Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:O95477 (membrane-bound)
 29,236 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tumor cells release membrane vesicles, named exosomes, capable of specific cytotoxic T-lymphocyte activation by transferring tumor antigens to dendritic cells. By contrast, the nonclassical human leucocyte antigen (HLA)-G class I molecule displays immunotolerant properties and can be ectopically expressed by tumor cells, thereby allowing their escape from immunosurveillance. We describe here that a melanoma cell line, named Fon, established from an HLA-G-positive melanoma biopsy, spontaneously expressed high levels of the HLA-G1 membrane-bound isoform. Exosomes released by Fon cells were purified and analyzed both for their density on sucrose gradient and their protein composition by Western blotting and flow cytometry. Besides the expression of well-described proteins such as Lamp-2, notably, these melanoma-derived exosomes bore HLA-G1. In addition, exosomes harboring HLA-G1 were secreted by the HLA-G-negative M8 melanoma cells transfected with the HLA-G1 cDNA. Thus, the presence of tolerogenic HLA-G molecules on melanoma-derived exosomes may provide a novel way for tumors to modulate host's immune response.
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PMID:Exosomes bearing HLA-G are released by melanoma cells. 1460 37

In contrast to the classical HLA class Ia molecules, the nonclassical HLA-G primary transcript is alternatively spliced to generate several mRNAs that encode four membrane-bound and three soluble isoforms. This study demonstrated that the soluble form of HLA-G can also be generated by metalloproteinase-dependent shedding at post-translational level. These soluble HLA-G1 molecules generated by the cleavage of membrane-bound HLA-G1 associate with beta2-microglobulin and contain bound peptides that are stable at physiological conditions. This report further showed that the soluble HLA-G1 is able to protect HLA class I-negative K562 cells from NK lysis, suggesting that soluble HLA-G could act as an immunoregulator in NK cell recognition and possibly in other immune responses.
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PMID:Soluble HLA-G generated by proteolytic shedding inhibits NK-mediated cell lysis. 1469 34

The expression of HLA-G by invading trophoblasts suggests a role for this molecule in embryo implantation. Putative targets for HLA-G are the uterine natural killer cells (uNK) that are abundantly present at the time of implantation. Since NK cells are potent producers of a variety of cytokines, interaction with HLA-G may result in the production of cytokines involved in trophoblast differentiation or tissue remodelling. In the present study we investigated the effect of membrane-bound HLA-G (mHLA-G) on the uterine mononuclear cell population (UMC) as a whole and on uNK cells in particular by measuring proliferation and cytokine production [interferon-gamma (IFN-gamma)/vascular endothelial growth factor (VEGF)/leukaemia inhibitory factor (LIF)/interleukin-3 (IL-3)]. Uterine cells were isolated from endometrium of non-pregnant women at the time that the endometrium is thought to be receptive to implantation, and then co-cultured with HLA-class I(-)/HLA-class II(+) 721.221 B-LCL cells transfected with mHLA-G. HLA-G suppressed the alloproliferative response of unfractionated UMC to 721.221 cells. Also, IFN-gamma and IL-3 production was strongly reduced. In contrast, purified uNK cells were stimulated by mHLA-G. Proliferation as well as IFN-gamma production was increased after co-culture with mHLA-G transfected 721.221 cells. HLA-G stimulated VEGF production by UMC as well as purified uNK cells. LIF-levels were below the detection level of our enzyme-linked immunosorbent assay. In conclusion, our data show that mHLA-G stimulates proliferation and cytokine production by NK cells, while down-modulating the response of unfractionated UMC.
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PMID:Membrane-bound HLA-G activates proliferation and interferon-gamma production by uterine natural killer cells. 1498 Nov 46

HLA-G displays immunotolerogenic properties towards the main effector cells involved in graft rejection through inhibition of NK- and CTL-mediated cytolysis and CD4+ T cell alloproliferation. HLA-G expression is restricted in healthy tissues to trophoblast and thymus but is extended to various tissues under pathological conditions. HLA-G was detected in allograft biopsies and sera from transplanted patients who displayed a better graft acceptance. However, the cells involved in such de novo expression of HLA-G remain to be characterized. By flow cytometry and confocal microscopy, we demonstrated that, following allogeneic stimulation in vitro, both CD4+ and CD8+ T cell subsets can express membrane-bound HLA-G1 and/or soluble HLA-G5 molecules. Such HLA-G1/-G5 expression is regulated at the transcriptional level. Soluble HLA-G5 could be detected by using a novel monoclonal antibody, 5A6G7, specific for the intron 4-retaining sequence of HLA-G5. Finally, the biological relevance of these data was provided by analysis of transplanted patients in whom we identified both CD4+ and CD8+ T cells expressing HLA-G. The HLA-G-positive T cells we describe here may constitute a cellular source of HLA-G after allotransplantation and may be involved in the improved graft acceptance which is observed in HLA-G-positive transplanted patients.
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PMID:Alloreactive CD4+ and CD8+ T cells express the immunotolerant HLA-G molecule in mixed lymphocyte reactions: in vivo implications in transplanted patients. 1499 94

The expression and importance of the non-classical human leukocyte antigen (HLA) class Ib gene, HLA-G, at the feto-maternal interface have been recognized. The HLA-G molecule is almost monomorphic and expressed in both membrane-bound and soluble isoforms. It has been shown to inhibit NK-mediated cell lysis and influence cytokine expression. Recently, a possible boarder immunoregulatory function of HLA-G also in adult life has been recognized. HLA-G gene polymorphism has been linked to differences in gene expression profile of alternatively spliced HLA-G transcripts and levels of specific HLA-G mRNA isoforms. On this background it is of general interest to further elucidate any associations between HLA-G polymorphism and protein expression. We have HLA-G genotyped 85 individuals attending IVF treatment, and further studied sHLA-G1/HLA-G5 and interleukin-10 (IL-10) in serum samples. In 21% of the serum samples sHLA-G1/HLA-G5 could be detected. There was no correlation between sHLA-G1/HLA-G5 and IL-10 concentrations in serum. Soluble HLA-G1/HLA-G5 was not detected in any samples homozygous for a 14-bp insertion polymorphism in exon 8 of the 3'-untranslated region (3'UTR) of the HLA-G gene ( P=0.03; Fisher's exact test). Polymorphisms in the 5'-upstream regulatory region (5'URR) of the HLA-G gene were also studied. In conclusion, this study indicates that polymorphisms in the 3'UTR and the 5'URR of the HLA-G gene may influence the expression of sHLA-G of possible importance in pathological pregnancies and also in organ transplantation.
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PMID:HLA-G and IL-10 in serum in relation to HLA-G genotype and polymorphisms. 1513 45

Placental hypoxia following the immature remodeling of spiral arteries by extravillous cytotrophoblasts (CTs) is focused on the pathogenesis of pre-eclampsia. At the same time, the expression of human leukocyte antigen (HLA)-G is decreased at the protein and mRNA levels in the pre-eclamptic placenta. In view of the potential function of HLA-G in immunological tolerance in the feto-maternal interface, we were much concerned to find whether the lowered expression of HLA-G in the pre-eclamptic placenta is a precursor or the result of placental hypoxia. The effect of oxygen on the expression of membrane-bound (mb) and soluble (s) HLA-G was investigated in primary cultures of extravillous CTs. The undifferentiated CTs isolated from the first-trimester placenta were cultured with different concentrations of oxygen (20%, 8% and 2%). The protein expression of mbHLA-G and of sHLA-G was assessed using flow cytometry, and mRNA expression was analyzed using real-time PCR. Expression of mbHLA-G and of sHLA-G protein was intensified with time in culture regardless of the oxygen concentration, and the expression intensities were synchronized between the 20% and the 2% oxygen concentrations at each time point. The mRNA expressions of mbHLA-G1 and sHLA-G1 at 2% oxygen were increased to twice those with 20% oxygen. Our findings demonstrate that no reduction of HLA-G was induced in CTs by short-term exposure to hypoxia, although further study may be required to find the effect of chronic hypoxia.
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PMID:Hypoxia does not reduce HLA-G expression on extravillous cytotrophoblasts. 1538 Sep 40

Expression of the nonclassical HLA class I antigen, HLA-G, is associated with immune tolerance in view of its role in maintaining the fetus in utero, allowing tumor escape, and favoring graft acceptance. Expressed on invasive trophoblast cells, HLA-G molecules bind inhibitory receptors on maternal T lymphocytes and NK cells, thereby blocking their cytolytic activities and protecting the fetus from maternal immune system attack. The HLA-G gene consists of 15 alleles, including a null allele, HLA-G*0105N. HLA-G*0105N presents a single base deletion, preventing translation of both membrane-bound (HLA-G1) and full-length soluble isoforms (HLA-G5) as well as of the spliced HLA-G4 isoform. The identification of healthy subjects homozygous for this HLA-G null allele suggests that the HLA-G*0105N allele may generate other HLA-G isoforms, such as membrane-bound HLA-G2 and -G3 and the soluble HLA-G6 and -G7 proteins, which may substitute for HLA-G1 and -G5, thus assuming the immune tolerogeneic function of HLA-G. To investigate this point, we cloned genomic HLA-G*0105N DNA and transfected it into an HLA-class I-positive human cell line. The results obtained indicated that HLA-G proteins were indeed present in HLA-G*0105N-transfected cells and were able to protect against NK cell lysis. These findings emphasize the role of the other HLA-G isoforms as immune tolerogeneic molecules that may also contribute to maternal tolerance of the semiallogenic fetus as well as tumor escape and other types of allogeneic tissue acceptance.
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PMID:HLA-G*0105N null allele encodes functional HLA-G isoforms. 1581

Both human leucocyte antigen (HLA)-G and indoleamine 2,3 dioxygenase (IDO) are key molecules involved in immune tolerance. HLA-G is a non-classical HLA class I molecule that can be expressed in both membrane-bound (HLA-G1) and soluble (HLA-G5) forms, both of which exhibit tolerogenic properties via interaction with inhibitory receptors present on natural killer (NK) cells, T cells and antigen-presenting cells (APC). IDO is an enzyme that acts by depleting the surrounding microenvironment of the essential amino acid, tryptophan, thereby inhibiting T-cell proliferation. Our present study was aimed at analysing the potential link that may exist between IDO and HLA-G. Our results showed that during allogeneic reactions, soluble HLA-G expression was not regulated by the addition of IDO substrate (i.e. tryptophan), metabolite (i.e. kynurenine) or inhibitor (i.e. 1-methyl-tryptophan), that IDO activity was not altered by HLA-G5 treatment, and that HLA-G5-mediated inhibition of the T-cell alloproliferative response was neither affected by the presence of tryptophan and kynurenine nor reversed after IDO activity blockage, demonstrating that HLA-G5 can exert its function in the absence of functional IDO. Similarly, inhibition of the T-cell alloresponse, induced by HLA-G1-expressing antigen-presenting cells, was not altered by IDO metabolites or inhibitor. Taken together, these findings show that the function and expression of IDO and HLA-G5 are not mutually influenced, but rather inhibit the T-cell alloproliferative response through two independent pathways. IDO and HLA-G are thus complementary for inducing and maintaining immune tolerance in physiological (pregnancy) and pathological (tumour and allograft) situations.
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PMID:Indoleamine 2,3 dioxygenase and human leucocyte antigen-G inhibit the T-cell alloproliferative response through two independent pathways. 1623 19

HLA-G is a nonclassical human major histocompatibility complex class I molecule. It may promote tolerance, leading to acceptance of the semiallogeneic fetus and tumor immune escape. We show here that two viruses-herpes simplex virus type 1 (HSV-1), a neuronotropic virus inducing acute infection and neuron latency; and rabies virus (RABV), a neuronotropic virus triggering acute neuron infection-upregulate the neuronal expression of several HLA-G isoforms, including HLA-G1 and HLA-G5, the two main biologically active isoforms. RABV induces mostly HLA-G1, and HSV-1 induces mostly HLA-G3 and HLA-G5. HLA-G expression is upregulated in infected cells and neighboring uninfected cells. Soluble mediators, such as beta interferon (IFN-beta) and IFN-gamma, upregulate HLA-G expression in uninfected cells. The membrane-bound HLA-G1 isoform was detected on the surface of cultured RABV-infected neurons but not on the surface of HSV-1-infected cells. Thus, neuronotropic viruses that escape the host immune response totally (RABV) or partially (HSV-1) regulate HLA-G expression on human neuronal cells differentially. HLA-G may therefore be involved in the escape of certain viruses from the immune response in the nervous system.
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PMID:Modulation of HLA-G expression in human neural cells after neurotropic viral infections. 1630 94

HLA-G is thought to play a key role in implantation by modulating cytokine secretion to control trophoblast invasion and to maintain a local immunosuppressive state. It differs from other class I molecules in that the gene can be alternatively spliced to produce four membrane-bound (G1, G2, G3 and G4) and three soluble isoforms (G5, G6 and G7). The soluble isoforms have recently attracted attention as their levels may be diagnostic of poor trophoblast invasion in miscarriage or pre-eclampsia and the implantation potential of IVF embryos. Although the expression and function of HLA-G2, G3, G4 and G7 has previously been a matter of debate, until now it has been generally accepted that soluble HLA-G5 and HLA-G6 are both expressed and secreted by trophoblast. However, Blaschitz et al. (2005) have reinvestigated this question and come to the surprising conclusion that they are not. They have shown that trophoblast only expresses the membrane-bound HLA-G1 isoform and not soluble HLA-G5 and -G6. Furthermore, although soluble HLA-G could be found in trophoblast culture supernatants, it appears not to be derived by alternative splicing but by the cleavage of HLA-G1. The source of the soluble HLA-G may not matter from a diagnostic perspective, but these findings, if confirmed, have important implications for our understanding of the biology of HLA-G.
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PMID:Does 'soluble' HLA-G really exist? Another twist to the tale. 1633 Apr 68


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