HLA-G remains a mystery

Bainbridge, D. R. J.; Ellis, Shirley A.; Bouteiller, Philippe Le; Sargent, Ian L.

doi:10.1016/s1471-4906(01)02031-2

Cited by 91 publications

(68 citation statements)

References 37 publications

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“…The membrane bound isoforms of HLA-G and Qa-2 have a 6-amino acid cytosolic tail and a glycosylphosphatidylinositol (GPI) tail in the outer leaflet of the membrane, respectively. The figure is derived from mRNA and protein data [4,16]. The S1 Qa-2 isoform is structurally similar to the soluble HLA-G5 isoform, while S2 Qa-2 would correspond with a soluble HLA-G4 isoform.…”

Section: Discussionmentioning

confidence: 99%

Evidence that HLA-G is the functional homolog of mouse Qa-2, the ped gene product

et al. 2003

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Qa-2, a murine class Ib major histocompatibility complex (MHC) molecule, is a possible functional homolog of human leukocyte antigen G (HLA-G). Both molecules have been implicated in immunoregulation and embryonic development and both occur in membrane-bound and soluble isoforms that arise by alternative splicing. Soluble splice variants have been implicated in the reproductive functions of HLA-G. While soluble variants of Qa-2 have been previously detected in T lymphocytes, we now demonstrate the presence of mRNA for one of the two known soluble forms of Qa-2 in eight-cell embryos and in blastocysts. Qa-2 is glycosylphosphatidy-linositol (GPI) linked in the outer leaflet of the cell membrane and is found in lipid raft microdomains where other raftassociated proteins transduce signals into the cell. In contrast, HLA-G has a truncated six amino acid cytoplasmic tail. By fluorescence co-localization in JEG-3 cells, using fluorescent cholera toxin β subunit (a lipid raft marker) and anti-HLA-G antibody, we have demonstrated that membrane-bound HLA-G also localizes to lipid rafts, consistent with functional homology between the two molecules. Finally, our experiments in which we have purified Qa-2 and transferred it via a process known as protein painting to Qa-2 negative cells represent a model for potential therapy involving HLA-G.

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Section: Discussionmentioning

confidence: 99%

Evidence that HLA-G is the functional homolog of mouse Qa-2, the ped gene product

et al. 2003

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“…Human leukocyte antigen-G (HLA-G), a nonclassical MHC I molecule, which is predominantly expressed by fetal extravillous trophoblasts, may be the answer [3]. Unlike classical MHC I antigens, HLA-G exhibits a tissue-restricted distribution pattern and its mRNA is alternatively spliced to encode seven different isoforms, namely the four membranebound proteins, HLA-G1, -G2, -G3, -G4 and three soluble isoforms, HLA-G5 (also termed sHLA-G1), -G6, -G7 [4][5]. HLA-G plays an important role not only during pregnancy, but also during allograft and xenograft [6].…”

Section: Introductionmentioning

confidence: 99%

Inhibition of the activating signals in NK92 cells by recombinant GST-sHLA-G1α chain

et al. 2004

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The soluble HLA-G1 (sHLA-G1) isoform was found to be secreted by trophoblast cells at the materno-fetal interface, which suggests that it may act as an immunomodulator during pregnancy. In this paper, we reported that GST-sHLA-G1α chain could bind to its receptor ILT-2 on NK92 cells and then the latter recruited Src homology 2 domaincontaining tyrosine phosphatase-1 (SHP-1), which consequently dephosphorylated some important protein tyrosine kinases and blocked the activation of downstream molecules such as MEK and ERK so that the cytotoxicity of natural killer (NK) cells was inhibited. These results indicated that GST-sHLA-G1α chain might be exploited in new immunotherapy strategies aiming at inducing immunotolerance during allograft, xenograft and autoimmune situations. In addition, we found that modification of O-linked β-N-acetylglucosamine (O-GlcNAc) was involved in NK cells' activating and inhibitory signals. This may provide a novel molecular target for inducing immunotolerance but needs further study.

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“…One of the key protective mechanisms is thought to be the selective expression of the nonclassical HLA class I gene HLA-G by the trophoblast in the absence of classical class I (HLA-A and HLA-B) Ags. In contrast to the classical class I Ags, HLA-G is virtually nonpolymorphic with a small number of HLA-G alleles encoding only three different amino acid primary sequences (1). In addition, HLA-G mRNA can be alternatively spliced into at least six transcripts, which encode four membrane bound isoforms (G1, G2, G3, and G4) and two soluble isoforms (G5 and G6, otherwise known as soluble HLA-G1 and soluble HLA-G2) (1).…”

mentioning

confidence: 99%

“…In contrast to the classical class I Ags, HLA-G is virtually nonpolymorphic with a small number of HLA-G alleles encoding only three different amino acid primary sequences (1). In addition, HLA-G mRNA can be alternatively spliced into at least six transcripts, which encode four membrane bound isoforms (G1, G2, G3, and G4) and two soluble isoforms (G5 and G6, otherwise known as soluble HLA-G1 and soluble HLA-G2) (1). HLA-G1 is the fulllength isoform containing eight exons and seven introns.…”

mentioning

confidence: 99%

Differential Expression of Alternatively Spliced Transcripts of HLA-G in Human Preimplantation Embryos and Inner Cell Masses

Yao

Barlow

Sargent

2005

The Journal of Immunology

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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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HLA-G remains a mystery

Cited by 91 publications

References 37 publications

Evidence that HLA-G is the functional homolog of mouse Qa-2, the ped gene product

Evidence that HLA-G is the functional homolog of mouse Qa-2, the ped gene product

Inhibition of the activating signals in NK92 cells by recombinant GST-sHLA-G1α chain

Differential Expression of Alternatively Spliced Transcripts of HLA-G in Human Preimplantation Embryos and Inner Cell Masses

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