Premium
A functional polymorphism in ITPK(C) and its impact in T cell‐mediated pathogenesis of Kawasaki disease
Author(s) -
Franco Alessandra,
Shimizu Chisato,
Watson Virginia,
Tremoulet Adriana,
Onouchi Yoshihiro,
Burns Jane
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.850.12
Subject(s) - pathogenesis , nfat , immunology , ctl* , biology , cytotoxic t cell , calcineurin , signal transduction , single nucleotide polymorphism , cd8 , immune system , medicine , cancer research , gene , genetics , genotype , transcription factor , transplantation , in vitro
Kawasaki disease (KD) is a self‐limited, acute vasculitis that is the most common cause of acquired heart disease in children. Death by coronary artery aneurysms occurs in up to 25% of untreated children. T cells are critically involved in the pathogenesis of KD, as suggested by the infiltration of CD8+ cytotoxic T‐cells (CTL) in the coronary arterial walls of autopsy samples. Has been recently discovered a novel functional single nucleotide polymorphism (SNP) (itpkc_3) located in intron 1 in the inositol 1,4,5‐triphosphate kinase (ITPK)C gene on Chromosome 19 responsible for the reduction of the expression of the ITPKC kinase that catalyzes the phosphorylation of Ins(1,4,5)P3 to Ins(1,3,4,5)P4. We are currently studying the impact of the ITPKC locus in influencing the generation of pro‐inflammatory vs. regulatory T cells (Tregs). If we can understand the biologic effect of this SNP and its influence on disease susceptibility and outcome, this will be the first breakthrough in correlating a genotype with a phenotype in KD. Understanding this connection will have very important therapeutic implications since Cyclosporin A (CsA) specifically inhibits T cell activation affecting IL2 signaling through binding to calcineurin, which is an important downstream substrate of IP3 in the TCR‐NFAT signaling pathway.