Immune response to intravenous immunoglobulin in patients with Kawasaki disease and MIS-C
Yanfang P. Zhu, … , Ben A. Croker, the Pediatric Emergency Medicine Kawasaki Disease Research Group Consortium
Yanfang P. Zhu, … , Ben A. Croker, the Pediatric Emergency Medicine Kawasaki Disease Research Group Consortium
Published August 31, 2021
Citation Information: J Clin Invest. 2021;131(20):e147076. https://doi.org/10.1172/JCI147076.
View: Text | PDF
Clinical Research and Public Health

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

Abstract

BACKGROUND Multisystem 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.METHODS The 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.RESULTS Circulating 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.CONCLUSIONS Activated neutrophils expressing IL-1β can be targeted by IVIG, supporting its use in both KD and MIS-C to ameliorate inflammation.FUNDING Patient Centered Outcomes Research Institute; NIH; American Asthma Foundation; American Heart Association; Novo Nordisk Foundation; NIGMS; American Academy of Allergy, Asthma and Immunology Foundation.

Authors

Yanfang P. Zhu, Isaac Shamie, Jamie C. Lee, Cameron J. Nowell, Weiqi Peng, Shiela Angulo, Linh N.N. Le, Yushan Liu, Huilai Miao, Hainan Xiong, Cathleen J. Pena, Elizabeth Moreno, Eric Griffis, Stephanie G. Labou, Alessandra Franco, Lori Broderick, Hal M. Hoffman, Chisato Shimizu, Nathan E. Lewis, John T. Kanegaye, Adriana H. Tremoulet, Jane C. Burns, Ben A. Croker, the Pediatric Emergency Medicine Kawasaki Disease Research Group Consortium

×

Figure 6

IVIG triggers rapid cell death of neutrophils.

Options: View larger image (or click on image) Download as PowerPoint
IVIG triggers rapid cell death of neutrophils. (A) Peripheral blood neut...
(A) Peripheral blood neutrophils undergo unique morphological changes upon exposure to 1% IVIG. Neutrophils were labeled with 50 nM CTG and incubated in the presence of AnnV-AF647 (red) and PI (yellow) to track changes in cell viability. Representative image from KD neutrophils. Two-hour time point shown. (B) Viability of neutrophils at the 8-hour time point in the presence or absence of 2 μM PIK-75, 10 μM GDC-0941, 10 μM DPI, 10 μM QVD-OPh, 100 ng/mL FcFasL, and 1% IVIG. (C) Kinetic changes in neutrophil viability classified according to staining with CTG, AnnV, and PI. (D) Changes in cell size of neutrophils treated with 100 ng/mL FcFasL or 1% IVIG.