ITPKC susceptibility in Kawasaki syndrome as a sensitizing factor for autoimmunity and coronary arterial wall relaxation induced by thimerosal's effects on calcium signaling via IP3

Abstract

Recently, a single nucleotide polymorphism (SNP) of the inositol 1,4,5-triphosphate kinase C (ITPKC), rs28493229, was found to passively confer susceptibility for Kawasaki syndrome (KS) and subsequent coronary arterial lesions. This association is believed to be the result of defective phosphorylation of inositol 1,4,5-triphosphate (IP3), which releases calcium from intracellular stores, resulting from reduced genetic expression of ITPKC in carriers of the SNP. Reduced ITPKC activity would increase IP3 levels, and thus, increase calcium release. We hypothesized that an environmental agent which influences IP3-mediated calcium release is potentiated by the ITPKC SNP. This led us to an attractive candidate, thimerosal, an organomercurial medical preservative still used in several pediatric vaccines. Thimerosal is well-known to sensitize IP3 receptors via its induction of oxidative stress, resulting in enhanced release of intracellular calcium with distinctive consequences for various cell types. Dysregulated calcium signaling in T cells and other immune cells can result in autoimmunity, while hyperpolarization of vascular smooth muscle cells secondary to the stimulation of calcium-activated potassium channels can result in increased vascular permeability and arterial relaxation. We propose that ITPKC susceptibility in KS is related to its synergy with environmental triggers, such as thimerosal, which alter calcium homeostasis and promote oxidative stress. Therefore, carriers of the ITPKC SNP are more susceptible to thimerosal-induced autoimmunity and coronary arterial lesions observed in KS. This would explain why only a susceptible subset of children develops KS although pediatric thimerosal exposure is nearly universal due to vaccination. As was experienced with the infantile acrodynia epidemic, only 1 in 500 children developed the disease although pediatric mercury exposure was nearly ubiquitous due to the use calomel teething powders. This hypothesis also mirrors the current leading theory for KS in which a widespread infection only induces the disease in susceptible children. We conclude that KS may be the acute febrile form of acrodynia.