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At least 19 recordsLinked to original sources

PubMed2005

Expansion and enhanced survival of natural killer cells expressing the killer immunoglobulin-like receptor KIR3DL2 in spondylarthritis.

OBJECTIVE: The spondylarthritides (SpA) are strongly associated with possession of HLA-B27. We hypothesized that the expression of abnormal forms of HLA-B27 in SpA may have a pathogenic role through interaction with cells bearing natural killer (NK) receptors, in particular, killer immunoglobulin-like receptor (KIR) KIR3DL2, a receptor for HLA-B27 homodimer (B27(2)). We therefore undertook the present study to determine the number and function of NK and T cells bearing KIR3DL2 in SpA. METHODS: Expression of KIR3DL2 on NK and T cells was quantified in peripheral blood (PB) from 35 patients with SpA and 5 patients with juvenile enthesitis-related arthritis (juvenile ERA); samples were compared with samples from healthy and rheumatoid arthritis (RA) controls. Paired synovial fluid (SF) was studied where available. Expression of other KIRs as well as activation, memory, and homing markers on KIR3DL2+ NK and T cells was quantified. NK cell survival was assessed using the apoptotic markers annexin V and 7-aminoactinomycin D, and cytotoxicity by (51)Cr release assay. RESULTS: In SpA, an increased number of PB and SF NK and CD4+ T cells expressed the KIR3DL2 receptor compared with controls. In ERA, KIR3DL2 expression was increased in PB and SF CD4 T cells (and SF NK cells) compared with RA controls. KIR3DL2+ NK cells had an activated phenotype, and were protected from apoptosis by culture with a cell line expressing B27(2). SpA PB mononuclear NK cells from SpA patients showed greater cytotoxicity than those from controls. CONCLUSION: KIR3DL2 expression on NK cells and CD4 lymphocytes is increased in SpA and ERA. These cells are activated and may have a pathogenic role.

Adolescent↗

PubMed2006

Investigation of killer cell immunoglobulin-like receptors gene KIR3DL2 diversity and confirmation of KIR3DL2*015 in a Chinese population.

Human killer cell immunoglobulin-like receptors (KIRs) are a subfamily of the immunoglobulin superfamily. Here, we established polymerase chain reaction-sequence-based typing (PCR-SBT) procedure to identify alleles of KIR3DL2 gene. The method was designed around the specific amplification of exon 3 to exon 4 and exon 8 to exon 9 of the KIR3DL2 gene. Genomic DNA from 104 healthy, unrelated Chinese Han individuals was typed for KIR3DL2 alleles. Each sample was assigned to the putative allele combination according to the sequences of all KIR3DL2 alleles. We observed 18 different genotypes and eight KIR3DL2 alleles in the population, with KIR3DL2*002 having the highest frequency of 0.558, and confirmed the new KIR3DL2*015 allele. Our data showed that the established PCR-SBT methods for KIR3DL2 allele typing were reliable, and Chinese Han population is distinct in KIR3DL2 allele frequencies.

Asian People↗

PubMed2004

Recognition of HLA-A3 and HLA-A11 by KIR3DL2 is peptide-specific.

The recognition of MHC class I molecules by killer cell immunoglobulin-like receptors (KIR) is central to the control of NK cell function and can also modulate the CTL activation threshold. Among KIR receptors, KIR3DL2 is thought to interact with HLA-A3 and -A11, although direct evidence has been lacking. In this study, we show that HLA-A3 and -A11 tetramers specifically bind to KIR3DL2*001 transfectants and that this recognition is peptide-specific. Single amino acid substitutions in the nonamer peptide underline a critical role for residue 8 in recognition of KIR3DL2. However, the role of this interaction in vivo still remains to be established.

Flow Cytometry↗

PubMed2006

KIR gene in ethnic and Mestizo populations from Mexico.

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.

American Indian or Alaska Native↗

PubMed2000

Development of a PCR-SSOP approach capable of defining the natural killer cell inhibitory receptor (KIR) gene sequence repertoires.

A molecular typing method based on polymerase chain reaction (PCR) amplification of three different target domains (immunoglobulin domains 1 and 3, and the transmembrane-cytoplasmic domain), followed by hybridisation with 26 digoxigenin-labelled sequence-specific oligonucleotide probes (SSOP) has been established for the polymorphic killer inhibitory receptor (KIR) genes. In addition to identifying the 12 KIR subfamilies, our PCR-SSOP typing approach could also distinguish the putative alleles, NKB1 and NKAT3, that comprise the KIR3DL1 subfamily. Ninety unrelated blood donors and 13 families (52 individuals), including both parents, were subjected to our KIR PCR-SSOP typing approach. All 12 KIR subfamilies, including a 2DS5 variant sequence, were present in the 90 individuals and displayed varied phenotype frequencies: 2DL1 (0.96), 2DL2 (0.31), 2DL3 (0.95), 2DS1 (0.56) 2DS2 (0.51), 2DS3 (0.27), 2DS4 (0.96), 2DS5v (0.35), 3DS1 (0.47), 3DL1 (0.96), 3DL2 (1.0) and 2DL4 (1.0). A total of 23 different KIR phenotypes were defined in this study, and 10 of these were only found on one occasion in one individual, indicating considerable diversity in the KIR phenotype profiles within the Irish population. Most individuals (93%) possessed the complement of inhibitory KIR specificities for the three well-defined HLA-B and -C ligands. An unusual probe pattern for 3DS1 was observed in 3 individuals indicating a variant 3DS1 gene sequence with changes at nucleotide positions 1185-1186, within the cytoplasmic domain. Sequencing analysis revealed a new single nucleotide polymorphism in exon 3 of 3DL1 NKB1(195, G-A) and a 22-bp deletion polymorphism in exon 5 of 2DS4 (nucleotides 777-798 deleted). A number of strong KIR associations were observed, namely 2DL1 with 2DL3, 2DS4 with 3DL1, 2DL2 with 2DS1/2DS2/2DS3, 2DS1 with 2DS3/2DS5v/3DS1, 2DS2 with 2DS3 and 2DS5v with 3DS1. Analysis of the KIR segregation observed in the 13 families confirmed these strong associations and permitted the definition of a number of partial KIR haplotypes, e.g. 2DL2-2DS1-2DS2-2DS3-3DL1. The segregation analysis concluded that at least 3 distinct gene loci encode 2DL1-4 and at least 4 gene loci encode the non-inhibitory KIR2DS1-2DS5. In the case of 3DL1-2 and 3DS1, our data suggests 3 gene loci, one for each subfamily.

Humans↗

PubMed2003

[Killer Ig-like receptor gene content diversity and haplotype analysis in Chinese Han population in Shanghai].

OBJECTIVE: To detect the diversity of killer Ig-like receptor(KIR) gene content and the combination of haplotypes in Chinese Han population in Shanghai area. METHODS: DNA samples from 87 randomly unrelated healthy individuals in Shanghai Han population were genotyped with SSP/PCR method. RESULTS: (1) Frequencies of KIR genes: All of 18 known KIRs genes, such as 2DL1-5, 2DS1-5, 3DL1-3, 3DS1, KIR1D and the pseudogenes X, Xv and Z(KIR2DP1) were observed in Shanghai Hans. All individuals contain 3DL3, 2DL4, 3DL2 and 3DL1; the most common genes were 2DL3, Z, 2DL1 and X; the following were 2DS4, 1D, 2DL5, 2DS1, 3DS1 and 2DS5; the next were 2DS2, 2DL2, 2DS3 and Xv. (2) Frequencies of KIR gene haplotypes; there were 13 haplotypes detected in 87 Han individuals, among them, the most frequent one was type 2 (haplotypeA-2DS4). (3) Frequencies of KIR genotypes: 18 kinds of the combinations of the haplotypes were observed; the most frequent ones were AJ(2,2), AF (1,2). Also, In this study were identified five new genotypes FZ1 2 9 , FZ2 1 16 , FZ3 6 17 , FZ4 4 13 and FZ5 2 6 ,which had not been observed in Caucasians so far. CONCLUSION: These findings suggest that there are distinctive frequencies of KIR gene content, haplotype as well as genotype in Chinese Han population in Shanghai area.

China↗

PubMed2004

[Killer immunoglobulin-like receptor gene distribution in Guangdong Han population].

OBJECTIVE: To investigate the distribution of killer immunoglobulin-like receptor (KIR) gene in Guangdong Han population. METHODS: KIR phenotype was examined by PCR with sequence-specific primers in 96 subjects of Han nationality in Guangdong Province of China, and KIR frequency was calculated and compared with those in Caucasian, north Indian and Japanese populations. RESULT: The gene expression frequency of KIR in Guangdong Han people was 2DL1(0.85), 2DL2(0.12), 2DL3(0.58), 2DL4(1), 2DL5(0.24), 3DL1(0.96), 3DL2(1), 3DL3(1), 2DP1(0.97), 2DP2(0.98), 2DS1(0.10), 2DS2(0.30), 2DS3(0.02), 2DS4(0.28), 1D(0.65), 2DS5(0.19), and 3DS1(0.23) respectively. Comparison of the KIR recognizing the same HLA ligand suggested significantly higher expression frequency of inhibitory KIR than that of activating KIR. Compared with Caucasian and north Indian populations, Guangdong Han population had significantly lower expression frequency of activating KIR gene with the exception of KIR2DS4. CONCLUSION: Different KIR genes have different expression frequencies in Guangdong Han population, and KIR gene distribution varies between populations of different races.

Adult↗

PubMed2004

Investigation of killer cell immunoglobulin-like receptor gene diversity V. KIR3DL2.

Allelic definition within the killer cell immunoglobulin-like receptor gene, KIR3DL2, has been achieved through a sequence-specific oligonucleotide probe methodology, designed around the specific amplification of the D0 and D1 domains and a section of the cytoplasmic tail of this gene. The system has been applied to a healthy Northern Irish control group, establishing frequencies for this Caucasian population. Additionally, the KIR3DL2 allele status of cell line DNA and Centre d'Etude du Polymorphisme Humain (CEPH) families, both from the 13th International Histocompatibility Workshop, has been established. A high level of KIR3DL2 allelic polymorphism has been identified.

Genetic Variation↗

PubMed2006

Influence of interleukin IL-2 and IL-12 + IL-18 on surface expression of immunoglobulin-like receptors KIR2DL1, KIR2DL2, and KIR3DL2 in natural killer cells.

Natural killer (NK) cells express killer cell inhibitory receptors (KIRs) that recognize polymorphic class I MHC molecules. In the present study, we analyze the modulatory effect of IL-2 alone or a combination of IL-12 with IL-18 on surface expression of killer cell immunoglobulin-like receptors KIR2DL1, KIR2DL2, and KIR3DL2 in NK cells. Thus, it was found that IL-2 causes a significant increase in the proportion of cells with given studied receptors. Stimulation by a mixture of IL-12 and IL-18 caused significant increase in the fraction of cells with the KIR2DL1 and KIR2DL2, however no significant change in the percentage of cells with KIR3DL2 receptor on their surface was observed. The results of the study show the presence of KIRs on both resting and activated NK cells, this may suggest that KIRs have also an important role in the regulatory processes after activation of this subpopulation of cells.

Cells, Cultured↗

PubMed1999

Structure/function relationship of activating Ly-49D and inhibitory Ly-49G2 NK receptors.

Murine NK cells express Ly-49 family receptors capable of either inhibiting or activating lytic function. The overlapping patterns of expression of the various receptors have complicated their precise biochemical characterization. Here we describe the use of the Jurkat T cell line as the model for the study of Ly-49s. We demonstrate that Ly-49D is capable of delivering activation signals to Jurkat T cells even in the absence of the recently described Ly-49D-associated chain, DAP-12. Ly-49D signaling in Jurkat leads to tyrosine phosphorylation of TCRzeta and requires Syk/Zap70 family kinases and arginine 54 of Ly-49D, suggesting that Ly-49D signals via association with TCRzeta. Coexpression studies in 293-T cells confirmed the ability of Ly-49D to associate with TCRzeta. In addition, we have used this model to study the functional interactions between an inhibitory Ly-49 (Ly-49G2) and an activating Ly-49 (Ly-49D). Ly-49G2 blocks activation mediated by Ly-49D in an immunoreceptor tyrosine-based inhibitory motif (ITIM)-dependent manner. In contrast, Ly-49G2 was incapable of inhibiting activation by the TCR even though human killer cell inhibitory receptor (KIR) (KIR3DL2(GL183)) effectively inhibits TCR. Both the ability of Ly-49G2 to block Ly-49D activation and the failure of Ly-49G2 to inhibit TCR signaling were confirmed in primary murine NK cells and NK/T cells, respectively. These data demonstrate the dominant effects of the inhibitory receptors over those that activate and suggest an inability of the Ly-49 type II inhibitory receptors to efficiently inhibit type I transmembrane receptor signaling in T cells and NK cells.

Amino Acid Motifs↗

PubMed2007

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

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.

Alleles↗

PubMed2006

[Epidermotropic T cell lymphomas as models for tumor progression].

Primary cutaneous T cell lymphomas (CTCL) represent the most frequently occurring group of extra-nodal T cell lymphomas, originating from skin-homing memory T cells. Sezary syndrome (SS) is a leukemic variant of CTCL that presents with erythroderma, lymphadenopathies and presence of malignant T cells in peripheral blood. SS has an unfavourable prognosis, and is refractory to current treatments. Progress in understanding the pathogenesis and tumor progression of SS is limited. In the past few years, we have identified and reported several CTCL-associated antigens, CD158k/KIR3DL2, CD85j/ILT2, and SC5/vimentin. KIR3DL2 is the first phenotypic marker of Sezary cells that can be used for the diagnostic and follow-up of Sezary syndrome. The SC5 antibody is the only monoclonal antibody reacting with vimentin on the surface of viable Sezary cells. CTCL are characterized by a predominance of Th2 cytokines. The recent suggestion that CTCL cells could be regulatory T (Tr) cells remains controversial. Gene expression studies suggest that in the future we may develop new diagnostic and prognostic tools, and identify subsets of patients who would benefit from more appropriate treatment protocols. Future challenges are to render tumor cells sensitive to apoptosis by inhibiting specific signalling pathways such as the constitutively activated NF-KB pathway, to identify specific surface kinase receptors and to develop specific inhibitors, to develop humanized monoclonal antibodies directed against tumor specific antigens, able to kill tumor cells via complement-dependent and antibody-dependent cytotoxicity, and to stimulate innate immunity.

Antibodies, Monoclonal↗

PubMed1994

Immunological evidence for co-expression of cluster-5 and cluster-5A small cell lung cancer antigen on a single molecule.

We have investigated immunologically the molecular association of the cell-surface sialoglycoprotein antigens cluster-5 (CL-5) and cluster-5A (CL-5A), known to be co-expressed in human small-cell lung cancer (SCLC). CL-5 antigen is exclusively defined by IgM antibodies as represented by MAb LAM8, whereas CL-5A antigen is exclusively defined by IgG antibodies as represented by MAbs SWA20 and SEN31. Because of the unavailability of purified antigens, the question of the molecular relationship between these antigens was addressed by immunological studies. We generated an anti-anti-idiotypic MAb of the IgG isotype using a CL-5-antigen-mimicking anti-idiotype defined by rat MAb Ly8-229 as an immunogen to circumvent the avidity problems observed with the IgM MAb LAM8 in binding-competition experiments. In addition, we developed a heterologous double antibody sandwich assay able to identify circulating CL-5/5A antigens in pre-treatment sera of patients with SCLC. The results of both types of immunological studies demonstrated the expression of CL-5 and CL-5A antigens on a single molecule, both in cellular assays and in assays detecting antigens shed into the serum of patients with SCLC.

Animals↗

PubMed2002

Distinctive KIR and HLA diversity in a panel of north Indian Hindus.

HLA and KIR are diverse and rapidly evolving gene complexes that work together in human immunity mediated by cytolytic lymphocytes. Understanding their complex immunogenetic interaction requires study of both HLA and KIR diversity in the same human population. Here a panel of 72 unrelated north Indian Hindus was analyzed. HLA- A, B, C, DRB1, DQA1, and DQB1 alleles and their frequencies were determined by sequencing or high-resolution typing of genomic DNA; KIR genotypes were determined by gene-specific typing and by allele-level DNA typing for KIR2DL1, 2DL3, 2DL5, 3DL1, and 3DL2. From HLA analysis, the north Indian population is seen to have several characteristics shared either with Caucasian or East Asian populations, consistent with the demographic history of north India, as well as specific features, including several alleles at high frequency that are rare or absent in other populations. A majority of the north Indian KIR gene profiles have not been seen in Caucasian and Asian populations. Most striking is a higher frequency of the B group of KIR haplotypes, resulting in equal frequencies for A and B group haplotypes in north Indians. All 72 members of the north Indian panel have different HLA genotype and different KIR genotype.

Alleles↗

PubMed2000

The genomic organization and evolution of the natural killer immunoglobulin-like receptor (KIR) gene cluster.

Natural killer (NK) immunoglobulin-like receptors (KIRs) are a family of polymorphic receptors which interact with specific motifs on HLA class I molecules and modulate NK cytolytic activity. In this study, we analyzed a recently sequenced subgenomic region on chromosome 19q13.4 containing eight members of the KIR receptor repertoire. Six members are clustered within a 100-kb continuous sequence. These genes include a previously unpublished member of the KIR gene family 2DS6, as well as 2DL1, 2DL4, 3DL1, 2DS4, 3DL2, from centromere to telomere. Two additional KIR genes, KIRCI and 2DL3, which may be located centromeric of this cluster were also analyzed. We show that the KIR genes have undergone repeated gene duplications. Diversification between the genes has occurred postduplication primarily as a result of retroelement indels and gene truncation. Using pre- and postduplication Alu sequences identified within these genes as evolutionary molecular clocks, the evolution and duplication of this gene cluster is estimated to have occurred 30-45 million years ago, during primate evolution. A proposed model of the duplication history of the KIR gene family leading to their present organization is presented.

Alleles↗

PubMed2005

NK-KIR transcript kinetics correlate with acute graft-versus-host disease occurrence after allogeneic bone marrow transplantation.

Natural killer (NK) cell alloreactivity observed during stem cell transplantation (SCT) can be either beneficial (graft-versus-leukemia effect) or detrimental to the host (graft-versus-host disease). Killer immunoglobulin-like receptors (KIRs), expressed on NK and CD8 memory T cells, are regulated at a posttranscriptional level and, because there are currently no KIR-specific antibodies available, the analysis of these receptors remains elusive. To better define the role of cells expressing KIR after SCT, we studied KIR transcript repertoires in 29 grafted patients who received myeloablative or nonmyeloablative regimens. We restricted our analysis to 3DL1, 3DL2, 2DL4, 2DS3, and 2DS4 KIR transcripts 6 months after SCT. Absolute counts of NK and CD8 T cells were determined by flow cytometry, and KIR transcripts were quantified by real-time reverse transcription polymerase chain reaction at days 14, 28, 60, 100, and 180 after transplantation. Three groups of patients were identified. Groups I and III were characterized by the absence or a delayed appearance of KIR transcripts, which correlated with the highest risk of acute graft-versus-host disease (aGvHD). In contrast, in group II, a significant transcript peak was observed early, and only one patient suffered from aGvHD (p = 0.025). Thus determining the kinetics of KIR transcription should make it possible to identify transplanted patients at a high risk of developing aGvHD.

Adolescent↗

PubMed2002

The killer cell immunoglobulin-like receptor (KIR) genomic region: gene-order, haplotypes and allelic polymorphism.

Recent genetic studies have established that the killer cell immunoglobulin-like receptor (KIR) genomic region displays extensive diversity through variation in gene content and allelic polymorphism within individual KIR genes. It is demonstrated by family segregation analysis, genomic sequencing, and gene order determination that genomic diversity by gene content alone gives rise to more than 20 different KIR haplotypes and at least 40-50 KIR genotypes. In the most reductionist format, KIR haplotypes can be accommodated within one of 10 different prototypes, each with multiple permutations. Our haplotype model considers the KIR haplotype as two separate halves: the centromeric half bordered upstream by KIR3DL3 and downstream by 2DL4, and the telomeric half bordered upstream by 2DL4 and downstream by 3DL2. There are rare KIR haplotypes that do not fit into this model. Recombination, gene duplication, and inversion can however, readily explain these haplotypes. Additional allelic polymorphism imposes extensive individual variability. Accordingly, this segment of the human genome displays a level of diversity similar to the one observed for the human major histocompatibility complex. Recent application of immunogenetic analysis of KIR genes in patient populations implicates these genes as important genetic disease susceptibility factors.

Alleles↗

PubMed1989

Expression of the small cell carcinoma antigens of cluster-5 and cluster-5A in primary lung tumours.

The expression of the small cell carcinoma (SCLC) antigens cluster-5 (antibody LAM8) and cluster-5A (antibody SWA20) was examined on a panel of routinely processed biopsy or surgical specimens of 290 lung tumours by immunoperoxidase staining. Antigen expression was largely restricted to SCLC. Of over 150 tissue samples evaluated, moderate or strong antigen expression was found in 49% (cluster-5) and 45% (cluster-5A). Concordance in expression of the two antigens was seen in 71% of SCLC samples, with 35% expressing both antigens strongly, 8% moderately and 28% being negative for both antigens. Antigen expression was independent of the morphological subtype of SCLC. Primary lung tumours of other histology, including squamous cell carcinoma, large cell carcinoma, adenocarcinoma, mesothelioma or carcinoid had no significant antigen expression. Of 135 tumours, strong or moderate expression of both antigens was seen only in two cases. 20%, mostly carcinoids, were weakly positive for cluster 5 and 4% for cluster 5A antigen. The remainder were antigen negative. No significant antigen expression was seen in 25 normal lung tissues. The membrane antigens of SCLC cluster 5 and 5A are markers for SCLC and their expression in tissues is tumour-associated.

Antigens, Neoplasm↗