Genetic epistasis between killer immunoglobulin-like receptors and human leukocyte antigens in Kawasaki disease susceptibility.
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).
Department of Pediatrics, IRCCS Policlinico San Matteo Foundation, viale Golgi 19, Pavia, Italy.
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G
Bossi
Department of Pediatrics, Pediatric Cardiology, IRCCS Policlinico San Matteo Foundation, viale Golgi 19, Pavia, Italy.
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S
Mannarino
Pediatric Clinic II, University of Milan, IRCCS Ca' Granda Foundation, Ospedale Maggiore Policlinico, via Francesco Sforza 28, Milan, Italy.
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MC
Pietrogrande
Pediatric Cardiology, Cardiology Unit, IRCCS Ca' Granda Foundation, Ospedale Maggiore Policlinico, via Francesco Sforza 28, Milan, Italy.
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Salice
Pediatric Clinic II, University of Milan, IRCCS Ca' Granda Foundation, Ospedale Maggiore Policlinico, via Francesco Sforza 28, Milan, Italy.
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RM
Dellepiane
Immunogenetics Laboratory, Immunohematology and Transfusion Center, IRCCS Policlinico San Matteo Foundation, viale Golgi 19, Pavia, Italy.
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AL
Cremaschi
Department of Pediatrics, Pediatric Cardiology, IRCCS Policlinico San Matteo Foundation, viale Golgi 19, Pavia, Italy.
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G
Corana
Department of Pediatrics, IRCCS Policlinico San Matteo Foundation, viale Golgi 19, Pavia, Italy.
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A
Tozzo
Biometry and Clinical Epidemiology, IRCCS Policlinico San Matteo Foundation, viale Golgi 19, Pavia, Italy.
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C
Capittini
Biometry and Clinical Epidemiology, IRCCS Policlinico San Matteo Foundation, viale Golgi 19, Pavia, Italy.
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http://orcid.org/0000-0003-3128-8441
A
De Silvestri
Biometry and Clinical Epidemiology, IRCCS Policlinico San Matteo Foundation, viale Golgi 19, Pavia, Italy.
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C
Tinelli
Immunogenetics Laboratory, Immunohematology and Transfusion Center, IRCCS Policlinico San Matteo Foundation, viale Golgi 19, Pavia, Italy.
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A
Pasi
Immunogenetics Laboratory, Immunohematology and Transfusion Center, IRCCS Policlinico San Matteo Foundation, viale Golgi 19, Pavia, Italy.
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M
Martinetti
D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D004198:Disease Susceptibility / Q000276:immunology; D004843:Epistasis, Genetic; D005260:Female; D005787:Gene Frequency; D006680:HLA Antigens / Q000235:genetics* / Q000276:immunology*; D059870:HLA-A11 Antigen / Q000235:genetics; D015235:HLA-B Antigens / Q000235:genetics; D015236:HLA-C Antigens / Q000235:genetics; D000949:Histocompatibility Antigens Class II / Q000235:genetics / Q000276:immunology; D006801:Humans; D007136:Immunoglobulins / Q000235:genetics / Q000276:immunology; D008297:Male; D009080:Mucocutaneous Lymph Node Syndrome / Q000235:genetics* / Q000276:immunology*; D011110:Polymorphism, Genetic; D054340:Receptors, KIR / Q000235:genetics* / Q000276:immunology*
D006680:HLA Antigens; D059870:HLA-A11 Antigen; D015235:HLA-B Antigens; D015236:HLA-C Antigens; D000949:Histocompatibility Antigens Class II; D007136:Immunoglobulins; D054340:Receptors, KIR