Immune response to intravenous immunoglobulin in patients with Kawasaki disease and MIS-C

J Clin Invest. 2021 Oct 15;131(20):e147076. doi: 10.1172/JCI147076.


BACKGROUNDMultisystem inflammatory syndrome in children (MIS-C) is a rare but potentially severe illness that follows exposure to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Kawasaki disease (KD) shares several clinical features with MIS-C, which prompted the use of intravenous immunoglobulin (IVIG), a mainstay therapy for KD. Both diseases share a robust activation of the innate immune system, including the IL-1 signaling pathway, and IL-1 blockade has been used for the treatment of both MIS-C and KD. The mechanism of action of IVIG in these 2 diseases and the cellular source of IL-1β have not been defined.METHODSThe effects of IVIG on peripheral blood leukocyte populations from patients with MIS-C and KD were examined using flow cytometry and mass cytometry (CyTOF) and live-cell imaging.RESULTSCirculating neutrophils were highly activated in patients with KD and MIS-C and were a major source of IL-1β. Following IVIG treatment, activated IL-1β+ neutrophils were reduced in the circulation. In vitro, IVIG was a potent activator of neutrophil cell death via PI3K and NADPH oxidase, but independently of caspase activation.CONCLUSIONSActivated neutrophils expressing IL-1β can be targeted by IVIG, supporting its use in both KD and MIS-C to ameliorate inflammation.FUNDINGPatient Centered Outcomes Research Institute; NIH; American Asthma Foundation; American Heart Association; Novo Nordisk Foundation; NIGMS; American Academy of Allergy, Asthma and Immunology Foundation.

Keywords: Apoptosis; COVID-19; Innate immunity; Neutrophils.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • COVID-19 / blood
  • COVID-19 / complications*
  • COVID-19 / immunology
  • COVID-19 / therapy
  • Case-Control Studies
  • Cell Death / immunology
  • Cell Lineage / immunology
  • Child
  • Child, Preschool
  • Fas Ligand Protein / immunology
  • Female
  • Humans
  • Immunoglobulins, Intravenous / therapeutic use*
  • Infant
  • Interleukin-1beta / antagonists & inhibitors
  • Interleukin-1beta / blood
  • Leukocyte Count
  • Male
  • Mucocutaneous Lymph Node Syndrome / blood
  • Mucocutaneous Lymph Node Syndrome / immunology*
  • Mucocutaneous Lymph Node Syndrome / therapy*
  • Neutrophil Activation
  • Neutrophils / classification
  • Neutrophils / immunology
  • Neutrophils / pathology
  • Systemic Inflammatory Response Syndrome / blood
  • Systemic Inflammatory Response Syndrome / immunology*
  • Systemic Inflammatory Response Syndrome / therapy*


  • FASLG protein, human
  • Fas Ligand Protein
  • IL1B protein, human
  • Immunoglobulins, Intravenous
  • Interleukin-1beta

Supplementary concepts

  • pediatric multisystem inflammatory disease, COVID-19 related