Kawasaki disease: novel insights into etiology and genetic susceptibility

Abstract

Kawasaki disease (KD) is a vasculitis of young childhood that particularly affects the coronary arteries. Molecular analysis of the oligoclonal IgA response in acute KD led to production of synthetic KD antibodies. These antibodies identify intracytoplasmic inclusion bodies in acute KD tissues. Light and electron microscopic studies indicate that the inclusion bodies are consistent with aggregates of viral proteins and RNA. Advances in molecular genetic analysis and completion of the Human Genome Project have sparked a worldwide effort to identify genes associated with KD. A polymorphism of one such gene, ITPKC, a negative regulator of T cell activation, confers susceptibility to KD in Japanese populations and increases the risk of developing coronary artery abnormalities in both Japanese and U.S. children. Identification of the etiologic agent and of genes conferring KD susceptibility are the best means of improving diagnosis and therapy and enabling prevention of this important disorder of childhood.

Figure 1

Intracytoplasmic inclusion bodies (ICI, arrows, in brown) in ciliated bronchial epithelium of an infant with acute fatal Kawasaki Disease, detected by immunohistochemistry using KD synthetic antibody. Nuclei stain blue with the hematoxylin counterstain. The ICI are consistent with aggregates of viral protein and RNA, and are likely the result of infection with a “new” RNA virus.

Figure 2

Functional significance of itpkc_3 on ITPKC mRNA and Ca2+/NFAT pathway. (A) Effect of itpkc_3 C allele on splicing of ITPKC pre mRNA. The C allele of itpkc_3 reduces splicing efficiency of IPTKC premRNA. mRNAs harboring unspliced intron 1 cannot be translated properly and will be degraded early by nonsense-mediated decay mechanism. (B) Proposed role of ITPKC as a negative regulator of Ca2+/NFAT pathway. When the T-cell receptor (TCR) is bound by antigen/MHC complex on antigen presenting cells (APCs), adaptor molecules and kinases are recruited and phospholipse C-γ1 (PLC-γ1) is activated by phosphorylation of its tyrosine residue. IP3 and diacylglycerol (DAG), another second messenger molecule, are generated by hydrolysis of phosphatidylinositol 3,4-bisphosphate (PIP2) by activated PLC-γ1. IP3 binds to its receptor expressed on endoplasmic reticulum (ER) membrane and causes the release of Ca2+ into the cytoplasm. Then depletion of Ca2+ store in ER evokes a process termed as store operated Ca2+ entry in which extracellular Ca2+ enters through calcium release-activated Ca2+ channels on the plasma membrane. Recent advances in research identified the role of stromal interaction molecule (STIM) as a sensor of Ca2+ in ER and ORAI as a calcium release-activated Ca2+ channel. Cytoplasmic Ca2+ binds calmodulin, which in turn activates calcineurin, a calmodulin-dependent phosphatase. Activated calcineurin dephosphorylate NFAT in the cytoplasm and lead nuclear translocation of NFAT. NFAT in the nucleus drives transcription of genes important in T cell activation as a homodimer or heterodimer with other transcription factors. AP1 is one of the transcription partners of NFAT, which is activated by a signal from TCR mediated by DAG (72–74). Reactions and amounts of molecules increased by the effect of itpkc_3 C alleles were represented by red characters and arrows and those reduced by blue, respectively. [Ca2+]i: intracellular free Ca2+ concentration. Reprinted with permission from Onouchi Y. Molecular Genetics of Kawasaki Disease. Pediatric Research 65(5 Part 2):46R–54R, 2009.