Disease relevance of HLA-G

• It is of note that CD56+CD4+ lymphomas displayed stronger HLA-G reactivity [1].
• The aim of this study was to assess the expression of nonclassical HLA-G antigens in ex vivo human melanoma biopsies [2].
• High levels of HLA-G transcription were detected in tumor specimens in 5 of 23 patients and found to be comparable in both lymph node and skin metastases [2].
• HLA-G expression was here investigated on paraffin-embedded tumor and adjacent normal renal tissues of 18 renal cell carcinoma (RCC) patients [3].
• PBL and isolated gammadelta T cells from healthy pregnant women as well as from those at risk for premature pregnancy termination were conjugated to choriocarcinoma cells (JAR) transfected with nonclassical HLA Ags (HLA-E, HLA-G) [4].
• This contribution reviews the HLA-G expression pattern in malignant melanoma lesions, its correlation to the loss of classical HLA class I antigens, and new aspects of HLA-G regulation [5].
• HLA-G seems to contribute to the impaired immune response in B-CLL supporting disease progression [6].

Psychiatry related information on HLA-G

• We examined whether HLA-G is expressed during the critical period of preimplantation human development and whether expression of this molecule could be correlated with the cleavage rate of embryos [7].
• To assess the role of HLA-G in CNS immunity, we investigated its expression in brain specimens from patients with multiple sclerosis (n = 11), meningitis (n = 2) and Alzheimer's disease (n = 2) and non-pathological CNS controls (n = 6) [8].

High impact information on HLA-G

• The expressed MHC class I genes of this species are more closely related to the human non-classical HLA-G gene than they are to genes of the human classical HLA-A, -B, and -C loci [9].
• We review these points, with special emphasis on the role of HLA-G in human pathologies, such as cancer, viral infection, and inflammatory diseases, as well as in organ transplantation [10].
• However, trophoblast cells directly in contact with the maternal tissues express the class I molecule HLA-G, which may be involved in protecting the trophoblast from recognition by NK cells [11].
• The receptors on NK cells that recognize HLA-G are also identified [11].
• Here evidence is provided that expression of HLA-G is sufficient to protect otherwise susceptible target cells from lysis by activated NK1 and NK2 cell lines and clones that are specific for distinct groups of HLA-C alleles [11].

Chemical compound and disease context of HLA-G

• To analyze the effect of this deletion on the stability of HLA-G mRNAs, we performed actinomycin D treatments on both JEG-3 choriocarcinoma cell line and M8 melanoma cell line transfected with HLA-G*010102 allele [12].
• Progesterone enhances HLA-G gene expression in JEG-3 choriocarcinoma cells and human cytotrophoblasts in vitro [13].
• Induction of HLA-G expression in a melanoma cell line OCM-1A following the treatment with 5-aza-2'-deoxycytidine [14].

Biological context of HLA-G

• It has been suggested that the maternal NK recognition of this downregulation is balanced by the expression of HLA-G, thus preventing damage to the placenta [15].
• Here, we describe the partial inhibition of NK lysis of the MHC class I negative cell line LCL721.221 upon HLA-G transfection [15].
• This region appears to be deleted in certain HLA haplotypes, shortening the distance between HLA-A and HLA-G by greater than 50 kilobase pairs (kbp) [16].
• Using probes derived from the ends of YAC inserts and from class I pseudogenes, we describe a highly polymorphic region between the HLA-A and HLA-G genes [16].
• Disulfide bond-mediated dimerization of HLA-G on the cell surface [17].

Anatomical context of HLA-G

• In contrast, HLA-G tetramers did bind to peripheral blood monocytes, staining a CD16(+)CD14(mid) subset with greater intensity [18].
• Primary cutaneous CD8+ and CD56+ T-cell lymphomas express HLA-G and killer-cell inhibitory ligand, ILT2 [1].
• We also demonstrated that HLA-G cell surface expression and secretion is maintained in a tumor cell line (DM) established from an HLA-G-positive RCC lesion [3].
• Further, HLA-G reduced alloproliferation, interfered with effective priming of antigen-specific cytotoxic T cells and reduced antigen-specific alloreactive lysis [19].
• Complexes of HLA-G protein on the cell surface are important for leukocyte Ig-like receptor-1 function [20].

Associations of HLA-G with chemical compounds

• Mutation of Cys-42 to a serine completely abrogated dimerization of HLA-G, suggesting that the disulfide linkage formed exclusively through this residue [17].
• Immunoprecipitation experiments demonstrated the involvement of the cysteine residues in the formation of HLA-G protein oligomers on the cell surface [20].
• HLA-G binds nonamer peptides with leucine or isoleucine at position 2, proline at position 3 and leucine at position 9 [21].
• Peptides presented by HLA-G usually consisted of 9 amino acids, and adhered to a specific sequence motif, with anchor residues at position 2 (isoleucine or leucine), position 3 (proline) and the carboxy-terminal position 9 (leucine) [22].
• Removal of polylactosamine chains by endo-beta D-galactosidase digestion significantly reduced the electrophoretic mobility of the immunoreactive bands, suggesting that HLA-G, unlike class Ib molecules studied to date, carries N-acetyllactosamine units [23].

Physical interactions of HLA-G

• These results suggest that subtle structural differences between LILRB family members cause the distinct binding specificities to various forms of HLA-G and other MHCIs, which may in turn regulate immune suppression [24].
• In addition, the HLA-G gene provides a suitable leader sequence peptide capable of binding to HLA-E [25].
• These HLA-G tetramers failed to bind to NK cells and cells transfected with CD94/NKG2 and killer immunoglobulin-like NK receptors [18].
• However, staining in the presence of antibodies reactive with ILT receptors revealed that the interaction of HLA-G tetramers with blood monocytes was largely due to binding to ILT4 [18].
• In this report, we demonstrate that CD8 can bind to HLA-G [26].

Regulatory relationships of HLA-G

• Here we show that recombinant soluble KIR2DL4 binds to cells expressing HLA-G but not to cells expressing other HLA class I molecules [27].
• Previous studies using human 721.221 cell line have shown that peptides derived from the leader sequence of the HLA-G binds and up-regulates the surface expression of HLA-E molecules, which was considered to consequently provide negative signals to human NK cells [28].
• Accordingly, the aim of this study was to define the behavior of HLA-G once it is co-expressed into an HLA-A, -B, -C and -E+ cell line [29].
• The formation of these complexes on the cell surface might represent a novel mechanism developed specifically by the HLA-G protein aimed to control the efficiency of the CD85J/LIR-1-mediated inhibition [30].
• In addition, while HLA-G-expressing transfectants of LCL.721.221 cells are protected from lymphokine-activated killer lysis, extravillous cytotrophoblast cells and HLA-G-expressing choriocarcinoma cells (CC) are not [31].

Other interactions of HLA-G

• Therefore, given that HLA-G expression is restricted to fetal trophoblast cells, KIR2DL4 may provide important signals to maternal NK decidual cells that interact with trophoblast cells at the maternal-fetal interface during pregnancy [27].
• An extensive network of contacts between the peptide and the antigen-binding cleft reveal a constrained mode of binding reminiscent of the nonclassical HLA-E molecule, thereby providing a structural basis for the limited peptide repertoire of HLA-G [32].
• LILRB2 exhibits an overlapping but distinct MHCI recognition mode compared with LILRB1 and dominantly recognizes the hydrophobic site of the HLA-G alpha3 domain [24].
• Both HLA-E and HLA-G bind peptides and are involved in natural killer (NK)-cell recognition, but the role of HLA-F is unclear [21].
• In humans, expression of the highly polymorphic classical HLA-A and HLA-B loci is suppressed, while expression of the nonclassical HLA-G locus is up-regulated at the maternal-fetal interface [33].

Analytical, diagnostic and therapeutic context of HLA-G

• Here, we characterize the sequence variation and haplotype structure of the HLA-G promoter and flanking sequences in 44 African Americans, 47 European Americans and 43 Han Chinese by haplotype-specific PCR and sequencing [34].
• Polymorphisms in the HLA-G promoter region have been associated with miscarriage and asthma, whereas expression levels have been associated with a wide range of pathologic conditions as well as survival of embryos after in vitro fertilization and of organs after transplantation [34].
• Together with the expression of IL-10, HLA-G might be one of the factors accounting for the evasion of immunosurveillance, thus contributing to aggressive phenotype of these lymphoma entities [1].
• HLA-G protein expression was detected in tumors that exhibited high levels of HLA-G transcription by immunofluorescence of frozen sections and Western blot analysis of both tumor and healthy skin biopsies, using anti-HLA-G-specific monoclonal antibodies [2].
• In this work, we report the production of a new mAb, 4H84, that specifically reacts with HLA-G in two formats: immunocytochemistry and immunoblotting [23].

References