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

Background Multisystem inflammatory syndrome in children (MIS-C) is a rare but potentially severe illness that follows exposure to severe acute respiratory syndrome-related 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 two diseases and the cellular source of IL-1b 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, 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 PI3-K 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.