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.

Kawasaki disease (KD) is a pediatric self-limited vasculitis characterized by immune-mediated destruction of the arterial wall and myocardium. Neither the trigger that incites the inflammation nor the switch that turns it off is known. To further our understanding of KD pathogenesis and the role of regulatory T-cells in modulating the inflammatory response, we studied circulating effector memory T-cells (CCR7 − and IL-15+ T^em) and central memory T-cells (CCR7+ and IL-15+ T^cm) in six KD subjects. In two of the subjects, we cloned the remaining T-cell population by limiting dilution. TaqMan analysis of T^em studied in two KD subjects suggested that T^em are pro-inflammatory CD4+T-helper 1 cells and CD8+ cytotoxic T-cells. Following memory T-cells over time, we defined that circulating T^em and T^cm are detectable during the acute phase in some KD subjects before treatment with intravenous immunoglobulin. Both T^em and T^cm expand rapidly within 2 weeks of treatment. The circulating T^em pool contracts, while T^cm further proliferate in the convalescent phase. Following depletion of memory T-cells, numerous T-cell clones were derived from two acute KD subjects. The large majority of these T-cells displayed the functional phenotype of peripherally induced regulatory T-cells (T^reg). These findings provide insight into the nature and kinetics of the adaptive immune response in KD.

We demonstrated that B-cell–dendritic cell (DC) interactions via transmembrane activator and calcium modulator and cyclophilin ligand (CAML) interactor (TACI) and B-lymphocyte stimulator (BLyS) provide an early signal critical to generate adequate numbers of mature antigen presenting cells (APCs) to prime naive CD8⁺ T cells (CTLs) in vivo. Evidence that B cells are required for efficient CTL generation in mice and that reconstitution with wild-type but not TACI-knockout B cells restored normal CTL responses support our conclusion. Moreover, low doses of a TACI fusion protein (TACI-Fc) that express the extracellular domain of TACI (amino acid [aa] 1-126) restored CTL priming in B-cell–deficient mice in vivo and induced DC maturation in vitro. In fact, following interactions with B cells, splenic DCs rapidly express the CD86 costimulatory molecule, to an extent comparable to the exposure to antigenic stimuli. BLyS^high peptide-pulsed bone marrow–derived DCs, used as vaccines in vivo, cannot generate CTLs in B-cell–deficient and TACI-deficient mice, strongly supporting a need for B-cell–DC cooperation through TACI-BLyS during CTL first encounter with antigens in vivo.