Predisposing factors, pathogenesis and therapeutic intervention of Kawasaki disease

Abstract

Kawasaki disease (KD) is an acute febrile childhood inflammatory disease, associated with coronary artery abnormalities. The disease is believed to result from an aberrant inflammatory response to an infectious trigger in a genetically predisposed individual. KD is associated with an endothelial cell injury as a consequence of T cell activation and cytotoxic effects of various proinflammatory cytokines. Intravenous immunoglobulin (IVIG) infusion and aspirin are the standard treatment of acute KD. However, 10-20% of patients show resistance to IVIG therapy and present higher risk of coronary vasculitis. The relative roles of second IVIG infusion, corticosteroids, calcineurin inhibitors, interleukin-1 antagonists and anti-tumor necrosis factor agents remain uncertain. In this review, we highlight the predisposing factors, pathogenesis and therapeutic intervention of KD, particularly new therapeutics for IVIG-resistant patients.

Figure 1

Pathogenesis of Kawasaki disease. It was proposed that an infectious trigger activates TLR and induces accumulation of pro-IL-1β. ITPKC controls Ca²⁺ homeostasis by phosphorylating IP3 and genome-wide association studies have reported that polymorphisms within the ITPKC gene were associated with susceptibility and severity of Kawasaki disease. IP3 binds to its receptor IP3R expressed on the endoplasmic reticulum membrane and causes the release of Ca²⁺ into the cytoplasm. Ca²⁺ mobilization mediates NLRP3 activation. Certain PAMPS are also capable of directly activating the NLRP3 inflammasome. Activation of the inflammasome results in the cleavage of pro-IL-1β into its biologically active form IL-1β, which shapes adaptive immune responses. IL-1β can enhance naive T cell survival and proliferation, via upregulation of the IL-2 receptor. Additionally, a role for IL-1R signaling in Th17 cell differentiation and homeostasis has been reported. Abbreviations: ER, endoplasmic reticulum; IL, interleukin; IP3, inositol 1,4,5-triphosphate; IP4, inositol tetrakisphosphate; ITPKC, inositol-triphosphate 3-kinase C; NLRP3, NOD-like receptor family pyrin domain containing 3; PAMPS, pathogen-associated molecular patterns; PIP2, phosphatidylinositol 4,5-bisphosphate; PLC, phospholipase C; ROS, reactive oxygen species; TLR, Toll-like receptor.