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1: Immunogenetics. 2007 Feb;59(2):145-58. Epub 2007 Jan 3.Click here to read Links

KIR haplotype content at the allele level in 77 Northern Irish families.

Middleton D, Meenagh A, Gourraud PA.

Northern Ireland Regional Histocompatibility and Immunogenetics Laboratory, Belfast City Hospital, Belfast, BT9 7TS, Northern Ireland, UK. derek.middleton@bll.n-i.nhs.uk

There has been an explosion in population studies determining the frequency of KIR genes. However, there is still limited knowledge of allele and haplotype frequencies in different populations. The present study aims to determine the haplotype frequencies using allele information on ten genes and presence/absence of the other seven genes in the parents of 77 families. There were 26 of 154 different genotypes without using allele information and 143 of 154 different genotypes using allele information. These genotypes came from 96 of 308 different haplotypes. Of these, 41 were A and 55 were B. Forty-nine haplotypes occurred only once. In total, 181 (58.8%) of haplotypes were A and 127 (41.2%) were B. Three different haplotypes carried two copies of KIR2DL4, two different haplotypes were truncated with both KIR2DL4 and KIR3DL1/S1 missing, and three different haplotypes were negative for both KIR2DL2 and KIR2DL3; two of these haplotypes carried KIR2DS2. A further haplotype, present in two individuals, appeared to have two alleles of KIR2DL5A present. The percentages of individuals who were homozygous for the A haplotype, heterozygous for the A and B haplotype and homozygous for the B haplotype were 35.1%, 47.4% and 17.5% respectively. The genes KIR3DL1, KIR2DS4 and KIR2DL3 were present on 31, 32 and 15 different B haplotypes, respectively, and 64, 65 and 40 of the total B haplotypes, respectively. Sixty B haplotypes had both KIR3DL1 and KIR2DS4, and four haplotypes had KIR2DS4 and KIR2DL3. However, in 40 of 41 different and 180 of 181 total A haplotypes, KIR3DL1, KIR2DS4 and KIR2DL3 were all present (we did not allele-type for KIR2DL1 and therefore could not determine presence/absence on those haplotypes). At the allele level, homozygosity was found in 22.1%, 9.7% and 12.6% for KIR2DL4, KIR3DL2 and KIR3DL1 genes, respectively, but 62.6% and 53% for KIR2DL3 and KIR2DS4 genes, respectively, despite the fact that no one allele dominated the frequency in any of these genes.

PMID: 17200871 [PubMed - indexed for MEDLINE]

2: J Clin Immunol. 2008 Jul;28(4):343-9. Epub 2008 Feb 23.Click here to read Links

Polymorphisms of KIRs gene and HLA-C alleles in patients with ankylosing spondylitis: possible association with susceptibility to the disease.

Jiao YL, Ma CY, Wang LC, Cui B, Zhang J, You L, Chen ZJ, Li JF, Zhao YR.

Central Laboratory, Shandong Provincial Hospital, Shandong University, Jinan 250021, People's Republic of China.

INTRODUCTION: An emerging body of evidence is accumulating to suggest that killer cell immunoglobulin-like receptors (KIRs) and human leukocyte antigen (HLA) class I ligands contribute to the pathogenesis of diverse kinds of autoimmune diseases. However, the functional effects of their polymorphism remain largely unknown to date. Thus, the present study was undertaken to determine the association of the polymorphisms KIRs gene and HLA-C alleles with the susceptibility to ankylosing spondylitis (AS) by means of polymerase chain reaction/sequence-specific primers for genotyping KIRs from genomic DNA of 119 patients with AS together with 128 healthy donors as a control group. RESULTS AND DISCUSSION: We found that the frequencies of KIR3DS1 and KIR2DL5 were statistically significantly higher in the patient group than those in the control group (P = 0.016 and P = 0.003, respectively). Meanwhile, the percentage of patients, who were carrying two or more of the activating KIRs, was higher than that of control group. With respect to HLA-C alleles, individuals with AS showed an increased frequency of HLA-Cw02. If HLA-C was divided into group 1 or group 2 based on whether there was an asparagine or lysine present at position 80 of the alpha-chain, HLA-C group 2 was more common in subjects with AS compared to control subjects. The genotype 2DS1+/HLA-C lys(80)+ was more common in subjects with AS. Moreover, the CD69 expression, a NK activation marker, remarkably increased in patient with AS. CONCLUSION: In conclusions, this study suggests that KIR3DS1 may severe as AS susceptive genes to trigger continuous injury of arthrosis. The imbalance of activating and inhibitory KIR as well as HLA-C group 1 and group 2 may be the key factor, which influences the pathogenesis of AS. Moreover, KIR2DS1 might associate with the susceptibility of AS by influencing NK cell activity once group 2 HLA-C ligands are present.

PMID: 18297378 [PubMed - indexed for MEDLINE]

3: J Immunol. 2007 Apr 1;178(7):4402-10.Click here to read Links

Human KIR2DL5 is an inhibitory receptor expressed on the surface of NK and T lymphocyte subsets.

Estefanía E, Flores R, Gómez-Lozano N, Aguilar H, López-Botet M, Vilches C.

Servicio de Inmunología, Hospital Universitario Puerta de Hierro, San Martín de Porres 4, 28035 Madrid, Spain.

Human NK cells, by means of a repertoire of clonally distributed killer cell Ig-like receptors (KIR), survey the expression of individual self HLA class I molecules, which is often altered in infections and tumors. KIR2DL5 (CD158f) is the last identified KIR gene and, with KIR2DL4, constitutes a structurally divergent lineage conserved in different primate species. Research on KIR2DL5 has thus far been limited to its genetic aspects due to a lack of reagents to detect its product. We report here the identification and characterization of the receptor encoded by KIR2DL5 using a newly generated specific mAb that recognizes its most commonly expressed allele, KIR2DL5A*001. KIR2DL5 displays a variegated distribution on the surface of CD56(dim) NK cells. This contrasts with the expression pattern of its structural homolog KIR2DL4 (ubiquitous transcription, surface expression restricted to CD56(bright) NK cells) and resembles the profile of KIR recognizing classical HLA class I molecules. Like other MHC class I receptors, KIR2DL5 is also found in a variable proportion of T lymphocytes. KIR2DL5 is detected on the cell surface as a monomer of approximately 60 kDa that, upon tyrosine phosphorylation, recruits the Src homology region 2-containing protein tyrosine phosphatase-2 and, to a lesser extent, Src homology region 2-containing protein tyrosine phosphatase-1. Ab-mediated cross-linking of KIR2DL5 inhibits NK cell cytotoxicity against murine FcR+ P815 cells. KIR2DL5 is thus an inhibitory receptor gathering a combination of genetic, structural, and functional features unique among KIR, which suggests that KIR2DL5 plays a specialized role in innate immunity.

PMID: 17371997 [PubMed - indexed for MEDLINE]

4: Hum Immunol. 2006 Jan-Feb;67(1-2):85-93. Epub 2006 Mar 30.Click here to read Links

KIR gene in ethnic and Mestizo populations from Mexico.

Gutiérrez-Rodríguez ME, Sandoval-Ramírez L, Díaz-Flores M, Marsh SG, Valladares-Salgado A, Madrigal JA, Mejía-Arangure JM, García CA, Huerta-Zepeda A, Ibarra-Cortés B, Ortega-Camarillo C, Cruz M.

Unidad de Investigación Médica en Bioquímica, Hospital de Especialidades, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Ciudad de México, México. mgutierrezr@hotmail.com

Killer cell immunoglobulin-like receptors are characterized by their great diversity of genes and alleles. Population studies have identified the presence of a broad variety of genotypes. In Mexico, there are diverse ethnic groups representing 9% of the total population and the rest is composed of Mestizos with a more varied biology. For the purpose of this study, genotyping was performed in Mestizos, in Mexico City inhabitants, and in three ethnic groups. The frequencies of genes KIR2DL2, 2DL5, 2DS1-3, 2DS5, and 3DS1 showed a greater variability in the groups studied. A total of 12 different genotypes were identified, the higher number for the Mestizos and the lower number for the Tarahumaras. Genotype 1 was found at a greater frequency in all the groups, except for the Tarahumaras, in which genotype 4 was more frequent. The frequency of genotypes 4 and 8 in Mexicans was higher than that for other populations analyzed. By subtyping of KIR3DL1, 3DL2, 2DL1, and 2DL3, two B haplotypes were identified in families; both were absent in Caucasian families. Our results indicated a greater diversity of genes in the Mestizos group than in the ethnic groups.

PMID: 16698429 [PubMed - indexed for MEDLINE]

5: J Immunol. 2004 Jun 15;172(12):7385-92.Click here to read Links

KIR2DL5 can inhibit human NK cell activation via recruitment of Src homology region 2-containing protein tyrosine phosphatase-2 (SHP-2).

Yusa S, Catina TL, Campbell KS.

Division of Basic Science, Fox Chase Cancer Center, Institute for Cancer Research, 333 Cottman Avenue, Philadelphia, PA 19111, USA.

Human NK cells use class I MHC-binding inhibitory receptors, such as the killer cell Ig-like receptor (KIR) family, to discriminate between normal and abnormal cells. Some tumors and virus-infected cells down-regulate class I MHC and thereby become targets of NK cells. Substantial evidence indicates that the mechanism of KIR-mediated inhibition involves recruitment of the protein tyrosine phosphatases, Src homology 2-containing protein tyrosine phosphatase-1 (SHP-1) and SHP-2, to two phosphorylated cytoplasmic immunoreceptor tyrosine-based inhibitory motifs (ITIMs). KIR2DL5 is a type II member of the KIR2D family with an atypical extracellular domain and an intracytoplasmic domain containing one typical ITIM and one atypical ITIM sequence. Although KIR2DL5 structure is expressed by approximately 50% of humans and is conserved among primate species, its function has not been determined. In the present study, we directly compared functional and biochemical properties of KIR2DL5, KIR3DL1 (a type I KIR with two ITIMs), and KIR2DL4 (the only other type II KIR, which has a single ITIM) in a human NK-like cell line. Our results show that KIR2DL5 is an inhibitory receptor that can recruit both SHP-1 and SHP-2, and its inhibitory capacity is more similar to that of the cytoplasmic domain of KIR2DL4 than KIR3DL1. Interestingly, inhibition of NK cell cytotoxicity by KIR2DL5 was blocked by dominant-negative SHP-2, but not dominant-negative SHP-1, whereas both dominant-negative phosphatases can block inhibition by KIR3DL1. Therefore, the cytoplasmic domains of type II KIRs (2DL4 and 2DL5) exhibit distinct inhibitory capacities when compared with type I KIRs (3DL1), due to alterations in the canonical ITIM sequences.

PMID: 15187115 [PubMed - indexed for MEDLINE]

6: Tissue Antigens. 2005 Jun;65(6):556-63.Click here to read Links

Distribution of killer cell immunoglobulin-like receptor genes in the Chinese Han population.

Jiang K, Zhu FM, Lv QF, Yan LX.

HLA Typing Laboratory, Blood Center of Zhejiang Province, Hangzhou, Zhejiang Province, China.

Killer cell immunoglobulin-like receptors (KIRs) on natural killer cells recognize groups of HLA class I alleles. Seventeen KIR genes have been identified at present, and two kinds of KIR haplotypes (group A and B) have been described based on their gene contents. Immunogenetic analysis of different ethnic populations shows significant differences in terms of the distribution of group A and B haplotypes. Here, genomic DNA from 104 healthy unrelated Chinese Han individuals was typed for the presence or absence of KIR genes. All 17 KIR genes were observed in the population, and framework genes 3DL3, 3DP1, 2DL4, and 3DL2 were present in all individuals. Twenty-six different genotypes were found, four of which could not be assigned to haplotypes according to the model of Hsu et al. (J Immunol 2002: 169: 5118). Group A haplotypes outnumbered group B haplotypes in frequency by approximately 3:1, with individuals having two group A haplotypes accounting for 58.7%. Analysis indicated that some pairs of KIR genes showed remarkable linkage disequilibrium. Our data demonstrated that the Chinese Han population is distinct in KIR gene frequencies and putative KIR haplotypes in comparison to some other populations.

PMID: 15896204 [PubMed - indexed for MEDLINE]

7: Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2005 Dec;13(6):1109-12.Links

[Polymorphism of killer cell immunoglobulin-like receptors gene family in Zhejiang Han population]

[Article in Chinese]

Zhu FM, Jiang K, Lü QF, Zhang W, Zhang HQ, Fu QH, Yan LX.

Blood Center of Zhejiang Province, Hangzhou 310006, China.

To analyze killer immunoglobulin (Ig)-like receptor (KIR) gene content and allelic polymorphism in Zhejiang Han population, samples were genotyped by polymerase chain reaction sequence-specific primers (PCR-SSP). The results demonstrated that all 17 KIR genes could be observed in the population. All individuals contained 2DL4, 3DL2 and 3DL3 genes. The frequencies of these genes was 1.00. 2DL1, 2DL3, 2DP1, 3DP1*003, 3DL1, 2DS4*001/002 loci were more common, their frequencies were 0.902, 0.902, 0.902, 0.902, 0.7598, 0.5615 respectively, while the frequencies of 2DL2, 2DL5A, 2DL5B, 2DS1, 2DS2, 2DS3, 2DS4*003, 2DS5, 3DS1 and 3DP1*001/002 were relatively lower. The A KIR haplotype was the most prevalent (74.7%) in Zhejiang Han population and there were 12 different KIR haplotypes in total, the most common was 2 (53.0%). Twenty six different genotypes have been found in the population, AJ (2, 2) and AF (1, 2) showed higher frequencies, followed by AH (2, 5), NN2 (2, 6), AI (1, 5) and AG (1, 1). Fifteen of these genotypes have not been found in Caucasians so far and four new KIR profiles could not be assigned to the haplotypes according to standard assign method. In conclusion, there are distinctive frequencies of KIR gene content, haplotype as well as genotype in Zhejiang Han population.

PMID: 16403292 [PubMed - indexed for MEDLINE]

8: Immunogenetics. 2007 Jul;59(7):525-37. Epub 2007 Apr 27.Click here to read Links

High-throughput killer cell immunoglobulin-like receptor genotyping by MALDI-TOF mass spectrometry with discovery of novel alleles.

Houtchens KA, Nichols RJ, Ladner MB, Boal HE, Sollars C, Geraghty DE, Davis LM, Parham P, Trachtenberg EA.

Center for Genetics, Children's Hospital Oakland Research Institute, 5700 Martin Luther King Jr. Way, Oakland, CA 94609, USA.

The killer cell immunoglobulin-like receptors (KIR) interact with major histocompatibility complex (MHC) class I ligands to regulate the functions of natural killer cells and T cells. Like human leukocyte antigens class I, human KIR are highly variable and correlated with infection, autoimmunity, pregnancy syndromes, and transplantation outcome. Limiting the scope of KIR analysis is the low resolution, sensitivity, and speed of the established methods of KIR typing. In this study, we describe a first-generation single nucleotide polymorphism (SNP)-based method for typing the 17 human KIR genes and pseudogenes that uses analysis by matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry. It is a high-throughput method that requires minute amounts of genomic DNA for discrimination of KIR genes with some allelic resolution. A study of 233 individuals shows that the results obtained by the SNP-based KIR/MALDI-TOF method are consistent with those obtained with the established sequence-specific oligonucleotide probe or sequence-specific polymerase chain reaction methods. The added sensitivity of the KIR/MALDI-TOF method allowed putative novel alleles of the KIR2DL1, KIR3DL1, KIR2DS5, and KIR2DL5 genes to be identified. Sequencing the KIR2DL5 variant proved it was a newly discovered allele, one that appears associated with Hispanic and Native American populations. This KIR/MALDI-TOF method of KIR typing should facilitate population and disease-association studies that improve knowledge of the immunological functions of KIR-MHC class I interactions.

PMID: 17464504 [PubMed - indexed for MEDLINE]

9: Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2007 Feb;15(1):35-8.Links

[Polymorphism of killer cell immunoglobulin-like receptor gene and its correlation with leukemia]

[Article in Chinese]

Chen AM, Guo XM, Yan WY, Xie SM, Zhu N, Wang XD, Xu R, Liu QP.

Department of Histology and Embryology, Inner Monglia Medical College, Huhhot 010059, China.

The study was purposed to investigate the polymorphism of killer cell immunoglobulin-like receptor (KIR) gene of the patients with leukemia and to explore the correlation between the KIR gene and susceptibility of leukemia. The KIR genotype of 50 patients with leukemia and 60 healthy controls in northern. Hans were analyzed by PCR-SSP. The results indicated that the present known 18 KIR genes were detected and identified. The frequencies of KIR 3DL3, 3DL2 and 2DL4 were 100% in all subjects, with the most frequent genotype KIR 3DP1 (0.86) followed by 2DP1, 2DL3, 3DL1, 2DL1, 3DS1, 2DL5, 2DS4, 2DS2, 1D, 2DS5, 2DL2, 2DS1, 2DS3 and 3DP1v in leukemia successively. Compared with the control, the KIR 3DL1 (0.60) and 2DL1 (0.57) were significantly lower in the leukemia patient group than that in the control group (1.00) (P < 0.01). It is concluded that the polymorphism of KIR gene is associated with susceptibility of leukemia in Hans. There may be a negative correlation between pathogenesis of leukemia and KIR 3DL1, KIR 3DS1, KIR 2DL1, KIR 2DL5 genes.

PMID: 17490516 [PubMed - indexed for MEDLINE]

10: Eur J Immunol. 2007 Jul;37(7):1954-65.Click here to read Links

Epigenetic silencing of potentially functional KIR2DL5 alleles: Implications for the acquisition of KIR repertoires by NK cells.

Gómez-Lozano N, Trompeter HI, de Pablo R, Estefanía E, Uhrberg M, Vilches C.

Servicio de Inmunología, Hospital Universitario Puerta de Hierro, Madrid, Spain.

NK cells detect altered patterns of HLA expression in infections and tumors using a variegated repertoire of killer cell Ig-like receptors (KIR). Each clone surveys different HLA molecules by expressing a limited subset of the KIR encoded in its genome, which is maintained throughout cell divisions by epigenetic mechanisms (methylation of the nonexpressed genes). How KIR repertoires are acquired remains, however, unexplained. Human KIR2DL5 is a useful model for studying KIR expression because it has alleles with similar coding regions, but drastically divergent expression - whilst some are transcribed in a typically clonal manner, others, with distinctive promoter polymorphisms, are nonexpressed. Here we investigate the relationship between the sequence diversity of KIR2DL5, including three novel alleles, and its variable transcription. The promoters of the transcribed alleles recruit the transcriptional regulator RUNX3, whilst a mutation shared by all silent alleles precludes this binding. However, all promoters are functional in vitro, and pharmacological DNA demethylation of NK cells rescues the transcription of silent alleles, indicating that only epigenetic mechanisms prevent their inclusion in a normal KIR repertoire. Our results are consistent with a model in which RUNX factors could function as switch elements in the acquisition of KIR repertoires by NK cell precursors.

PMID: 17557377 [PubMed - indexed for MEDLINE]

11: J Immunol. 2000 Jun 1;164(11):5797-804.Click here to read Links

KIR2DL5, a novel killer-cell receptor with a D0-D2 configuration of Ig-like domains.

Vilches C, Rajalingam R, Uhrberg M, Gardiner CM, Young NT, Parham P.

Departments of Structural Biology and Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA.

Four novel killer-cell Ig-like receptor (KIR) genes were discovered by analysis of genomic DNA from a human donor. One gene, KIR2DL5, is expressed by subpopulations of NK cells and T cells, whereas expression of the other three genes could not be detected. KIR2DL5 has two extracellular Ig-like domains of the D0 and D2 type, a structural configuration that was previously unique to KIR2DL4. Although having a similar structure overall, the KIR2DL4 and KIR2DL5 receptors have distinctive amino acid sequences in the ligand-binding extracellular domains and differ in the transmembrane and cytoplasmic motifs that determine signal transduction. Whereas the KIR2DL4 gene is present on all KIR haplotypes and is expressed by all human NK cells, the KIR2DL5 gene is restricted to the "B" subset of KIR haplotypes and is clonally expressed by NK cells within an individual. Chimpanzee genes for KIR2DL4 and KIR2DL5 have been defined and are very similar in sequence to their human orthologs. The donor in whom KIR2DL5 was first detected bears two variants of it that differ by five nucleotide substitutions in the coding region. Although the substitutions are not predicted to affect gene expression, transcription of only one of the two KIR2DL5 variants could be detected.

PMID: 10820258 [PubMed - indexed for MEDLINE]

12: Eur J Immunogenet. 2002 Aug;29(4):287-91.Click here to read Links

Analysis of candidate genes on chromosome 19 in coeliac disease: an association study of the KIR and LILR gene clusters.

Moodie SJ, Norman PJ, King AL, Fraser JS, Curtis D, Ellis HJ, Vaughan RW, Ciclitira PJ.

Gastroenteroly Unit, GKT, the Rayne Institute, St. Trhomas Hospital, London, UK.

Coeliac disease is strongly heritable, with more than half of the genetic susceptibility estimated to come from genes outside the HLA region. Several candidate regions have been suggested from genome-wide linkage studies including chromosome 19q13.4 where linkage has been replicated between populations. The natural killer (NK) cell immunoglobulin-like receptors (KIRs) and leukocyte immunoglobulin-like receptor (LILR, also known as ILT and LIR) gene clusters lie within this region in the leukocyte receptor cluster (LRC). KIR molecules are involved in cytotoxic lymphocyte function and expressed by intraepithelial T and NK cells in the duodenum. We studied 132 unrelated UK Caucasian coeliac patients and their parents together with a control group of 171 UK Caucasians. PCR-SSP for KIR2DL1, KIR2DL2, KIR2DL3, KIR2DL5, LILRA3 (ILT6), LILRA3 deletion and an LILRA3 exon 3 single nucleotide polymorphism (SNP) allowed classification of KIR genotypes into five categories and determination of homozygosity or heterozygosity for the common A and B type KIR haplotypes (as defined in the text) and for the LILRA3 deletion. Case-control analysis found no association of the five KIR genotype categories, the A or B KIR haplotypes, the LILRA3 gene deletion or the LILRA3 exon 3 SNP with coeliac disease. A transmission disequilibrium test also found no association of the A and B KIR haplotypes or the LILRA3 gene deletion with coeliac disease.

PMID: 12121272 [PubMed - indexed for MEDLINE]

13: J Immunol. 2000 Dec 1;165(11):6416-21.Click here to read Links

Gene structure and promoter variation of expressed and nonexpressed variants of the KIR2DL5 gene.

Vilches C, Gardiner CM, Parham P.

Departments of Structural Biology and Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA.

Two variants of the novel KIR2DL5 gene (KIR2DL5.1 and.2) were identified in genomic DNA of a single donor. However, only the KIR2DL5.1 variant was transcribed in PBMC. In this study, analysis of seven additional donors reveals two new variants of the KIR2DL5 gene and indicates that transcription, or its lack, are consistently associated with particular variants of this gene. Comparison of the complete nucleotide sequences of the exons and introns of KIR2DL5.1 and KIR2DL5.2 reveals no structural abnormalities, but similar open reading frames for both variants. In contrast, the promoter region of KIR2DL5 shows a high degree of sequence polymorphism that is likely relevant for expression. Substitution within a putative binding site for the transcription factor acute myeloid leukemia gene 1 could determine the lack of expression for some KIR2DL5 variants.

PMID: 11086080 [PubMed - indexed for MEDLINE]

14: Tissue Antigens. 2007 Jun;69(6):568-76.Click here to read Links

KIR genes polymorphism in Argentinean Caucasoid and Amerindian populations.

Flores AC, Marcos CY, Paladino N, Capucchio M, Theiler G, Arruvito L, Pardo R, Habegger A, Williams F, Middleton D, Fainboim L.

Laboratorio de Inmunogenética, Hospital de Clínicas, Facultad de Medicina, UBA, Buenos Aires, Argentina.

In natural killer cells, killer immunoglobulin-like receptors (KIRs) loci code for either inhibitory or activating receptors, and according to the number of genes present in each individual, it is possible to identify a high rate of polymorphism in the populations. We performed KIR typing by polymerase chain reaction-sequence-specific oligonucleotide probing in 402 Argentinean Caucasoid and in two Amerindian populations (101 Wichis and 54 Chiriguanos) from the North of Argentina. KIR2DL4, KIR3DL2, KIR3DL3 and KIR3DP1 were always present, whereas the frequencies of KIR2DL1, KIR2DL3, KIR2DS4, KIR3DL1 and KIR2DP1 ranged between 84% and 96%. The frequencies of KIR2DS2, KIR2DL2, KIR2DL5, KIR2DS5, KIR2DS1 and KIR3DS1 ranged between 41% and 62%. The KIR2DS3 with a frequency of 29% in Argentinean Caucasoid population was present at a very low frequency in Amerindian populations. Haplotype segregation studies performed in 10 Wichi families showed the presence of only three haplotypes: A, B5 and B1. The Amerindian populations showed several similarities to Asian but not to Caucasoid populations with regard to the frequency of KIR2DS3, full-length KIR2DS4 gene and KIR2DL4 alleles.

PMID: 17498266 [PubMed - indexed for MEDLINE]

15: Genes Immun. 2007 Mar;8(2):171-6. Epub 2007 Jan 11.Click here to read Links

Association of KIR2DL5B gene with celiac disease supports the susceptibility locus on 19q13.4.

Santin I, Castellanos-Rubio A, Perez de Nanclares G, Vitoria JC, Castaño L, Bilbao JR.

Endocrinology and Diabetes Research Group, Hospital de Cruces, Barakaldo, Bizkaia, Spain.

Genome-wide scans have detected linkage to celiac disease (CD) in several genomic locations, including 19q13.4. Killer immunoglobulin-like receptor (KIR) genes map to the region and encode receptors of natural killer (NK) cells and certain T cells that modulate cytolitic activity through interactions with HLA class I ligands, participating in the innate immune response. We performed KIR genotyping in a group of 70 CD patients of Basque origin and compared gene content, genotype and haplotype frequencies to ethnically matched blood-donors. The frequency of gene combination KIR2DL5B(+)/KIR2DL5A(-) was significantly higher in the disease group, and this result was confirmed in a second group of 343 CD patients and 160 controls of Spanish origin, suggesting an implication of this 'unexpressed' gene with increased susceptibility to CD (combined OR of 3.63 (95% CI: 1.76-7.51; P=0.0004)), possibly due to the lack of an efficient inhibitory signal. Our results support the role of the KIR gene cluster in celiac disease and replicate the CD-susceptibility locus at 19q13.4.

PMID: 17215859 [PubMed - indexed for MEDLINE]

16: Immunogenetics. 2002 Aug;54(5):314-9. Epub 2002 Jun 26.Click here to read Links

Some human KIR haplotypes contain two KIR2DL5 genes: KIR2DL5A and KIR2DL5B.

Gómez-Lozano N, Gardiner CM, Parham P, Vilches C.

Servicio de Inmunología, Hospital Universitario Puerta de Hierro, San Martín de Porres 4, 28035 Madrid, Spain.

Killer-cell immunoglobulin-like receptors (KIR) comprise a family of structurally diverse proteins encoded by a compact cluster of genes located in human Chromosome 19q13.4. The most recently described member of the KIR family, KIR2DL5, is represented in human populations by at least four gene variants, whose exons differ by two to eight nucleotides. We show here that these structurally similar variants are encoded by alleles of two different loci, KIR2DL5A and KIR2DL5B, which map to different regions of the KIR-gene cluster. Regarding KIR2DL5, four groups of KIR haplotypes can be distinguished: those having both KIR2DL5A and KIR2DL5B, those having either KIR2DL5A or KIR2DL5B, and those lacking KIR2DL5. Positive association between KIR2DL5A and KIR2DL5B was detected but did not reach statistical significance. These results are consistent with a model in which KIR2DL5A and KIR2DL5B are products of a gene duplication, which through the action of subsequent recombination have became separated on some haplotypes.

PMID: 12185535 [PubMed - indexed for MEDLINE]

17: Tissue Antigens. 2008 Jul;72(1):11-20. Epub 2008 May 20.Click here to read Links

Investigation of killer cell immunoglobulin-like receptor (KIR) gene diversity: KIR2DL2, KIR2DL5 and KIR2DS5.

Gonzalez A, Meenagh A, Sleator C, Middleton D.

Northern Ireland Regional Histocompatibility and Immunogenetics Laboratory, City Hospital, Belfast, UK. asensio.gonzalez@belfasttrust.hscni.net

Human killer cell immunoglobulin-like receptor (KIR) genes are important for restraining natural killer cytotoxicity toward cells with autologous human leukocyte antigen (HLA) while targeting cells lacking or expressing low levels of self-HLA molecules. KIR gene content and alleles vary across individual genomes and populations, requiring specialized laboratory tools for their characterization. Here, we detail methods based on sequence-specific polymerase chain reaction amplification and oligonucleotide probe hybridization to identify alleles of KIR2DL2, KIR2DL5A, KIR2DL5B and KIR2DS5. Allele frequencies for a Northern Irish population of 354 individuals typed with this system are given, along with results from 132 cell lines from the International Histocompatibility Workshop that cover many world populations. This information complements published reports by our laboratory for allele-level typing of other KIR members, totaling 12 of the 17 known genes. These methods are allowing us to characterize KIR haplotypes in our population.

PMID: 18498296 [PubMed - indexed for MEDLINE]

18: Hum Immunol. 2008 Jun;69(6):349-53. Epub 2008 May 9.Click here to read Links

KIR and HLA gene combinations in Vogt-Koyanagi-Harada disease.

Levinson RD, Du Z, Luo L, Holland GN, Rao NA, Reed EF, Rajalingam R.

Ocular Inflammatory Disease Center, Jules Stein Eye Institute, David Geffen School of Medicine at UCLA, University of California at Los Angeles, Los Angeles, CA.

Vogt-Koyanagi-Harada (VKH) disease is a putative autoimmune ocular inflammatory disease and is known to be associated with HLA-DR4 and -DR1 in Mestizos. We examined the genes encoding KIR receptors and human leukocyte antigen (HLA) class I ligands in patients with VKH disease and compared to published controls. We found trends toward more group B KIR haplogroups (p=0.059), with more activating KIR genes, in patients compared to controls. All putative activating KIR-HLA combinations were more common in patients, and some inhibitory KIR-HLA combinations were more common in controls, although the differences were not statistically significant. The trends observed in this study are consistent with those reported for other autoimmune diseases.

PMID: 18571006 [PubMed - indexed for MEDLINE]

19: J Invest Dermatol. 2004 May;122(5):1133-6.Click here to read Links

Genetic polymorphisms of killer cell immunoglobulin-like receptors are associated with susceptibility to psoriasis vulgaris.

Suzuki Y, Hamamoto Y, Ogasawara Y, Ishikawa K, Yoshikawa Y, Sasazuki T, Muto M.

Department of Dermatology and Biomolecular Recognition, School of Medicine, Yamaguchi University, Yamaguchi, Japan.

To elucidate the association between killer cell immunoglobulin-like receptors (KIRs) and psoriasis vulgaris (PV), we typed 14 KIR genes in 96 Japanese cases and 50 healthy controls using PCR with sequence-specific primers (PCR-SSP). Here we report an interesting association between certain KIRs and Japanese cases with PV. The frequencies of KIR2DS1 and KIR2DL5 were significantly increased in PV cases compared with controls (KIR2DS1, 43 of 96 (45%) in cases vs 14 of 50 (28%) in controls; KIR2DL5, 46 of 96 (48%) in cases vs 15 of 50 (30%) in controls, p<0.05 for both), and the frequency of carriage of at least one presumed "B" haplotype, inferred from patterns including KIR2DL2, KIR2DL5, and/or various combinations of activating KIRs, was also statistically increased in the PV cases (53 of 96 (55%) in cases vs 18 of 50 (36%) in controls, p<0.04). The increase in KIR2DS1 has also been observed in psoriatic arthritis, another HLA-Cw6-associated disease (Martin et al, 2002). Accordingly, KIR2DS1 may be a common denominator of both diseases.

PMID: 15140215 [PubMed - indexed for MEDLINE]

20: Tissue Antigens. 2006 Jul;68(1):66-71.Click here to read Links

Distribution of killer cell immunoglobulin-like receptors genotypes in the Lebanese population.

Mahfouz R, Rayes R, Mahfoud Z, Bazarbachi A, Zaatari G.

Department of Pathology & Laboratory Medicine, American University of Beirut Medical Center, Riad El Solh 1107, 2020 Beirut, Lebanon. rm11@aub.edu.lb

This study represents the first report on the distribution of 16 Killer cell Immunoglobulin-like Receptors (KIR) genes in 120 unrelated healthy Lebanese individuals. We observed that 2DL2 frequency (61%) comes second highest after South Asians (64%) and 2DL5 frequency (58.3%) is the second highest reported so far after the South Asians (74%). Interestingly, a large number of AA1 genotype individuals with no loci for activating KIR and three completely new BB profiles not previously reported were found in our population with a group A : group B haplotypes ratio of 1.3:1. The frequency of the KIR loci suggests that the Lebanese population shares common general features with the Caucasoid populations studied before, but still has its own unique decreased or increased frequencies of several loci.

PMID: 16774542 [PubMed - indexed for MEDLINE]

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