64
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      Controlling the Immunological Crosstalk during Conception and Pregnancy: HLA-G in Reproduction

      review-article

      Read this article at

      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          In several years after its discovery in the placenta, the human leukocyte antigen (HLA) class Ib protein, HLA-G, was not given much attention, nor was it assigned great importance. As time has unraveled, HLA-G has proven to have distinctive functions and an unforeseen and possibly important role in reproduction. HLA-G is characterized mainly by its low polymorphism and restricted tissue distribution in non-pathological conditions. In fact, its expression pattern is primarily limited to extravillous cytotrophoblast cells at the maternal-fetal interface during pregnancy. Due to low polymorphism, almost the same protein is expressed by virtually all individuals. It is these unique features that make HLA-G differ from its highly polymorphic HLA class Ia counterparts, the HLA-A, -B, and -C molecules. Its function, seemingly diverse, is typically receptor-mediated, and involves interactions with a wide range of immune cells. As the expression of HLA-G primarily is limited to gestation, this has given rise to the hypothesis that HLA-G plays an important role in the immunological tolerance of the fetus by the mother. In keeping with this, it might not be surprising that polymorphisms in the HLA-G gene, and levels of HLA-G expression, have been linked to reproductive failure and pre-eclampsia. Based on recent studies, we speculate that HLA-G might be involved in mechanisms in reproductive immunology even before conception because HLA-G can be detected in the genital tract and in the blood of non-pregnant women, and is present in seminal fluid from men. In addition, HLA-G expression has been found in the pre-implanted embryo. Therefore, we propose that a combined contribution from the mother, the father, and the embryo/fetus is likely to be important. Furthermore, this review presents important aspects of HLA-G in relation to reproduction: from genetics to physiological effects, from pregnancy and pregnancy complications to a short discussion on future possible means of preventative measures and therapy.

          Related collections

          Most cited references102

          • Record: found
          • Abstract: found
          • Article: not found

          Differentiation of type 1 T regulatory cells (Tr1) by tolerogenic DC-10 requires the IL-10-dependent ILT4/HLA-G pathway.

          Type 1 T regulatory (Tr1) cells suppress immune responses in vivo and in vitro and play a key role in maintaining tolerance to self- and non-self-antigens. Interleukin-10 (IL-10) is the crucial driving factor for Tr1 cell differentiation, but the molecular mechanisms underlying this induction remain unknown. We identified and characterized a subset of IL-10-producing human dendritic cells (DCs), termed DC-10, which are present in vivo and can be induced in vitro in the presence of IL-10. DC-10 are CD14(+), CD16(+), CD11c(+), CD11b(+), HLA-DR(+), CD83(+), CD1a(-), CD1c(-), express the Ig-like transcripts (ILTs) ILT2, ILT3, ILT4, and HLA-G antigen, display high levels of CD40 and CD86, and up-regulate CD80 after differentiation in vitro. DC-10 isolated from peripheral blood or generated in vitro are potent inducers of antigen-specific IL-10-producing Tr1 cells. Induction of Tr1 cells by DC-10 is IL-10-dependent and requires the ILT4/HLA-G signaling pathway. Our data indicate that DC-10 represents a novel subset of tolerogenic DCs, which secrete high levels of IL-10, express ILT4 and HLA-G, and have the specific function to induce Tr1 cells.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            A class I antigen, HLA-G, expressed in human trophoblasts.

            The alpha chain of the human histocompatibility antigen HLA-G was identified as an array of five 37- to 39-kilodalton isoforms by the use of two-dimensional gel electrophoresis. Both cell-associated and secreted HLA-G antigens are prominent in first trimester villous cytotrophoblasts and are greatly reduced in third trimester cytotrophoblasts. Allelic variation was not detected, an indication that HLA-G is not obviously polymorphic in cytotrophoblasts. Among the following choriocarcinoma cell lines studied, HLA-G is expressed in JEG but not in Jar or BeWo. Expression of endogenous HLA-G genes has not been found in normal lymphoid cells. Thus, HLA-G is subject to both cell type-specific and developmental regulation and is expressed in early gestation human cytotrophoblasts.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: found
              Is Open Access

              A Human Histocompatibility Leukocyte Antigen (HLA)-G–specific Receptor Expressed on All Natural Killer Cells

              Human natural killer (NK) cells express several killer cell immunoglobulin (Ig)-like receptors (KIRs) that inhibit their cytotoxicity upon recognition of human histocompatibility leukocyte antigen (HLA) class I molecules on target cells. Additional members of the KIR family, including some that deliver activation signals, have unknown ligand specificity and function. One such KIR, denoted KIR2DL4, is structurally divergent from other KIRs in the configuration of its two extracellular Ig domains and of its transmembrane and cytoplasmic domains. Here we show that recombinant soluble KIR2DL4 binds to cells expressing HLA-G but not to cells expressing other HLA class I molecules. Unlike other HLA class I–specific KIRs, which are clonally distributed on NK cells, KIR2DL4 is expressed at the surface of all NK cells. Furthermore, functional transfer of KIR2DL4 into the cell line NK-92 resulted in inhibition of lysis of target cells that express HLA-G, but not target cells that express other class I molecules including HLA-E. 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.
                Bookmark

                Author and article information

                Contributors
                URI : http://frontiersin.org/people/u/117877
                URI : http://frontiersin.org/people/u/124518
                URI : http://frontiersin.org/people/u/117930
                Journal
                Front Immunol
                Front Immunol
                Front. Immunol.
                Frontiers in Immunology
                Frontiers Media S.A.
                1664-3224
                13 May 2014
                2014
                : 5
                : 198
                Affiliations
                [1] 1Centre for Immune Regulation and Reproductive Immunology, Department of Clinical Biochemistry, Copenhagen University Hospital , Roskilde, Denmark
                Author notes

                Edited by: Sinuhe Hahn, University Clinics Basel, Switzerland

                Reviewed by: Silvia Gregori, San Raffaele Telethon Institute for Gene Therapy, Italy; Daisuke Kamimura, Osaka University, Japan; Heinz Hutter, Medical University of Graz, Austria

                *Correspondence: Thomas Vauvert F. Hviid, Centre for Immune Regulation and Reproductive Immunology (CIRRI), Department of Clinical Biochemistry, Copenhagen University Hospital, Roskilde Hospital, 7-13 Køgevej, Roskilde DK-4000, Denmark e-mail: tvh@ 123456regionsjaelland.dk

                Line Lynge Nilsson and Snezana Djurisic have contributed equally to this work.

                This article was submitted to Inflammation, a section of the journal Frontiers in Immunology.

                Article
                10.3389/fimmu.2014.00198
                4026753
                24860568
                0f0251c1-ea63-45a0-826b-3269d47568e2
                Copyright © 2014 Lynge Nilsson, Djurisic and Hviid.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 01 March 2014
                : 22 April 2014
                Page count
                Figures: 3, Tables: 0, Equations: 0, References: 106, Pages: 10, Words: 9932
                Categories
                Immunology
                Review Article

                Immunology
                mhc,hla class ib,hla-g,human reproduction,pregnancy complications
                Immunology
                mhc, hla class ib, hla-g, human reproduction, pregnancy complications

                Comments

                Comment on this article