Killer Cell Immunoglobulin-like Receptors Genotypes Research Articles

Natural killer cell activity and frequency of killer cell immunoglobulin‐like receptors in children with different forms of juvenile idiopathic arthritis

Juvenile idiopathic arthritis (JIA) has three major onset types with widely varying clinical features: systemic, polyarticular and pauciarticular. We assessed natural killer (NK) cell function and killer cell immunoglobulin-like receptor (KIR) genotypes in patients with different JIA subtypes. Peripheral blood samples from 72 children with active JIA (systemic, 25; polyarticular, 24; pauciarticular, 23) and 25 controls were used for flow cytometric assessments of NK cell count, cytotoxicity, perforin, granzyme B, interferon (IFN)-γ and tumour necrosis factor (TNF)-α. Samples from 220 children with JIA (systemic, 84; polyarticular, 72; pauciarticular, 64) and 150 controls were used for KIR2DS2, KIR2DS4, KIR3DS1, KIR2DL1, KIR2DL2, KIR2DL3 and KIR3DL1 typing by polymerase chain reaction with sequence-specific oligonucleotide probes. Compared with the controls, the patients with systemic JIA showed lower NK cell counts, cytotoxicity and perforin and granzyme B expression (p<0.05), while the patients with pauci- and polyarticular JIA showed higher perforin and granzyme B expression (p<0.05). NK cells produced higher level of TNF-α while lower level of IFN-γ in the pauci- and polyarticular JIA groups than in the systemic JIA group (p<0.05). No significant differences in KIR gene frequencies were found between the JIA subgroups and healthy controls, except for the positive frequency and locus frequency of KIR2DS4, which were lower in the systemic JIA group. Compared with poly- and pauciarticular JIA, systemic JIA is associated with decreased NK cell function, more IFN-γ and less TNF-α secretion of NK cell and lower KIR2DS4 frequency.

Support vector machine algorithms in the search of KIR gene associations with disease

Killer-cell immunoglobulin-like receptors (KIR) are membrane proteins expressed by natural killer cells and CD8 lymphocytes. The KIR system consists of 17 genes and 614 alleles, some of which bind human leukocyte antigens (HLA). Both KIR and HLA modulate susceptibility to haematological malignancies, viral infections and autoimmune diseases. Molecular epidemiology studies employ traditional statistical methods to identify links between KIR genes and disease. Here we describe our results at applying artificial intelligence algorithms (support vector machines) to identify associations between KIR genes and disease. We demonstrate that these algorithms are capable of classifying samples into healthy and diseased groups based solely on KIR genotype with potential use in clinical decision support systems.

High prevalence of HHV8 infection and specific killer cell immunoglobulin-like receptors allotypes in Sardinian patients with type 2 diabetes mellitus

The development of type 2 diabetes is thought to involve both environmental, possibly infectious, and genetic factors. Recently, a high prevalence of human herpesvirus 8 (HHV8) infection was observed in type 2 diabetes patients, and specific killer cell immunoglobulin-like receptors (KIR) allotypes were associated to both increased susceptibility to herpesvirus infection and risk to develop diabetes. However, no clear gene-disease or virus-disease associations have been established. To investigate the possible interplay between HHV8 infection, KIR allotype and type 2 diabetes, virus prevalence and KIR genotype were analyzed by PCR in 168 patients affected by type 2 diabetes and 108 control individuals belonging to the Sardinian population. Results showed a significant increase of HHV8 prevalence in type 2 diabetes patients versus controls (57% vs. 17%, P < 0.001), and a significant increase of KIR2DL2/DS2 homozygosity in diabetes patients infected with HHV8 compared to uninfected ones (64% vs. 14%, P < 0.0001), resulting in a significant OR of 11.31. In addition, the analysis of the frequency of the KIR2DL2/DS2 receptor and its HLA-C1 ligand, accordingly to the status of HHV8 infection, showed a significant increased correlation between KIR2DL2/DS2, type 2 diabetes and HLA-C1C1 genotype in the type 2 diabetes patients infected with HHV8 compared to uninfected ones (62% vs. 15%, P < 0.0001, OR = 8.64). These findings provide preliminary evidence that HHV8 infection might be a cofactor for type 2 diabetes in a specific subset of genetically susceptible individuals, and suggest the possibility that such patients might have an impaired immune-mediated component contributing to the development of type 2 diabetes.

KIR gene content does not contribute to susceptibility to Graves' disease.

Killer cell immunoglobulin-like receptors (KIR) are expressed on NK cells and a subset of T cells. The variable KIR receptors along with their ligands, HLA class I, influence risk for autoimmune and malignant diseases. To investigate the KIR gene profiles in relation to susceptibility to Graves' disease in patients with ophthalmopathy. KIR genes profiles were analyzed in 90 patients presenting Graves' disease with ophthalmopathy representing upper eyelid retraction, swelling, redness, conjunctivitis, and bulging eyes and were compared with the KIR gene profiles of 112 healthy controls. The presence and absence of 11 variable KIR genes were characterized using a gene-specific PCR typing system. There was no significant difference in the distribution of KIR gene profiles between patients and controls. Our data show that none of the KIR genotypes contribute in susceptibility to Graves' disease; although the role of HLA ligand remains to be characterized.

Killer cell immunoglobulin-like receptor (KIR) genes and their HLA-C ligands in a Ugandan population

Killer cell immunoglobulin-like receptor (KIR) genes are expressed by natural killer cells and encoded by a family of genes exhibiting considerable haplotypic and allelic variation. HLA-C molecules, the dominant ligands for KIR, are present in all individuals and are discriminated by two KIR epitopes, C1 and C2. We studied the frequencies of KIR genes and HLA-C1 and C2 groups in a large cohort (n = 492) from Kampala, Uganda, East Africa and compared our findings with published data from other populations in sub-Saharan Africa (SSA) and several European populations. We find considerably more KIR diversity and weaker linkage disequilibrium in SSA compared to the European populations and describe several novel KIR genotypes. C1 and C2 frequencies were similar to other SSA populations with a higher frequency of the C2 epitope (54.9 %) compared to Europe (average 39.7 %). Analysis of this large cohort from Uganda in the context of other African populations reveals variations in KIR and HLA-C1 and C2 that are consistent with migrations within Africa and potential selection pressures on these genes. Our results will help understand how KIR/HLA-C interactions contribute to resistance to pathogens and reproductive success.Electronic supplementary materialThe online version of this article (doi:10.1007/s00251-013-0724-7) contains supplementary material, which is available to authorized users.

Association of KIR genotype with susceptibility to HLA-B27-positive ankylosing spondylitis

Objective Recent studies have explored the role of killer cell immunoglobulin-like receptors (KIRs) in chronic autoimmune diseases. The purpose of this study was to demonstrate whether KIR genes contribute to the pathogenesis of ankylosing spondylitis (AS) in Chinese populations.Methods Sixteen KIR genes were genotyped from 60 unrelated patients with AS and 60 HLA-B27-positive matched healthy controls by PCR-SSP. The frequencies of the KIR alleles and genotypes in the AS and control groups were assessed by the χ2 test.Results Our results showed that the frequency of the activator receptor KIR3DS1 gene in the AS group was significantly increased compared to the controls (χ2 = 5.263, P = 0.006, OR = 3.059, 95 % CI = 1.357–6.896). Moreover, the frequency of the KIR3DL1/3DS1 genotype was greater in the AS group than in the control group (P = 0.039, OR = 3.059, 95 % CI = 1.357–6.896). In contrast, the frequency of the no KIR3DL1/no 3DS1 genotype was lower in patients with AS compared with the controls (P = 0.032, OR = 0.110, 95 % CI = 0.013–0.911).Conclusion KIR3DS1, in addition to HLA-B27, may play an important independent role in the pathogenesis of AS in the Chinese population.

Natural Killer Cell Immunoglobulin-like Receptor (KIR) genotypes in Follicular Lymphoma patients: Results of a pilot study

AimsThe Natural Killer Cell Immunoglobulin-like Receptor (KIR) genotype profiling in Follicular Lymphoma has not been reported before in the literature. Materials and methodsDNA extracted from 20 Follicular Lymphoma patients and 62 healthy controls was analyzed for KIR genotyping using a polymerase chain reaction/sequence specific primers technique (PCR/SSP) for the presence of 16 KIR gene and pseudogene loci. ResultsThe AA, AB, and BB genotype frequencies were, respectively, 20%, 60% and 20% with an A:B ratio of 1:1. KIR 2DL4, KIR 3DL2, KIR 3DL3, and KIR 3DP1*003 were presented in all individuals. No significant difference between patients and controls was detected. ConclusionKIR genotyping profile does not seem to be associated with Follicular Lymphoma. The results presented in this pilot research represent the first international report about this important clinical entity.

Distribution of KIR genes in Han population in Yunnan Province: comparison with other Han populations in China

Killer cell immunoglobulin-like receptors (KIRs) show extensive variation among different populations. In this study, 404 unrelated individuals in Han population in Yunnan Province, China, were genotyped for the presence or the absence of 16 KIR genes using the multiplex PCR-SSP method. Our data showed that the inhibitory gene frequency of genes KIR2DL1, KIR2DL3, KIR3DL1, KIR2DL5 and KIR2DL2 was 0.930, 0.889, 0.789, 0.206 and 0.095, respectively, and the activating gene frequency of KIR2DS4, KIR3DS1, KIR2DS1, KIR2DS5, KIR2DS2 and KIR2DS3 was 0.795, 0.218, 0.196, 0.165, 0.095 and 0.087, respectively. In all, 44 distinct KIR genotypes were identified; genotype 1 was predominant with a frequency of 0.478, followed by genotypes 2 and 8 with a frequency of 0.121 and 0.077, respectively. Haplotype A outnumbered haplotype B by 2.39:1. In addition, phylogenetic tree and multidimensional scaling analysis (MDS) based on KIR genes in populations including Asian, African and Caucasians have been performed. Neighbour-joining tree analysis and the MDS plot showed that Han populations were clustered together with Asian and were separate from other populations. The Han populations in China were separated into northern and southern groups; the Yunnan Han population investigated in this study was clustered in the southern group. These results implied that the difference between northern and southern Han populations might reflect responses to a variety of locally acting epidemiological challenges.

Are Killer Cell Immunoglobulin-Like Receptor Genes Important for the Prediction of Kidney Graft Rejection?

Killer cell immunoglobulin-like receptors (KIRs) are expressed on natural killer cells and minor subpopulations of thymus-derived (T) lymphocytes. KIRs may have a long cytoplasmic tail and inhibit cell activation upon ligand (HLA class I) binding, or they may have a short cytoplasmic tail and activate a cell after ligand binding. They are encoded by up to 14 genes present in different individuals in different combinations, whence their associations with several human diseases. KIR involvement in the fate of kidney allograft has not been extensively studied; nevertheless some associations had already been noticed. Their results are not concordant: some authors found no effect of KIR genotype, whereas others detected protective effect of KIR2DL2/KIR2DS2 or KIR-KIR ligand mismatch. We found an association of KIR2DS4 gene with acute rejection and a protective effect of KIR2DS5 gene. Interestingly, in patients, whose end-stage renal disease was caused by glomerulonephritis, the effect of KIR2DS4 was stronger than HLA mismatch, whereas opposite was true for recipients with other causes of renal failure.

No Impact of KIR-Ligand Mismatch on Allograft Outcome in HLA-Compatible Kidney Transplantation

Natural killer (NK) cell function can be modulated by the killer cell immunoglobulin-like receptors (KIR) which interact with human leukocyte antigen (HLA) class I molecules on target cells. KIR-ligand mismatching has recently been shown by van Bergen et al. (American Journal of Transplantation 2011; 11(9): 1959-1964) to be a significant risk factor for long-term graft loss in HLA-A, -B and -DR compatible kidney transplants. To verify this potentially important finding, we performed genotyping of 608 deceased-donor kidney graft recipients and their HLA-A, -B and -DR compatible donors for KIR and HLA, using samples and clinical data provided by the Collaborative Transplant Study. Graft survival of KIR-ligand-matched and -mismatched transplants was compared. We found no impact of KIR-ligand mismatching on 10-year graft survival in HLA-A, -B, -DR compatible kidney transplants. Further analysis did not reveal a significant effect of recipient activating/inhibitory KIR or KIR genotypes on graft survival. Our data do not support the concept that KIR-HLA matching might serve as a tool to improve long-term renal allograft survival.

Diversity of Killer Cell Immunoglobulin-like Receptor Genes in Uveitis Associated with Autoimmune Diseases: Ankylosing Spondylitis and Behçet Disease

Purpose: To determine whether the frequencies of specific killer cell immunoglobulin-like receptors (KIR) genotypes are associated with the incidence of uveitis in ankylosing spondylitis (AS) and Behçet disease (BD).Methods: The authors analyzed the frequency of 16 KIR genes in Koreans with either AS (110 patients, all HLA-B27-positive) or BD (86 patients), using polymerase chain reaction sequence-specific oligonucleotide probing.Results: The frequency of the inhibitory receptor KIR3DL1 was lower in AS patients affected by uveitis than that in the general population (p < 0.05). The frequency of the KIR3DL1−/2DS3− was significantly higher in AS patients with uveitis (odds ratio = 9.306, p = 0.007).Conclusions: The study suggests that KIR3DL1 might associate with the resistance to AS–associated uveitis by influencing natural killer cell activity.

Diversity of killer cell immunoglobulin like receptor genes in the Mongolian population

Killer cell immunoglobulin like receptor (KIR) is highly polymorphic in genotype, haplotype and allele levels. This study was done to investigate KIR genes frequencies, genotypes and inheritance in Mongolian. Gene-specific PCR amplification was used to identify the presence or absence of 16 KIR loci.KIR genotypes were obtained by a KIR genotypes website. The KIR genes frequencies of Mongolian were compared to 24 different populations around the world. The distribution of haplotype B in Mongolian was higher than that in Mongoloid and less than that in Caucasian. Thirty discovered genotypes and five novel genotypes were identified from 1 to 34 individuals. 37.8% of Mongolian carried KIR haplotype AA.Mongolian was exhibited between North Mongoloid and Caucasus by principal component and genetic tree analysis.

A database for curating the associations between killer cell immunoglobulin-like receptors and diseases in worldwide populations

The killer cell immunoglobulin-like receptors (KIR) play a fundamental role in the innate immune system, through their interactions with human leucocyte antigen (HLA) molecules, leading to the modulation of activity in natural killer (NK) cells, mainly related to killing pathogen-infected cells. KIR genes are hugely polymorphic both in the number of genes an individual carries and in the number of alleles identified. We have previously developed the Allele Frequency Net Database (AFND, http://www.allelefrequencies.net), which captures worldwide frequencies of alleles, genes and haplotypes for several immune genes, including KIR genes, in healthy populations, covering >4 million individuals. Here, we report the creation of a new database within AFND, named KIR and Diseases Database (KDDB), capturing a large quantity of data derived from publications in which KIR genes, alleles, genotypes and/or haplotypes have been associated with infectious diseases (e.g. hepatitis C, HIV, malaria), autoimmune disorders (e.g. type I diabetes, rheumatoid arthritis), cancer and pregnancy-related complications. KDDB has been created through an extensive manual curation effort, extracting data on more than a thousand KIR-disease records, comprising >50 000 individuals. KDDB thus provides a new community resource for understanding not only how KIR genes are associated with disease, but also, by working in tandem with the large data sets already present in AFND, where particular genes, genotypes or haplotypes are present in worldwide populations or different ethnic groups. We anticipate that KDDB will be an important resource for researchers working in immunogenetics.Database URL: http://www.allelefrequencies.net/diseases/

Potential Implication of Activating Killer Cell Immunoglobulin‐Like Receptor and HLA in Onset of Pulmonary Tuberculosis

Killer cell immunoglobulin-like receptor (KIR) and human leucocyte antigen (HLA) play crucial role in maintaining immune homoeostasis and controlling immune responses. To investigate the influence of KIR and HLA-C ligands on the risk of pulmonary tuberculosis (PTB), we studied 200 patients who were confirmed to have PTB and 200 healthy controls on the different frequencies of KIR and HLA-C ligands. Genotyping of these genes was conducted by sequence-specific primer polymerase chain reaction (SSP-PCR) method. Gene frequencies were compared between PTB group and the control group by χ(2) test, and P < 0.05 was regarded as statistically significant. As a result, the frequency of KIR genotype A/B was increased in PTB than controls but A/A was decreased. Moreover, striking differences were observed in the frequencies of HLA-Cw*08 between the two groups. Besides, the frequencies of '2DL2/3 with C1' in PTB were increased compared with control group. In addition, individuals with no KIR2DS3 and no Cw*08 were higher in controls than in PTB. KIR2DS1 was increased in PTB when HLA-C group 2 alleles were missing. In conclusion, KIR and HLA-C gene polymorphisms were related to susceptibility to PTB.

18-OR

Aim Natural Killer cells cause elimination of malignant and virus-infected cells by their cell surface receptors namely Killer-cell Immunoglobulin-like Receptors (KIR). Current KIR genotyping methods use sequence-based typing or sequence-specific primer or oligonucleotide probe (SSP/SSO) based PCR followed by agarose gel electrophoresis. Our aim was to evaluate the feasibility of using a quantitative PCR (qPCR) based research assay for KIR genotyping with minimal DNA input and reduced turn around time with potential for a multiplex KIR genotyping assay in a single tube. Methods A panel of 24 DNA containing common KIR genotypes was obtained from UCLA. 85 ng total DNA for 16 KIR reactions was used for the qPCR research assays compared to 2-3 μg DNA in a SSP-PCR commercial kit. DNA genotypes were confirmed with a SSP-PCR commercial kit and results were compared using the developed qPCR research assay. 32 primers and 16 FAM labeled probes were designed for this assay. The same primer set was also validated using a SYBR Green qPCR assay. A qPCR internal positive control accounts for true absence of KIR alleles. Results KIR research qPCR and SYBR Green qPCR assay genotyping results were 100% concordant with the commercial SSP-PCR kit. Our developed assay could identify the presence or absence of each KIR allele with a 35× reduction in DNA input with no post-PCR analyses or additional specialized equipment. Conclusions We have developed, optimized and validated a qPCR research assay for KIR genotyping that is robust and flexible for both small and large scale genetic analysis studies with potential for high throughput protocols. With more associations of KIR and disease outcomes in autoimmunity, infectious diseases, pregnancy-related complications and in transplantation, a more efficient and sensitive qPCR assay with faster detection might aid earlier therapy intervention making genotyping KIRs using qPCR based assays ideal in clinical and in basic research settings. Wadia: Quest Diagnostics: Employee; Stockholder. Bost: Quest Diagnostics: Employee.

HLA-C–Dependent Prevention of Leukemia Relapse by Donor Activating KIR2DS1

BackgroundOf the cancers treated with allogeneic hematopoietic stem-cell transplantation (HSCT), acute myeloid leukemia (AML) is most sensitive to natural killer (NK)–cell reactivity. The activating killer-cell immunoglobulin-like receptor (KIR) 2DS1 has ligand specificity for HLA-C2 antigens and activates NK cells in an HLA-dependent manner. Donor-derived NK reactivity controlled by KIR2DS1 and HLA could have beneficial effects in patients with AML who undergo allogeneic HSCT.MethodsWe assessed clinical data, HLA genotyping results, and donor cell lines or genomic DNA for 1277 patients with AML who had received hematopoietic stem-cell transplants from unrelated donors matched for HLA-A, B, C, DR, and DQ or with a single mismatch. We performed donor KIR genotyping and evaluated the clinical effect of donor KIR genotype and donor and recipient HLA genotypes.ResultsPatients with AML who received allografts from donors who were positive for KIR2DS1 had a lower rate of relapse than those with allografts from donors who were negative for KIR2DS1 (26.5% vs. 32.5%; hazard ratio, 0.76; 95% confidence interval [CI], 0.61 to 0.96; P=0.02). Of allografts from donors with KIR2DS1, those from donors who were homozygous or heterozygous for HLA-C1 antigens could mediate this antileukemic effect, whereas those from donors who were homozygous for HLA-C2 did not provide any advantage (24.9% with homozygosity or heterozygosity for HLA-C1 vs. 37.3% with homozygosity for HLA-C2; hazard ratio, 0.46; 95% CI, 0.28 to 0.75; P=0.002). Recipients of KIR2DS1-positive allografts mismatched for a single HLA-C locus had a lower relapse rate than recipients of KIR2DS1-negative allografts with a mismatch at the same locus (17.1% vs. 35.6%; hazard ratio, 0.40; 95% CI, 0.20 to 0.78; P=0.007). KIR3DS1, in positive genetic linkage disequilibrium with KIR2DS1, had no effect on leukemia relapse but was associated with decreased mortality (60.1%, vs. 66.9% without KIR3DS1; hazard ratio, 0.83; 95% CI, 0.71 to 0.96; P=0.01).ConclusionsActivating KIR genes from donors were associated with distinct outcomes of allogeneic HSCT for AML. Donor KIR2DS1 appeared to provide protection against relapse in an HLA-C–dependent manner, and donor KIR3DS1 was associated with reduced mortality. (Funded by the National Institutes of Health and others.)

Association of KIR genotype with susceptibility to HLA-B27-positive ankylosing spondylitis

Recent studies have explored the role of killer cell immunoglobulin-like receptors (KIRs) in chronic autoimmune diseases. The purpose of this study was to demonstrate whether KIR genes contribute to the pathogenesis of ankylosing spondylitis (AS) in Chinese populations. Sixteen KIR genes were genotyped from 60 unrelated patients with AS and 60 HLA-B27-positive matched healthy controls by PCR-SSP. The frequencies of the KIR alleles and genotypes in the AS and control groups were assessed by the χ(2) test. Our results showed that the frequency of the activator receptor KIR3DS1 gene in the AS group was significantly increased compared to the controls (χ(2) = 5.263, P = 0.006, OR = 3.059, 95 % CI = 1.357-6.896). Moreover, the frequency of the KIR3DL1/3DS1 genotype was greater in the AS group than in the control group (P = 0.039, OR = 3.059, 95 % CI = 1.357-6.896). In contrast, the frequency of the no KIR3DL1/no 3DS1 genotype was lower in patients with AS compared with the controls (P = 0.032, OR = 0.110, 95 % CI = 0.013-0.911). KIR3DS1, in addition to HLA-B27, may play an important independent role in the pathogenesis of AS in the Chinese population.

HLA-cw polypmorphism and killer cell immunoglobulin-like receptor (KIR) gene analysis in Korean patients with colorectal cancer.

525 Background: Many kinds of genetic and environment factors are involved in colorectal cancer development. Natural killer cells (NK cells) play important roles to protect from viral infections and the early development of cancers, and it is activated or inhibited by killer cell immunoglobulin-like receptors (KIR) which bind to HLA class I. KIR genes are encoded on chromosome 19q13.4. And there are 7 kinds of activating KIRs, and another 7 kinds of inhibiting KIRs. The genetic polymorphisms of KIR genes effect the expression of KIR on NK cells, and there are ethnic differences. In this study, we were trying to investigate the KIR genotype of Korean colorectal cancer patients. Methods: DNAs were extracted from the peripheral bloods from normal populations and Korean colorectal cancer patients. KIR genes were amplified using PCR-SSP methods, and HLA-Cw genes were characterized using PCR methods. The results were analyzed between cancer patients and normal control group. Results: KIR2DL2 and KIR2DS2 were found at low rate and KIR2DL3 were found at high rate compare to the Eastern studies, but the rates were similar with Japan study. In this study, KIR2DS5 (33.2% vs. 20.8%, p-value&lt;0.007) was increased in colorectal cancer group, and in rectal cancer subgroup, KIR3DL1 (93.2%, vs. 98.1%, p-value&lt;0.05), KIR2DS2 (7.8% vs. 19.5%, p-value&lt;0.01), KIR2DS4 (93.2% vs. 98.1%, p-value&lt;0.05) were decreased significantly. HLA-Cw6 (9.1% vs. 15.7%, p-value&lt;0.05) and HLA-Cw7 (17.4% vs. 27.7%, p-value&lt;0.02) were decreased in colorectal cancer group, but no difference was found when they were classified to HLA-C1 and HLA-C2 group. Among the patients with HLA-C1 homozygote, KIR2DS2 was decreased significantly (5.8% vs. 14.5%, p-value&lt;0.004). Conclusions: There are ethnic differences of KIR genotypes. KIR2DS5 is increased in Korean colorectal cancer patients, and in rectal cancer subgroup, KIR3DL1, KIR2DS2 and KIR2DS4 are decreased, so there are immunologic differences between colon and rectal cancers. And among the patients with HLA-C1 homozygote, KIR2DS2 is decreased. Therefore KIR2DS2 in presence of their ligand (HLA-C1 group) may have protective effect against colorectal cancer.

Killer‐cell immunoglobulin‐like receptors and malaria caused by Plasmodium falciparum in The Gambia

The relevance of innate immune responses to Plasmodium falciparum infection, in particular the central role of natural killer (NK) cell-derived interferon gamma (IFN-γ), is becoming increasingly recognised. Recently, it has been shown that IFN-γ production in response to P. falciparum antigens is in part regulated by killer-cell immunoglobulin-like receptor (KIR) genes, and a study from malaria-exposed Melanesians suggested an association between KIR genotypes and susceptibility to infection. This prompted us to determine and compare the frequencies of 15 KIR genes in Gambian children presenting with either severe malaria (n = 133) or uncomplicated malaria (n = 188) and in cord-blood population control samples (n = 314) collected from the same area. While no significant differences were observed between severe and uncomplicated cases, proportions of individuals with KIR2DS2+C1 and KIR2DL2+C1 were significantly higher among malaria cases overall than in population control samples. In an exploratory analysis, activating KIR genes KIR2DS2, KIR3DS1 and KIR2DS5 were slightly higher in children in disease subgroups associated with the highest mortality. In addition, our data suggest that homozygosity for KIR genotype A might be associated with different malaria outcomes including protection from infection and higher blood parasitaemia levels in those that do get infected. These findings are consistent with a probable role of KIR genes in determining susceptibility to malaria, and further studies are warranted in different populations.

Susceptibility to pulmonary tuberculosis in Iranian individuals is not affected by compound KIR/HLA genotype

Natural killer (NK) cells have distinctive functional capacities that are likely to contribute both to innate and adaptive immunity to Mycobacterium tuberculosis. Killer cell immunoglobulin-like receptors (KIR) and their ligands, i.e. human leukocyte antigen (HLA) class I molecules contribute partly in regulation of NK cell activity. In this study, the impact of compound KIR/HLA genotype on susceptibility to pulmonary tuberculosis (TB) has been evaluated in Iranian individuals. A total of 107 TB patients and 100 matched healthy controls were genotyped for 17 KIR genes and their three major HLA class I ligand groups (-C1, -C2 and -Bw4: -B Bw4(Ile80) , -B Bw4(Thr80) and -A Bw4) by a polymerase chain reaction-sequence-specific primers assay. Various analyses including distribution of KIR and HLA ligand genes and genotypes, frequency of inhibitory and activating KIR+HLA combinations and compound genotype status regarding balance of inhibitory and activating components showed no significant difference between patient and control groups. These findings may suggest that compound KIR/HLA genotype has no major impact on limiting Mycobacterium tuberculosis infection.