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

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Figure 5

IVIG treatment in patients with KD or MIS-C is associated with a decrease of IL-1β–producing neutrophils and reduced activation.

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IVIG treatment in patients with KD or MIS-C is associated with a decreas...
(A) Left panel: flow cytometry gating strategy demonstrating reduced mature neutrophils after IVIG treatment in a representative KD patient (top) and a representative MIS-C patient (bottom). The percentages of neutrophils in live CD45+ cells are indicated on the contour plots. Right panel: absolute cell numbers of mature neutrophils per mL of whole blood. (B) Flow cytometry evaluation of NePs per mL of whole blood. (C) Serum G-CSF in patients with KD before treatment (n = 5) and 2 to 6 weeks after IVIG treatment (n = 5). (D) Flow cytometry evaluation of total numbers of IL-1β+ mature neutrophils (left panel) and IL-1β– mature neutrophils (right panel) per mL of whole blood. (E) Flow cytometry evaluation of total numbers of IL-1β+ NePs (left panel) and IL-1β– NePs per mL of whole blood (right panel). (F) Heatmap shows the median metal intensity of each marker in neutrophils from 5 MIS-C patients before treatment and 1 day after IVIG treatment evaluated by CyTOF. (G) Heatmap showing FLOWSOM automated clustering of neutrophil subsets from 5 MIS-C patients before treatment and 1 day after IVIG treatment. (H–J) CyTOF evaluation of total cell numbers of neutrophils (H), mature neutrophil subsets (I), and NeP subsets (J) per mL of whole blood. Samples were analyzed from 5 patients with MIS-C prior to treatment and 1 day after IVIG treatment. Differences between before and after IVIG treatment were determined via unpaired t tests (2-tailed) based on IVIG-alone samples (A, B, D, and E) or by ratio paired t tests (C, H, I, and J). Lines on dot plots indicate median with IQR. *P < 0.05; **P < 0.005; ***P < 0.0005