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

G. Bossi, S. Mannarino, M. C. Pietrogrande, P. Salice, R. M. Dellepiane, A. L. Cremaschi, G. Corana, A. Tozzo, C. Capittini, A. De Silvestri, C. Tinelli, A. Pasi, M. Martinetti

Research output: Contribution to journalArticle

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).

Original languageEnglish
Pages (from-to)481-487
Number of pages7
JournalGenes and Immunity
Volume16
Issue number7
DOIs
Publication statusPublished - Oct 1 2015

Fingerprint

Genetic Epistasis
KIR Receptors
Mucocutaneous Lymph Node Syndrome
Disease Susceptibility
HLA Antigens
Oligodeoxyribonucleotides
Odds Ratio
Confidence Intervals
Ligands
Vasculitis
Natural Killer Cells

ASJC Scopus subject areas

  • Genetics(clinical)
  • Immunology
  • Genetics

Cite this

@article{092eda40b6b94a26b469329018a00d2b,
title = "Genetic epistasis between killer immunoglobulin-like receptors and human leukocyte antigens in Kawasaki disease susceptibility",
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).",
author = "G. Bossi and S. Mannarino and Pietrogrande, {M. C.} and P. Salice and Dellepiane, {R. M.} and Cremaschi, {A. L.} and G. Corana and A. Tozzo and C. Capittini and {De Silvestri}, A. and C. Tinelli and A. Pasi and M. Martinetti",
year = "2015",
month = "10",
day = "1",
doi = "10.1038/gene.2015.34",
language = "English",
volume = "16",
pages = "481--487",
journal = "Genes and Immunity",
issn = "1466-4879",
publisher = "Nature Publishing Group",
number = "7",

}

TY - JOUR

T1 - Genetic epistasis between killer immunoglobulin-like receptors and human leukocyte antigens in Kawasaki disease susceptibility

AU - Bossi, G.

AU - Mannarino, S.

AU - Pietrogrande, M. C.

AU - Salice, P.

AU - Dellepiane, R. M.

AU - Cremaschi, A. L.

AU - Corana, G.

AU - Tozzo, A.

AU - Capittini, C.

AU - De Silvestri, A.

AU - Tinelli, C.

AU - Pasi, A.

AU - Martinetti, M.

PY - 2015/10/1

Y1 - 2015/10/1

N2 - 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).

AB - 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).

UR - http://www.scopus.com/inward/record.url?scp=84945450807&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84945450807&partnerID=8YFLogxK

U2 - 10.1038/gene.2015.34

DO - 10.1038/gene.2015.34

M3 - Article

C2 - 26335810

AN - SCOPUS:84945450807

VL - 16

SP - 481

EP - 487

JO - Genes and Immunity

JF - Genes and Immunity

SN - 1466-4879

IS - 7

ER -