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Immunogenetics of Kawasaki disease

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Abstract

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.

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Abbreviations

KD:

Kawasaki disease

IVIg:

Intravenous immunoglobulin

CAA:

Coronary artery aneurysms

SNP:

Single-nucleotide polymorphism

LD:

Linkage disequilibrium

TGF-β:

Transforming growth factor β

GWAS:

Genome-wide association studies

ITPKC:

Inositol 1,4,5-trisphosphate 3-kinase C

CASP3:

Caspase-3

NFAT1:

Nuclear factor of activated T cells

CRP:

C-reactive protein

ESR:

Erythrocyte sedimentation rate

CAMK2D:

Calcium/calmodulin-dependent protein kinase (CaM Kinase) II delta

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Acknowledgments

We sincerely acknowledge Dr. Jane Burns, Professor and Director, Kawasaki Disease Research Centre, Department of Pediatrics, University of California, San Diego, USA, and Dr. Yoshihiro Onouchi, Associate Professor, Department of Public Health, Chiba University Graduate School of Medicine, Chiba, Japan, for critical review of the manuscript and useful suggestions for the improvement of the manuscript.

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Kumrah, R., Vignesh, P., Rawat, A. et al. Immunogenetics of Kawasaki disease. Clinic Rev Allerg Immunol 59, 122–139 (2020). https://doi.org/10.1007/s12016-020-08783-9

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