA (cfDNA) and plasma cytokine measurements to identify the spectrum of tissue injury and glean mechanistic insights. Compared to pediatric healthy controls (pHC) and pCOVID-19, MIS-C patients had higher levels of cfDNA primarily derived from innate immune cells, megakaryocyte-erythroid precursor cells, and non-hematopoietic tissues such as hepatocytes, cardiac myocytes, and kidney cells. Non-hematopoietic tissue cfDNA levels demonstrated significant inter-individual 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 innate immune cells cfDNA in MIS-C correlated with levels of innate immune inflammatory cytokines and non-hematopoietic tissue-derived cfDNA, suggesting a primarily innate immunity-mediated response to account for multi-system 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 multi-organ inflammatory conditions.
Keywords: Cytokines; Epigenetics; Infectious disease; Inflammation; Molecular diagnosis.