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Kawasaki disease (KD) is a medium vessel vasculitis that affects young children. Despite extensive research over the last 50 years, the etiology of KD remains an enigma. Seasonal change in wind patterns was shown to have correlation with the epidemics of KD in Japan. Occurrence of disease in epidemiological clusters, seasonal variation, and a very low risk of recurrence suggest that KD is triggered by an infectious agent. The identification of oligoclonal IgA response in the affected tissues suggests an antigen-driven inflammation. The recent identification of a viral antigen in the cytoplasm of bronchial ciliated epithelium also favors infection as the main trigger for KD. Pointers that suggest a genetic basis of KD include a high disease prevalence in North-East Asian populations, a high risk among siblings, and familial occurrence of cases. Dysregulated innate and adaptive immune responses are evident in the acute stages of KD. In addition to the coronary wall inflammation, endothelial dysfunction and impaired vascular remodeling contribute to the development of coronary artery abnormalities (CAAs) and thrombosis. Genetic aberrations in certain intracellular signaling pathways involving immune effector functions are found to be associated with increased susceptibility to KD and development of coronary artery abnormalities (CAAs). Several susceptible genes have been identified through genome-wide association studies (GWAS) and linkage studies (GWLS). The genes that are studied in KD can be classified under 4 major groups-enhanced T cell activation (ITPKC,ORAI1,STIM1), dysregulated B cell signaling (CD40,BLK,FCGR2A), decreased apoptosis (CASP3), and altered transforming growth factor beta signaling (TGFB2,TGFBR2,MMP,SMAD). The review aims to highlight the role of several genetic risk factors that are linked with the increased susceptibility to KD.

Purpose of review This review will highlight recent advances in our understanding of the pathogenesis of Kawasaki disease, highlighting the molecular players involved in regulation of T-cell activation and their affect on disease incidence and outcome in both humans and mouse. Recent findings Kawasaki disease is the most common cause of multisystem vasculitis in childhood. The vessels most commonly damaged are the coronary arteries, making Kawasaki disease the number one cause of acquired heart disease in children from the developed world. The contribution of genetics to disease predisposition is clearly implicated, but the mechanisms involved in regulating predisposition to disease susceptibility and outcome are not clearly understood. Two independent approaches have recently identified regulation of T-cell activation as the critical factor in determining susceptibility and severity of Kawasaki disease. Firstly, genetic analysis of affected Japanese children identified ITPKC, 1,4,5-triphosphate 3-kinase C, a kinase involved in regulation of T-cell activation, to be significantly associated with susceptibility to and increased severity of Kawasaki disease. A second independent approach using an animal model of Kawasaki disease has also identified regulation of T-cell activation, specifically costimulation, the second signal regulating optimal T-cell activation as the critical regulator of susceptibility to and severity of disease. Summary Understanding the molecular players responsible for dysregulation of the immune response in Kawasaki disease will foster development of improved diagnostic/predictive tools and more rational use of therapeutic agents to improve outcome in affected children.