Immunoglobulin-Like Receptors

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Peter Parham - One of the best experts on this subject based on the ideXlab platform.

  • Reproduction, infection and killer-cell Immunoglobulin-Like receptor haplotype evolution
    Immunogenetics, 2016
    Co-Authors: Bridget S. Penman, Ashley Moffett, Olympe Chazara, Sunetra Gupta, Peter Parham
    Abstract:

    Killer-cell Immunoglobulin-Like Receptors (KIRs) are encoded by one of the most polymorphic families in the human genome. KIRs are expressed on natural killer (NK) cells, which have dual roles: (1) in fighting infection and (2) in reproduction, regulating hemochorial placentation. Uniquely among primates, human KIR genes are arranged into two haplotypic combinations: KIR A and KIR B . It has been proposed that KIR A is specialized to fight infection, whilst KIR B evolved to help ensure successful reproduction. Here we demonstrate that a combination of infectious disease selection and reproductive selection can drive the evolution of KIR B -like haplotypes from a KIR A -like founder haplotype. Continued selection to survive and to reproduce maintains a balance between KIR A and KIR B .

  • natural variation at position 45 in the d1 domain of lineage iii killer cell immunoglobulin like Receptors kir has major effects on the avidity and specificity for mhc class i
    Immunogenetics, 2011
    Co-Authors: Anastazia Older M Aguilar, Lisbeth A. Guethlein, Laurent Abirached, Peter Parham
    Abstract:

    Alternative lysine and methionine residues at position 44 in the D1 domain determine the specificities of human lineage III killer cell Immunoglobulin-Like Receptors (KIR) for the C1 and C2 epitopes of HLA-C. KIR having glutamate 44 are also present in orangutans (Popy2DLB) and chimpanzees (Pt-2DL9) but notably absent from humans. Popy2DLB exhibits broad specificity for both the C1 and C2 epitopes, whereas Pt-2DL9 has narrow specificity for C2. Mutation of phenylalanine 45 in Popy2DLB to the cysteine residue present in Pt-2DL9 was sufficient to narrow the Popy2DLB specificity to be like that of Pt-2DL9. In contrast, replacement of cysteine 45 in Pt-2DL9 by phenylalanine had no effect on its C2 specificity, but reduced the avidity. In a similar manner, replacement of phenylalanine 45 with cysteine in Popy2DLA, which has lysine 44 and recognizes C1, maintained this specificity while reducing avidity. Position 45 is exceptionally variable, exhibiting twelve residues that distinguish KIR of different lineages and species. Our study demonstrates the potential for variation at position 45 to modulate KIR avidity and specificity for HLA-C. The various effects of position 45 mutation are consistent with a model in which a Popy2DLB-like receptor, having glutamate 44 and broad specificity for C1 and C2, facilitated the evolution of the C2 epitope from the C1 epitope and C2-specific KIR from C1-specific KIR. With the acquisition of C2 and C2-specific Receptors, the selection against this broadly specific receptor led to its loss from the human line and narrowing of its specificity on the chimpanzee line.

  • mhc class i molecules and kirs in human history health and survival
    Nature Reviews Immunology, 2005
    Co-Authors: Peter Parham
    Abstract:

    MHC class I molecules are ligands for the killer-cell Immunoglobulin-Like Receptors (KIRs), which are expressed by natural killer cells and T cells. The interactions between these molecules contribute to both innate and adaptive immunity. KIRs and MHC class I molecules are encoded by unlinked polymorphic gene families that distinguish all but the most related individuals. Combinations of MHC class I and KIR variants influence resistance to infections, susceptibility to autoimmune diseases and complications of pregnancy, as well as outcome after haematopoietic stem-cell transplantation. Such correlations raise the possibility that interplay between KIR and MHC class I polymorphisms has facilitated human survival in the presence of epidemic infections and has influenced both reproduction and population growth.

  • Complex Interactions: The Immunogenetics of Human Leukocyte Antigen and Killer Cell Immunoglobulin-Like Receptors
    Seminars in hematology, 2005
    Co-Authors: Paul Norman, Peter Parham
    Abstract:

    The killer cell Immunoglobulin-Like Receptors (KIR) for human leukocyte antigen (HLA) modulate innate and adaptive immunity by controlling effector cells. HLA and KIR are encoded in genomic regions that have complex organization and exhibit exceptional diversity within and among human population groups. This diversity is likely to have arisen to combat a constantly evolving pathogen challenge. Numerous variations influence the expression level or function of KIR molecules and can affect their interaction with HLA, with important implications for the immune response. The functional variety of natural immune responses that are controlled by HLA and KIR interactions is genetically determined and maintained by natural selection.

  • Immunogenetics of killer-cell Immunoglobulin-Like Receptors.
    Tissue antigens, 2003
    Co-Authors: Peter Parham
    Abstract:

    The immunogenetics of cell-surface antigens began with the study of red cells and then moved onto the white cells. HLA class I antigens were analyzed on leukocytes and HLA class II antigens on B cells. In the last decade the natural killer (NK) cell has become a target for immunogeneticists, in particular the family of genes encoding the killer-cell Immunoglobulin-Like Receptors (KIRs).

Peter D Sun - One of the best experts on this subject based on the ideXlab platform.

  • a structural perspective on mhc class i recognition by killer cell immunoglobulin like Receptors
    Molecular Immunology, 2002
    Co-Authors: Jeffrey C Boyington, Peter D Sun
    Abstract:

    Killer cell Immunoglobulin-Like Receptors (KIR) play a critical role in the regulation of natural killer (NK) cell activity through their recognition of class I MHC molecules expressed on target cells. KIR recognition provides vital information to NK cells about whether a target cell should be lysed or spared. Understanding the molecular mechanism of this recognition has remained a strong focus of investigation. This has resulted in the crystal structures of several members of the KIR family and more recently the determinations of the three dimensional structures of KIR2DL2 and KIR2DL1 complexed with their respective ligands, HLA-Cw3 and HLA-Cw4. A strong structural conservation has been revealed both in the receptor design and in the overall mode of KIR binding to class I molecules. Nevertheless, distinct differences in the receptor binding sites allow for high specificity between ligands. Furthermore, unexpected similarities with T-cell receptor (TCR) recognition of MHC molecules are also observed. The detailed interactions between KIR and HLA-C molecules and their functional implications will be reviewed here.

  • structure of killer cell immunoglobulin like Receptors and their recognition of the class i mhc molecules
    Immunological Reviews, 2001
    Co-Authors: Jeffrey C Boyington, Andrew G Brooks, Peter D Sun
    Abstract:

    The recognition of class I MHC molecules by killer cell Immunoglobulin-Like Receptors (KIR) constitutes an integral part of immune surveillance by the innate immune system. To understand the molecular basis of this recognition, the structures of several members of this superfamily have been determined. Despite their functional diversity, members of this superfamily share many conserved structural features. A central question is how these Receptors recognize their ligands. The recent determination of the crystal structure of KIR2DL2 in complex with HLA-Cw3 has revealed the molecular mechanisms underpinning this interaction, which ultimately modulates the cytolytic activity of natural killer cells. While the recognition of MHC molecules by KIR is characterized by a number of unique features, some unexpected similarities with T-cell receptor recognition of MHC molecules are also observed. The detailed interactions between KIR2DL2 and HLA-Cw3 and their functional implications will be reviewed here.

Raja Rajalingam - One of the best experts on this subject based on the ideXlab platform.

  • Diversity of Killer Cell Immunoglobulin-Like Receptors and Disease.
    Clinics in laboratory medicine, 2018
    Co-Authors: Raja Rajalingam
    Abstract:

    Natural killer (NK) cells are bone marrow-derived large granular lymphocytes defined by CD3negCD56pos and represent 5% to 25% of peripheral blood mononuclear cell fraction of the healthy humans. NK cells have a highly specific and sophisticated target cell recognition receptor system arbitrated by the integration of signals triggered by a multitude of inhibitory and activating Receptors. Human NK cells express distinct families of Receptors, including (1) killer cell Immunoglobulin-Like Receptors, (2) killer cell lectin-like Receptors, (3) leukocyte Immunoglobulin-Like Receptors, and (4) natural cytotoxicity Receptors.

  • the impact of hla class i specific killer cell immunoglobulin like Receptors on antibody dependent natural killer cell mediated cytotoxicity and organ allograft rejection
    Frontiers in Immunology, 2016
    Co-Authors: Raja Rajalingam
    Abstract:

    Natural killer (NK) cells of the innate immune system are cytotoxic lymphocytes that play an important roles following transplantation of solid organs and hematopoietic stem cells. Recognition of self-human leukocyte antigen (HLA) class I molecules by inhibitory killer cell Immunoglobulin-Like Receptors (KIRs) is involved in the calibration of NK cell effector capacities during the developmental stage, allowing the subsequent recognition and elimination of target cells with decreased expression of self-HLA class I (due to virus infection or tumor transformation) or HLA class I disparities (in the setting of allogeneic transplantation). NK cells expressing an inhibitory KIR-binding self-HLA can be activated when confronted with allografts lacking a ligand for the inhibitory receptor. Following the response of the adaptive immune system, NK cells can further destroy allograft endothelium by antibody-dependent cell-mediated cytotoxicity (ADCC), triggered through cross-linking of the CD16 Fc receptor by donor-specific antibodies bound to allograft. Upon recognizing allogeneic target cells, NK cells also secrete cytokines and chemokines that drive maturation of dendritic cells to promote cellular and humoral adaptive immune responses against the allograft. The cumulative activating and inhibitory signals generated by ligation of the Receptors regulates mature NK cell killing of target cells and their production of cytokines and chemokines. This review summarizes the role of NK cells in allograft rejection and proposes mechanistic concepts that indicate a prominent role for KIR-HLA interactions in facilitating NK cells for Fc receptor-mediated ADCC effector function involved in antibody-mediated rejection of solid organ transplants.

  • Manual of Molecular and Clinical Laboratory Immunology - Killer Cell Immunoglobulin-Like Receptors in Clinical Transplantation
    Manual of Molecular and Clinical Laboratory Immunology, 2016
    Co-Authors: Raja Rajalingam, Sarah Cooley, Jeroen Van Bergen
    Abstract:

    Both in hematopoietic stem cell transplantation (HSCT) and in solid-organ transplantation (SOT), T and B cell-mediated immunity toward nonshared HLA alleles can have a detrimental outcome. In the past decade, many studies have investigated whether natural killer (NK) cell-mediated immunity might also play a role in clinical transplantation. This work has focused on killer cell Immunoglobulin-Like Receptors (KIRs), as these NK cell Receptors interact with HLA class I molecules in an allele-specific manner. In this chapter, we describe the genetics and functions of KIRs and discuss their role in HSCT and SOT.

  • Gene-specific PCR typing of killer cell Immunoglobulin-Like Receptors.
    Methods in molecular biology (Clifton N.J.), 2013
    Co-Authors: Raja Rajalingam, Elham Ashouri
    Abstract:

    By interacting with specific HLA class I molecules, the killer cell Immunoglobulin-Like Receptors (KIR) regulate the effector function of natural killer (NK) cells and subsets of CD8 T cells. The KIR Receptors and HLA class I ligands are encoded by unlinked polymorphic gene families located on different human chromosomes, 19 and 6, respectively. The number and type of KIR genes are substantially variable between individuals, which may contribute to human diversity in responding to infection, malignancy and allogeneic transplants. PCR typing using sequence-specific primers (PCR-SSP) is the most commonly used method to determine KIR gene content. This chapter describes a step-by-step protocol for PCR-SSP typing to identify the presence and absence of all 16 known KIR genes. Moreover, the chapter provides the basic rules to verify the accuracy of KIR genotyping results and explains specific methods for the data analysis.

  • killer cell immunoglobulin like Receptors in hla b27 associated acute anterior uveitis with and without axial spondyloarthropathy
    Investigative Ophthalmology & Visual Science, 2010
    Co-Authors: Ralph D Levinson, Elham Ashouri, Tammy M Martin, James T Rosenbaum, Justine R Smith, Carrie R Austin, Joseph R Lutt, Raja Rajalingam
    Abstract:

    Purpose To determine associations between polymorphic genes that encode KIRs and their HLA class I ligands in patients with HLA-B27-associated acute anterior uveitis (AAU), with and without axial spondyloarthropathy (axial SpA). Methods Molecular DNA typing methods were used to define the frequencies of variable KIR genes and their relevant HLA class I ligands in HLA-B27(+) (B27(+)) Caucasian subjects with AAU and 429 healthy Caucasian control subjects. The patients were evaluated for axial SpA based on their histories using published criteria. Results Of 143 Caucasian subjects with AAU, 71 (49.6%) had features of axial SpA. The only difference between cases and controls in KIR gene frequencies was a trend toward fewer activating KIRs in subjects with AAU with axial SpA, which reached statistical significance for 2DS5 (P = 0.025, corrected P [P(c)] = 0.05; odds ratio [OR], 0.48; 95% CI, 0.25-0.90). The 3DL1+Bw4(T80) combination implicated in weak inhibition was more frequent in subjects with AAU than in control subjects (P = 2.73 x 10(-28), P(c) = 8.2 x 10(-27); OR, 13.5; 95% CI, 7.73-23.68). The 2DL1+HLA-C2 combination was decreased in subjects with axial SpA compared with subjects with AAU without axial SpA (P = 0.022; P(c) = NS; OR, 0.43; 95% CI, 0.21-0.88). Conclusions Evidence was found of a role for KIR-HLA combinations that trigger weaker inhibition in subjects with AAU. Furthermore, there was a trend toward fewer KIR3DS1, -2DS1, and -2DS5 in AAU patients with axial SpA, which have been implicated in NK cell activation. HLA-B27(+) without KIR2DS3 (and -2DS1 and -3DS1) may fail to trigger an early NK cell response to clear antigenic stimuli, which may in part contribute to disease pathogenesis.

Ashley Moffett - One of the best experts on this subject based on the ideXlab platform.

  • Variations in killer-cell Immunoglobulin-Like receptor and human leukocyte antigen genes and immunity to malaria
    Cellular & Molecular Immunology, 2020
    Co-Authors: Stephen Tukwasibwe, Ashley Moffett, Olympe Chazara, Annettee Nakimuli, James Traherne, Jyothi Jayaraman, John Trowsdale, Prasanna Jagannathan, Philip J. Rosenthal, Stephen Cose
    Abstract:

    Malaria is one of the deadliest infectious diseases in the world. Immune responses to Plasmodium falciparum malaria vary among individuals and between populations. Human genetic variation in immune system genes is likely to play a role in this heterogeneity. Natural killer (NK) cells produce inflammatory cytokines in response to malaria infection, kill intraerythrocytic Plasmodium falciparum parasites by cytolysis, and participate in the initiation and development of adaptive immune responses to plasmodial infection. These functions are modulated by interactions between killer-cell Immunoglobulin-Like Receptors (KIRs) and human leukocyte antigens (HLAs). Therefore, variations in KIR and HLA genes can have a direct impact on NK cell functions. Understanding the role of KIRs and HLAs in immunity to malaria can help to better characterize antimalarial immune responses. In this review, we summarize the different KIRs and HLAs associated with immunity to malaria thus far.

  • Reproduction, infection and killer-cell Immunoglobulin-Like receptor haplotype evolution
    Immunogenetics, 2016
    Co-Authors: Bridget S. Penman, Ashley Moffett, Olympe Chazara, Sunetra Gupta, Peter Parham
    Abstract:

    Killer-cell Immunoglobulin-Like Receptors (KIRs) are encoded by one of the most polymorphic families in the human genome. KIRs are expressed on natural killer (NK) cells, which have dual roles: (1) in fighting infection and (2) in reproduction, regulating hemochorial placentation. Uniquely among primates, human KIR genes are arranged into two haplotypic combinations: KIR A and KIR B . It has been proposed that KIR A is specialized to fight infection, whilst KIR B evolved to help ensure successful reproduction. Here we demonstrate that a combination of infectious disease selection and reproductive selection can drive the evolution of KIR B -like haplotypes from a KIR A -like founder haplotype. Continued selection to survive and to reproduce maintains a balance between KIR A and KIR B .

  • Distribution of killer cell Immunoglobulin-Like Receptors (KIR) and their HLA-C ligands in two Iranian populations
    Immunogenetics, 2010
    Co-Authors: Susan E. Hiby, Maziar Ashrafian-bonab, Lydia Farrell, Richard M. Single, Francois Balloux, Mary Carrington, Ashley Moffett
    Abstract:

    Killer cell Immunoglobulin-Like Receptors ( KIR ) gene frequencies vary between populations and contribute to functional variation in immune responses to viruses, autoimmunity and reproductive success. This study describes the frequency distribution of 12 variable KIR genes and their HLA-C ligands in two Iranian populations who have lived for many generations in different environments: the Azerbaijanis at high altitude and the Jonobi people at sea level. The results are compared with those published for other human populations and a large group of English Caucasians. Differences were seen in KIR and HLA-C group frequencies, in linkage disequilibrium and inhibitory/activating KIR ratios between the groups. Similarities with geographically close populations in the frequencies of the KIR A and B haplotypes and KIR AA genotype reflected their common ancestry. The extreme variability of the KIR gene family and their HLA-C ligands is highlighted and their importance in defining differences between geographically and culturally isolated communities subject to different environmental pressures who come from the same ethnic grouping.

  • association of maternal killer cell immunoglobulin like Receptors and parental hla c genotypes with recurrent miscarriage
    Human Reproduction, 2008
    Co-Authors: Susan E. Hiby, Lydia Farrell, Mary Carrington, L Regan, Ashley Moffett
    Abstract:

    BACKGROUND: The natural killer (NK) cells at the site of placentation express killer-cell Immunoglobulin-Like Receptors (KIR) that can bind to human leukocyte antigen (HLA)-C molecules on trophoblast cells. Both these gene systems are polymorphic and an association of particular maternal KIR/fetal HLA-C genotypes has been shown in pre-eclampsia. Pre-eclampsia and recurrent miscarriage (RM) share the pathogenesis of defective placentation and therefore we have now genotyped couples with RM. METHODS AND RESULTS: DNA was obtained from the male (n 5 67) and female (n 5 95) partners of couples with three or more spontaneous miscarriages and genotyped for HLA-C groups and 11 KIR genes using the PCR-sequence-specific primer method (SSP). The frequency of the HLA-C2 group was increased in both parents (reaching significance only in the male partners, P 5 0.018) compared with a parous control population. The KIR gene frequencies of the male partners were similar to controls, but the women had a high frequency of KIR AA haplotypes that lack activating KIR. In particular, the activating KIR for HLA-C2 groups (KIR2DS1) was significantly lower in these women (P 5 0.00035, odds ratio 2.63, confidence interval 1.54‐4.49). CONCLUSIONS: This is the first report to identify a genetic male factor that confers risk in RM. These findings support the idea that successful placentation depends on the correct balance of NK cell inhibition and activation in response to trophoblast.

Torsten Witte - One of the best experts on this subject based on the ideXlab platform.

  • Leukocyte Immunoglobulin-Like Receptors as new players in autoimmunity.
    Clinical reviews in allergy & immunology, 2009
    Co-Authors: Rachel Thomas, Torsten Matthias, Torsten Witte
    Abstract:

    Leukocyte Immunoglobulin-Like Receptors (LILR) are a family of at least 13 Receptors mainly expressed on lymphoid and myelomonocytic cells. They are involved in the activation of the immune system. Inhibitory LILR (termed LILRB) signal through immunoreceptor tyrosine-based inhibitory motives in the cytoplasmic domain, whereas LILRA with short cytoplasmic domains are stimulatory Receptors. Polymorphisms and deletions of leukocyte Immunoglobulin-Like Receptors have been shown to be associated with autoimmune disorders, and some of the Receptors are involved in the generation of regulatory T cells. Therefore, leukocyte Immunoglobulin-Like Receptors may be central in the pathogenesis of autoimmunity. The data linking these Receptors to autoimmune diseases is reviewed here.

  • Association of killer cell Immunoglobulin-Like Receptors with scleroderma.
    Arthritis and rheumatism, 2004
    Co-Authors: T Momot, S. Koch, Nicolas Hunzelmann, Thomas Krieg, K U Ulbricht, Reinhold E. Schmidt, Torsten Witte
    Abstract:

    Objective Scleroderma is an autoimmune disorder of unknown etiology. A genetic contribution has been demonstrated, and genes influencing activation of the immune system have been potentially identified as candidate genes in this process. The repertoire of killer cell Immunoglobulin-Like Receptors (KIRs) that are involved in the activation of T cells and natural killer cells is highly variable. Recently, an association of KIR2DS2 with vasculitis in patients with rheumatoid arthritis has been reported. Because scleroderma is characterized by an involvement of the vascular system, we sought to determine whether KIR2DS2 is associated with scleroderma. Methods We typed 9 KIR genes in 102 patients with scleroderma and in 100 blood donors, using polymerase chain reaction on genomic DNA. Results Twelve patients with scleroderma, compared with only 2 blood donors, had KIR phenotypes characterized by the presence of the activating KIR2DS2 and the absence of the corresponding inactivating KIR2DL2 (P = 0.005). Conclusion The genetic combination of KIR2DS2+ and KIR2DL2− is associated with scleroderma.