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Genetic epistasis between killer immunoglobulin-like receptors and human leukocyte antigens in Kawasaki disease susceptibility

Genes & Immunity volume 16, pages 481–487 (2015)Cite this article

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Abstract

Kawasaki disease (KD) is a pediatric acute multisystemic vasculitis complicated by development of coronary artery lesions. The breakthrough theory on KD etiopathogenesis points to pathogens/environmental factors triggered by northeastern wind coming from China. Natural Killer cells and T lymphocytes express the inhibitory/activating Killer Immunoglobulin-like Receptors (KIR) to elicit an immune response against pathogens by binding to human leukocyte antigens (HLA) class I epitopes. We first report on the role of KIR/HLA genetic epistasis in a sample of 100 Italian KD children. We genotyped KIR, HLA-A, HLA-B and HLA-C polymorphisms, and compared KD data with those from 270 Italian healthy donors. The HLA-A*11 ligand for KIR2DS2/2DS4/3DL2 was a KD susceptibility marker by itself (odds ratio (OR)=3.85, confidence interval (CI)=1.55–9.53, P=0.004). Although no epistasis between HLA-A*11 and KIR2DS2/S4 emerged, HLA-A*11 also engages KIR3DL2, a framework gene encoding for a pathogen sensor of CpG-oligodeoxynucleotides (CpG-ODN), and KD blood mononuclear cells are actually prone to pathogen CpG-ODN activation in the acute phase. Moreover, carriers of KIR2DS2/HLA-C1 and KIR2DL2/HLA-C1 were more frequent among KD, in keeping with data demonstrating the involvement of these HLA/KIR couples in autoimmune endothelial damage. The highest KD risk factor was observed among carriers of KIR2DL2 and two or more HLA ligands (OR=10.24, CI=1.87–56.28; P=0.007).

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Acknowledgements

This work has been financially supported by IRCCS Foundation, Policlinico San Matteo: Research Project N. 563, from 2009 to 2015.

Author contributions

MM is responsible for the accuracy and reliability of all genetic data; GB, SM, CT, MM: conception and design of study; GB, SM, MCP, PS, RMD, ALC, GC, AT, AP: data acquisition; GB, SM, CC, ADS, CT, MM: interpretation of data; CC, CT, MM: drifting the article for conceptual contents.

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Authors and Affiliations

  1. Department of Pediatrics, IRCCS Policlinico San Matteo Foundation, viale Golgi 19, Pavia, Italy

    G Bossi & A Tozzo

  2. Department of Pediatrics, Pediatric Cardiology, IRCCS Policlinico San Matteo Foundation, viale Golgi 19, Pavia, Italy

    S Mannarino & G Corana

  3. Pediatric Clinic II, University of Milan, IRCCS Ca’ Granda Foundation, Ospedale Maggiore Policlinico, via Francesco Sforza 28, Milan, Italy

    M C Pietrogrande & R M Dellepiane

  4. Pediatric Cardiology, Cardiology Unit, IRCCS Ca’ Granda Foundation, Ospedale Maggiore Policlinico, via Francesco Sforza 28, Milan, Italy

    P Salice

  5. Immunogenetics Laboratory, Immunohematology and Transfusion Center, IRCCS Policlinico San Matteo Foundation, viale Golgi 19, Pavia, Italy

    A L Cremaschi, A Pasi & M Martinetti

  6. Biometry and Clinical Epidemiology, IRCCS Policlinico San Matteo Foundation, viale Golgi 19, Pavia, Italy

    C Capittini, A De Silvestri & C Tinelli

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  1. G Bossi
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Correspondence to M Martinetti.

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Bossi, G., Mannarino, S., Pietrogrande, M. et al. Genetic epistasis between killer immunoglobulin-like receptors and human leukocyte antigens in Kawasaki disease susceptibility. Genes Immun 16, 481–487 (2015). https://doi.org/10.1038/gene.2015.34

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