TY - JOUR
T1 - Emergency Myelopoiesis Distinguishes Multisystem Inflammatory Syndrome in Children From Pediatric Severe Coronavirus Disease 2019
AU - Roznik, Katerina
AU - Andargie, Temesgen E.
AU - Johnston, T. Scott
AU - Gordon, Oren
AU - Wang, Yi
AU - Akindele, Nadine Peart
AU - Persaud, Deborah
AU - Antar, Annukka A.R.
AU - Manabe, Yukari C.
AU - Zhou, Weiqiang
AU - Ji, Hongkai
AU - Agbor-Enoh, Sean
AU - Karaba, Andrew H.
AU - Thompson, Elizabeth A.
AU - Cox, Andrea L.
N1 - Publisher Copyright:
© The Author(s) 2024.
PY - 2024/8/15
Y1 - 2024/8/15
N2 - Background. Multisystem inflammatory syndrome in children (MIS-C) is a hyperinflammatory condition caused by recent infection with severe acute respiratory syndrome coronavirus 2, but the underlying immunological mechanisms driving this distinct syndrome are unknown. Methods. We utilized high-dimensional flow cytometry, cell-free (cf) DNA, and cytokine and chemokine profiling to identify mechanisms of critical illness distinguishing MIS-C from severe acute coronavirus disease 2019 (SAC). Results. Compared to SAC, MIS-C patients demonstrated profound innate immune cell death and features of emergency myelopoiesis (EM), an understudied phenomenon observed in severe inflammation. EM signatures were characterized by fewer mature myeloid cells in the periphery and decreased expression of HLA-DR and CD86 on antigen-presenting cells. Interleukin 27 (IL-27), a cytokine known to drive hematopoietic stem cells toward EM, was increased in MIS-C, and correlated with immature cell signatures in MIS-C. Upon recovery, EM signatures decreased and IL-27 plasma levels returned to normal levels. Despite profound lymphopenia, we report a lack of cfDNA released by adaptive immune cells and increased CCR7 expression on T cells indicative of egress out of peripheral blood. Conclusions. Immune cell signatures of EM combined with elevated innate immune cell-derived cfDNA levels distinguish MIS-C from SAC in children and provide mechanistic insight into dysregulated immunity contributing toward MIS-C, offering potential diagnostic and therapeutic targets.
AB - Background. Multisystem inflammatory syndrome in children (MIS-C) is a hyperinflammatory condition caused by recent infection with severe acute respiratory syndrome coronavirus 2, but the underlying immunological mechanisms driving this distinct syndrome are unknown. Methods. We utilized high-dimensional flow cytometry, cell-free (cf) DNA, and cytokine and chemokine profiling to identify mechanisms of critical illness distinguishing MIS-C from severe acute coronavirus disease 2019 (SAC). Results. Compared to SAC, MIS-C patients demonstrated profound innate immune cell death and features of emergency myelopoiesis (EM), an understudied phenomenon observed in severe inflammation. EM signatures were characterized by fewer mature myeloid cells in the periphery and decreased expression of HLA-DR and CD86 on antigen-presenting cells. Interleukin 27 (IL-27), a cytokine known to drive hematopoietic stem cells toward EM, was increased in MIS-C, and correlated with immature cell signatures in MIS-C. Upon recovery, EM signatures decreased and IL-27 plasma levels returned to normal levels. Despite profound lymphopenia, we report a lack of cfDNA released by adaptive immune cells and increased CCR7 expression on T cells indicative of egress out of peripheral blood. Conclusions. Immune cell signatures of EM combined with elevated innate immune cell-derived cfDNA levels distinguish MIS-C from SAC in children and provide mechanistic insight into dysregulated immunity contributing toward MIS-C, offering potential diagnostic and therapeutic targets.
KW - IL-27
KW - MIS-C
KW - cell-free DNA
KW - emergency myelopoiesis
KW - pediatric COVID-19
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U2 - 10.1093/infdis/jiae032
DO - 10.1093/infdis/jiae032
M3 - Article
C2 - 38299308
AN - SCOPUS:85201438391
SN - 0022-1899
VL - 230
SP - e305-e317
JO - Journal of Infectious Diseases
JF - Journal of Infectious Diseases
IS - 2
ER -