The calcium-mobilizing enzyme inositol-triphosphate 3-kinase C (ITPKC) has a key role in the immunopathogenesis of Kawasaki disease (KD), according to research just published in The Journal of Immunology.

Credit: Debbie Maizels/Nature Medicine/NPG

The results of the study, which combined analyses of peripheral blood samples from 185 children with KD and mechanistic studies of the effects of Itpkc deficiency in a mouse model of KD, clearly show that ITPKC controls NLRP3 expression and activation via regulation of intracellular calcium levels, thereby promoting production of IL-1β and IL-18. Of note, this novel mechanism also accounts for the observed efficacy of rescue therapy with IL-1 blockers in children with treatment-refractory KD.

“A perfect storm of data led us to this specific project,” comments Rae Yeung, the study's corresponding author, referring to the group's prior findings linking an IL-1β–IL-18 cytokine signature to NLPR3 inflammasome activation in KD, as well as the known role of calcium in regulation of the NLRP3 inflammasome and recent genetic data strongly associating ITPKC variants with susceptibility to and outcome of KD. “[However,] the paradigm shift [lay in] thinking of KD as an IL-1β-mediated disease,” she continues. “We [have] identified regulation of calcium mobilization as fundamental to the underlying immunobiology of KD leading to this IL-1β signature, thus changing the way we think about KD,” Yeung explains. The researchers hypothesize that an infectious or environmental trigger of KD in an individual with low ITPKC levels (ITPKC CC risk genotype) results in increased inflammasome activation and, potentially, refractory KD.