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).

An immune‐molecular hypothesis supporting infectious aetiopathogenesis of Kawasaki disease in children

“…1 bottom). Consistent with our hypothesis, we previously found a high frequency of HLA-A*11 allele among KD patients compared to controls [9], thus confirming the overabundant presence of an HLA ligand for KIR3DL2.…”

“…Here, we tried to verify this genetic balance in KD children. We subdivided 100 KD children and 3533 healthy cord blood (CB) donors into the three HLA‐B Bw genotype groups, and analyzed the surrogate role of HLA‐A alleles coding ligands for KIR3DL1 and KIR3DL2 through their distribution in the three HLA‐B Bw genotype groups . All subjects were Caucasoids from Italy.…”

Pathogenetic determinants in Kawasaki disease: the haematological point of view

“…Several further evidence suggested that genetic determinants could contribute to the pathogenesis or progression of KD, such as: ( i ) the relationship found between interleukin IL‐1 polymorphisms and initial IVIG treatment failure in KD children , ( ii ) the finding that KCNN2 gene, a member of the KCNN family of potassium channel genes located on chromosome 5q22.3, could have a role as a new risk locus for coronary aneurysms , ( iii ) the genome‐wide association studies suggesting FCGR2A gene, encoding for low‐affinity immunoglobulin gamma Fc region receptor II‐a protein, as a susceptibility locus for KD onset and, finally, ( iv ) the hypothesis that genetic variations at the human leucocyte antigen (HLA) and killer immunoglobulin‐like receptors (KIR) loci could exert a modulatory activity either individually or in combination (HLA‐KIR epistasis) . Candidate genes in the etiopathogenesis of KD are listed in Table .…”

Decreased interferon‐γ production by NK cells from KIR haplotype B carriers in hepatitis C virus infection

“…HLA‐A, HLA‐B and HLA‐C polymorphisms were defined by the reverse PCR sequence‐specific oligonucleotide hybridization method (revPCR‐SSO) using LabType SSO Class I Locus A and Locus B kit , (One Lambda, ThermoFisher Scientific, Waltham, MA, USA), following the manufacturer's instructions. When only one allele was detected, the subject was considered homozygote …”