Variation in the 3 untranslated region (3UTR) of the HLA-C locus determines binding of the microRNA Hsa-miR-148a, resulting in lower cell surface expression of alleles that bind miR-148a relative to those alleles that escape its binding.. The HLA-C 3UTR variant was shown to associate with HIV control, but like the vast majority of disease associations in a region dense with causal candidates, a direct effect of HLA-C expression level on HIV control was not proven. We demonstrate that a MIR148A insertion/deletion polymorphism associates with its own expression levels, affecting the extent to which HLA-C is down-regulated, the level of HIV control, and the risk of Crohn disease only among those carrying an intact miR-148a binding site in the HLA-C 3UTR.. These data illustrate a direct effect of HLA-C expression level on HIV control that cannot be attributed to other HLA loci in linkage disequilibrium with HLA-C and highlight the rich complexity of genetic interactions in human disease. ...

The HLA-C locus is distinct relative to the other classical HLA class I loci in that it has relatively limited polymorphism, lower expression on the cell surface, and more extensive ligand-receptor interactions with killer-cell immunoglobulin-like receptors. A single nucleotide polymorphism (SNP) 35 …

Differential HLA-C levels influence several human diseases, but the mechanisms responsible are incompletely characterized. Using a validated prediction algorithm, we imputed HLA-C cell surface levels in 228 individuals from the 1000 Genomes dataset.. We tested 68,726 SNPs within the MHC for association with HLA-C level. The HLA-C promoter region variant, rs2395471, 800 bp upstream of the transcription start site, gave the most significant association with HLA-C levels (p = 4.2 x 10-66). This imputed expression quantitative trait locus, termed impeQTL, was also shown to associate with HLA-C expression in a genome-wide association study of 273 donors in which HLA-C mRNA expression levels were determined by quantitative PCR (qPCR) (p = 1.8 x 10-20) and in two cohorts where HLA-C cell surface levels were determined directly by flow cytometry (n = 369 combined, p < 10-15).. rs2395471 is located in an Oct1 transcription factor consensus binding site motif where the A allele is predicted to have higher ...

This work demonstrates that virion-associated HLA-C molecules, when present on cells expressing gp120/gp41, significantly enhance fusion efficiency and pseudovirus transduction. Our conclusions are supported by the following findings: a) CHO cells co-expressing HIV-1 gp120/gp41 and human HLA-C fuse more rapidly and produce larger syncytia than the original CHO-gp120/gp41 cells from which they are derived; b) transient transfection of gp120/gp41 from different primary isolates in CHO cells co-expressing HLA-C results in a significant increase in fusion; c) silencing of HLA-C in human cell lines expressing HIV-1 gp120/gp41 of R5 and X4 tropic strains, significantly suppresses fusion, d) pseudoviruses produced in HLA-C silenced 293T cells display a significant reduction of infectivity; e) the fusion enhancement property of HLA-C is specific for HIV-1 Env, since a virus pseudotyped with the G envelope protein of VSV is not influenced by the presence of HLA-C.. The effect of HLA-C on fusion was ...

|jats:title|ABSTRACT|/jats:title| |jats:p|Despite the fact that the cell surface expression level of HLA-C on both uninfected and HIV-infected cells is lower than those of HLA-A and -B, increasing evidence suggests an important role for HLA-C and HLA-C-restricted CD8|jats:sup|+|/jats:sup| T cell responses in determining the efficiency of viral control in HIV-1-infected individuals. Nonetheless, HLA-C-restricted T cell responses are much less well studied than HLA-A/B-restricted ones, and relatively few optimal HIV-1 CD8|jats:sup|+|/jats:sup| T cell epitopes restricted by HLA-C alleles have been defined. Recent improvements in the sensitivity of mass spectrometry (MS)-based approaches for profiling the immunopeptidome present an opportunity for epitope discovery on a large scale. Here, we employed an MS-based immunopeptidomic strategy to characterize HIV-1 peptides presented by a protective allele, HLA-C*12:02. We identified a total of 10,799 unique 8- to 12-mer peptides, including 15 HIV-1 peptides. The

The biochemical properties of the HLA-C antigen differ substantially from those of HLA-A and -B molecules. For this reason, HLA-C diversity and expression at the cell surface are much lower than its counterparts and in consequence HLA-C-restricted responses have been infrequently detected and described. In this review we summarise the key differences between HLA-C and other class I molecules and provide an update on natural killer and T-cell responses restricted by HLA-C. We also discuss the different clinical settings associated with HLA-C alleles which mainly consist of autoimmune disorders, cancers and chronic infections.

The potential importance of HLA-C-restricted CD8+ cytotoxic T lymphocytes (CTL) in HIV infection remains undetermined. We studied the dominant HLA-Cw*03-restricted CTL response to YVDRFFKTL(296-304) (YL9), within the conserved major homology region (MHR) of the Gag protein, in 80 HLA-Cw*03-positive individuals with chronic HIV infection to better define the efficacy of the YL9 HLA-C-restricted response. The HLA-Cw*03 allele is strongly associated with HIV sequence changes from Thr-303 to Val, Ile, or Ala at position 8 within the YL9 epitope (P=1.62×10(-10)). In vitro studies revealed that introduction of the changes T303I and T303A into the YL9 epitope both significantly reduced CTL recognition and substantially reduced the viral replicative capacity. However, subsequent selection of the Val-303 variant, via intracodon variation from Ile-303 (I303V) or Ala-303 (A303V), restored both viral fitness and CTL recognition, as supported by our in vivo data. These results illustrate that HLA-C-restricted CTL

Our aim is to understand how the complex system of interacting maternal KIR receptors and fetal HLA-C ligands affect trophoblast behaviour during placentation. Both KIR and HLA-C are polymorphic and genetic studies show that NK cells respond inadequately in certain maternal KIR/HLA-C combinations. KIR/HLA-C interactions are predicted to have particular biological importance during placentation because of high expression levels of KIR on uNK cells and HLA-C on trophoblast. We will study functional responses of primary uterine NK cells in women with known KIR genotypes using in vitro assays that mimic different maternal KIR/fetal HLA-C combinations. A particular focus will be on KIR2DS1, the activating KIR for HLA-C2 group alleles, because women with a C2+ fetus are at particular risk of pre-eclampsia if they lack the KIR2DS1 gene. Using functional read-outs - including CD107 assays, cytokine production and microarrays, we will determine the uterus NK repertoire, expression and functional ...

HLA-C was recognized as a classical transplantation determinant long after HLA-A and HLA-B. Its low level of expression and lack of robust serologic typing reagents impeded investigation of this locus. In the DNA era, the availability of PCR-based methods has afforded investigators the tools with which to study HLA-C diversity and the implications of this variation on alloreactivity in blood, marrow and cord blood transplantation. Available evidence demonstrates that HLA-C is a polymorphic locus, shows strong positive linkage disequilibrium with HLA-B on extended HLA haplotypes. Matching between the patient and the stem cell source is associated with lower overall risks of graft-versus-host disease (GVHD). The likelihood of identifying suitable stem cell sources for patients who lack HLA-matched donors, however, remains a challenge, and emphasizes the need to define mismatches that do not increase post-transplant risks. Information on the role of HLA-C ligands in NK cell-mediated alloreactivity is a

p>The checksum is a form of redundancy check that is calculated from the sequence. It is useful for tracking sequence updates.,/p> ,p>It should be noted that while, in theory, two different sequences could have the same checksum value, the likelihood that this would happen is extremely low.,/p> ,p>However UniProtKB may contain entries with identical sequences in case of multiple genes (paralogs).,/p> ,p>The checksum is computed as the sequence 64-bit Cyclic Redundancy Check value (CRC64) using the generator polynomial: x,sup>64,/sup> + x,sup>4,/sup> + x,sup>3,/sup> + x + 1. The algorithm is described in the ISO 3309 standard. ,/p> ,p class=publication>Press W.H., Flannery B.P., Teukolsky S.A. and Vetterling W.T.,br /> ,strong>Cyclic redundancy and other checksums,/strong>,br /> ,a href=http://www.nrbook.com/b/bookcpdf.php>Numerical recipes in C 2nd ed., pp896-902, Cambridge University Press (1993),/a>),/p> Checksum:i ...

p>The checksum is a form of redundancy check that is calculated from the sequence. It is useful for tracking sequence updates.,/p> ,p>It should be noted that while, in theory, two different sequences could have the same checksum value, the likelihood that this would happen is extremely low.,/p> ,p>However UniProtKB may contain entries with identical sequences in case of multiple genes (paralogs).,/p> ,p>The checksum is computed as the sequence 64-bit Cyclic Redundancy Check value (CRC64) using the generator polynomial: x,sup>64,/sup> + x,sup>4,/sup> + x,sup>3,/sup> + x + 1. The algorithm is described in the ISO 3309 standard. ,/p> ,p class=publication>Press W.H., Flannery B.P., Teukolsky S.A. and Vetterling W.T.,br /> ,strong>Cyclic redundancy and other checksums,/strong>,br /> ,a href=http://www.nrbook.com/b/bookcpdf.php>Numerical recipes in C 2nd ed., pp896-902, Cambridge University Press (1993),/a>),/p> Checksum:i ...

Natural killer (NK) cells provide a central defense against viral infection by using inhibitory and activation receptors for major histocompatibility complex class I molecules as a means of controlling their activity. We show that genes encoding the inhibitory NK cell receptor KIR2DL3 and its human leukocyte antigen C group1 (HLA-C1) ligand directly influence resolution of hepatitis C virus (HCV) infection. This effect was observed in Caucasians and African Americans with expected low infectious doses of HCV but not in those with high-dose exposure, in whom the innate immune response is likely overwhelmed. The data strongly suggest that inhibitory NK cell interactions are important in determining antiviral immunity and that diminished inhibitory responses confer protection against HCV. ...

After more than 30 years of active research on HIV/AIDS, many challenging questions remain unanswered. For example, some individuals progress to AIDS within a year after HIV acquisition, whereas others never develop the disease. Host genetic factors play a role in disease progression, but the precise pathways are still unknown. Studies aimed at deciphering this are hampered by interindividual variability and the high propensity of HIV to mutate: as a consequence, the host-virus interactions can vary significantly between different infected people. How innate and adaptive immune mechanisms slow HIV replication is still ill defined and differs substantially among different ethnic groups. As most studies to date have focused on patients of European ancestry, it has become a global health priority to determine how HIV control is achieved in nonwhites (27). In the current study, we assessed the protective effect of −35 SNP in Han Chinese subjects who were infected in a short time frame by a very ...

RefSeq Summary (NM_002117): HLA-C belongs to the HLA class I heavy chain paralogues. This class I molecule is a heterodimer consisting of a heavy chain and a light chain (beta-2 microglobulin). The heavy chain is anchored in the membrane. Class I molecules play a central role in the immune system by presenting peptides derived from endoplasmic reticulum lumen. They are expressed in nearly all cells. The heavy chain is approximately 45 kDa and its gene contains 8 exons. Exon one encodes the leader peptide, exons 2 and 3 encode the alpha1 and alpha2 domain, which both bind the peptide, exon 4 encodes the alpha3 domain, exon 5 encodes the transmembrane region, and exons 6 and 7 encode the cytoplasmic tail. Polymorphisms within exon 2 and exon 3 are responsible for the peptide binding specificity of each class one molecule. Typing for these polymorphisms is routinely done for bone marrow and kidney transplantation. Over one hundred HLA-C alleles have been described [provided by RefSeq, Jul 2008 ...

RefSeq Summary (NM_002117): HLA-C belongs to the HLA class I heavy chain paralogues. This class I molecule is a heterodimer consisting of a heavy chain and a light chain (beta-2 microglobulin). The heavy chain is anchored in the membrane. Class I molecules play a central role in the immune system by presenting peptides derived from endoplasmic reticulum lumen. They are expressed in nearly all cells. The heavy chain is approximately 45 kDa and its gene contains 8 exons. Exon one encodes the leader peptide, exons 2 and 3 encode the alpha1 and alpha2 domain, which both bind the peptide, exon 4 encodes the alpha3 domain, exon 5 encodes the transmembrane region, and exons 6 and 7 encode the cytoplasmic tail. Polymorphisms within exon 2 and exon 3 are responsible for the peptide binding specificity of each class one molecule. Typing for these polymorphisms is routinely done for bone marrow and kidney transplantation. Over one hundred HLA-C alleles have been described [provided by RefSeq, Jul 2008 ...

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Mouse monoclonal antibody raised against HLA-A/HLA-B/HLA-C. Purified human HLA-A/HLA-B/HLA-C complex. (MAB6383) - Products - Abnova

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Human leucocyte antigen (HLA)-C molecules regulate the function of natural killer cells and may be subdivided into two groups, C(1) and C(2), based on their specificity for inhibitory killer immunoglobulin-like receptors. We analysed the impact of the HLA-C genotype on outcome of HLA-C-matched unrelated donor haematopoietic stem cell transplantation (URD-HSCT) recipients. HLA-C(2) homozygous patients (n = 18) had lower probability of overall survival (P = 0.01) and disease-free survival (P = 0.02), resulting from increased relapse rate (P = 0.02) when compared with both HLA-C(1) homozygous (n = 43) and HLA-C(1),C(2) heterozygous (n = 50) subgroups. Patients lacking HLA-C(1) should, therefore, be considered at increased risk of relapse following HLA-C-matched URD-HSCT.. ...

TY - JOUR. T1 - Killer immunoglobulin-like receptor and human leukocyte antigen-C genotypes in rheumatoid arthritis primary responders and non-responders to anti-TNF-α therapy. AU - McGeough, Cathy. AU - Berrar, Daniel. AU - Wright, Gary. AU - Mathews, Clare. AU - Gilmore, Paula. AU - Cunningham, Rodat T.. AU - Bjourson, AJ. PY - 2011. Y1 - 2011. U2 - 10.1007/s00296-011-1838-6. DO - 10.1007/s00296-011-1838-6. M3 - Article. VL - 32. SP - 1647. JO - Rheumatology International. JF - Rheumatology International. SN - 0172-8172. IS - 6. ER - ...

For successful establishment of the placenta, fetal trophoblast cells need to infiltrate the decidua and transform spiral arteries in the first few weeks of pregnancy. As a result, the fetus receives sufficient oxygen and nutrients for normal growth and development. This invasion must be balanced, so that excessive trophoblast penetration of the uterus does not occur (which would endanger the mother), or so that arterial transformation is not defective (which would starve the feto-placental unit). Our findings suggest that the immune system plays a part in defining this maternal-fetal boundary. The different experimental approaches we used all indicate that interactions of maternal KIRs with trophoblast HLA-C molecules influence placentation. Using the mAb WK4C11, we show that trophoblast cells strongly express both parental HLA-C allotypes. At the site of placentation, these fetal cells mingle with maternal NK cells expressing activating (2DS1) and inhibitory (2DL1) KIRs. Fresh uNK cells do not ...

Maternal inhibitory KIR2DL1 associates with pregnancy disorders linked to inadequate placentation, whereas maternal-activating KIR2DS1 associates with increased birth weight. These results suggest that variations in immune system genes, KIR and HLA-C, are under selection as a result of the necessity to keep human birth weight within the limits defined by the harmful consequences of low and high birth weight. A territorial demarcation between the mother and her fetus resulting from the interaction of maternal KIR on uNK and fetal HLA-C expressed by invading trophoblast could be the basis for achieving such a compromise. Both the KIR2DL1 and KIR2DS1 associations, at opposite ends of the birth weight spectrum, occur particularly in pregnancies where the fetus carries an additional HLA-C group 2 allele compared with the mother or the fetus has a single C2 allele that is of paternal but not maternal origin. Because C2 is the ligand for KIR2DL1/S1, this argues strongly for a role of the maternal KIR. ...

IntroductionUnderstanding the mechanisms by which some individuals are able to naturally control HIV-1 infection is an important goal of AIDS research. We here describe the case of an HIV-1+ woman, CASE1, who has spontaneously controlled her viremia for the last 14 of her 20 years of infection.MethodsCASE1 has been clinically monitored since 1993. Detailed immunological, virological and histological analyses were performed on samples obtained between 2009 and 2011.ResultsAs for other Elite Controllers, CASE1 is characterized by low to undetectable levels of plasma HIV-1 RNA, peripheral blood mononuclear cell (PBMC) associated HIV-1 DNA a reduced in vitro susceptibility of target cells to HIV-1 infection. Furthermore, a slow rate of virus evolution was demonstrated in spite the lack of assumption of any antiretroviral agent. CASE1 failed to transmit HIV-1 to either her sexual male partner or to her child born by vaginal delivery. Normal values and ratios of T and B cells were observed, along with ...

Abstract:. MHC class I molecules (HLA-I in humans) present peptides derived from endogenous proteins to CTLs. Whereas the peptide-binding specificities of HLA-A and -B molecules have been studied extensively, little is known about HLA-C specificities. Combining a positional scanning combinatorial peptide library approach with a peptide-HLA-I dissociation assay, in this study we present a general strategy to determine the peptide-binding specificity of any MHC class I molecule. We applied this novel strategy to 17 of the most common HLA-C molecules, and for 16 of these we successfully generated matrices representing their peptide-binding motifs. The motifs prominently shared a conserved C-terminal primary anchor with hydrophobic amino acid residues, as well as one or more diverse primary and auxiliary anchors at P1, P2, P3, and/or P7. Matrices were used to generate a large panel of HLA-C-specific peptide-binding data and update our pan-specific NetMHCpan predictor, whose predictive performance ...

TY - JOUR. T1 - Identification of a novel HLA-Cw*05 allele, Cw*0503. AU - Huang, L. Q.. AU - Boon, T.. AU - Van Pel, Aline. PY - 2000. Y1 - 2000. N2 - HLA-Cw*05 is one of the least polymorphic subgroups of HLA-C; so far only two alleles, namely Cw*0501 and Cw*0502, have been reported. We report here the identification of a third allele, Cw*0503, in a Caucasian individual. Cw*0503 is closely related to Cw*0501 with only six nucleotide substitutions clustering over a fragment of 48 nucleotides at the beginning of exon 4. All these six substitutions at the same positions have been found only in HLA-B*44 alleles, suggesting that Cw*0503 is a result of recombination between Cw*0501 and one of B*44 alleles.. AB - HLA-Cw*05 is one of the least polymorphic subgroups of HLA-C; so far only two alleles, namely Cw*0501 and Cw*0502, have been reported. We report here the identification of a third allele, Cw*0503, in a Caucasian individual. Cw*0503 is closely related to Cw*0501 with only six nucleotide ...

The highly polymorphic MHC class I molecule HLA-C is expressed on fetal trophoblast cells. This is the dominant ligand for NK cells in blood but we have increasing evidence that a major function of the NK receptors that bind HLA-C (known as KIR) are pivotal in determining how far trophoblast invades into the uterus, and the extent of remodeling of the maternal spiral arteries, establishing blood flow to the placenta. Dr Sue Hiby s work on the immunogenetics of this interaction shows that one particular maternal KIR and fetal HLA-C combination is associated with the major diseases of pregnancy recurrent miscarriage, fetal growth restriction and pre-eclampsia. I work as a technician with Dr Hiby and Proffessor Moffett on these genetic studies.. Funding: Wellcome Trust. ...

A better understanding of the mechanisms by which host immunity contributes to HIV control in the absence of antiretroviral treatment will be needed to guide future immune-based interventions, especially in the therapeutic vaccination setting. To date, the fine specificity of HIV-specific CD8+ T cells, the maintenance of their polyfunctionality, and the ability of virus-specific CD8+ T cells to suppress in vitro viral replication has been most consistently associated with reduced viral loads in chronic HIV infection (20-23). Here, we applied, for the first time, an innovative communicome approach that was initially utilized to predict early onset of Alzheimer disease (8) to identify potential soluble biomarkers involved in cellular communication that are associated with HIV control. Our data show that elevated levels of IL-27 are associated with higher viral load and increased size of the viral reservoir, and that these effects may be mediated by a dysregulated Wnt/β-catenin signaling ...

The CD158a and CD158h molecules are monomeric integral membrane glycoproteins existing in different forms. CD158a, or p58.1, is a 58 kDa molecule, and CD158h, or p50.1, is a 50 kDa molecule, both having identical extracellular portions, but different transmembrane and cytoplasmic regions. Another comprehensive nomenclature refers to these molecules as KIR2DL1 for CD158a and KIR2DS1 for CD158h. These acronyms stand for Killer cell Immunoglobulin (Ig)-like Receptor (KIR), with extracellular part containing 2 Ig Domains (2D), and cytoplasmic tails being either long (L) or small (S). The long intracellular portion of CD158a, or p58.1, makes it an inhibitory form, since it contains two characteristic ITIM motifs (Immunoreceptor tyrosine based inhibition motif) and is involved in the transduction of the inhibitory signal. Whereas the stimulatory form CD158h, or p50.1, lacks these ITIM motifs. CD158a/p58.1 functions as an inhibitory receptor for a group of HLA-C molecules (Cw2, cw4, Cw5 and Cw6 supertypes).

genes expressed by fetal trophoblast. Inhibitory KIR2DL1 and activating KIR2DS1 both bind HLA-C2, but confer increased risk or protection from pregnancy disorders, respectively. The mechanisms underlying these genetic associations with opposing outcomes are unknown. We show that KIR2DS1 is highly expressed in dNK, stimulating strong activation of KIR2DS1+ dNK. We used microarrays to identify additional responses triggered by binding of KIR2DS1 or KIR2DL1 to HLA-C2 and found different responses in dNK coexpressing KIR2DS1 with KIR2DL1 compared with dNK only expressing KIR2DL1. Activation of KIR2DS1+ dNK by HLA-C2 stimulated production of soluble products including GM-CSF, detected by intracellular FACS and ELISA. We demonstrated that GM-CSF enhanced migration of primary trophoblast and JEG-3 trophoblast cells in vitro. These findings provide a molecular mechanism explaining how recognition of HLA class I molecules on fetal trophoblast by an activating KIR on maternal dNK may be beneficial for ...

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To assess the feasibility of the selection and reinfusion of 5x10E6 haploidentical natural killer (NK) cells /Kg of body weight (target cell dose) in at least 40% of adult patients with active acute myeloblastic leukemia (AML) entering the ...

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TY - JOUR. T1 - A human monoclonal antibody against HLA-Cw1 and a human monoclonal antibody against an HLA-A locus determinant derived from a single uniparous female. AU - Mulder, A. AU - Kardol, M J. AU - Uit het Broek, C M. AU - Tanke-Visser, J. AU - Young, Neil Thomas. AU - Claas, F H. PY - 1998/10/1. Y1 - 1998/10/1. N2 - Two human monoclonal antibodies (HuMAbs) with widely different HLA specificities were raised from a uniparous HLA-seropositive female. Screening against a large panel of serologically HLA-typed lymphocytes in the complement-dependent cytotoxicity test showed that one of these HuMAbs, VP6G3, was specific for HLA-Cw1, thereby constituting the first HuMAb against an HLA-C locus product. The second HuMAb, VP5G3, was directed against an HLA-A-encoded determinant shared by HLA-A11, -A25, -A26 and -A66. The epitopes responsible for binding were determined by comparing the aminoacid sequences and were pinpointed to the 6K/9F combination for HuMAb VP6G3, and 163R with a critical ...

OBJECTIVES: The HIV-1 Nef protein selectively downregulates human leukocyte antigen (HLA)-A and HLA-B but not HLA-C molecules on the surface of infected cells. This allows HIV-infected cells to evade recognition by most cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells. We investigated the recognition of an HLA-Cw4-restricted HIV-1 gp120 epitope SFNCGGEFF (SF9) and its variant SFNCGGEFL (SL9) by T cells and NK receptors. DESIGN AND METHOD: Recognition of HIV-1 gp120 peptides (SF9 and SL9) by T-cell clones was measured by staining with HLA-Cw4-peptide tetrameric complexes and cytolytic assays using target cell pulsed with either peptides. KIR2DL1 binding to these two peptides was measured using surface plasmon resonance and tetramer staining of an NK cell line. RESULT: : CTLs could recognize SF9 better than the variant SL9, as shown by both tetramer staining and cytolytic assays. Intriguingly, an HLA-Cw4 tetramer folded with the escape variant SL9 could bind to KIR2DL1 on NK cell lines with

OBJECTIVES: The HIV-1 Nef protein selectively downregulates human leukocyte antigen (HLA)-A and HLA-B but not HLA-C molecules on the surface of infected cells. This allows HIV-infected cells to evade recognition by most cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells. We investigated the recognition of an HLA-Cw4-restricted HIV-1 gp120 epitope SFNCGGEFF (SF9) and its variant SFNCGGEFL (SL9) by T cells and NK receptors. DESIGN AND METHOD: Recognition of HIV-1 gp120 peptides (SF9 and SL9) by T-cell clones was measured by staining with HLA-Cw4-peptide tetrameric complexes and cytolytic assays using target cell pulsed with either peptides. KIR2DL1 binding to these two peptides was measured using surface plasmon resonance and tetramer staining of an NK cell line. RESULT: : CTLs could recognize SF9 better than the variant SL9, as shown by both tetramer staining and cytolytic assays. Intriguingly, an HLA-Cw4 tetramer folded with the escape variant SL9 could bind to KIR2DL1 on NK cell lines with

Natural killer (NK) receptor signaling can lead to reduced cytotoxicity by NK cells and cytolytic T lymphocytes (CTLs) in vitro. Whether T cells are inhibited in vivo remains unknown, since peptide antigen-specific CD8(+) T cells have so far not been found to express NK receptors in vivo. Here we demonstrate that melanoma patients may bear tumor-specific CTLs expressing NK receptors. The lysis of melanoma cells by patient-derived CTLs was inhibited by the NK receptor CD94/NKG2A. Thus, tumor-specific CTL activity may be decreased through NK receptor triggering in vivo.

Asumalahti K, Laitinen T, Itkonen-Vatjus R, Lokki ML, et al. (2000). A candidate gene for psoriasis near HLA-C, HCR (Pg8), is highly polymorphic with a disease-associated susceptibility allele. Hum. Mol. Genet. 9: 1533-1542. http://dx.doi.org/10.1093/hmg/9.10.1533 PMid:10888604 Attia J, Thakkinstian A and DEste C (2003). Meta-analyses of molecular association studies: methodologic lessons for genetic epidemiology. J. Clin. Epidemiol. 56: 297-303. http://dx.doi.org/10.1016/S0895-4356(03)00011-8 Brandrup F, Holm N, Grunnet N, Henningsen K, et al. (1982). Psoriasis in monozygotic twins: variations in expression in individuals with identical genetic constitution. Acta Derm. Venereol. 62: 229-236. PMid:6179364 Brazzelli V, Quaglini M, Martinetti M, Nolli G, et al. (2000). A peculiar sequence motif in the alpha-1-domain of the HLA-C molecule in psoriasis. Dermatology 200: 99-103. http://dx.doi.org/10.1159/000018338 PMid:10773694 Chandran V and Raychaudhuri SP (2010). Geoepidemiology and environmental ...

Class I human histocompatibility (HLA) antigens encoded by a small cluster of structural genes at the C locus on chromosome 6. They have significantly lower immunogenicity than the HLA-A and -B determinants and are therefore of minor importance in donor/recipient crossmatching. Their primary role is their high-risk association with certain disease manifestations (e.g., spondylarthritis, psoriasis, multiple myeloma ...

Results Of the combined HIV+ subjects 63 [90%] were male; mean 51 years; 92.8% taking antiretrovirals. HIV+ subjects (combined HIV+ cases and HIV+ controls) were more likely to smoke (34 [30.6%] vs 3 [7.3%], p , 0.001) than healthy controls. HIV+ cases were hypertensive (13 [54.1%] vs 5 [10.8%], p , 0.001) and had a family history of CAD (12 [52.1%] vs 9 [25.0%], p 0.033) at higher rates than HIV+ controls. sGPVI was higher in HIV+ subjects (combined) then healthy controls (129.9 ng/ml [SD 59.5] vs 84.4 ng/ml [SD 46.1], p , 0.001). 12 months before event there was no difference in sGPVI between HIV+ cases and HIV+ controls (123.2 ng/ml [SD 61.7] vs 137.8 ng/ml [SD 63.5], p 0.369). 1 month before event sGPVI was significantly lower in HIV+ cases (111.1 ng/ml [SD 45.0] vs 143.9 ng/ml [SD 56.1], p 0.016). ...

Previous research has shown that specific qualities of the immune systems killer T cells influence the rare ability of some individuals to control HIV infection with their immune system alone.

TY - JOUR. T1 - The transmembrane sequence of human histocompatibility leukocyte antigen (HLA)-C as a determinant in inhibition of a subset of natural killer cells. AU - Davis, Daniel M.. AU - Mandelboim, Ofer. AU - Luque, Isabel. AU - Baba, Eishi. AU - Boyson, Jonathan. AU - Strominger, Jack L.. PY - 1999/4/19. Y1 - 1999/4/19. N2 - Molecular interactions with the extracellular domains of class I major histocompatibility complex proteins are major determinants of immune recognition that have been extensively studied both physically and biochemically. However, no immunological function has yet been placed on the transmembrane or cytoplasmic amino acid sequences of these proteins despite strict conservation of unique features within each class I major histocompatibility complex locus. Here we report that lysis by a subset of natural killer (NK) cells inhibited by target cell expression of human histocompatibility leukocyte antigen (HLA)-Cw6 or -Cw7 was not inhibited by expression of chimeric ...

The question we are addressing is: how does the maternal immune system regulate placentation in humans? Our view of the fetal allograft is one of cooperation between mother and fetus. We focus on how the dominant population of uterine leukocytes, Natural Killer (NK) cells, that have receptors for HLA class I ligands on fetal trophoblast cells, regulate trophoblast function.. We work in close collaboration with Dr Francesco Colucci in the Department of Obstetrics and Gynaecology.. The main areas of current research are:. 1) Interactions between maternal Killer-cell Immunoglobulin-like Receptor (KIR) and fetal HLA-C molecules. Because both KIR and HLA-C genes are highly polymorphic, each pregnancy is likely to be different. Our genetic and functional studies in Europeans and Africans show certain KIR/HLA-C genetic combinations are associated with extremes of the normal birth weight distribution.. 2) Culture of human trophoblast cells. Studies on pregnancy disorders are limited because trophoblast ...

It has been suggested that receptor-ligand complexes segregate or co-localise within immune synapses according to their size, and this is important for receptor signaling. Here, we set out to test the importance of receptor-ligand complex dimensions for immune surveillance of target cells by human Natural Killer (NK) cells. NK cell activation is regulated by integrating signals from activating receptors, such as NKG2D, and inhibitory receptors, such as KIR2DL1. Elongating the NKG2D ligand MICA reduced its ability to trigger NK cell activation. Conversely, elongation of KIR2DL1 ligand HLA-C reduced its ability to inhibit NK cells. Whereas normal-sized HLA-C was most effective at inhibiting activation by normal-length MICA, only elongated HLA-C could inhibit activation by elongated MICA. Moreover, HLA-C and MICA that were matched in size co-localised, whereas HLA-C and MICA that were different in size were segregated. These results demonstrate that receptor-ligand dimensions are important in NK ...

Previous studies have identified a central role for HLA-B alleles in influencing control of HIV infection. An alternative possibility is that a small number of HLA-B alleles may have a very strong impact on HIV disease outcome, dominating the contribution of other HLA alleles. Here, we find that even following the exclusion of subjects expressing any of the HLA-B class I alleles (B*57, B*58, and B*18) identified to have the strongest influence on control, the dominant impact of HLA-B alleles on virus set point and absolute CD4 count variation remains significant. However, we also find that the influence of HLA on HIV control in this C-clade-infected cohort from South Africa extends beyond HLA-B as HLA-Cw type remains a significant predictor of virus and CD4 count following exclusion of the strongest HLA-B associations. Furthermore, there is evidence of interdependent protective effects of the HLA-Cw*0401-B*8101, HLA-Cw*1203-B*3910, and HLA-A*7401-B*5703 haplotypes that cannot be explained solely by

Understanding why some people establish and maintain effective control of HIV-1 and others do not is a priority in the effort to develop new treatments for HIV/AIDS. Using a whole-genome association strategy, we identified polymorphisms that explain nearly 15% of the variation among individuals in viral load during the asymptomatic set-point period of infection. One of these is found within an endogenous retroviral element and is associated with major histocompatibility allele human leukocyte antigen (HLA)-B*5701, whereas a second is located near the HLA-C gene. An additional analysis of the time to HIV disease progression implicated two genes, one of which encodes an RNA polymerase I subunit. These findings emphasize the importance of studying human genetic variation as a guide to combating infectious agents. Fellay, Jacques; Shianna, Kevin V.; Ge, Dongliang; Colombo, Sara; Ledergerber, Bruno; Weale, Mike; Zhang, Kunlin; Gumbs, Curtis; Castagna, Antonella; Cossarizza, Andrea; Cozzi-Lepri, Alessandro;

Studies across population groups reveal the great diversity of HLA-KIR dimorphisms. The Southern Han centromeric KIR region encodes strong, conserved, inhibitory HLA-C-specific receptors, and the telomeric region provides a high number and diversity of inhibitory HLA-A and -B-specific receptors. In all these characteristics, the Chinese Southern Han represent other East Asians, whose NK cell repertoires are thus enhanced in quantity, diversity, and effector strength, likely augmenting resistance to endemic viral infections.. One study goes much further suggesting that functional interactions between KIR and HLA modify risks of basal cell carcinoma (BCC) and squamous cell carcinomas (SCC) and that KIR B haplotypes provide selective pressure for altered p53 in BCC tumors. This preference implicates multi-modal p53 mechanisms that are also known to upregulate NK ligands, induce HLA-A11 assembly against Epstein Bar Virus and bind a frequently mutated p53 peptide in a complex with HLA-A and presented ...

Genetic susceptibility factors are known to be important in NPC pathogenesis. Given the strong link between EBV and NPC, and the role of HLA gene products in the presentation of viral antigens to the adaptive immune response, HLA genes have been extensively studied as risk factors for NPC. In the present report, we have extended previous findings by demonstrating an association between two HLA-Cw alleles and NPC: HLA-Cw*0302 and HLA-Cw*0401. Whereas the association with HLA-Cw*0302 might mirror the previously reported association between HLA-B*5801 and NPC (due to tight linkage disequilibrium between the two alleles), the association between HLA-Cw*0401 and NPC seems to be independent of previously reported associations.. In contrast to the extensive work done to date to evaluate the role of adaptive immune response in the etiology of NPC, surprisingly little is known about the role of innate immunity in the control of EBV infection and its contribution to NPC risk. To address this issue, we ...

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BOSTON - HIV is a master of evading the immune system, using a variety of methods to prevent the body from being able to find and kill it. The vast majority of people living with HIV require daily medication to suppress the virus and therefore prevent the development of AIDS.. But for a small subset of people, this battle between the immune system and the virus looks quite different. Known as controllers, they have immune systems that can suppress the virus without any need for medication. While most controllers can suppress the virus indefinitely, some eventually lose control over the virus and require medication to achieve viral suppression. In a paper recently published in Immunity, researchers at the Ragon Institute of MGH, MIT and Harvard reported that, in these cases, control is lost after a type of immune cell, called a cytotoxic T cell, loses the ability to proliferate and kill HIV-infected cells.. In order to find these differences, the researchers, led by Ragon Research Fellow David ...

Spatial distributions of HIV Infection in an endemic area of western Kenya: Guiding information for localized HIV control and preventionSpatial distributions of HIV Infection in an endemic area of western Kenya: Guiding information for localized HIV control and prevention ...

The broad, long term goal ofthe proposed research is to understand the structure and function of MHC proteins and cellular factors that interact with therin. Th...