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Biology of the immunomodulatory molecule HLA-G in human liver diseases

  • Laurence Amiot
    Correspondence
    Corresponding author. Address: IRSET U.1085 Inserm, University of Rennes 1, 2 Avenue du Pr. Leon Bernard CS 34317, 35043 Rennes Cedex, France. Tel.: +33 299 289 141; fax: +33 223 234 794.
    Affiliations
    Institut National de la Santé et de la Recherche Médicale (Inserm), U.1085, Institut de Recherche Santé Environnement & Travail (IRSET), F-35043 Rennes, France

    Université de Rennes 1, F-35043 Rennes, France

    Fédération de Recherche BioSit de Rennes UMS 3480, F-35043 Rennes, France

    Department of Biology, University Hospital Pontchaillou, CHU Pontchaillou, Rennes, France
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  • Nicolas Vu
    Affiliations
    Institut National de la Santé et de la Recherche Médicale (Inserm), U.1085, Institut de Recherche Santé Environnement & Travail (IRSET), F-35043 Rennes, France

    Université de Rennes 1, F-35043 Rennes, France

    Fédération de Recherche BioSit de Rennes UMS 3480, F-35043 Rennes, France
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  • Michel Samson
    Affiliations
    Institut National de la Santé et de la Recherche Médicale (Inserm), U.1085, Institut de Recherche Santé Environnement & Travail (IRSET), F-35043 Rennes, France

    Université de Rennes 1, F-35043 Rennes, France

    Fédération de Recherche BioSit de Rennes UMS 3480, F-35043 Rennes, France
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Open AccessPublished:March 14, 2015DOI:https://doi.org/10.1016/j.jhep.2015.03.007

      Summary

      The non-classical human leukocyte antigen-G (HLA-G), plays an important role in inducing tolerance, through its immunosuppressive effects on all types of immune cells. Immune tolerance is a key issue in the liver, both in liver homeostasis and in the response to liver injury or cancer. It would therefore appear likely that HLA-G plays an important role in liver diseases. Indeed, this molecule was recently shown to be produced by mast cells in the livers of patients infected with hepatitis C virus (HCV). Furthermore, the number of HLA-G-positive mast cells was significantly associated with fibrosis progression. The generation of immune tolerance is a role common to both HLA-G, as a molecule, and the liver, as an organ. This review provides a summary of the evidence implicating HLA-G in liver diseases. In the normal liver, HLA-G transcripts can be detected, but there is no HLA-G protein. However, HLA-G protein is detectable in the liver tissues and/or plasma of patients suffering from hepatocellular carcinoma, hepatitis B or C, or visceral leishmaniasis and in liver transplant recipients. The cells responsible for producing HLA-G differ between diseases. HLA-G expression is probably induced by microenvironmental factors, such as cytokines. The expression of HLA-G receptors, such as ILT2, ILT4, and KIRD2L4, on liver cells has yet to be investigated, but these receptors have been detected on all types of immune cells, and such cells are present in liver. The tolerogenic properties of HLA-G explain its deleterious effects in cancers and its beneficial effects in transplantation. Given the key role of HLA-G in immune tolerance, new therapeutic agents targeting HLA-G could be tested for the treatment of these diseases in the future.

      Keywords

      Introduction

      Human leukocyte antigen-G (HLA-G) is the best characterized non-classical major histocompatibility complex (MHC) class Ib molecule [
      • Geraghty D.E.
      • Koller B.H.
      • Orr H.T.
      A human major histocompatibility complex class I gene that encodes a protein with a shortened cytoplasmic segment.
      ]. It is best known for its tolerogenic function at the maternal-fetal interface, where it protects the fetus from destruction by its mother’s immune system [
      • Kovats S.
      • Main E.K.
      • Librach C.
      • Stubblebine M.
      • Fisher S.J.
      • DeMars R.
      A class I antigen, HLA-G, expressed in human trophoblasts.
      ]. There have been many studies of the role of HLA-G in tumors and infectious diseases, autoimmunity and transplantation. We suggest that HLA-G may play an important role in liver diseases because: (i) it is tolerogenic; (ii) in the basal state, its expression is restricted to tissues involved in immune tolerance, such as the cornea and thymus [
      • Le Discorde M.
      • Moreau P.
      • Sabatier P.
      • Legeais J.M.
      • Carosella E.D.
      Expression of HLA-G in human cornea, an immune-privileged tissue.
      ,
      • Mallet V.
      • Blaschitz A.
      • Crisa L.
      • Schmitt C.
      • Fournel S.
      • King A.
      • et al.
      HLA-G in the human thymus: a subpopulation of medullary epithelial but not CD83(+) dendritic cells expresses HLA-G as a membrane-bound and soluble protein.
      ]; and (iii) the liver is an organ known to induce immunological tolerance to T lymphocytes [
      • Racanelli V.
      • Rehermann B.
      The liver as an immunological organ.
      ].
      Mice have no HLA-G. Therefore, there is no murine model of HLA-G deficiency, such as knockout (KO) mice, and Qa-2 is the putative functional homolog of HLA-G [
      • Melo-Lima B.L.
      • Evangelista A.F.
      • de Magalhaes D.A.
      • Passos G.A.
      • Moreau P.
      • Donadi E.A.
      Differential transcript profiles of MHC class Ib(Qa-1, Qa-2, and Qa-10) and Aire genes during the ontogeny of thymus and other tissues.
      ]. The only HLA-G transgenic mice developed to date express H-2kb/HLA-G [
      • Horuzsko A.
      • Antoniou J.
      • Tomlinson P.
      • Portik-Dobos V.
      • Mellor A.L.
      HLA-G functions as a restriction element and a transplantation antigen in mice.
      ]. However, this model differs from humans in that HLA-G is expressed in all cells. The lack of an appropriate murine model clearly hinders investigations of the function of HLA-G in pathophysiology, including its role in liver diseases.
      Figure thumbnail fx1

      Basic properties of HLA-G

      The HLA-G gene is located on the short arm of chromosome 6, in the HLA region (6p21.2-21.3), between the HLA-A and HLA-F genes [
      • Koller B.H.
      • Geraghty D.E.
      • DeMars R.
      • Duvick L.
      • Rich S.S.
      • Orr H.T.
      Chromosomal organization of the human major histocompatibility complex class I gene family.
      ]. Its structure is similar to that of other HLA class I genes, consisting of seven introns and eight introns, encoding the heavy chain of the molecule (Fig. 1). Exon 1 encodes the signal peptide, whereas exons 2, 3, and 4 encode the extracellular domains, α1, α2, and α3, of the heavy chain, respectively. Exons 5 and 6 encode the transmembrane and cytoplasmic domains. Exon 7 is never present in the mature mRNA, due to the presence of a stop codon in exon 6, and exon 8 is also not translated [
      • Donadi E.A.
      • Castelli E.C.
      • Arnaiz-Villena A.
      • Roger M.
      • Rey D.
      • Moreau P.
      Implications of the polymorphism of HLA-G on its function, regulation, evolution and disease association.
      ]. The HLA-G gene promoter has an enhancer A (enh A), S and X1 sequence slightly different from that of other class I genes, and a few alternative regulatory elements to regulate HLA-G gene transcription [
      • Gobin S.J.
      • van den Elsen P.J.
      Transcriptional regulation of the MHC class Ib genes HLA-E, HLA-F, and HLA-G.
      ]. The 3′-UTR of the HLA-G gene also contains several regulatory elements, including AU-rich motifs and a poly-A signal, influencing mRNA stability, turnover, mobility and splicing patterns [
      • Donadi E.A.
      • Castelli E.C.
      • Arnaiz-Villena A.
      • Roger M.
      • Rey D.
      • Moreau P.
      Implications of the polymorphism of HLA-G on its function, regulation, evolution and disease association.
      ].
      Figure thumbnail gr1
      Fig. 1The HLA-G gene, transcripts and proteins. The HLA-G gene consists of 8 exons and 7 introns. Exon 1(E1) encodes the signal peptide, exon 7(E7) is not transcribed and exons 2, 3 (E2, E3) and 4 (E4) encode the a-1 domain, the a-2 domain, and the a-3 domain, respectively; exon 5 (E5) encodes the transmembrane domain and exons 6 (E6) and 7 (E7) encode the cytoplasmic domain, with the final exon, exon 8 corresponding to the 3′ UTR region. The star () in E6 as the symbols in intron 2 and 4 are corresponding to stop codon. The primary transcript produced by transcription of the HLA-G gene undergoes alternative splicing, which generates four isoforms with transmembrane and cytoplasmic domains — HLA-G1, -G2, -G3, -G4 — and three different soluble isoforms —sHLA-G1 or HLA-G5, HLA-G6, and HLA-G7.
      HLA-G displays only limited polymorphism, with 50 alleles (IMGT HLA database, December 2013) and 16 proteins, far fewer than for some of the more highly polymorphic HLA class I molecules.
      The alternative splicing of primary transcripts is a key feature of HLA-G, because it is strictly controlled and may be subject to cell type-dependent regulation. Indeed, the primary transcript of HLA-G is spliced into seven alternative mRNAs encoding membrane-bound (HLA-G1, -G2, -G3, -G4) and soluble (HLA- G5, -G6, -G7) protein isoforms [
      • Carosella E.D.
      • Moreau P.
      • Le Maoult J.
      • Le Discorde M.
      • Dausset J.
      • Rouas-Freiss N.
      HLA-G molecules: from maternal-fetal tolerance to tissue acceptance.
      ]. In addition, HLA-G1 is released into the medium by proteolytic cleavage, as shed HLA-G1 [
      • Fujii T.
      • Ishitani A.
      • Geraghty D.E.
      A soluble form of the HLA-G antigen is encoded by a messenger ribonucleic acid containing intron 4.
      ].
      The HLA-G1 mRNA encodes the full-length HLA-G molecule; the HLA-G2 mRNA lacks exon 3, the HLA-G3 mRNA lacks exons 3 and 4, and the HLA-G4 mRNA lacks exon 4. HLA-G1 to -G4 encode membrane-bound molecules, due to the presence of the transmembrane domain and cytoplasmic tail encoded by exons 5 and 6. The HLA-G5 mRNA is similar to HLA-G1 but retains intron 4, whereas the HLA-G6 mRNA lacks exon 3 but retains intron 4, and the HLA-G7 mRNA lacks exon 3 but retains intron 2. HLA-G5 and -G6 encode soluble forms, due to the presence of intron 4, which contains a premature stop codon, preventing translation of the transmembrane domain and the cytoplasmic tail [
      • Fujii T.
      • Ishitani A.
      • Geraghty D.E.
      A soluble form of the HLA-G antigen is encoded by a messenger ribonucleic acid containing intron 4.
      ]. HLA-G7 encodes a soluble form, due to the presence of intron 2, which contains a premature stop codon [
      • Paul P.
      • Cabestre F.A.
      • Ibrahim E.C.
      • Lefebvre S.
      • Khalil-Daher I.
      • Vazeux G.
      • et al.
      Identification of HLA-G7 as a new splice variant of the HLA-G mRNA and expression of soluble HLA-G5, -G6, and -G7 transcripts in human transfected cells.
      ].
      HLA-G is a transmembrane protein with a molecular weight of 39 kDa. It is a heterodimer of a heavy chain associated with a light chain (β2-microglobulin). The heavy chain consists of three globular domains (the α1, α2, and α3 domains), a transmembrane region and a short cytoplasmic domain. Seven protein isoforms are generated by alternative splicing of the primary transcript. HLA-G molecules can also form dimers through the establishment of disulfide bonds between the two single cysteine residues at positions 42 (Cys42-Cys42 bonds) and 147 (Cys42-Cys147 bonds) of the HLA-G heavy chain [
      • Boyson J.E.
      • Erskine R.
      • Whitman M.C.
      • Chiu M.
      • Lau J.M.
      • Koopman L.A.
      • et al.
      Disulfide bond-mediated dimerization of HLA-G on the cell surface.
      ]. The resulting HLA-G dimers bind receptors with a higher affinity and slower dissociation rates than monomers [
      • Shiroishi M.
      • Kuroki K.
      • Ose T.
      • Rasubala L.
      • Shiratori I.
      • Arase H.
      • et al.
      Efficient leukocyte Ig-like receptor signaling and crystal structure of disulfide-linked HLA-G dimer.
      ]. Another characteristic of the HLA-G protein distinguishing it from other class I proteins is its short cytoplasmic tail, which contains no endocytosis motifs [
      • Park B.
      • Lee S.
      • Kim E.
      • Chang S.
      • Jin M.
      • Ahn K.
      The truncated cytoplasmic tail of HLA-G serves a quality-control function in post-ER compartments.
      ].
      Unlike ubiquitously expressed HLA class I antigens, HLA-G displays a restricted pattern of expression in healthy individuals in basal conditions. The HLA-G protein is found only in trophoblast cells, the placenta, cornea, thymus, proximal nail matrix, erythroblasts and mesenchymal stem cells [
      • Kovats S.
      • Main E.K.
      • Librach C.
      • Stubblebine M.
      • Fisher S.J.
      • DeMars R.
      A class I antigen, HLA-G, expressed in human trophoblasts.
      ,
      • Le Discorde M.
      • Moreau P.
      • Sabatier P.
      • Legeais J.M.
      • Carosella E.D.
      Expression of HLA-G in human cornea, an immune-privileged tissue.
      ,
      • Mallet V.
      • Blaschitz A.
      • Crisa L.
      • Schmitt C.
      • Fournel S.
      • King A.
      • et al.
      HLA-G in the human thymus: a subpopulation of medullary epithelial but not CD83(+) dendritic cells expresses HLA-G as a membrane-bound and soluble protein.
      ,
      • Crisa L.
      • McMaster M.T.
      • Ishii J.K.
      • Fisher S.J.
      • Salomon D.R.
      Identification of a thymic epithelial cell subset sharing expression of the class Ib HLA-G molecule with fetal trophoblasts.
      ,
      • Ito T.
      • Ito N.
      • Saathoff M.
      • Stampachiacchiere B.
      • Bettermann A.
      • Bulfone-Paus S.
      • et al.
      Immunology of the human nail apparatus: the nail matrix is a site of relative immune privilege.
      ,
      • Menier C.
      • Rabreau M.
      • Challier J.C.
      • Le Discorde M.
      • Carosella E.D.
      • Rouas-Freiss N.
      Erythroblasts secrete the nonclassical HLA-G molecule from primitive to definitive hematopoiesis.
      ,
      • Montespan F.
      • Deschaseaux F.
      • Sensebe L.
      • Carosella E.D.
      • Rouas-Freiss N.
      Osteodifferentiated mesenchymal stem cells from bone marrow and adipose tissue express HLA-G and display immunomodulatory properties in HLA-mismatched settings: implications in bone repair therapy.
      ,
      • Rebmann V.
      • Busemann A.
      • Lindemann M.
      • Grosse-Wilde H.
      Detection of HLA-G5 secreting cells.
      ]. By contrast, soluble HLA-G (sHLA-G) is detectable in the serum/plasma of both men and women. It is produced principally by monocytes [
      • Rebmann V.
      • Busemann A.
      • Lindemann M.
      • Grosse-Wilde H.
      Detection of HLA-G5 secreting cells.
      ] and, to a lesser degree, T lymphocytes, in particular conditions [
      • Lila N.
      • Rouas-Freiss N.
      • Dausset J.
      • Carpentier A.
      • Carosella E.D.
      Soluble HLA-G protein secreted by allo-specific CD4+ T cells suppresses the allo-proliferative response: a CD4+ T cell regulatory mechanism.
      ,
      • Sebti Y.
      • Le Friec G.
      • Pangault C.
      • Gros F.
      • Drenou B.
      • Guilloux V.
      • et al.
      Soluble HLA-G molecules are increased in lymphoproliferative disorders.
      ].
      Furthermore, HLA-G expression is induced in many diseases, including cancers, multiple sclerosis, inflammatory diseases and viral infections and in transplantation [
      • Gonzalez A.
      • Rebmann V.
      • LeMaoult J.
      • Horn P.A.
      • Carosella E.D.
      • Alegre E.
      The immunosuppressive molecule HLA-G and its clinical implications.
      ].
      HLA-G expression is controlled principally at the transcriptional level, by a unique gene promoter, and at the posttranscriptional level by mechanisms involving alternative splicing, mRNA stability, translation and protein transport to the cell surface. Many factors potentially affecting the transcriptional and posttranscriptional mechanisms of HLA-G regulation have been described previously [
      • Moreau P.
      • Adrian-Cabestre F.
      • Menier C.
      • Guiard V.
      • Gourand L.
      • Dausset J.
      • et al.
      IL-10 selectively induces HLA-G expression in human trophoblasts and monocytes.
      ].

      Factors involved in HLA-G liver expression

      HLA-G expression generally depends strongly on factors present in the microenvironment, such as cytokines. Indeed, various cytokines, including interferons, interleukin (IL)-10, GM-CSF, IL-2, and TGF-β increase HLA-G expression in several in vitro models [
      • Moreau P.
      • Adrian-Cabestre F.
      • Menier C.
      • Guiard V.
      • Gourand L.
      • Dausset J.
      • et al.
      IL-10 selectively induces HLA-G expression in human trophoblasts and monocytes.
      ,
      • Gros F.
      • Sebti Y.
      • de Guibert S.
      • Branger B.
      • Bernard M.
      • Fauchet R.
      • et al.
      Soluble HLA-G molecules increase during acute leukemia, especially in subtypes affecting monocytic and lymphoid lineages.
      ,
      • Yang Y.
      • Geraghty D.E.
      • Hunt J.S.
      Cytokine regulation of HLA-G expression in human trophoblast cell lines.
      ]. Other local factors, such as hypoxia [
      • Mouillot G.
      • Marcou C.
      • Zidi I.
      • Guillard C.
      • Sangrouber D.
      • Carosella E.D.
      • et al.
      Hypoxia modulates HLA-G gene expression in tumor cells.
      ] and Indoleamine 2,3-dioxygenase [
      • Gonzalez-Hernandez A.
      • LeMaoult J.
      • Lopez A.
      • Alegre E.
      • Caumartin J.
      • Le Rond S.
      • et al.
      Linking two immuno-suppressive molecules: indoleamine 2,3 dioxygenase can modify HLA-G cell-surface expression.
      ], influence HLA-G expression. These microenvironmental factors probably also play a role in the liver. Support for this hypothesis is provided by the controversies on HLA class I antigen expression on hepatocytes in basal conditions and the induction of HLA class I molecule expression in most hepatic diseases and its correlation with the intensity of intralobular inflammation [
      • Fukusato T.
      • Gerber M.A.
      • Thung S.N.
      • Ferrone S.
      • Schaffner F.
      Expression of HLA class I antigens on hepatocytes in liver disease.
      ,
      • Senaldi G.
      • Lobo-Yeo A.
      • Mowat A.P.
      • Mieli-Vergani G.
      • Vergani D.
      Class I and class II major histocompatibility complex antigens on hepatocytes: importance of the method of detection and expression in histologically normal and diseased livers.
      ].
      The expression profiles of microenvironmental factors differ between diseases, but they may go some way towards explaining HLA-G expression patterns in liver cancers, hepatitis and transplantation. Moreover, epigenetic mechanisms, such as DNA methylation and histone deacetylation, have been implicated in cancers and in some anti-tumor treatments, and are known to regulate HLA-G expression. In viral infections, the viral proteins interfere with the intracellular trafficking of HLA-G [
      • Amiot L.
      • Vu N.
      • Samson M.
      Immunomodulatory properties of HLA-G in infectious diseases.
      ], providing an additional mechanism for the modulation of HLA-G expression.

      Tolerogenic properties

      The tolerogenic properties of HLA-G are mediated by the direct binding of both soluble and membrane-bound HLA-G to inhibitory receptors.
      The binding to HLA-G of the immunoglobulin-like transcript (ILT) receptor 2 (CD85j; LILRB1) on natural killer (NK) cells and T lymphocytes leads to an inhibition of T lymphocyte or NK cell function due to changes in proliferation, cytotoxicity or the induction of regulatory T or NK cells [
      • Colonna M.
      • Navarro F.
      • Bellon T.
      • Llano M.
      • Garcia P.
      • Samaridis J.
      • et al.
      A common inhibitory receptor for major histocompatibility complex class I molecules on human lymphoid and myelomonocytic cells.
      ]. The expression of ILT2 on NK cells accounts for the restoration of NK cell cytotoxicity to hepatocellular carcinoma (HCC) cells transfected with HLA-G1 after the addition of a blocking ILT2 HLA-G receptor [
      • Lin A.
      • Chen H.X.
      • Zhu C.C.
      • Zhang X.
      • Xu H.H.
      • Zhang J.G.
      • et al.
      Aberrant human leucocyte antigen-G expression and its clinical relevance in hepatocellular carcinoma.
      ]. This receptor is also present on B lymphocytes and may account for the higher tolerance of liver allografts expressing HLA-G, due to the inhibition of B-cell antibody secretion [
      • Naji A.
      • Menier C.
      • Morandi F.
      • Agaugue S.
      • Maki G.
      • Ferretti E.
      • et al.
      Binding of HLA-G to ITIM-bearing Ig-like transcript 2 receptor suppresses B cell responses.
      ].
      The interaction of the CD8 receptor present on NK cells and T8 lymphocytes with sHLA-G triggers apoptosis [
      • Contini P.
      • Ghio M.
      • Poggi A.
      • Filaci G.
      • Indiveri F.
      • Ferrone S.
      • et al.
      Soluble HLA-A, -B, -C, and -G molecules induce apoptosis in T and NK CD8+ cells and inhibit cytotoxic T cell activity through CD8 ligation.
      ]. This property is shared by other soluble HLA class I antigens but elevated sHLA-G levels are observed in neoplastic diseases. This results in an inhibition of the immune response, particularly for the anti-tumor response to liver cancers.
      The role of the killer cell immunoglobulin-like receptor (KIR) 2DL4/p49 (CD158d) or KIR2DL4 expressed on NK cells and on some CD8 T lymphocytes is complex, because this receptor may have activating or inhibitory function [
      • Faure M.
      • Long E.O.
      KIR2DL4 (CD158d), an NK cell-activating receptor with inhibitory potential.
      ]. The immunoglobulin-like transcript 4 receptor, ILT-4 (CD85d; LILRB2) is known to be expressed by dendritic cells (DCs), macrophages and monocytes [
      • Colonna M.
      • Samaridis J.
      • Cella M.
      • Angman L.
      • Allen R.L.
      • O’Callaghan C.A.
      • et al.
      Human myelomonocytic cells express an inhibitory receptor for classical and nonclassical MHC class I molecules.
      ], all of which are present in the liver. The ILT-4/HLA-G interaction may inhibit the antigen-presenting function of these cells, weakening adaptive immunity and allowing liver tumors to escape host immunity. This interaction may also inhibit DC maturation, resulting in anergic DCs that induce the differentiation of regulatory T cells, thereby helping to prolong allograft survival [
      • Basturk B.
      • Karakayali F.
      • Emiroglu R.
      • Sozer O.
      • Haberal A.
      • Bal D.
      • et al.
      Human leukocyte antigen-G, a new parameter in the follow-up of liver transplantation.
      ]. However, primary human neutrophils also express the ILT4 inhibitory receptor and the interaction of this receptor with HLA-G inhibits the phagocytic function of neutrophils [
      • Baudhuin J.
      • Migraine J.
      • Faivre V.
      • Loumagne L.
      • Lukaszewicz A.C.
      • Payen D.
      • et al.
      Exocytosis acts as a modulator of the ILT4-mediated inhibition of neutrophil functions.
      ]. This modulation of neutrophil activity may be beneficial in patients with sepsis, preventing the neutrophil dysfunctions observed during inflammatory disorders.
      CD160 is a HLA-G receptor expressed on endothelial cells, which are abundant in the liver. The soluble HLA-G1 (sHLA-G1) isoform has been reported to inhibit fibroblast growth factor-2 (FGF2)–induced capillary-like tubule formation and, thus, to inhibit FGF2-induced angiogenesis in vivo [
      • Fons P.
      • Chabot S.
      • Cartwright J.E.
      • Lenfant F.
      • L’Faqihi F.
      • Giustiniani J.
      • et al.
      Soluble HLA-G1 inhibits angiogenesis through an apoptotic pathway and by direct binding to CD160 receptor expressed by endothelial cells.
      ].
      No data are currently available concerning the expression of HLA-G receptors in liver. However, all of the immune cells expressing these receptors, as described above, are found in the liver, originating in most cases from the margination and extravasation of cells circulating in the blood during pathological conditions (Fig. 2). It also seems likely that the endothelial cells of the liver express CD160. However, the expression of these receptors on Kupffer cells, hepatocytes and hepatic stellate cells has yet to be studied.
      Figure thumbnail gr2
      Fig. 2Cellular source and putative targets of HLA-G in the liver. HLA-G has been reported to be expressed by hepatocytes and mast cells, but there remains some debate concerning its possible expression by hepatocytes. In certain conditions, HLA-G may also be detected in T lymphocytes and in cells of the monocytic lineage, such as monocytes or dendritic cells. The putative target cells of HLA-G are peripheral cells expressing HLA-G receptors (T and B lymphocytes, NK cells, monocytes), T lymphocytes and cells of the monocytic lineage present in inflammatory areas, endothelial cells and mast cells.
      HLA-G is not expressed in the liver in physiological conditions, however sHLA-G can be found, provided by peripheral blood or from transendothelial migration of circulating cells in the liver. HLA-G is able to induce tolerogenic DCs or regulatory T (Treg) cells which are implicated in the maintenance of liver homeostasis. Thus, it participates indirectly in inducing tolerogenic properties on immune cells to avoid activation of immune cells and inflammation.

      HLA-G in the normal liver

      HLA-G gene transcription has been observed in both fetal and adult livers, but transcript levels are higher in fetal tissues. The HLA-G transcript detected corresponded to the full-length form [
      • Onno M.
      • Guillaudeux T.
      • Amiot L.
      • Renard I.
      • Drenou B.
      • Hirel B.
      • et al.
      The HLA-G gene is expressed at a low mRNA level in different human cells and tissues.
      ]. The mesenchymal stem cells (MSC) present in fetal liver contains intracellular deposits of HLA-G [
      • Gotherstrom C.
      • West A.
      • Liden J.
      • Uzunel M.
      • Lahesmaa R.
      • Le Blanc K.
      Difference in gene expression between human fetal liver and adult bone marrow mesenchymal stem cells.
      ]. Hepatocyte-like cells (HLCs) generated from human amniotic epithelial cells (hAECs) from the placenta continue to secrete HLA-G [
      • Tee J.Y.
      • Vaghjiani V.
      • Liu Y.H.
      • Murthi P.
      • Chan J.
      • Manuelpillai U.
      Immunogenicity and immunomodulatory properties of hepatocyte-like cells derived from human amniotic epithelial cells.
      ], but in smaller amounts, and this secretion is maintained in HLCs differentiating from hAECs engrafted into the mouse liver [
      • Manuelpillai U.
      • Lourensz D.
      • Vaghjiani V.
      • Tchongue J.
      • Lacey D.
      • Tee J.Y.
      • et al.
      Human amniotic epithelial cell transplantation induces markers of alternative macrophage activation and reduces established hepatic fibrosis.
      ]. No HLA-G protein is detected in hepatocytes and bile duct cells from the normal liver (www.proteinatlas.org).

      HLA-G and liver cancer

      Both HLA-G mRNA and protein are detectable in human HCC cell lines [
      • Zeng X.C.
      • Zhang T.
      • Huang D.H.
      • Wang G.Y.
      • Chen W.
      • Li H.
      • et al.
      RNA interfering targeting human leukocyte antigen-G enhanced immune surveillance mediated by the natural killer cells on hepatocellular carcinoma.
      ].
      HLA-G expression was found in 50.2% (110/219) of the primary HCCs assessed in one study; staining was heterogeneous in these HCCs, but undetectable in the adjacent normal liver tissues [
      • Lin A.
      • Chen H.X.
      • Zhu C.C.
      • Zhang X.
      • Xu H.H.
      • Zhang J.G.
      • et al.
      Aberrant human leucocyte antigen-G expression and its clinical relevance in hepatocellular carcinoma.
      ]. HLA-G expression has also been detected in biliary cancers [
      • Hansel D.E.
      • Rahman A.
      • Wilentz R.E.
      • Shih Ie M.
      • McMaster M.T.
      • Yeo C.J.
      • et al.
      HLA-G upregulation in pre-malignant and malignant lesions of the gastrointestinal tract.
      ]. The HepG2 hepatocarcinoma cell line was found to contain HLA-G mRNA, but not protein (www.proteinatlas.org). The transfection of HepG2 cells with HLA-G1 decreases NK cytolysis, whereas a blockade of HLA-G or its receptor ILT2 reverses this effect [
      • Lin A.
      • Chen H.X.
      • Zhu C.C.
      • Zhang X.
      • Xu H.H.
      • Zhang J.G.
      • et al.
      Aberrant human leucocyte antigen-G expression and its clinical relevance in hepatocellular carcinoma.
      ]. HLA-G expression is strongly associated with advanced disease stage and patient age. In another series, cytoplasmic HLA-G overexpression (99/173 cases), as revealed by immunohistochemistry, was associated with a high risk of poor survival and recurrence in patients in the early stages of HCC. A positive correlation has also been found between HLA-G levels and the Treg/CD8 T lymphocyte ratio [
      • Cai M.Y.
      • Xu Y.F.
      • Qiu S.J.
      • Ju M.J.
      • Gao Q.
      • Li Y.W.
      • et al.
      Human leukocyte antigen-G protein expression is an unfavorable prognostic predictor of hepatocellular carcinoma following curative resection.
      ]. These findings are consistent with those of Wang [
      • Wang Y.
      • Ye Z.
      • Meng X.Q.
      • Zheng S.S.
      Expression of HLA-G in patients with hepatocellular carcinoma.
      ], who detected HLA-G by Western blot of liver tissues, at 66.7% (24/36) of the HCC sites studied, but not in benign cirrhotic lesions. Survival after surgery was shorter for patients with HLA-G-positive tumors than for patients with HLA-G-negative tumors.
      Blood sHLA-G concentration was shown to be significantly higher in HCC patients (n = 36) than in patients with liver cirrhosis (n = 25) and healthy subjects (n =25) [
      • Wang Y.
      • Ye Z.
      • Meng X.Q.
      • Zheng S.S.
      Expression of HLA-G in patients with hepatocellular carcinoma.
      ]. Lin et al. also reported a significantly higher plasma sHLA-G concentration in HCC patients (n = 19) than in healthy subjects (n = 86), with no correlation between sHLA-G concentration and the staining of the tumor for HLA-G [
      • Lin A.
      • Chen H.X.
      • Zhu C.C.
      • Zhang X.
      • Xu H.H.
      • Zhang J.G.
      • et al.
      Aberrant human leucocyte antigen-G expression and its clinical relevance in hepatocellular carcinoma.
      ]. The 14 bp insertion/deletion (in/del) polymorphism of the 3′ UTR of HLA-G is known to regulate HLA-G expression. This led to studies of this polymorphism in HCC patients. HLA-G expression was found to be stronger in HCC tissues with a 14 bp del/del genotype than in those with a heterozygous or 14-bp ins/ins genotype [
      • Jiang Y.
      • Chen S.
      • Jia S.
      • Zhu Z.
      • Gao X.
      • Dong D.
      • et al.
      Association of HLA-G 3′ UTR 14-bp insertion/deletion polymorphism with hepatocellular carcinoma susceptibility in a Chinese population.
      ].
      To conclude, HLA-G expression in liver tumor or high level of sHLA-G in HCC patients allows escape of tumoral cells from immune response in inhibiting the properties of immune cells i.e. T8 lymphocytes, NK cells, B cells, DCs. HLA-G expression is a factor of bad prognosis similarly to other cancers.

      HLA-G and viral hepatitis

      HLA-G expression has been reported in the hepatocytes and biliary epithelial cells of the livers of patients with chronic hepatitis B [
      • Souto F.J.
      • Crispim J.C.
      • Ferreira S.C.
      • da Silva A.S.
      • Bassi C.L.
      • Soares C.P.
      • et al.
      Liver HLA-G expression is associated with multiple clinical and histopathological forms of chronic hepatitis B virus infection.
      ]. Similar findings have been obtained for chronic hepatitis C [
      • de Oliveira Crispim J.C.
      • Silva T.G.
      • Souto F.J.
      • Souza F.F.
      • Bassi C.L.
      • Soares C.P.
      • et al.
      Upregulation of soluble and membrane-bound human leukocyte antigen G expression is primarily observed in the milder histopathological stages of chronic hepatitis C virus infection.
      ]. In a previous work, we found a strong HLA-G staining of numerous cells in fibrosis septa and not in hepatocyte nodules of paraffin-embedded HCV liver. The HLA-G-positive cell number is significantly correlated with fibrosis area on tissue sections of HCV-induced liver fibrosis. HLA-G-positive cells were identified as being mast cells and not cells of monocytic lineage and T lymphocytes as previously reported in other models. Mast cells promote fibrosis in other organs such as heart, lung and kidney. As in other sites, hepatic mast cells may promote the activation of liver fibrosis via the proliferation of hepatic stellate cells [
      • Gruber B.L.
      • Kew R.R.
      • Jelaska A.
      • Marchese M.J.
      • Garlick J.
      • Ren S.
      • et al.
      Human mast cells activate fibroblasts: tryptase is a fibrogenic factor stimulating collagen messenger ribonucleic acid synthesis and fibroblast chemotaxis.
      ]. Cytokines involved in liver fibrosis such as TGF-β, IL-4, IL-33 are chemoattracting or activating for mast cell [
      • Iikura M.
      • Suto H.
      • Kajiwara N.
      • Oboki K.
      • Ohno T.
      • Okayama Y.
      • et al.
      IL-33 can promote survival, adhesion and cytokine production in human mast cells.
      ]. We hypothesise that HLA-G can serve as a fibrosis marker in reflecting the number of mast cells [
      • Amiot L.
      • Vu N.
      • Rauch M.
      • L’Helgoualc’h A.
      • Chalmel F.
      • Gascan H.
      • et al.
      Expression of HLA-G by mast cells is associated with hepatitis C virus-induced liver fibrosis.
      ] and in addition HLA-G makes fibrosis worse in favoring Th-2 cytokines profile.
      Plasma sHLA-G levels were higher in patients with hepatitis B than in healthy subjects, regardless of disease stage, and HLA-G levels were found to differ between stages. Indeed significant differences were observed between; (i) acute hepatitis B (n = 90) and chronic hepatitis B (n = 131); (ii) acute hepatitis B and resolved hepatitis B (n = 152); and (iii) chronic hepatitis B and resolved hepatitis B [
      • Shi W.W.
      • Lin A.
      • Xu D.P.
      • Bao W.G.
      • Zhang J.G.
      • Chen S.Y.
      • et al.
      Plasma soluble human leukocyte antigen-G expression is a potential clinical biomarker in patients with hepatitis B virus infection.
      ]. Similarly, chronic hepatitis C patients (n = 67), were found to have a much higher plasma sHLA-G concentration than healthy subjects (n = 129) [
      • Weng P.J.
      • Fu Y.M.
      • Ding S.X.
      • Xu D.P.
      • Lin A.
      • Yan W.H.
      Elevation of plasma soluble human leukocyte antigen-G in patients with chronic hepatitis C virus infection.
      ].

      HLA-G and hepatotropic parasite infections

      Visceral leishmaniasis (Leishmania infantum) (VL) causes morphological and functional disturbances in the liver, resulting in focal fibrosis rather than cirrhosis. We showed that sHLA-G levels were higher in 35% of HIV-negative patients with VL and in 57% of patients coinfected with HIV and Leishmania infantum than in healthy individuals [
      • Donaghy L.
      • Gros F.
      • Amiot L.
      • Mary C.
      • Maillard A.
      • Guiguen C.
      • et al.
      Elevated levels of soluble non-classical major histocompatibility class I molecule human leucocyte antigen (HLA)-G in the blood of HIV-infected patients with or without visceral leishmaniasis.
      ]. This upregulation of sHLA-G was reported to be correlated with cyst activity [
      • Vuitton D.A.
      • Millon L.
      • Gottstein B.
      • Giraudoux P.
      Proceedings of the International Symposium.
      ]. HLA-G expression could constitute an immune-evasion strategy in the host-parasite interplay.

      HLA-G and liver failure

      HLA-G expression during liver failure has not yet been investigated, to the best of our knowledge. Data are available only for septic shock. There is a critical reduction of tissue perfusion during severe sepsis and septic shock that may trigger the acute failure of multiple organs, including the liver. A sustained, marked increase in plasma sHLA-G levels was found to be predictor of survival [
      • Monneret G.
      • Voirin N.
      • Krawice-Radanne I.
      • Bohe J.
      • Lepape A.
      • Rouas-Freiss N.
      • et al.
      Soluble human leukocyte antigen-G5 in septic shock: marked and persisting elevation as a predictor of survival.
      ]. A tissue expression of HLA-G or an increase of plasma levels would reflect an appropriate and efficient response to the inflammatory process in limiting this process.

      HLA-G and autoimmune hepatic diseases

      The role of HLA-G has been investigated in several inflammatory diseases, including multiple sclerosis, rheumatoid arthritis, systemic lupus erythematous, and psoriasis, and it has been suggested that HLA-G is both a biomarker useful for the monitoring of disease activity and an anti-inflammatory molecule [
      • Gonzalez A.
      • Rebmann V.
      • LeMaoult J.
      • Horn P.A.
      • Carosella E.D.
      • Alegre E.
      The immunosuppressive molecule HLA-G and its clinical implications.
      ]. However, no data have yet been published for autoimmune hepatic diseases, such as autoimmune hepatitis, sclerosing cholangitis and primary biliary cirrhosis. Similarly to other inflammatory diseases, HLA-G molecules may play a protective role in autoimmune hepatic diseases by its anti-inflammatory activity.

      HLA-G and liver transplantation

      In combined liver-kidney transplantation, immunohistochemistry revealed HLA-G expression in 14 of the 40 liver biopsy specimens and five of the nine kidney transplant biopsy specimens examined. HLA-G is expressed de novo by known target cells of acute rejection: liver epithelial cells, but not in hepatocytes and renal tubular epithelial cells. HLA-G expression in the liver allograft is associated with a lower frequency of hepatic and renal graft rejection [
      • Creput C.
      • Le Friec G.
      • Bahri R.
      • Amiot L.
      • Charpentier B.
      • Carosella E.
      • et al.
      Detection of HLA-G in serum and graft biopsy associated with fewer acute rejections following combined liver-kidney transplantation: possible implications for monitoring patients.
      ]. An inverse correlation was also found between serum HLA-G concentration and liver function in liver transplant patients (n = 37). Indeed, a decrease in serum HLA-G concentration was found to be predictive of liver dysfunction or rejection one month later.
      Serum sHLA-G concentration was high in liver-kidney transplant patients but not in kidney transplant patients [
      • Creput C.
      • Le Friec G.
      • Bahri R.
      • Amiot L.
      • Charpentier B.
      • Carosella E.
      • et al.
      Detection of HLA-G in serum and graft biopsy associated with fewer acute rejections following combined liver-kidney transplantation: possible implications for monitoring patients.
      ]. Thus, sHLA-G levels and cell surface HLA-G expression on regulatory T cells increase during cyclosporine treatment and can be used in the follow-up of liver transplant patients [
      • Basturk B.
      • Karakayali F.
      • Emiroglu R.
      • Sozer O.
      • Haberal A.
      • Bal D.
      • et al.
      Human leukocyte antigen-G, a new parameter in the follow-up of liver transplantation.
      ]. Similarly, increases in serum HLA-G levels in pediatric and young adult liver transplant patients can be used to detect tolerance of the liver graft and to predict favorable outcomes in liver transplant recipients [
      • Zarkhin V.
      • Talisetti A.
      • Li L.
      • Wozniak L.J.
      • McDiarmid S.V.
      • Cox K.
      • et al.
      Expression of soluble HLA-G identifies favorable outcomes in liver transplant recipients.
      ]. Serum sHLA-G concentration appears to be higher in adult liver transplant recipients treated with tacrolimus as an immunosuppressive agent, but this difference is not statistically significant [
      • Levitsky J.
      • Miller J.
      • Wang E.
      • Rosen A.
      • Flaa C.
      • Abecassis M.
      • et al.
      Immunoregulatory profiles in liver transplant recipients on different immunosuppressive agents.
      ]. Higher levels of expression have also been reported on the circulating monocytoid DCs (mDCs) of patients with operational liver transplant tolerance than in patients on maintenance immunosuppression or healthy controls, although these differences were, again, not statistically significant [
      • Castellaneta A.
      • Mazariegos G.V.
      • Nayyar N.
      • Zeevi A.
      • Thomson A.W.
      HLA-G level on monocytoid dendritic cells correlates with regulatory T-cell Foxp3 expression in liver transplant tolerance.
      ]. The immunosuppressive treatments used in liver transplantation can modulate HLA-G expression, and this may partly account for their impact on prognosis. Indeed, some therapeutic agents such as dexamethasone and hydrocortisone, upregulate HLA-G expression [
      • Akhter A.
      • Das V.
      • Naik S.
      • Faridi R.M.
      • Pandey A.
      • Agrawal S.
      Upregulation of HLA-G in JEG-3 cells by dexamethasone and hydrocortisone.
      ]. Cyclosporine and tacrolimus are the principal immunosuppressive agents used in liver transplantation, and mycophenolate is used to treat renal failure. Cyclosporine A and mycophenolate have no effect on HLA-G expression [
      • Sheshgiri R.
      • Gustafsson F.
      • Sheedy J.
      • Rao V.
      • Ross H.J.
      • Delgado D.H.
      Everolimus but not mycophenolate mofetil therapy is associated with soluble HLA-G expression in heart transplant patients.
      ], whereas tacrolimus increases sHLA-G levels [
      • Levitsky J.
      • Miller J.
      • Wang E.
      • Rosen A.
      • Flaa C.
      • Abecassis M.
      • et al.
      Immunoregulatory profiles in liver transplant recipients on different immunosuppressive agents.
      ].
      To conclude this section, expression of HLA-G in liver tissue or increase of circulating sHLA-G is associated with a better graft acceptance, that hypothesis is reinforced by the upregulation of HLA-G by some therapeutic agents used to prevent rejection.

      HLA-G and graft vs. host response

      Liver is one of the sites at which graft vs. host (GVH) disease following hematopoietic stem cell transplantation is observed. Examination of the liver during acute GVH reveals foci of eosinophilic necrosis, bile duct destruction, Kupffer cell hypertrophy and peribiliary lymphocytic infiltrates. Fibrosis and atrophy are observed in chronic cases of GVH disease.
      It seems likely that sHLA-G is involved in acute GVH disease (aGVHD) prevention, because increases in sHLA-G5 concentration on post-transplant days 15 and 30 were found to be inversely correlated with aGVHD severity [
      • Liu H.
      • Chen Y.
      • Xuan L.
      • Wu X.
      • Zhang Y.
      • Fan Z.
      • et al.
      Soluble human leukocyte antigen G molecule expression in allogeneic hematopoietic stem cell transplantation: good predictor of acute graft-versus-host disease.
      ]. This role of sHLA-G5 may be accounted for by the positive correlation between sHLA-G level and natural Treg cell frequency in the blood of transplant patients [
      • Le Maux A.
      • Noel G.
      • Birebent B.
      • Grosset J.M.
      • Vu N.
      • De Guibert S.
      • et al.
      Soluble human leucocyte antigen-G molecules in peripheral blood haematopoietic stem cell transplantation: a specific role to prevent acute graft-versus-host disease and a link with regulatory T cells.
      ].

      General discussion

      The cellular source of HLA-G differs between diseases. HLA-G is produced by some tumor cells, but it may also be generated by cells of the monocytic lineage, including monocytes, and DCs or T lymphocytes may express HLA-G in particular conditions. Furthermore, we have demonstrated the involvement of another cell type in HCV-induced liver fibrosis. Indeed, in this condition, it is the mast cells that produce HLA-G [
      • Amiot L.
      • Vu N.
      • Rauch M.
      • L’Helgoualc’h A.
      • Chalmel F.
      • Gascan H.
      • et al.
      Expression of HLA-G by mast cells is associated with hepatitis C virus-induced liver fibrosis.
      ]. In the context of transplantation, HLA-G may be secreted by the biliary epithelial cells of the liver graft [
      • Creput C.
      • Le Friec G.
      • Bahri R.
      • Amiot L.
      • Charpentier B.
      • Carosella E.
      • et al.
      Detection of HLA-G in serum and graft biopsy associated with fewer acute rejections following combined liver-kidney transplantation: possible implications for monitoring patients.
      ]. Alternatively, HLA-G5 may be secreted by allo-specific CD4+ T lymphocytes, as shown in mixed lymphocyte cultures in vitro [
      • Lila N.
      • Rouas-Freiss N.
      • Dausset J.
      • Carpentier A.
      • Carosella E.D.
      Soluble HLA-G protein secreted by allo-specific CD4+ T cells suppresses the allo-proliferative response: a CD4+ T cell regulatory mechanism.
      ]. Kupffer cells or DCs may also serve as a source of HLA-G during transplantation, because both monocytes and DCs can express or secrete sHLA-G [
      • Rebmann V.
      • Busemann A.
      • Lindemann M.
      • Grosse-Wilde H.
      Detection of HLA-G5 secreting cells.
      ,
      • Le Friec G.
      • Gros F.
      • Sebti Y.
      • Guilloux V.
      • Pangault C.
      • Fauchet R.
      • et al.
      Capacity of myeloid and plasmacytoid dendritic cells especially at mature stage to express and secrete HLA-G molecules.
      ].
      Numerous studies in the field of transplantation have demonstrated an association between high levels of HLA-G expression in biopsy specimens or high blood sHLA-G levels and higher rates of graft acceptance. Indeed, this association with a better post-transplantation outcome was first demonstrated for heart transplantation [
      • Lila N.
      • Amrein C.
      • Guillemain R.
      • Chevalier P.
      • Latremouille C.
      • Fabiani J.N.
      • et al.
      Human leukocyte antigen-G expression after heart transplantation is associated with a reduced incidence of rejection.
      ,
      • Luque J.
      • Torres M.I.
      • Aumente M.D.
      • Marin J.
      • Garcia-Jurado G.
      • Gonzalez R.
      • et al.
      Soluble HLA-G in heart transplantation: their relationship to rejection episodes and immunosuppressive therapy.
      ], and then for the transplantation of liver [
      • Basturk B.
      • Karakayali F.
      • Emiroglu R.
      • Sozer O.
      • Haberal A.
      • Bal D.
      • et al.
      Human leukocyte antigen-G, a new parameter in the follow-up of liver transplantation.
      ,
      • Creput C.
      • Le Friec G.
      • Bahri R.
      • Amiot L.
      • Charpentier B.
      • Carosella E.
      • et al.
      Detection of HLA-G in serum and graft biopsy associated with fewer acute rejections following combined liver-kidney transplantation: possible implications for monitoring patients.
      ,
      • Creput C.
      • Durrbach A.
      • Menier C.
      • Guettier C.
      • Samuel D.
      • Dausset J.
      • et al.
      Human leukocyte antigen-G (HLA-G) expression in biliary epithelial cells is associated with allograft acceptance in liver-kidney transplantation.
      ], kidney [
      • Crispim J.C.
      • Duarte R.A.
      • Soares C.P.
      • Costa R.
      • Silva J.S.
      • Mendes-Junior C.T.
      • et al.
      Human leukocyte antigen-G expression after kidney transplantation is associated with a reduced incidence of rejection.
      ,
      • Zarkhin V.
      • Bezchinsky M.
      • Li L.
      • Sarwal M.M.
      Soluble human leukocyte antigen-G in pediatric renal transplantation.
      ] and lung [
      • Brugiere O.
      • Thabut G.
      • Pretolani M.
      • Krawice-Radanne I.
      • Dill C.
      • Herbreteau A.
      • et al.
      Immunohistochemical study of HLA-G expression in lung transplant recipients.
      ] grafts and for the transplantation of hematopoietic stem cells [
      • Le Maux A.
      • Noel G.
      • Birebent B.
      • Grosset J.M.
      • Vu N.
      • De Guibert S.
      • et al.
      Soluble human leucocyte antigen-G molecules in peripheral blood haematopoietic stem cell transplantation: a specific role to prevent acute graft-versus-host disease and a link with regulatory T cells.
      ]. This beneficial effect may reflect a peripheral increase in the size of the CD3+CD4low and CD3+CD8low T-cell subpopulations associated with high levels of peripheral IL-10 production [
      • Naji A.
      • Le Rond S.
      • Durrbach A.
      • Krawice-Radanne I.
      • Creput C.
      • Daouya M.
      • et al.
      CD3+CD4low and CD3+CD8low are induced by HLA-G: novel human peripheral blood suppressor T-cell subsets involved in transplant acceptance.
      ]. These two subsets constitute novel blood suppressor T-cell populations and are induced by HLA-G, potentially accounting for transplant tolerance. Patients with high sHLA-G levels after transplantation overproduce these suppressor T cells. HLA-G induces several types of regulatory/suppressive cells of various subtypes. The orientation towards tolerance can be accounted for by the effects of HLA-G on the different subtypes of immune cells, including B cells in particular, resulting in the inhibition of antibody secretion by B cells in a mouse xenograft model [
      • Naji A.
      • Menier C.
      • Morandi F.
      • Agaugue S.
      • Maki G.
      • Ferretti E.
      • et al.
      Binding of HLA-G to ITIM-bearing Ig-like transcript 2 receptor suppresses B cell responses.
      ]. Graft acceptance has been shown to be better in patients undergoing liver transplantation or combined liver-kidney transplantation than in those undergoing kidney transplantation alone [
      • Creput C.
      • Le Friec G.
      • Bahri R.
      • Amiot L.
      • Charpentier B.
      • Carosella E.
      • et al.
      Detection of HLA-G in serum and graft biopsy associated with fewer acute rejections following combined liver-kidney transplantation: possible implications for monitoring patients.
      ]. These data are consistent with the immunological status of the liver [
      • Racanelli V.
      • Rehermann B.
      The liver as an immunological organ.
      ]. The better graft tolerance observed in patients overexpressing HLA-G may be attributed to liver factors. These liver factors may be cytokines, such as the IL-10 produced by the liver during liver transplantation [
      • Ingelsten M.
      • Gustafsson K.
      • Olausson M.
      • Haraldsson B.
      • Karlsson-Parra A.
      • Nystrom J.
      Rapid increase of interleukin-10 plasma levels after combined auxiliary liver-kidney transplantation in presensitized patients.
      ,
      • Le Moine O.
      • Marchant A.
      • Durand F.
      • Ickx B.
      • Pradier O.
      • Belghiti J.
      • et al.
      Systemic release of interleukin-10 during orthotopic liver transplantation.
      ], HLA-G secreted by the biliary epithelial cells of the grafted liver [
      • Creput C.
      • Durrbach A.
      • Menier C.
      • Guettier C.
      • Samuel D.
      • Dausset J.
      • et al.
      Human leukocyte antigen-G (HLA-G) expression in biliary epithelial cells is associated with allograft acceptance in liver-kidney transplantation.
      ] or allo-specific CD4+ T lymphocytes, as shown in mixed lymphocyte culture in vitro [
      • Lila N.
      • Rouas-Freiss N.
      • Dausset J.
      • Carpentier A.
      • Carosella E.D.
      Soluble HLA-G protein secreted by allo-specific CD4+ T cells suppresses the allo-proliferative response: a CD4+ T cell regulatory mechanism.
      ]. Two other possible sources of HLA-G during transplantation are the Kupffer cells and hepatic DCs, which belong to the monocytic lineage able to produce or secrete HLA-G. Alternatively, HLA-G expression, which may be restricted to a few cells, could be propagated to neighboring cells by trogocytosis [
      • LeMaoult J.
      • Caumartin J.
      • Carosella E.D.
      Exchanges of membrane patches (trogocytosis) split theoretical and actual functions of immune cells.
      ].
      The tolerogenic properties of HLA-G account for its deleterious effects in cancers and beneficial effects in transplantation.
      The abnormal expression of HLA-G in HCC cell lines plays an important role in protecting these cells against NK cell attack. The significant correlation between HLA-G expression and NK cell lysis implies that abnormal HLA-G expression may contribute to the mechanism of escape from host immune surveillance in HCC. Indeed, the effects of HLA-G on immune cells greatly affect both innate and adaptive immune responses, allowing the HCC to escape host immunity, resulting in tumor progression. Moreover, a comparison of HLA-G with the carcinoembryonic antigen AFP as markers of cancer has shown that HLA-G is specific to malignant liver cancers, like AFP in breast and ovarian cancers [
      • Singer G.
      • Rebmann V.
      • Chen Y.C.
      • Liu H.T.
      • Ali S.Z.
      • Reinsberg J.
      • et al.
      HLA-G is a potential tumor marker in malignant ascites.
      ]. A positive correlation between HLA-G and Treg/CD8 T-cell ratio, with a negative impact of HLA-G on outcome, can be accounted for by the immunosuppressive properties of HLA-G and Treg cells. Other studies have demonstrated an association between HLA-G and Treg, due to the induction, by HLA-G, of different populations of Treg cells. Thus HLA-G appears to be an independent indicator of poor outcome in HCC, particularly during the early stages of the disease [
      • Cai M.Y.
      • Xu Y.F.
      • Qiu S.J.
      • Ju M.J.
      • Gao Q.
      • Li Y.W.
      • et al.
      Human leukocyte antigen-G protein expression is an unfavorable prognostic predictor of hepatocellular carcinoma following curative resection.
      ].
      Plasma HLA-G concentration may be useful for the monitoring of immunosuppressive therapy after transplantation. The function of HLA-G in viral infections remains to be determined and may be detrimental, as in cancers, or beneficial, as in septic shock.
      The receptors of HLA-G have not yet been investigated in the liver, and such studies are required if we are to understand the function of HLA-G.

      Conclusions

      HLA-G could generally be considered a potent tolerogenic molecule. Its immunosuppressive properties play a role in liver diseases and transplantation, with negative effects on cancers and beneficial effects in liver transplantation. HLA-G may constitute a novel therapeutic target in the future. Indeed, new therapeutic agents for modulating HLA-G expression are being developed and tested, including synthetic HLA-G proteins potentially useful in transplantation [
      • LeMaoult J.
      • Daouya M.
      • Wu J.
      • Loustau M.
      • Horuzsko A.
      • Carosella E.D.
      Synthetic HLA-G proteins for therapeutic use in transplantation.
      ] and antibodies blocking HLA-G activity in cancer [
      • Agaugue S.
      • Carosella E.D.
      • Rouas-Freiss N.
      Role of HLA-G in tumor escape through expansion of myeloid-derived suppressor cells and cytokinic balance in favor of Th2 versus Th1/Th17.
      ]. Further exploration of the role of HLA-G receptors in liver diseases and a better knowledge of its function in liver are also required before considering their potential use in liver diseases.

      Conflict of interest

      The authors who have taken part in this review declared that they do not have anything to disclose regarding funding or conflict of interest.

      Acknowledgments

      This work was supported by University of Rennes1 and Institut National de la Santé et de la Recherche Médicale (Inserm). This work was supported by grants from Ligue Nationale Contre le Cancer (Comité d’Ille et Vilaine, Comité des Côtes d’Armor, Comité de Loire-Atlantique).

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