Killer Cell Immunoglobulin-like Receptors Loci Research Articles

Concept and design of a genome-wide association genotyping array tailored for transplantation-specific studies.

BackgroundIn addition to HLA genetic incompatibility, non-HLA difference between donor and recipients of transplantation leading to allograft rejection are now becoming evident. We aimed to create a unique genome-wide platform to facilitate genomic research studies in transplant-related studies. We designed a genome-wide genotyping tool based on the most recent human genomic reference datasets, and included customization for known and potentially relevant metabolic and pharmacological loci relevant to transplantation.MethodsWe describe here the design and implementation of a customized genome-wide genotyping array, the ‘TxArray’, comprising approximately 782,000 markers with tailored content for deeper capture of variants across HLA, KIR, pharmacogenomic, and metabolic loci important in transplantation. To test concordance and genotyping quality, we genotyped 85 HapMap samples on the array, including eight trios.ResultsWe show low Mendelian error rates and high concordance rates for HapMap samples (average parent-parent-child heritability of 0.997, and concordance of 0.996). We performed genotype imputation across autosomal regions, masking directly genotyped SNPs to assess imputation accuracy and report an accuracy of >0.962 for directly genotyped SNPs. We demonstrate much higher capture of the natural killer cell immunoglobulin-like receptor (KIR) region versus comparable platforms. Overall, we show that the genotyping quality and coverage of the TxArray is very high when compared to reference samples and to other genome-wide genotyping platforms.ConclusionsWe have designed a comprehensive genome-wide genotyping tool which enables accurate association testing and imputation of ungenotyped SNPs, facilitating powerful and cost-effective large-scale genotyping of transplant-related studies.Electronic supplementary materialThe online version of this article (doi:10.1186/s13073-015-0211-x) contains supplementary material, which is available to authorized users.

KIR gene genotype frequencies in donors of German, Turkish, and Polish descent

Aim Killer cell immunoglobulin-like receptors (KIRs) are expressed on cells of the innate immune system. The KIR system has been found to be important in donor selection for hematopoietic stem cell transplantation in certain circumstances (Cooley et al. Blood, 2010). In addition to the frequency of these 17 KIR loci in donors of German, Polish, and Turkish descent, we present the most common KIR genotypes in these ethnic groups as well as the frequency of KIR haplotypes. Methods More than 82,000 donors have been recruited from January through April 2015 by DKMS in Germany and typed for absence or presence of 17 KIR genes and pseudogenes using an NGS-based amplicon approach targeting exons 4, 5, and 7 of the respective genes. While KIR2DL5A and KIR2DL5B genes are not distinguished, KIR2DS4 and KIR2DS4N are reported separately, as null alleles are not biologically functional. Frequencies are given by the relative fraction of typing results. Results 70,411 of the donors recruited indicated to be of German descent, 4989 of Turkish and 860 of Polish descent. The most common KIR genotype in all 3 ethnicities includes the presence of only 2DL1, 2DL3, 2DL4, 2DP1, 2DS4N, 3DL1, 3DL2, 3DL3, and 3DP1 genes. For all populations, the most frequent KIR genotype, according to the classification of Cooley et al., is B/2, while B/4 is most rare. Download : Download full-size image Download : Download full-size image

NK cells: tuned by peptide?

Natural killer cells express multiple receptors for major histocompatibility complex (MHC) class I, including the killer cell immunoglobulin-like receptors (KIRs) and the C-type lectin-like CD94:NKG2 receptors. The KIR locus is extremely polymorphic, paralleling the diversity of its classical MHC class I ligands. Similarly, the conservation of the NKG2 family of receptors parallels the conservation of MHC-E, the ligand for CD94:NKG2A/C/E. Binding of both CD94:NKG2 heterodimers and KIR to their respective MHC class I ligand is peptide dependent, and despite the evolution of these receptors, they have retained the property of peptide selectivity. Such peptide selectivity affects these two systems in different ways. HLA-E binding non-inhibitory peptides augment inhibition at CD94:NKG2A, while HLA-C binding non-inhibitory peptides antagonize inhibition at KIR2DL2/3, implying that KIRs are specialized to respond positively to changes in peptide repertoire. Thus, while specific KIRs, such as KIR2DL3, are associated with beneficial outcomes from viral infections, viral peptides augment inhibition at CD94:NKGA. Conversely, NKG2A-positive NK cells sense MHC class I downregulation more efficiently than KIRs. Thus, these two receptor:ligand systems appear to have complementary functions in recognizing changes in MHC class I.

Co-evolution of MHC class I and variable NK cell receptors in placental mammals.

Shaping natural killer (NK) cell functions in human immunity and reproduction are diverse killer cell immunoglobulin-like receptors (KIRs) that recognize polymorphic MHC class I determinants. A survey of placental mammals suggests that KIRs serve as variable NK cell receptors only in certain primates and artiodactyls. Divergence of the functional and variable KIRs in primates and artiodactyls predates placental reproduction. Among artiodactyls, cattle but not pigs have diverse KIRs. Catarrhine (humans, apes, and Old World monkeys) and platyrrhine (New World monkeys) primates, but not prosimians, have diverse KIRs. Platyrrhine and catarrhine systems of KIR and MHC class I are highly diverged, but within the catarrhines, a stepwise co-evolution of MHC class I and KIR is discerned. In Old World monkeys, diversification focuses on MHC-A and MHC-B and their cognate lineage II KIR. With evolution of C1-bearing MHC-C from MHC-B, as informed by orangutan, the focus changes to MHC-C and its cognate lineage III KIR. Evolution of C2 from C1 and fixation of MHC-C drove further elaboration of MHC-C-specific KIR, as exemplified by chimpanzee. In humans, the evolutionary trajectory changes again. Emerging from reorganization of the KIR locus and selective attenuation of KIR avidity for MHC class I are the functionally distinctive KIR A and KIR B haplotypes.

Pre-eclampsia Protectors and Promoters

A new study identifies genes linked to the risk for preeclampsia in a population from sub-Saharan Africa. These genes encode for human leukocyte antigen (HLA) ligands on trophoblasts and receptors that recognize these ligands, which are present on maternal Natural Killer (NK) cells [1]. Trophoblast invasion of the uterine tissue leads to the remodeling of uterine arteries into large vessels, thereby tapping the mother’s blood supply. This is a carefully equilibrated event. Too aggressive of an invasion can result in outsized babies, exposure to excess nutrients and oxygen in utero, and placental overgrowth conditions that can lead to hemorrhage. Poor invasion can result in such conditions as fetal growth restriction and pre-eclampsia. Maternal NK cells modulate the activity of trophoblasts, determining the extent of invasion in humans. This modulation occurs via HLA-C ligands on trophoblast cells, which recognize a key family of receptors on NK cells: killer-cell immunoglobulin-like receptors (KIRs). In previous studies, Ashley Moffett and colleagues found that genetic risk for pre-eclampsia, and some related conditions such as fetal growth restriction, is linked to various genetic variants at the KIR and HLA-C loci. But their studies, conducted primarily in European populations, limit their analysis. In the new study, the researchers turned to women of sub-Saharan African ancestry, who have elevated rates of pre-eclampsia and also a high diversity of KIR genotypes, and found some parallels and some differences with European women. Moffett and colleagues studied pregnant women at a hospital in Kampala, Uganda: 251 with pre-eclampsia and 483 without the condition. As with Europeans, they found elevated risk for pre-eclampsia in women homozygous for one of two major haplotypes, the KIR A haplotype. This risk was even higher if the fetus also had particular HLA-C alleles, which encode C2 epitopes (all HLA-C alleles encode either a C1 or C2 epitope). The researchers also identified three KIR genes that seemed to protect against pre-eclampsia in the women in Kampala—alleles that are rare in Europeans. A KIR gene known to be protective in Europeans was found at only low frequency in the women from Kampala. The study highlights the need for global genetic studies to assess pre-eclampsia risk—curiously, distinct human populations seem to have evolved to have distinct mixes of favorable KIR-HLA-C combinations. Future research should flesh out the biological mechanisms. One study, for instance, showed that favorable KIR-HLA-C combinations result in increased production of soluble factors that promote trophoblast invasion.

Killer cell immunoglobulin-like receptor (KIR) locus profiles in the Tunisian population

Killer cell immunoglobulin-like receptors (KIRs) are a family of inhibitory and activatory receptors that are expressed by most natural killer (NK) cells. The KIR gene family is polymorphic: genomic diversity is achieved through differences in gene content and allelic polymorphism. The number of KIR loci has been reported to vary among individuals, resulting in different KIR haplotypes. In this study we report the genotypic structure of KIRs in 267 unrelated and healthy Tunisian subjects by polymerase chain reaction-sequence-specific primer (PCR-SSP) method.All 16 KIR genes were observed in the population with different frequencies; framework genes KIR3DP1 and KIR3DL2 and the nonframework genes KIR2DL1 and KIR2DP1 were present in all individuals. A total of 26 different KIR gene profiles and 54 subgenotypes were observed in the tested population samples. Genotype 1, with a frequency of 36.6%, is the most commonly observed in the Tunisian population.Our results showed that the Tunisian population possesses the previously reported general features of the Caucasian as well as African populations, with some additional interesting differences.Such knowledge of the KIR gene distribution in populations is very useful in the study of associations with diseases and in selection of donors for haploidentical bone marrow transplantation.

Donor KIR Tel-B Haplotypes Beneficially Affect Outcome after Allogeneic Stem Cell Transplantation in Patients with Myeloid Malignancies

Introduction. Leukemia relapse after allogeneic hematopoietic stem-cell transplantation (allo-HSCT) remains a major clinical issue. Myelogenous leukemias are the most sensitive to natural killer (NK)-cell reactivity among blood malignancies treated with allo-HSCT. NK-cell function is controlled by an array of inhibitory and activating receptors, including killer cell immunoglobulin-like receptors (KIRs), whose genes vary in number and content. Inhibitory KIRs recognize the HLA class I ligands and mediate tolerance to self when they encounter self-HLA molecules on putative target cells. HLA-C allotypes with asparagine at position 80 (C1 ligands) are recognized by KIR2DL2/3, HLA-C allotypes with lysine at position 80 (C2 ligands) are recognized by KIR2DL1. HLA-A and –B allotypes with Bw4 motif are recognized by KIR3DL1. The ligands and function of activating KIRs are not well identified with the exception of KIR2DS1which recognizes HLA-C2 ligand group. KIR A haplotypes have simple, fixed gene content; B haplotypes have variable gene content and one or more of the B-specific genes: KIR2DS1, 2, 3, 5 KIR2DL2, KIR2DL5.The KIR locus divides into centromeric (Cen) and telomeric(Tel) regions. In both regions there are two distinctive types of variable KIR gene content motif - Cen-A/Cen-B and Tel-A/Tel-B. The aim of our prospective study was to evaluate the influence of immunogenetic factors (KIRs and their HLA ligands) on the outcome after allo-HSCT in patients with myeloid malignancies.Methods. 29 patients with different clonal myeloid disorders who underwent allo-HSCT in Research Center for Hematology (Moscow, Russian Federation) in 2011-2013 from HLA-identical related (n=19) and HLA-matched unrelated (n=10) donors were included in the study. The pre-transplantation risk category included standard or high risk. Acute myelogenous leukemia (AML) in complete remission 1 (CR1, n=15), chronic myelogenous leukemia (chronic phase 1, n=4), and myelodysplastic syndromes (n=2) classified as refractory anemia/refractory anemia with ringed sideroblasts were categorized as standard risk (n=21), whereas AML > CR1were considered as high risk (n=8). KIR genotyping was performed before allo-HSCT simultaneously with HLA-typing using a PCR-SSP kit (Invitrogen, WI, USA). Overall survival (OS) and event-free survival (EFS) were calculated by the Kaplan-Meier method, and compared with the log-rank test. OS was defined as survival without lethal event from any cause, EFS was defined as survival in complete remission without lethal event from any cause.Results. We found that the 3-year estimated OS and EFS in all patients were 59.7 and 50.0%, respectively. Conditioning regimen and graft source (related or unrelated) had no significant effect on transplant outcome. The pre-transplantation risk category was the main factor influencing survival. The probability of the 3-year OS and EFS for standard-risk patients was 85.7 and 69.0%, respectively; all high-risk patients died during 20 months after allo-HSCT. For standard-risk patients there was better EFS in patients whose donors had KIR Tel-B haplotypes in comparison with patients whose donors had no KIR Tel-B haplotypes (87.5 vs. 58.3%, p=0.08). Standard-risk recipients with HLA-C1/C1 ligands (i.e., C1 epitope present on both HLA-C alleles) had a tendency to an improved EFS compared with patients having either C1/C2 or C2/C2 ligands (88.9 vs. 55.6%, p=0.15). Also there was a tendency to better EFS in patients lacking HLA-Bw4 ligands compared with patients having those ligands (88.9 vs. 55.6%, p=0.15).Conclusions. Our small one single-center prospective study supports the hypothesis about the specific, genetically determined role of NK cell in the graft versus leukemia effect in myeloid malignancies. We suggest that donors having KIR Tel-B haplotypes are preferable for patients with myelogenous leukemias, and selection of the donors with KIR Tel-B haplotypes can improve outcome after allo-HSCT for myelogenous leukemias. DisclosuresNo relevant conflicts of interest to declare.

OR44: KIR ALLELE AND HAPLOTYPE DIVERSITY OF MAORI AND POLYNESIANS

Aim Genetic variation of killer cell immunoglobulin-like receptors (KIR) diversifies human natural killer (NK) cell responses within and among individuals. With critical roles in immunity and reproduction, allotype variation affects how KIR molecules are expressed, interact with their HLA targets and transmit intracellular signals. Here we investigate KIR diversity at high resolution in the Maori and Polynesian populations. Methods Genomic DNA samples from 49 Māori (from New Zealand) and 34 Polynesians (from Cook Islands, Samoa and Tokelau) were drawn from the Victoria University of Wellington DNA Bank. In order to genotype the KIR locus at the allelic level, the DNA samples were amplified by PCR using KIR specific primers and sequenced by Pyrosequencing. Results Analyzing all 13 KIR genes we uncovered rich diversity in these populations. We identified a total of 80 KIR variants including four common newly-discovered alleles, and observed 35 centromeric and 22 telomeric KIR region haplotypes. This level of haplotypic diversity persisted even when non-expressed and synonymous KIR variants were not considered, and when analyzed in tandem with HLA class I every individual in each of the populations was unique. There was a mean of seven unique viable HLA-KIR interactions per individual. Conclusion In examining Māori and Polynesians we present one of the first population scale studies of KIR allele and haplotype variation. High KIR diversity is maintained through the entire locus both in Māori and Polynesians. Comparing with the few similar studies performed to date we show striking similarity between the worldwide dispersal of KIR and that of HLA; some of the alleles or haplotypes have a worldwide distribution and others are more localized geographically. Our findings reinforce the notion that sufficient NK cell diversity is critical to human survival, particularly as populations become exposed to new environments and evolving pathogens.

KIR diversity in Māori and Polynesians: populations in which HLA-B is not a significant KIR ligand.

HLA class I molecules and killer cell immunoglobulin-like receptors (KIR) form a diverse system of ligands and receptors that individualize human immune systems in ways that improve the survival of individuals and populations. Human settlement of Oceania by island-hopping East and Southeast Asian migrants started ~3,500years ago. Subsequently, New Zealand was reached ~750years ago by ancestral Māori. To examine how this history impacted KIR and HLA diversity, and their functional interaction, we defined at high resolution the allelic and haplotype diversity of the 13 expressed KIR genes in 49 Māori and 34 Polynesians. Eighty KIR variants, including four 'new' alleles, were defined, as were 35 centromeric and 22 telomeric KIR region haplotypes, which combine to give >50 full-length KIR haplotypes. Two new and divergent variant KIR form part of a telomeric KIR haplotype, which appears derived from Papua New Guinea and was probably obtained by the Asian migrants en route to Polynesia. Māori and Polynesian KIR are very similar, but differ significantly from African, European, Japanese, and Amerindian KIR. Māori and Polynesians have high KIR haplotype diversity with corresponding allotype diversity being maintained throughout the KIR locus. Within the population, each individual has a unique combination of HLA class I and KIR. Characterizing Māori and Polynesians is a paucity of HLA-B allotypes recognized by KIR. Compensating for this deficiency are high frequencies (>50%) of HLA-A allotypes recognized by KIR. These HLA-A allotypes are ones that modern humans likely acquired from archaic humans at a much earlier time.

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 gene 2DL1 and its HLA-C2 ligand with family history of cancer in oral squamous cell carcinoma.

Killer cell immunoglobulin-like receptors (KIR) are involved in regulating natural killer cell activation through recognition of their human leukocyte antigen (HLA) class I ligands. We conducted a case-control study with 169 oral squamous cell carcinoma (OSCC) patients and 177 healthy participants to study the genomic diversity of KIR and HLA loci and KIR gene expression in context of family history of cancer (FHC) in OSCC. Polymerase chain reaction (PCR) sequence-specific priming approach was used to type 16 KIR genes in individuals. SSP-real-time PCR was used for HLA class I ligand genotyping and real-time quantitative reverse transcriptase PCR was used to determine the expression of KIR gene. KIR2DL1(+)-HLA-C2(+) genotype was higher and positively associated with OSCC. Notably, all KIR2DL1(+)-HLA-C2(+) genotypes occurred exclusively in patients with FHC, showing a strong positive association of KIR2DL1(+)-HLA-C2(+) genotype with FHC. In addition, all younger age group patients (<55 years) with FHC were positive for KIR2DL1(+)-HLA-C2(+) genotype suggesting association of the genotype with early onset of disease. RNA transcript abundance of inhibitory KIR2DL1 in FHC patients, particularly of lower age groups (<45 and 45-54 years), supports the contention. Further, KIR2DL3(+)-HLA-C(+) genotype was negatively associated with OSCC. Our findings suggest KIR2DL1(+)-HLA-C2(+) genotype as heritable risk factor in OSCC predisposing to OSCC at younger age. Interestingly, KIR2DL3(+)-HLA-C(+) genotype was seen to be protective in OSCC. This study may be useful towards cancer surveillance and early detection of oral cancer in patients with FHC.

Co-evolution of Human Leukocyte Antigen (HLA) Class I Ligands with Killer-Cell Immunoglobulin-Like Receptors (KIR) in a Genetically Diverse Population of Sub-Saharan Africans

Interactions between HLA class I molecules and killer-cell immunoglobulin-like receptors (KIR) control natural killer cell (NK) functions in immunity and reproduction. Encoded by genes on different chromosomes, these polymorphic ligands and receptors correlate highly with disease resistance and susceptibility. Although studied at low-resolution in many populations, high-resolution analysis of combinatorial diversity of HLA class I and KIR is limited to Asian and Amerindian populations with low genetic diversity. At the other end of the spectrum is the West African population investigated here: we studied 235 individuals, including 104 mother-child pairs, from the Ga-Adangbe of Ghana. This population has a rich diversity of 175 KIR variants forming 208 KIR haplotypes, and 81 HLA-A, -B and -C variants forming 190 HLA class I haplotypes. Each individual we studied has a unique compound genotype of HLA class I and KIR, forming 1–14 functional ligand-receptor interactions. Maintaining this exceptionally high polymorphism is balancing selection. The centromeric region of the KIR locus, encoding HLA-C receptors, is highly diverse whereas the telomeric region encoding Bw4-specific KIR3DL1, lacks diversity in Africans. Present in the Ga-Adangbe are high frequencies of Bw4-bearing HLA-B*53:01 and Bw4-lacking HLA-B*35:01, which otherwise are identical. Balancing selection at key residues maintains numerous HLA-B allotypes having and lacking Bw4, and also those of stronger and weaker interaction with LILRB1, a KIR-related receptor. Correspondingly, there is a balance at key residues of KIR3DL1 that modulate its level of cell-surface expression. Thus, capacity to interact with NK cells synergizes with peptide binding diversity to drive HLA-B allele frequency distribution. These features of KIR and HLA are consistent with ongoing co-evolution and selection imposed by a pathogen endemic to West Africa. Because of the prevalence of malaria in the Ga-Adangbe and previous associations of cerebral malaria with HLA-B*53:01 and KIR, Plasmodium falciparum is a candidate pathogen.

Allele-Level Haplotype Frequencies and Pairwise Linkage Disequilibrium for 14 KIR Loci in 506 European-American Individuals

The immune responses of natural killer cells are regulated, in part, by killer cell immunoglobulin-like receptors (KIR). The 16 closely-related genes in the KIR gene system have been diversified by gene duplication and unequal crossing over, thereby generating haplotypes with variation in gene copy number. Allelic variation also contributes to diversity within the complex. In this study, we estimated allele-level haplotype frequencies and pairwise linkage disequilibrium statistics for 14 KIR loci. The typing utilized multiple methodologies by four laboratories to provide at least 2x coverage for each allele. The computational methods generated maximum-likelihood estimates of allele-level haplotypes. Our results indicate the most extensive allele diversity was observed for the KIR framework genes and for the genes localized to the telomeric region of the KIR A haplotype. Particular alleles of the stimulatory loci appear to be nearly fixed on specific, common haplotypes while many of the less frequent alleles of the inhibitory loci appeared on multiple haplotypes, some with common haplotype structures. Haplotype structures cA01 and/or tA01 predominate in this cohort, as has been observed in most populations worldwide. Linkage disequilibrium is high within the centromeric and telomeric haplotype regions but not between them and is particularly strong between centromeric gene pairs KIR2DL5∼KIR2DS3S5 and KIR2DS3S5∼KIR2DL1, and telomeric KIR3DL1∼KIR2DS4. Although 93% of the individuals have unique pairs of full-length allelic haplotypes, large genomic blocks sharing specific sets of alleles are seen in the most frequent haplotypes. These high-resolution, high-quality haplotypes extend our basic knowledge of the KIR gene system and may be used to support clinical studies beyond single gene analysis.

Ligand specificity of Killer cell Immunoglobulin-like Receptors: a brief history of KIR

Ligand specificity of Killer cell Immunoglobulin-like Receptors: a brief history of KIR

KIR and HLA Loci Are Associated with Hepatocellular Carcinoma Development in Patients with Hepatitis B Virus Infection: A Case-Control Study

BackgroundNatural killer (NK) cells activation has been reported to contribute to inflammation and liver injury during hepatitis B virus (HBV) infection both in transgenic mice and in patients. However, the role of NK cells in the process of HBV-associated hepatocellular carcinoma (HCC) development has not been addressed. Killer cell immunoglobulin-like receptors (KIRs) are involved in regulating NK cell activation through recognition of specific human leukocyte antigen (HLA) class I allotypes.Methodology/Principal FindingsTo investigate whether KIR and HLA genes could influence the risk of HBV-associated HCC development, 144 HBV-infected patients with HCC and 189 well-matched HBV infectors with chronic hepatitis or cirrhosis as non-HCC controls were enrolled in this study. The presence of 12 loci of KIR was detected individually. HLA-A, -B, -C loci were genotyped with high-resolution. HLA-C group 1 homozygote (OR = 2.02; p = 0.005), HLA-Bw4-80I (OR = 2.67; p = 2.0E-04) and combination of full-length form and 22 bp-deleted form of KIR2DS4 (KIR2DS4/1D) (OR = 1.89; p = 0.017) were found associated with HCC incidence. When the combined effects of these three genetic factors were evaluated, more risk factors were observed correlating with higher odds ratios for HCC incidence (P trend = 7.4E-05). Because all the risk factors we found have been reported to result in high NK cell functional potential by previous studies, our observations suggest that NK cell activation may contribute to HBV-associated HCC development.Conclusions/SignificanceIn conclusion, this study has identified significant associations that suggest an important role for NK cells in HCC incidence in HBV-infected patients. Our study is useful for HCC surveillance and has implications for novel personalized therapy strategy development aiming at HCC prevention in HBV-infected patients.

Doğal Öldürücü Hücre Immunglobulin-Benzeri Reseptör Genleri

Dogal oldurucu hucre immunglobulin-benzeri reseptorler (Killer cell immunoglobulin-like receptors, KIR), dogal oldurucu hucrelerin yuzeylerinde eksprese olan ve dogal immunitenin duzenlenmesinde onemli rol oynayan molekullerdir. KIR’lar 19q13.4 kromozomundaki bir gen demeti tarafindan kodlanmaktadir. KIR gen demeti oldukca polimorfiktir, bireysel genler allelik polimorfizm icerirken, bireysel haplotipler gen iceriyi acisindan farkliliklar gosterir. Human Lokosit Antijen (HLA) genlerine paralel olan KIR lokusunun polimorfizmleri, immun sistemin dinamik ve gelisen cevreye adaptasyonunu kolaylastirmaktadir. Bu varyasyon pek cok hastalikla iliskilidir. Bu derlemede pek cok hastalikta ve transplantasyon immunolojisinde onem tasiyan KIR molekullerinin, biyolojisi ve genetigi konulari ele alinmistir.

Diversity of the KIR gene cluster in an urban Brazilian population.

The activity of natural killer cells depends on the balance between activating and inhibitory signals coming from their receptors. Among these are the killer cell immunoglobulin-like receptors (KIR) that recognize specific HLA class I allotypes. Here we characterized KIR genetic diversity and their HLA ligands in the population of Curitiba, Paraná State (n = 164), and compared it with other worldwide populations. The distribution of 2DL4 alleles was also analyzed. The Curitiba population did not differ significantly from European and Euro-descendant populations, but as an admixed population showed higher genetic diversity. We found 27 KIR profiles, many of them uncommon in European populations, in agreement with the elevated historically recent gene flow in the study population. The frequencies of KIR genes and their respective HLA ligands were distributed independently and none of the analyzed individuals lacked functional KIR-HLA ligand combinations. KIR gene frequencies of 33 worldwide populations were consistent with geographic and ethnic distribution, in agreement with demography being the major factor shaping the observed gene content diversity of the KIR locus.

Diversity distributions of killer cell immunoglobulin-like receptor genes and their ligands in the Chinese Shaanxi Han population

In the present study, 17 killer cell immunoglobulin-like receptors (KIR) genes and KIR ligands (human leukocyte antigen [HLA] –A and -B) were detected by using a polymerase chain reaction–sequence-specific primer (PCR-SSP) method in 104 unrelated healthy Han individuals living in Shaanxi province, China. The observed carrier frequencies of the 12 KIR genes ranged from 0.14 to 0.96. KIR2DL4, 3DL2, 3DL3, 2DP1 and 3DP1 were found to be present in every individual. A total of 51 different KIR gene profiles were identified, in which 11 gene profiles exclusively belonged to the study population. Neighbor-joining phylogenetic tree between the studing population and its neighboring ethnic groups was constructed using the observed carrier frequencies of 13 KIR loci. The phylogenetic tree shows that the Shaanxi Han population, Han populations in different regions, Yi, Japanese, and Koreans were in the same cluster. KIR/HLA relationships show that KIR3DS1 −/3DL1 +/Bw4 + was the most common association in the population. In conclusion, the present study findings reveal the high polymorphism of KIRs in the Shaanxi Han population, demonstrate the KIR/HLA association in the study population, and enrich the KIR and HLA gene resources. The obtained KIR data will further the understanding of genetic relationships among populations in different geographic areas, and assist in answering questions regarding KIR/HLA relationships.

Telomeric Rather than Centromeric Activating KIR Genes Protect from Cytomegalovirus Infection after Kidney Transplantation

Cytomegalovirus (CMV) infection is a common complication after organ transplantation. Previous studies have demonstrated that activating killer-cell immunoglobulin-like receptors (KIR) may reduce the rate of CMV infection. KIR genes can be divided into haplotype A (containing a fixed set of inhibitory receptors) and haplotype B (carrying additional activating KIR genes). The KIR locus is divided into a centromeric and a telomeric portion, both of which may carry A or B haplotype motifs. We studied a cohort of 339 kidney transplant recipients to elucidate which KIR genes protect from CMV infection. CMV infection occurred in 139 patients (41%). Possession of telomeric (hazard ratio 0.64, 95% confidence interval 0.44-0.94, p = 0.02) but not centromeric (HR 0.86, 95% CI 0.60-1.23, p = 0.41) B motifs was associated with statistically significant protection from CMV infection. Due to linkage disequilibrium, we were not able to identify a single protective gene within the telomeric B complex (which may contain the KIR2DS1, KIR3DS1, KIR2DL5A and KIR2DS5 genes). The presence of known or putative ligands to activating KIR did not significantly modify the influence of telomeric B group genes. We confirm that B haplotypes protect from CMV infection after kidney transplantation and show that this arises from telomeric B haplotype genes.

Genetic polymorphism of the killer cell immunoglobulin-like receptor genes in the Inner Mongolian population

To investigate the killer cell immunoglobulin-like receptor (KIR) gene frequencies and genotypes distributions in the Inner Mongolian population. Ninety genomic DNA samples were extracted from blood samples of randomly chosen Mongolian individuals. Gene-specific PCR amplification was used to identify genes present or absent for 16 KIR loci. KIR genotype distributions were obtained and compared to that of 24 populations published in literatures using principal component analysis by SAS8.0 software. Genetic tree was constructed by the calculate Nei's genetic distance. (1) The frequency of KIR 2DL2, 2DS2 in Mongolian individual is higher than that in north Mongoloid and less than that in Caucasian. (2) Haplotype AA was identified in 37.78% of individuals, which is higher than that in north Mongoloid and lower than that in Caucasian. (3) Mongolian was considered between north Mongoloid and Caucasian by principal component and genetic tree analysis. Mongolian might be affected by the north Mongoloid and Caucasian, and showed intermediate between the two populations.