KIR2DS1, 2DS5, 3DS1 and KIR2DL5 are associated with the risk of head and neck squamous cell carcinoma in Iranians.

BACKGROUND: Activating and inhibitory KIR receptors (aKIR, iKIR) control the development and function of NK cells whose function alterations adjust the tumor microenvironment immunity. This research was conducted to determine the KIRs gene impact on genetic predisposition to Head and Neck Squamous Cell Carcinoma (HNSCC) in Iranians. METHODS: KIR genotyping using sequence-specific primers-polymerase chain reaction (SSP-PCR) method was performed to identify the presence of all 16 KIR genes in 285 HNSCC patients, including laryngeal, oral cavity and pharyngeal SCC and 273 controls (CNs). RESULTS: Comparison of KIRs gene frequency between HNSCC and CNs revealed a highly significant increase in KIR2DL5, 2DS1, 2DS5, 3DS1 and CxT4 genotype and a decrease in KIR2DS4 deleted variant and AA genotype carriers. A significant increase was noted in individuals withhigher iKIRs than aKIRs in HNSCC compared with CNs. Individuals with ≥4 iKIR and those with ≥5 aKIRs were significantly more common in HNSCC than CNs. 68distinct KIR genotypes were identified in 558 individuals. CONCLUSION: Our findings determined the detrimental impact of KIR2DS1, 2DS5, 3DS1, 2DL5 and CxT4 genotype as well as the protective impact of KIR2DS4del and AA genotype on genetic predisposition to HNSCC in Iranians.

Natural killer (NK) cell receptor-HLA ligand genotype combinations associated with protection from HIV infection: investigation of how protective genotypes influence anti HIV NK cell functions.

The anti-HIV activity of natural killer (NK) cells could be induced fast enough to potentially prevent the establishment of HIV infection. Epidemiological studies identified two genotypes encoding NK receptors that contribute to NK cell function, that were more frequent in people who remained uninfected despite multiple HIV exposures than in HIV-susceptible subjects. NK cells from carriers of the *h/*y+B*57 genotype have higher NK cell functional potential and inhibit HIV replication in autologous HIV-infected CD4+ T cells (iCD4) more potently than those from carriers of non-protective genotypes. HIV suppression depends on the secretion of CC-chemokines that block HIV entry into CD4+ cells. NK cell education and the effect of HIV infection on iCD4 cell surface expression of MHC-I antigens both influenced NK cell responses to autologous iCD4. The second KIR3DS1 homozygous protective genotype encodes an activating receptor that upon interacting with its HLA-F ligand on iCD4 induces anti-viral activity.

Human Leukocyte Antigen C*12:02:02 and Killer Immunoglobulin-Like Receptor 2DL5 are Distinctly Associated with Ankylosing Spondylitis in the Taiwanese.

Human leukocyte antigen (HLA) class I ligands and Killer immunoglobulin-like receptors (KIRs) regulate the cytolytic activity of natural killer (NK) cells and certain T cells. We examined their genetic predisposition to disease susceptibility and clinical phenotypes in Taiwanese ankylosing spondylitis (AS) patients. KIR genotyping and Human Leucocyte Antigen C (HLA-C) sequencing were performed in 653 Taiwanese AS patients and 952 healthy controls. KIR genotype distributions and HLA-C allele frequencies were compared in patients and controls and among patients with and without HLA-B27 positivity, early age onset and spinal syndesmophytes. HLA-C alleles were functionally characterized using 3D structural modelling with peptide simulation. This study discovered that the HLA-C*12:02:02 allele (43.42% vs. 3.31%; p < 0.00001 odds ratio (OR), 16.88; 95% confidence intervals (CI): 11.27-25.28) confers a strong risk for Taiwanese AS development. The 3D modelling results identified four unique amino acid polymorphisms, Ala73, Trp156, Arg219 and Met304, that may affect the function of the HLA-C*12:02:02 allele. KIR2DL5 (p = 0.0047; pFDR = 0.0423) and the KIR Bx haplotype (p = 0.0000275) were protective against Taiwanese AS, while KIR 2DS4/1D (22 base pair truncated deletion; p = 0.0044; pFDR = 0.1998) appeared to be a risk factor for it. KIR2DL5 combined with the HLA-C1/C2 heterozygous genotype showed a protective effect (AS 5.97% vs. normal 11.66%; p = 0.002; pFDR = 0.0127, OR, 0.48 95% CI: 0.33-0.70); in contrast, KIR 2DS4/1D combined with the HLA-C1C1 homozygous genotype (AS 45.33% vs. normal 35.92%; p = 0.002; pFDR = 0.0127, OR, 1.48 95% CI: 1.21-1.81) represented a risk factor for AS development. Our data suggested that interactions between KIRs and their cognate HLA-C ligands may contribute to the pathogenesis of AS.

Identification of the novel KIR2DL4*00503 allele from a southern Chinese Han individual.

The novel KIR2DL4*00503 allele differs from the closest allele 2DL4*00501 by a single synonymous mutation.

Killer-cell immunoglobulin-like receptors and cytomegalovirus reactivation during late pregnancy.

Human cytomegalovirus (CMV) represents an important public health concern as it is associated with severe morbidity and mortality in transplant recipients, HIV-infected individuals and pregnant women given the risk of congenital infection. Congenital CMV is a leading cause of neurological sequelae, developmental delay and birth defects worldwide. Cytomegalovirus can be transmitted to the foetus following maternal infection or reactivation. NK cells expressing killer-cell immunoglobulin-like receptors (KIR) are part of the innate immune system and the first line of defence against viral incursions. Previous reports have shown that KIR genes are associated with CMV infections in the post-transplant setting. In this study, we set out to determine whether a protective effect of KIR genes over CMV infection is seen in Mexican pregnant women. Cytomegalovirus infection was assessed through nucleic acid testing in 200 pregnant women and 600 healthy blood donors comprising the Mexican mestizo reference population. Killer-cell immunoglobulin-like receptors and HLA-C genotypes were obtained from 200 pregnant women and 300 reference samples using a comprehensive PCR-SSP approach. We observed statistically lower carrier frequencies of cB03|tA01 gene-content haplotype, of cB03 haplotype motif, of the KIR2DL5 + 2DS3/2DS5 gene pair and of KIR2DL5 amongst CMV-positive pregnant women in comparison with those CMV negative. None of these were associated with CMV status in the reference population. Logistic regression analysis revealed that the most important factor determining CMV status during third-trimester pregnancies was the KIR2DL5 + 2DS3/2DS5 gene pair (OR 0.376 (95%CI 0.174, 0.811, P = 0.013). Our results indicate that CMV-protective KIR gene associations described in Caucasoid populations are also present in the genetically distinct Mexican mestizo population. Our results suggest that certain KIR gene combinations provide protection against CMV infections occurring during late-term pregnancies, a finding of utmost epidemiological importance given its implication with congenital CMV infections.

Killer-cell immunoglobulin-like receptors and falciparum malaria in southwest Nigeria.

Killer-cell immunoglobulin-like receptors (KIRs) are a group of natural killer cell receptors (NKRs) that regulate NK-cell-mediated production of interferon gamma (IFN-γ) in response to infection. These receptors have recently been suggested to influence the severity of clinical Plasmodium falciparum malaria infection. We examined the KIR locus in relation to malaria in children from southwest Nigeria. Sequence specific priming (SSP)-PCR was used to detect the KIR genes. The presence or absence of fifteen different KIR genes was determined in each individual and the proportions compared across 3 clinical groups; asymptomatic malaria, uncomplicated clinical malaria and severe clinical malaria. The genes KIR2DL5, KIR2DS3 and KIR2DS5 were present in a significantly higher proportion of individuals in the asymptomatic control group than in the malaria cases. Furthermore, KIR2DS3 and KIR2DS5 were present in a higher proportion of uncomplicated malaria cases than severe malaria cases. Carriage c-AB2 genotype (which comprises all centromeric KIR genes including KIR2DL5, KIR2DS3 and KIR2DS5) decreases with severity of the disease suggesting that the KIR AB profile might be associated with protection from severe malaria infection in this population in Nigeria.

Association of killer cell immunoglobulin-like receptor 2DL5 with systemic lupus erythematosus and accompanying infections.

OBJECTIVE: Identification of the association of killer cell immunoglobulin-like receptor (KIR) genes with SLE and accompanying infections. METHODS: Presence or absence of all 14 KIR genes was studied for association with SLE by case-control studies. A total of 417 SLE cases, 72 RA cases and 256 controls, all of Japanese descent, were enrolled. RESULTS: The carrier frequency of KIR2DL5 was significantly decreased in SLE patients compared with healthy controls [39.3 vs 50.4%; odds ratio (OR) = 0.64; 95% CI 0.36, 0.92; P = 0.005). When the prevalence of severe infections was analysed in 184 SLE patients, whose medical records were available, KIR2DL5 carriers were at an increased risk of overall infection and viral infection (crude OR = 2.66; 95% CI 1.43, 4.92; P = 0.017 and crude OR = 2.31; 95% CI 1.15, 4.62; P = 0.017, respectively). After adjusting for methylprednisolone pulse and/or cyclophosphamide pulse therapy, KIR2DL5 carriers were at significantly greater risk of infectious events overall (adjusted OR = 2.45; 95% CI 1.24, 4.81; P = 0.0095). However, KIR2DL5 carriers were marginally associated with an increased risk of viral infectious events (adjusted OR = 2.03; 95% CI 0.94, 4.41; P = 0.0718). CONCLUSION: KIR2DL5 was significantly associated with a decreased risk of SLE as well as an increased risk of infectious events overall in SLE patients. Our data suggest a further role of KIRs in the pathogenesis of autoimmune diseases and infection.