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)

It has been reported that preimplantation human embryos secrete HLA-G, and the levels may be predictive of their ability to implant. However, it is not known which of the membrane-bound (HLA-G 1-4) and soluble (HLA-G 5-6) alternatively spliced forms are present, nor the developmental stage at which they appear. Therefore, we have investigated HLA-G mRNA isoform expression on single embryos at the two-, four-, six-, and eight-cell, morula, and blastocyst stages. The percentage of embryos expressing each HLA-G isoform mRNA increased with developmental stage, but contrary to expectation, HLA-G5 mRNA was not detected in single two- to eight-cell embryos and was only expressed by 20% of morulae and blastocysts. Similarly, soluble HLA-G6 mRNA was not detected until the blastocyst stage and then in only one-third of embryos. In contrast, labeling with MEM G/9 Ab (specific for HLA-G1 and -G5) was observed in 15 of 20 two- to eight-cell embryos and 5 of 5 blastocysts. This disparity between mRNA and protein may be due to HLA-G protein remaining from maternal oocyte stores produced before embryonic genome activation and brings into question the measurement of soluble HLA-G for clinical evaluation of embryo quality. Although HLA-G is expressed in the preimplantation embryo, later it is primarily expressed in the invasive trophoblast of the placenta rather than the fetus. Therefore, we have investigated whether down-regulation of HLA-G first occurs in the inner cell mass (precursor fetal cells) of the blastocyst and, in support of this concept, have shown the absence HLA-G1 and -G5 protein and mRNA.
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PMID:Differential expression of alternatively spliced transcripts of HLA-G in human preimplantation embryos and inner cell masses. 1633 79

HLA-G belongs to the non-classical HLA class-I family of genes presently designated as class-Ib genes. There are four membrane-bound (HLA-G1 to -G4) and three soluble forms (HLA-G5 to -G7) generated by alternative splicing of the primary transcript. HLA-G in the soluble form is found in the plasma, amniotic fluid, and cord blood of healthy individuals. Quantitative determination suggested that HLA-G levels are genetically controlled. While quantifying soluble HLA-G by ELISA, we observed that when plasma and serum levels were measured for the same individual, HLA-G plasma values were almost invariably higher than those from serum. Our results suggest that HLA-G is trapped and/or consumed during clot formation. The amount trapped within the clot is variable and inconsistent. To obtain values which reflect the true biological levels, it is therefore recommended that HLA-G should be determined in the plasma. If serum levels are determined, they should be compared with matched control sera. It should always be borne in mind that conclusions concerning sera levels might be erroneous, because the true plasma level of the protein can be significantly higher.
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PMID:HLA-G levels in serum and plasma. 1644 81

Pregnancy in mammals featuring hemochorial placentation introduces a major conflict with the mother's immune system, which is dedicated to repelling invaders bearing foreign DNA and RNA. Numerous and highly sophisticated strategies for preventing mothers from rejecting their genetically different fetus(es) have now been identified. These involve production of novel soluble and membrane-bound molecules by uterine and placental cells. In humans, the placenta-derived molecules include glycoproteins derived from the HLA class Ib gene, HLA-G. Isoforms of HLA-G saturate the maternal-fetal interface and circulate in mothers throughout pregnancy. Uteroplacental immune privilege for the fetus and its associated tissues is believed to result when immune cells encounter HLA-G. Unequivocally demonstration of this concept requires experiments in animal models. Both the monkey and the baboon express molecules that are similar but not identical to HLA-G, and may comprise suitable animal models for establishing a central role for these proteins in pregnancy.
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PMID:The role of HLA-G in human pregnancy. 1711 65

Soluble forms of HLA-G (sHLA-G) have been implicated in immune regulation. Fetal trophoblast cells are a prime source of HLA-G. Hence, an interaction between sHLA-G and uterine lymphocytes in the decidual tissues can easily be envisaged. These lymphocytes, when properly activated, are implicated in successful trophoblast invasion, placental maturation and maintenance of pregnancy. However, so far, no data are available on the effect of sHLA-G on the function and phenotype of these cells. Herein, we used a recombinant sHLA-G construct to determine the effect of sHLA-G on uterine lymphocyte cells present in endometrium at the time that it is optimally receptive to trophoblast invasion. In addition, we ascertained the effect of sHLA-G on peripheral lymphocytes. We found that upon co-culture with sHLA-G, proliferation of unfractionated IL-15-stimulated uterine mononuclear cells (UMCs) was inhibited. However, sHLA-G increased both interferon (IFN)-gamma and tumour necrosis factor (TNF)-alpha production by these cells. Vascular endothelial growth factor (VEGF) production was reduced. Notably, in contrast to membrane-bound HLA-G, sHLA-G did not affect the natural cytolytic activity of UMCs. Similarly, sHLA-G inhibited proliferation but stimulated pro-inflammatory cytokine production by cytokine-activated, unfractionated peripheral blood mononuclear cells (PBMCs). In addition, we showed that the overall inhibitory effect of sHLA-G on proliferation of the whole cell population could be ascribed to selective inhibition of CD4(+) T cells. In contrast, sHLA-G induced proliferation and IFN-gamma production by both uterine and peripheral natural killer (NK) cells. In conclusion, our data show that the sHLA-G modulates both UMC and PBMC function. sHLA-G, by promoting IFN-gamma production by uterine NK cells, may contribute to vascular remodelling of spiral arteries to allow for successful embryo implantation.
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PMID:Soluble HLA-G promotes Th1-type cytokine production by cytokine-activated uterine and peripheral natural killer cells. 1712 49

HLA-G is a tolerogenic molecule involved in maternal-fetal tolerance and in allograft acceptance. Soluble HLA-G proteins are present at high levels in plasma from transplanted patients who better accept their graft. In addition, infiltrating mononuclear cells expressing HLA-G can be detected within grafted tissues. To define the role of these HLA-G proteins in preventing graft rejection, we investigated the ability of HLA-G1 expressing antigen presenting cells (APC) and of soluble HLA-G proteins (i.e., HLA-G5 and shed HLA-G1) to inhibit T-cell alloproliferation and analyzed the molecules involved in such inhibition. Results demonstrated that both membrane-bound and soluble HLA-G proteins inhibited T-cell alloproliferation. This inhibition involved engagement of immunoglobulinlike transcript (ILT)-2 and ILT-4 receptors by HLA-G. Moreover, blocking Fas ligand (FasL) reversed HLA-G mediated inhibition, demonstrating that the Fas/FasL pathway is also recruited by HLA-G to exert its immunosuppressive function on T cells. These data highlight the role played by HLA-G in better graft acceptance status observed in transplanted patients with HLA-G(+) grafted cells and high HLA-G plasma levels. Evidence to support such role in vivo was provided by the capacity of purified HLA-G5 from the plasma of the transplanted patient to suppress T-cell alloresponses.
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PMID:Soluble HLA-G and HLA-G1 expressing antigen-presenting cells inhibit T-cell alloproliferation through ILT-2/ILT-4/FasL-mediated pathways. 1740 57

In order to study how to induce tolerogenic dendritic cells in vitro and its mechanism, the K562 cells transduced with HLA-G construct were used to co-culture with DC. Then their related immunological changes, such as membrane molecules CD80, CD86, ILT3 and ILT4 expression levels were detected by flow cytometry. Allogeneic proliferation of peripheral blood mononuclear cells (PBMNC) was detected by mixed lymphocyte reaction. The results showed that CD80 and CD86 expressions on DC were downregulated, while ILT3 and ILT4 expressions were upregulated after co-culturing with K562-HLA-G cells. The DCs were less able to stimulate the allogenic PBMNC. It is concluded that the membrane-bound HLA-G can upregulate expression of inhibitory receptors ILT3 and ILT4, inducing tolerogenic DC in vitro, which may provide a novel strategy for transplant tolerance induction.
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PMID:[Induction of tolerogenic dendritic cells by membrane-bound HLA-G in vitro]. 1749 49

HLA-G is overexpressed in different tumors and plays a role in immune escape. Because no information is available on HLA-G in relation to human neuroblastoma, we have investigated the expression of membrane-bound and secretion of soluble isoforms of HLA-G in neuroblastoma and functionally characterized their immunosuppressive activities. At diagnosis, serum soluble HLA-G (sHLA-G) levels were significantly higher in patients than in age-matched healthy subjects. In addition, patients who subsequently relapsed exhibited higher sHLA-G levels than those who remained in remission. Neuroblastoma patient sera selected according to high sHLA-G concentrations inhibited natural killer (NK) cell and CTL-mediated neuroblastoma cell lysis. Such lysis was partially restored by serum depletion of sHLA-G. In 6 of 12 human neuroblastoma cell lines, low HLA-G surface expression was not up-regulated by IFN-gamma. Only the ACN cell line secreted constitutively sHLA-G. IFN-gamma induced de novo sHLA-G secretion by LAN-5 and SHSY5Y cells and enhanced that by ACN cells. Primary tumor lesions from neuroblastoma patients tested negative for HLA-G. Neuroblastoma patients displayed a higher number of sHLA-G-secreting monocytes than healthy controls. Incubation of monocytes from normal donors with IFN-gamma or pooled neuroblastoma cell line supernatants significantly increased the proportion of sHLA-G-secreting cells. In addition, tumor cell supernatants up-regulated monocyte expression of CD68, HLA-DR, CD69, and CD71 and down-regulated IL-12 production. Our conclusions are the following: (a) sHLA-G serum levels are increased in neuroblastoma patients and correlate with relapse, (b) sHLA-G is secreted by monocytes activated by tumor cells rather than by tumor cells themselves, and (c) sHLA-G dampens anti-neuroblastoma immune responses.
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PMID:Human neuroblastoma cells trigger an immunosuppressive program in monocytes by stimulating soluble HLA-G release. 1761 4

Studies on HLA-G, a nonpolymorphic antigen of non-classical HLA class I, is of basic and clinical significance. In the present study, the expression of HLA-G proteins in the human skin tissue sections of normal and autoimmune pemphigus vulgaris (PV) individuals were investigated using monoclonal antibodies. The antibodies recognized both membrane-bound and soluble isoforms of HLA-G. RT-PCR was performed to assess the patterns of HLA-G mRNA transcripts in the epidermal cells of PV and normal subjects. HLA-G expression could only be detected at transcriptional level in normal skin tissues. However cells derived from PV subjects expressed detectable HLA-G molecules at both transcriptional and translational levels. In addition, the RT-PCR patterns of HLA-G amplification revealed a reduction in HLA-G2 and an increase in HLA-G1 transcripts in epidermal cells of PV patients as compared to normal cells. These observations further support suggestions in the literature regarding the role of HLA-G in induction of tolerance in autoimmune individuals.
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PMID:Expression of HLA-G in the skin of patients with pemphigus vulgaris. 1832 6

In human pregnancies mothers and their embryo/fetuses are invariably genetically different. Thus, attenuation of the adaptive maternal immune response, which is programmed to reject 'foreign' entities, is required for pregnancy to be initiated and maintained. Unexpectedly, given the propensity of the immune system to dispose of non-self entities, at least 50% of expected human pregnancies reliably go forward. This indicates that to a large extent, effective systems of tolerance have evolved. Although overlapping and redundant mechanisms of tolerance have been identified, production of HLA-G by trophoblast cells derived from the external trophectoderm layer of the blastocyst appears to be of major importance. At this point in time, no pregnancies in which all of the proteins derived from the HLA-G gene are absent have as yet been reported. Many studies have shown that both membrane-bound and soluble isoforms of the proteins derived from this HLA class Ib gene are produced by placental trophoblast cells, with consequences that include but are not restricted to immune suppression at the maternal-fetal interface. Here we report new studies that are leading to a better understanding of the HLA-G proteins, their unique structures, unusual modes of regulation, diverse functions, and potential for use in diagnostic and therapeutic procedures related to suboptimal fertility in women.
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PMID:HLA-G: a human pregnancy-related immunomodulator. 1957 Jul 12

Bacterial LPS induces the release of ATP from immune cells. Accruing evidence suggests that extracellular ATP participates in the inflammatory response as a proinflammatory mediator by activating the inflammasome complex, inducing secretion of cytokines (IL-1, IL-18) and cell damaging agents such as oxygen radicals, cationic proteins, and metalloproteases. It is not known whether ATP can also act as a proinflammatory mediator by inhibiting production of molecules down-modulating the immune response. Here, we show that extracellular ATP impairs in an IL-10-dependent fashion the expression of the tolerogenic soluble and membrane-bound HLA-G Ag in human monocytes. The effect of ATP was mimicked by BzATP (3'-O-(4-benzoyl)benzoyl-ATP) and greatly reduced by pretreatment with oATP (periodate-oxidized ATP), KN-62 (1-[N,O-bis(5-isoquinoline-sulfonyl)-N-methyl-l-tyrosyl]-4-phenylpiperazine), and an anti-P2X(7) mAb, thus pointing to a specific role of the P2X(7) receptor. The effect of ATP was time- and dose-dependent and was not due to a decrease in expression of IL-10 receptor. Inhibition by ATP was reverted by supplementation of culture medium with exogenous IL-10. Due to the well-known immunosuppressive activity of IL-10 and soluble HLA-G, this novel effect of ATP might be relevant for the pathophysiology and therapy of inflammatory disorders.
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PMID:Extracellular ATP acting at the P2X7 receptor inhibits secretion of soluble HLA-G from human monocytes. 1974 89


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