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HLA class Ib in pregnancy and pregnancy-related disorders

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Abstract

The HLA class Ib genes, HLA-E, HLA-F, and HLA-G, were discovered long after the classical HLA class Ia genes. The elucidation of their functions had a modest beginning. However, their basic functions and involvement in pathophysiology and a range of diseases are now emerging. Although results from a range of studies support the functional roles for the HLA class Ib molecules in adult life, especially HLA-G and HLA-F have most intensively been, and were also primarily, studied in relation to reproduction and pregnancy. The expression of HLA class Ib proteins at the feto-maternal interface in the placenta seems to be important for the maternal acceptance of the semi-allogenic fetus. In contrast to the functions of HLA class Ia, HLA-G possesses immune-modulatory and tolerogenic functions. Here, we review an accumulating amount of data describing the functions of HLA class Ib molecules in relation to fertility, reproduction, and pregnancy, and a possible role for these molecules in certain pregnancy complications, such as implantation failure, recurrent spontaneous abortions, and pre-eclampsia. The results from different kinds of studies point toward a role for HLA class Ib, especially HLA-G, throughout the reproductive cycle from conception to the birth weight of the child.

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References

  • Abbas A, Tripathi P, Naik S, Agrawal S (2004) Analysis of human leukocyte antigen (HLA)-G polymorphism in normal women and in women with recurrent spontaneous abortions. Eur J Immunogenet 31:275–278

    Article  CAS  PubMed  Google Scholar 

  • Aldrich C, Verp MS, Walker MA, Ober C (2000) A null mutation in HLA-G is not associated with preeclampsia or intrauterine growth retardation. J Reprod Immunol 47:41–48

    Article  CAS  PubMed  Google Scholar 

  • Aldrich CL, Stephenson MD, Karrison T, Odem RR, Branch DW, Scott JR, Schreiber JR, Ober C (2001) HLA-G genotypes and pregnancy outcome in couples with unexplained recurrent miscarriage. Mol Hum Reprod 7:1167–1172

    Article  CAS  PubMed  Google Scholar 

  • Allan DS, Lepin EJ, Braud VM, O’Callaghan CA, McMichael AJ (2002) Tetrameric complexes of HLA-E, HLA-F, and HLA-G. J Immunol Methods 268:43–50

    Article  CAS  PubMed  Google Scholar 

  • Aruna M, Sudheer PS, Andal S, Tarakeswari S, Reddy AG, Thangaraj K, Singh L, Reddy BM (2010) HLA-G polymorphism patterns show lack of detectable association with recurrent spontaneous abortion. Tissue Antigens 76:216–222

    Article  CAS  PubMed  Google Scholar 

  • Bamberger AM, Jenatschke S, Schulte HM, Loning T, Bamberger MC (2000) Leukemia inhibitory factor (LIF) stimulates the human HLA-G promoter in JEG3 choriocarcinoma cells. J Clin Endocrinol Metab 85:3932–3936

    Article  CAS  PubMed  Google Scholar 

  • Braud VM, Allan DS, O’Callaghan CA, Soderstrom K, D’Andrea A, Ogg GS, Lazetic S, Young NT, Bell JI, Phillips JH, Lanier LL, McMichael AJ (1998) HLA-E binds to natural killer cell receptors CD94/NKG2A, B and C. Nature 391:795–799

    Article  CAS  PubMed  Google Scholar 

  • Burrows CK, Kosova G, Herman C, Patterson K, Hartmann KE, Velez Edwards DR, Stephenson MD, Lynch VJ, Ober C (2016) Expression quantitative trait locus mapping studies in mid-secretory phase endometrial cells identifies HLA-F and TAP2 as fecundability-associated genes. PLoS Genet 12:e1005858

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Carosella ED, Rouas-Freiss N, Tronik-Le Roux D, Moreau P, LeMaoult J (2015) HLA-G: an immune checkpoint molecule. Adv Immunol 127:33–144

    Article  PubMed  Google Scholar 

  • Castelli EC, Ramalho J, Porto IO, Lima TH, Felicio LP, Sabbagh A, Donadi EA, Mendes-Junior CT (2014a) Insights into HLA-G genetics provided by worldwide haplotype diversity. Front Immunol 5:476

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Castelli EC, Veiga-Castelli LC, Yaghi L, Moreau P, Donadi EA (2014b) Transcriptional and posttranscriptional regulations of the HLA-G gene. J Immunol Res 2014:734068

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Celik AA, Kraemer T, Huyton T, Blasczyk R, Bade-Doding C (2016) The diversity of the HLA-E-restricted peptide repertoire explains the immunological impact of the Arg107Gly mismatch. Immunogenetics 68:29–41

    Article  CAS  PubMed  Google Scholar 

  • Chen XY, Yan WH, Lin A, Xu HH, Zhang JG, Wang XX (2008) The 14 bp deletion polymorphisms in HLA-G gene play an important role in the expression of soluble HLA-G in plasma. Tissue Antigens 72:335–341

    Article  CAS  PubMed  Google Scholar 

  • Colonna M, Samaridis J, Cella M, Angman L, Allen RL, O’Callaghan CA, Dunbar R, Ogg GS, Cerundolo V, Rolink A (1998) Human myelomonocytic cells express an inhibitory receptor for classical and nonclassical MHC class I molecules. J Immunol 160:3096–3100

    CAS  PubMed  Google Scholar 

  • Comiskey M, Domino KE, Warner CM (2007) HLA-G is found in lipid rafts and can act as a signaling molecule. Hum Immunol 68:1–11

    Article  CAS  PubMed  Google Scholar 

  • Contini P, Ghio M, Poggi A, Filaci G, Indiveri F, Ferrone S, Puppo F (2003) 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. Eur J Immunol 33:125–134

    Article  CAS  PubMed  Google Scholar 

  • Crisa L, McMaster MT, Ishii JK, Fisher SJ, Salomon DR (1997) Identification of a thymic epithelial cell subset sharing expression of the class Ib HLA-G molecule with fetal trophoblasts. J Exp Med 186:289–298

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dahl M, Perin TL, Djurisic S, Rasmussen M, Ohlsson J, Buus S, Lindhard A, Hviid TV (2014) Soluble human leukocyte antigen-G in seminal plasma is associated with HLA-G genotype: possible implications for fertility success. Am J Reprod Immunol 72:89–105

    Article  CAS  PubMed  Google Scholar 

  • Dekker G, Sukcharoen N (2004) Etiology of preeclampsia: an update. J Med Assoc Thail 87(Suppl 3):S96–103

    Google Scholar 

  • Dekker GA, Robillard PY (2005) Preeclampsia: a couple’s disease with maternal and fetal manifestations. Curr Pharm Des 11:699–710

    Article  CAS  PubMed  Google Scholar 

  • Djurisic S, Teiblum S, Tolstrup CK, Christiansen OB, Hviid TV (2015) Allelic imbalance modulates surface expression of the tolerance-inducing HLA-G molecule on primary trophoblast cells. Mol Hum Reprod 21:281–295

    Article  CAS  PubMed  Google Scholar 

  • Dong Y, Lieskovska J, Kedrin D, Porcelli S, Mandelboim O, Bushkin Y (2003) Soluble nonclassical HLA generated by the metalloproteinase pathway. Hum Immunol 64:802–810

    Article  CAS  PubMed  Google Scholar 

  • Emmery J, Christiansen OB, Nilsson LL, Dahl M, Skovbo P, Moller AM, Steffensen R, Hviid TV (2017) Associations between fetal HLA-G genotype and birth weight and placental weight in a large cohort of pregnant women—possible implications for HLA diversity. J Reprod Immunol 120:8–14

    Article  PubMed  Google Scholar 

  • Fan W, Li S, Huang Z, Chen Q (2014) Relationship between HLA-G polymorphism and susceptibility to recurrent miscarriage: a meta-analysis of non-family-based studies. J Assist Reprod Genet 31:173–184

    Article  PubMed  Google Scholar 

  • Fisher SJ (2015) Why is placentation abnormal in preeclampsia? Am J Obstet Gynecol 213:S115–S122

    Article  PubMed  PubMed Central  Google Scholar 

  • Fotoohi M, Ghasemi N, Mirghanizadeh SA, Vakili M, Samadi M (2016) Association between HLA-E gene polymorphism and unexplained recurrent spontaneous abortion (RSA) in Iranian women. Int J Reprod Biomed (Yazd) 14:477–482

    Google Scholar 

  • Fuzzi B, Rizzo R, Criscuoli L, Noci I, Melchiorri L, Scarselli B, Bencini E, Menicucci A, Baricordi OR (2002) HLA-G expression in early embryos is a fundamental prerequisite for the obtainment of pregnancy. Eur J Immunol 32:311–315

    Article  CAS  PubMed  Google Scholar 

  • Garcia-Beltran WF, Holzemer A, Martrus G, Chung AW, Pacheco Y, Simoneau CR, Rucevic M, Lamothe-Molina PA, Pertel T, Kim TE, Dugan H, Alter G, Dechanet-Merville J, Jost S, Carrington M, Altfeld M (2016) Open conformers of HLA-F are high-affinity ligands of the activating NK-cell receptor KIR3DS1. Nat Immunol 17:1067–1074

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gelmini GF, Costa CH, Nardi FD, Wowk PF, Mattar SB, Schuffner A, Bicalho MD, Roxo VM (2016) Is HLA-E a possible genetic marker relevant for natural conception? Am J Reprod Immunol 76:439–442

    Article  CAS  PubMed  Google Scholar 

  • Geraghty DE, Koller BH, Orr HT (1987) A human major histocompatibility complex class I gene that encodes a protein with a shortened cytoplasmic segment. Proc Natl Acad Sci U S A 84:9145–9149

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Geraghty DE, Stockschleader M, Ishitani A, Hansen JA (1992) Polymorphism at the HLA-E locus predates most HLA-A and -B polymorphism. Hum Immunol 33:174–184

    Article  CAS  PubMed  Google Scholar 

  • Geraghty DE, Wei XH, Orr HT, Koller BH (1990) Human leukocyte antigen F (HLA-F). An expressed HLA gene composed of a class I coding sequence linked to a novel transcribed repetitive element. J Exp Med 171:1–18

    Article  CAS  PubMed  Google Scholar 

  • Gobin SJ, van den Elsen PJ (2000) Transcriptional regulation of the MHC class Ib genes HLA-E, HLA-F, and HLA-G. Hum Immunol 61:1102–1107

    Article  CAS  PubMed  Google Scholar 

  • Goldman-Wohl DS, Ariel I, Greenfield C, Hochner-Celnikier D, Cross J, Fisher S, Yagel S (2000) Lack of human leukocyte antigen-G expression in extravillous trophoblasts is associated with pre-eclampsia. Mol Hum Reprod 6:88–95

    Article  CAS  PubMed  Google Scholar 

  • Gonzalez A, Rebmann V, LeMaoult J, Horn PA, Carosella ED, Alegre E (2012) The immunosuppressive molecule HLA-G and its clinical implications. Crit Rev Clin Lab Sci 49:63–84

    Article  CAS  PubMed  Google Scholar 

  • Goodridge JP, Burian A, Lee N, Geraghty DE (2013) HLA-F and MHC class I open conformers are ligands for NK cell Ig-like receptors. J Immunol 191:3553–3562

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Grimsley C, Ober C (1997) Population genetic studies of HLA-E: evidence for selection. Hum Immunol 52:33–40

    Article  CAS  PubMed  Google Scholar 

  • Guma M, Busch LK, Salazar-Fontana LI, Bellosillo B, Morte C, Garcia P, Lopez-Botet M (2005) The CD94/NKG2C killer lectin-like receptor constitutes an alternative activation pathway for a subset of CD8+ T cells. Eur J Immunol 35:2071–2080

    Article  CAS  PubMed  Google Scholar 

  • Hackmon R, Pinnaduwage L, Zhang J, Lye SJ, Geraghty DE, Dunk CE (2017) Definitive class I human leukocyte antigen expression in gestational placentation: HLA-F, HLA-E, HLA-C, and HLA-G in extravillous trophoblast invasion on placentation, pregnancy, and parturition. Am J Reprod Immunol. doi:10.1111/aji.1215143

  • Hara N, Fujii T, Yamashita T, Kozuma S, Okai T, Taketani Y (1996) Altered expression of human leukocyte antigen G (HLA-G) on extravillous trophoblasts in preeclampsia: immunohistological demonstration with anti-HLA-G specific antibody “87G” and anti-cytokeratin antibody “CAM5.2”. Am J Reprod Immunol 36:349–358

    Article  CAS  PubMed  Google Scholar 

  • Havlicek J, Roberts SC (2009) MHC-correlated mate choice in humans: a review. Psychoneuroendocrinology 34:497–512

    Article  CAS  PubMed  Google Scholar 

  • Horuzsko A, Lenfant F, Munn DH, Mellor AL (2001) Maturation of antigen-presenting cells is compromised in HLA-G transgenic mice. Int Immunol 13:385–394

    Article  CAS  PubMed  Google Scholar 

  • Humphrey KE, Harrison GA, Cooper DW, Wilton AN, Brennecke SP, Trudinger BJ (1995) HLA-G deletion polymorphism and pre-eclampsia/eclampsia. Br J Obstet Gynaecol 102:707–710

    Article  CAS  PubMed  Google Scholar 

  • Hviid TV (2006) HLA-G in human reproduction: aspects of genetics, function and pregnancy complications. Hum Reprod Update 12:209–232

    Article  CAS  PubMed  Google Scholar 

  • Hviid TV, Hylenius S, Hoegh AM, Kruse C, Christiansen OB (2002) HLA-G polymorphisms in couples with recurrent spontaneous abortions. Tissue Antigens 60:122–132

    Article  CAS  PubMed  Google Scholar 

  • Hviid TV, Hylenius S, Lindhard A, Christiansen OB (2004a) Association between human leukocyte antigen-G genotype and success of in vitro fertilization and pregnancy outcome. Tissue Antigens 64:66–69

    Article  CAS  PubMed  Google Scholar 

  • Hviid TV, Hylenius S, Rorbye C, Nielsen LG (2003) HLA-G allelic variants are associated with differences in the HLA-G mRNA isoform profile and HLA-G mRNA levels. Immunogenetics 55:63–79

    CAS  PubMed  Google Scholar 

  • Hviid TV, Rizzo R, Christiansen OB, Melchiorri L, Lindhard A, Baricordi OR (2004b) HLA-G and IL-10 in serum in relation to HLA-G genotype and polymorphisms. Immunogenetics 56:135–141

    Article  CAS  PubMed  Google Scholar 

  • Hylenius S, Andersen AM, Melbye M, Hviid TV (2004) Association between HLA-G genotype and risk of pre-eclampsia: a case-control study using family triads. Mol Hum Reprod 10:237–246

    Article  CAS  PubMed  Google Scholar 

  • Ishitani A, Sageshima N, Hatake K (2006) The involvement of HLA-E and -F in pregnancy. J Reprod Immunol 69:101–113

    Article  CAS  PubMed  Google Scholar 

  • Ishitani A, Sageshima N, Lee N, Dorofeeva N, Hatake K, Marquardt H, Geraghty DE (2003) Protein expression and peptide binding suggest unique and interacting functional roles for HLA-E, F, and G in maternal-placental immune recognition. J Immunol 171:1376–1384

    Article  CAS  PubMed  Google Scholar 

  • Iversen AC, Nguyen OT, Tommerdal LF, Eide IP, Landsem VM, Acar N, Myhre R, Klungland H, Austgulen R (2008) The HLA-G 14bp gene polymorphism and decidual HLA-G 14bp gene expression in pre-eclamptic and normal pregnancies. J Reprod Immunol 78:158–165

    Article  CAS  PubMed  Google Scholar 

  • Jassem RM, Shani WS, Loisel DA, Sharief M, Billstrand C, Ober C (2012) HLA-G polymorphisms and soluble HLA-G protein levels in women with recurrent pregnancy loss from Basrah province in Iraq. Hum Immunol 73:811–817

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Juch H, Blaschitz A, Daxbock C, Rueckert C, Kofler K, Dohr G (2005) A novel sandwich ELISA for alpha1 domain based detection of soluble HLA-G heavy chains. J Immunol Methods 307:96–106

    Article  CAS  PubMed  Google Scholar 

  • Jurisicova A, Casper RF, MacLusky NJ, Mills GB, Librach CL (1996) HLA-G expression during preimplantation human embryo development. Proc Natl Acad Sci U S A 93:161–165

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kanai T, Fujii T, Keicho N, Tokunaga K, Yamashita T, Hyodo H, Miki A, Unno N, Kozuma S, Taketani Y (2001) Polymorphism of human leukocyte antigen-E gene in the Japanese population with or without recurrent abortion. Am J Reprod Immunol 45:168–173

    Article  CAS  PubMed  Google Scholar 

  • Kapasi K, Albert SE, Yie S, Zavazava N, Librach CL (2000) HLA-G has a concentration-dependent effect on the generation of an allo-CTL response. Immunology 101:191–200

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Klitkou L, Dahl M, Hviid TV, Djurisic S, Piosik ZM, Skovbo P, Moller AM, Steffensen R, Christiansen OB (2015) Human leukocyte antigen (HLA)-G during pregnancy part I: correlations between maternal soluble HLA-G at midterm, at term, and umbilical cord blood soluble HLA-G at term. Hum Immunol 76:254–259

    Article  CAS  PubMed  Google Scholar 

  • Kofod L, Lindhard A, Bzorek M, Eriksen JO, Larsen LG, Hviid TV (2017) Endometrial immune markers are potential predictors of normal fertility and pregnancy after in vitro fertilization. Am J Reprod Immunol. doi:10.1111/aji.12684

  • Koller BH, Geraghty DE, Shimizu Y, DeMars R, Orr HT (1988) HLA-E. A novel HLA class I gene expressed in resting T lymphocytes. J Immunol 141:897–904

    CAS  PubMed  Google Scholar 

  • Kovats S, Main EK, Librach C, Stubblebine M, Fisher SJ, DeMars R (1990) A class I antigen, HLA-G, expressed in human trophoblasts. Science 248:220–223

    Article  CAS  PubMed  Google Scholar 

  • Laresgoiti-Servitje E, Gomez-Lopez N, Olson DM (2010) An immunological insight into the origins of pre-eclampsia. Hum Reprod Update 16:510–524

    Article  CAS  PubMed  Google Scholar 

  • Larsen MH, Bzorek M, Pass MB, Larsen LG, Nielsen MW, Svendsen SG, Lindhard A, Hviid TV (2011) Human leukocyte antigen-G in the male reproductive system and in seminal plasma. Mol Hum Reprod 17:727–738

    Article  CAS  PubMed  Google Scholar 

  • Larsen MH, Hviid TV (2009) Human leukocyte antigen-G polymorphism in relation to expression, function, and disease. Hum Immunol 70:1026–1034

    Article  CAS  PubMed  Google Scholar 

  • Larsen MH, Hylenius S, Andersen AM, Hviid TV (2010) The 3′-untranslated region of the HLA-G gene in relation to pre-eclampsia: revisited. Tissue Antigens 75:253–261

    Article  CAS  PubMed  Google Scholar 

  • Lashley LE, van der Westerlaken LA, Haasnoot GW, Drabbels JJ, Spruyt-Gerritse MJ, Scherjon SA, Claas FH (2014) Maternal HLA-C2 and 14 bp insertion in HLA-G is associated with recurrent implantation failure after in vitro fertilization treatment. Tissue Antigens 84:536–544

    Article  CAS  PubMed  Google Scholar 

  • Lauterbach N, Wieten L, Popeijus HE, Vanderlocht J, van Zon PM, Voorter CE, Tilanus MG (2015) Peptide-induced HLA-E expression in human PBMCs is dependent on peptide sequence and the HLA-E genotype. Tissue Antigens 85:242–251

    Article  CAS  PubMed  Google Scholar 

  • Le Bouteiller P, Fons P, Herault JP, Bono F, Chabot S, Cartwright JE, Bensussan A (2007) Soluble HLA-G and control of angiogenesis. J Reprod Immunol 76:17–22

    Article  CAS  PubMed  Google Scholar 

  • Le Discorde M, Moreau P, Sabatier P, Legeais JM, Carosella ED (2003) Expression of HLA-G in human cornea, an immune-privileged tissue. Hum Immunol 64:1039–1044

    Article  CAS  PubMed  Google Scholar 

  • Le Gal FA, Riteau B, Sedlik C, Khalil-Daher I, Menier C, Dausset J, Guillet JG, Carosella ED, Rouas-Freiss N (1999) HLA-G-mediated inhibition of antigen-specific cytotoxic T lymphocytes. Int Immunol 11:1351–1356

    Article  CAS  PubMed  Google Scholar 

  • Lee N, Llano M, Carretero M, Ishitani A, Navarro F, Lopez-Botet M, Geraghty DE (1998) HLA-E is a major ligand for the natural killer inhibitory receptor CD94/NKG2A. Proc Natl Acad Sci U S A 95:5199–5204

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • LeMaoult J, Krawice-Radanne I, Dausset J, Carosella ED (2004) HLA-G1-expressing antigen-presenting cells induce immunosuppressive CD4+ T cells. Proc Natl Acad Sci U S A 101:7064–7069

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • LeMaoult J, Zafaranloo K, Le Danff C, Carosella ED (2005) HLA-G up-regulates ILT2, ILT3, ILT4, and KIR2DL4 in antigen presenting cells, NK cells, and T cells. FASEB J 19:662–664

    CAS  PubMed  Google Scholar 

  • Li J, Goldstein I, Glickman-Nir E, Jiang H, Chess L (2001) Induction of TCR Vbeta-specific CD8+ CTLs by TCR Vbeta-derived peptides bound to HLA-E. J Immunol 167:3800–3808

    Article  CAS  PubMed  Google Scholar 

  • Lila N, Carpentier A, Amrein C, Khalil-Daher I, Dausset J, Carosella ED (2000) Implication of HLA-G molecule in heart-graft acceptance. Lancet 355:2138

    Article  CAS  PubMed  Google Scholar 

  • Loisel DA, Billstrand C, Murray K, Patterson K, Chaiworapongsa T, Romero R, Ober C (2013) The maternal HLA-G 1597DeltaC null mutation is associated with increased risk of pre-eclampsia and reduced HLA-G expression during pregnancy in African-American women. Mol Hum Reprod 19:144–152

    Article  CAS  PubMed  Google Scholar 

  • Lynge Nilsson L, Djurisic S, Hviid TV (2014) Controlling the immunological crosstalk during conception and pregnancy: HLA-G in reproduction. Front Immunol 5:198

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Maejima M, Fujii T, Kozuma S, Okai T, Shibata Y, Taketani Y (1997) Presence of HLA-G-expressing cells modulates the ability of peripheral blood mononuclear cells to release cytokines. Am J Reprod Immunol 38:79–82

    Article  CAS  PubMed  Google Scholar 

  • Marsh SG, Albert ED, Bodmer WF, Bontrop RE, Dupont B, Erlich HA, Fernandez-Vina M, Geraghty DE, Holdsworth R, Hurley CK, Lau M, Lee KW, Mach B, Maiers M, Mayr WR, Muller CR, Parham P, Petersdorf EW, Sasazuki T, Strominger JL, Svejgaard A, Terasaki PI, Tiercy JM, Trowsdale J (2010) Nomenclature for factors of the HLA system, 2010. Tissue Antigens 75:291–455

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • McIntire RH, Morales PJ, Petroff MG, Colonna M, Hunt JS (2004) Recombinant HLA-G5 and -G6 drive U937 myelomonocytic cell production of TGF-beta1. J Leukoc Biol 76:1220–1228

    Article  CAS  PubMed  Google Scholar 

  • Menier C, Rabreau M, Challier JC, Le Discorde M, Carosella ED, Rouas-Freiss N (2004) Erythroblasts secrete the nonclassical HLA-G molecule from primitive to definitive hematopoiesis. Blood 104:3153–3160

    Article  CAS  PubMed  Google Scholar 

  • Meuleman T, Lashley LE, Dekkers OM, van Lith JM, Claas FH, Bloemenkamp KW (2015) HLA associations and HLA sharing in recurrent miscarriage: a systematic review and meta-analysis. Hum Immunol 76:362–373

    Article  CAS  PubMed  Google Scholar 

  • Morales PJ, Pace JL, Platt JS, Langat DK, Hunt JS (2007) Synthesis of beta(2)-microglobulin-free, disulphide-linked HLA-G5 homodimers in human placental villous cytotrophoblast cells. Immunology 122:179–188

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Morandi F, Rizzo R, Fainardi E, Rouas-Freiss N, Pistoia V (2016) Recent advances in our understanding of HLA-G biology: lessons from a wide spectrum of human diseases. J Immunol Res 2016:4326495

    PubMed  PubMed Central  Google Scholar 

  • Moreau P, Adrian-Cabestre F, Menier C, Guiard V, Gourand L, Dausset J, Carosella ED, Paul P (1999) IL-10 selectively induces HLA-G expression in human trophoblasts and monocytes. Int Immunol 11:803–811

    Article  CAS  PubMed  Google Scholar 

  • Moreau P, Contu L, Alba F, Lai S, Simoes R, Orru S, Carcassi C, Roger M, Rabreau M, Carosella ED (2008) HLA-G gene polymorphism in human placentas: possible association of G*0106 allele with preeclampsia and miscarriage. Biol Reprod 79:459–467

    Article  CAS  PubMed  Google Scholar 

  • Moreau P, Faure O, Lefebvre S, Ibrahim EC, O’Brien M, Gourand L, Dausset J, Carosella ED, Paul P (2001) Glucocorticoid hormones upregulate levels of HLA-G transcripts in trophoblasts. Transplant Proc 33:2277–2280

    Article  CAS  PubMed  Google Scholar 

  • Moscoso J, Serrano-Vela JI, Arnaiz-Villena A (2007) MHC-F polymorphism and evolution. Tissue Antigens 69(Suppl 1):136–139

    Article  CAS  PubMed  Google Scholar 

  • Munoz-Suano A, Hamilton AB, Betz AG (2011) Gimme shelter: the immune system during pregnancy. Immunol Rev 241:20–38

    Article  CAS  PubMed  Google Scholar 

  • Nardi Fda S, Konig L, Wagner B, Giebel B, Santos Manvailer LF, Rebmann V (2016) Soluble monomers, dimers and HLA-G-expressing extracellular vesicles: the three dimensions of structural complexity to use HLA-G as a clinical biomarker. HLA 88:77–86

    Article  PubMed  CAS  Google Scholar 

  • Navarro F, Llano M, Bellon T, Colonna M, Geraghty DE, Lopez-Botet M (1999) The ILT2(LIR1) and CD94/NKG2A NK cell receptors respectively recognize HLA-G1 and HLA-E molecules co-expressed on target cells. Eur J Immunol 29:277–283

    Article  CAS  PubMed  Google Scholar 

  • Nilsson LL, Djurisic S, Andersen AM, Melbye M, Bjerre D, Ferrero-Miliani L, Hackmon R, Geraghty DE, Hviid TV (2016) Distribution of HLA-G extended haplotypes and one HLA-E polymorphism in a large-scale study of mother-child dyads with and without severe preeclampsia and eclampsia. HLA 88:172–186

    Article  CAS  PubMed  Google Scholar 

  • Niu Z, Wang L, Pang RT, Guo Y, Yeung WS, Yao Y (2017) A meta-analysis of the impact of human leukocyte antigen-G on the outcomes of IVF/ICSI. Reprod Biomed Online S1472–6483(17)30094–9. doi:10.1016/j.rbmo.2017.03.002

  • O’Brien M, McCarthy T, Jenkins D, Paul P, Dausset J, Carosella ED, Moreau P (2001) Altered HLA-G transcription in pre-eclampsia is associated with allele specific inheritance: possible role of the HLA-G gene in susceptibility to the disease. Cell Mol Life Sci 58:1943–1949

    Article  PubMed  Google Scholar 

  • Ober C, Aldrich CL, Chervoneva I, Billstrand C, Rahimov F, Gray HL, Hyslop T (2003) Variation in the HLA-G promoter region influences miscarriage rates. Am J Hum Genet 72:1425–1435

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Odegard RA, Vatten LJ, Nilsen ST, Salvesen KA, Austgulen R (2000) Preeclampsia and fetal growth. Obstet Gynecol 96:950–955

    CAS  PubMed  Google Scholar 

  • Pabalan N, Jarjanazi H, Sun C, Iversen AC (2015) Meta-analysis of the human leukocyte antigen-G (HLA-G) 14 bp insertion/deletion polymorphism as a risk factor for preeclampsia. Tissue Antigens 86:186–194

    Article  CAS  PubMed  Google Scholar 

  • Park GM, Lee S, Park B, Kim E, Shin J, Cho K, Ahn K (2004) Soluble HLA-G generated by proteolytic shedding inhibits NK-mediated cell lysis. Biochem Biophys Res Commun 313:606–611

    Article  CAS  PubMed  Google Scholar 

  • Penzes M, Rajczy K, Gyodi E, Reti M, Feher E, Petranyi G (1999) HLA-G gene polymorphism in the normal population and in recurrent spontaneous abortion in Hungary. Transplant Proc 31:1832–1833

    Article  CAS  PubMed  Google Scholar 

  • Pfeiffer KA, Fimmers R, Engels G, van der Ven H, van der Ven K (2001) The HLA-G genotype is potentially associated with idiopathic recurrent spontaneous abortion. Mol Hum Reprod 7:373–378

    Article  CAS  PubMed  Google Scholar 

  • Pfeiffer KA, Rebmann V, Passler M, van der Ven K, van der Ven H, Krebs D, Grosse-Wilde H (2000) Soluble HLA levels in early pregnancy after in vitro fertilization. Hum Immunol 61:559–564

    Article  CAS  PubMed  Google Scholar 

  • Ponte M, Cantoni C, Biassoni R, Tradori-Cappai A, Bentivoglio G, Vitale C, Bertone S, Moretta A, Moretta L, Mingari MC (1999) Inhibitory receptors sensing HLA-G1 molecules in pregnancy: decidua-associated natural killer cells express LIR-1 and CD94/NKG2A and acquire p49, an HLA-G1-specific receptor. Proc Natl Acad Sci U S A 96:5674–5679

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Quach K, Grover SA, Kenigsberg S, Librach CL (2014) A combination of single nucleotide polymorphisms in the 3′untranslated region of HLA-G is associated with preeclampsia. Hum Immunol 75:1163–70

  • Rajagopalan S, Long EO (1999) A human histocompatibility leukocyte antigen (HLA)-G-specific receptor expressed on all natural killer cells. J Exp Med 189:1093–1100

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rebmann V, Busemann A, Lindemann M, Grosse-Wilde H (2003) Detection of HLA-G5 secreting cells. Hum Immunol 64:1017–1024

    Article  CAS  PubMed  Google Scholar 

  • Rebmann V, Pfeiffer K, Passler M, Ferrone S, Maier S, Weiss E, Grosse-Wilde H (1999) Detection of soluble HLA-G molecules in plasma and amniotic fluid. Tissue Antigens 53:14–22

    Article  CAS  PubMed  Google Scholar 

  • Redman CW, McMichael AJ, Stirrat GM, Sunderland CA, Ting A (1984) Class 1 major histocompatibility complex antigens on human extra-villous trophoblast. Immunology 52:457–468

    CAS  PubMed  PubMed Central  Google Scholar 

  • Redman CW, Sacks GP, Sargent IL (1999) Preeclampsia: an excessive maternal inflammatory response to pregnancy. Am J Obstet Gynecol 180:499–506

    Article  CAS  PubMed  Google Scholar 

  • Redman CW, Sargent IL (2005) Latest advances in understanding preeclampsia. Science 308:1592–1594

    Article  CAS  PubMed  Google Scholar 

  • Rizzo R, Andersen AS, Lassen MR, Sorensen HC, Bergholt T, Larsen MH, Melchiorri L, Stignani M, Baricordi OR, Hviid TV (2009a) Soluble human leukocyte antigen-G isoforms in maternal plasma in early and late pregnancy. Am J Reprod Immunol 62:320–338

    Article  CAS  PubMed  Google Scholar 

  • Rizzo R, Dal Canto MB, Stignani M, Fadini R, Fumagalli D, Renzini MM, Borgatti M, Gambari R, Baricordi OR (2009b) Production of sHLA-G molecules by in vitro matured cumulus-oocyte complex. Int J Mol Med 24:523–530

    CAS  PubMed  Google Scholar 

  • Roberts JM (1998) Endothelial dysfunction in preeclampsia. Semin Reprod Endocrinol 16:5–15

    Article  CAS  PubMed  Google Scholar 

  • Robinson J, Halliwell JA, Hayhurst JD, Flicek P, Parham P, Marsh SG (2015) The IPD and IMGT/HLA database: allele variant databases. Nucleic Acids Res 43:D423–D431

    Article  CAS  PubMed  Google Scholar 

  • Rouas-Freiss N, Goncalves RM, Menier C, Dausset J, Carosella ED (1997) Direct evidence to support the role of HLA-G in protecting the fetus from maternal uterine natural killer cytolysis. Proc Natl Acad Sci U S A 94:11520–11525

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rousseau P, Le Discorde M, Mouillot G, Marcou C, Carosella ED, Moreau P (2003) The 14 bp deletion-insertion polymorphism in the 3′ UT region of the HLA-G gene influences HLA-G mRNA stability. Hum Immunol 64:1005–1010

    Article  CAS  PubMed  Google Scholar 

  • Roussev RG, Coulam CB (2007) HLA-G and its role in implantation (review). J Assist Reprod Genet 24:288–295

    Article  PubMed  PubMed Central  Google Scholar 

  • Saito S, Shiozaki A, Nakashima A, Sakai M, Sasaki Y (2007) The role of the immune system in preeclampsia. Mol Asp Med 28:192–209

    Article  CAS  Google Scholar 

  • Sargent IL, Borzychowski AM, Redman CW (2006) Immunoregulation in normal pregnancy and pre-eclampsia: an overview. Reprod BioMed Online 13:680–686

    Article  CAS  PubMed  Google Scholar 

  • Shaikly VR, Morrison IE, Taranissi M, Noble CV, Withey AD, Cherry RJ, Blois SM, Fernandez N (2008) Analysis of HLA-G in maternal plasma, follicular fluid, and preimplantation embryos reveal an asymmetric pattern of expression. J Immunol 180:4330–4337

    Article  CAS  PubMed  Google Scholar 

  • Shiroishi M, Kuroki K, Ose T, Rasubala L, Shiratori I, Arase H, Tsumoto K, Kumagai I, Kohda D, Maenaka K (2006) Efficient leukocyte Ig-like receptor signaling and crystal structure of disulfide-linked HLA-G dimer. J Biol Chem 281:10439–10447

    Article  CAS  PubMed  Google Scholar 

  • Shobu T, Sageshima N, Tokui H, Omura M, Saito K, Nagatsuka Y, Nakanishi M, Hayashi Y, Hatake K, Ishitani A (2006) The surface expression of HLA-F on decidual trophoblasts increases from mid to term gestation. J Reprod Immunol 72:18–32

    Article  CAS  PubMed  Google Scholar 

  • Sipak-Szmigiel O, Cybulski C, Wokolorczyk D, Lubinski J, Kurzawa R, Baczkowski T, Radwan M, Radwan P, Ronin-Walknowska E (2009) HLA-G polymorphism and in vitro fertilization failure in a Polish population. Tissue Antigens 73:348–352

    Article  CAS  PubMed  Google Scholar 

  • Sipak-Szmigiel O, Ronin-Walknowska E, Cybulski C, Plonka T, Lubinski J (2007) Antigens HLA-G, sHLA-G and sHLA-class I in reproductive failure. Folia Histochem Cytobiol 45(Suppl 1):S137–S141

    PubMed  Google Scholar 

  • Steffensen R, Christiansen OB, Bennett EP, Jersild C (1998) HLA-E polymorphism in patients with recurrent spontaneous abortion. Tissue Antigens 52:569–572

    Article  CAS  PubMed  Google Scholar 

  • Strong RK, Holmes MA, Li P, Braun L, Lee N, Geraghty DE (2003) HLA-E allelic variants. Correlating differential expression, peptide affinities, crystal structures, and thermal stabilities. J Biol Chem 278:5082–5090

    Article  CAS  PubMed  Google Scholar 

  • Sullivan LC, Clements CS, Rossjohn J, Brooks AG (2008) The major histocompatibility complex class Ib molecule HLA-E at the interface between innate and adaptive immunity. Tissue Antigens 72:415–424

    Article  CAS  PubMed  Google Scholar 

  • Tan CY, Ho JF, Chong YS, Loganath A, Chan YH, Ravichandran J, Lee CG, Chong SS (2008) Paternal contribution of HLA-G*0106 significantly increases risk for pre-eclampsia in multigravid pregnancies. Mol Hum Reprod 14:317–324

    Article  CAS  PubMed  Google Scholar 

  • Tan Z, Shon AM, Ober C (2005) Evidence of balancing selection at the HLA-G promoter region. Hum Mol Genet 14:3619–3628

    Article  CAS  PubMed  Google Scholar 

  • Tang Y, Liu H, Li H, Peng T, Gu W, Li X (2015) Hypermethylation of the HLA-G promoter is associated with preeclampsia. Mol Hum Reprod 21:736–744

    Article  PubMed  Google Scholar 

  • Thibodeau V, Lajoie J, Labbe AC, Zannou MD, Fowke KR, Alary M, Poudrier J, Roger M (2011) High level of soluble HLA-G in the female genital tract of Beninese commercial sex workers is associated with HIV-1 infection. PLoS One 6:e25185

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tripathi P, Naik S, Agrawal S (2006) HLA-E and immunobiology of pregnancy. Tissue Antigens 67:207–213

    Article  CAS  PubMed  Google Scholar 

  • van der Meer A, Lukassen HG, van Lierop MJ, Wijnands F, Mosselman S, Braat DD, Joosten I (2004) Membrane-bound HLA-G activates proliferation and interferon-gamma production by uterine natural killer cells. Mol Hum Reprod 10:189–195

    Article  PubMed  CAS  Google Scholar 

  • Verloes A, Spits C, Vercammen M, Geens M, LeMaoult J, Sermon K, Coucke W, Van de Velde H (2017) The role of methylation, DNA polymorphisms and microRNAs on HLA-G expression in human embryonic stem cells. Stem Cell Res 19:118–127

    Article  CAS  PubMed  Google Scholar 

  • Wainwright SD, Biro PA, Holmes CH (2000) HLA-F is a predominantly empty, intracellular, TAP-associated MHC class Ib protein with a restricted expression pattern. J Immunol 164:319–328

    Article  CAS  PubMed  Google Scholar 

  • Wang X, Jiang W, Zhang D (2013) Association of 14-bp insertion/deletion polymorphism of HLA-G gene with unexplained recurrent spontaneous abortion: a meta-analysis. Tissue Antigens 81:108–115

    Article  CAS  PubMed  Google Scholar 

  • Wedekind C, Seebeck T, Bettens F, Paepke AJ (1995) MHC-dependent mate preferences in humans. Proc Biol Sci 260:245–249

    Article  CAS  PubMed  Google Scholar 

  • Wei XH, Orr HT (1990) Differential expression of HLA-E, HLA-F, and HLA-G transcripts in human tissue. Hum Immunol 29:131–142

    Article  CAS  PubMed  Google Scholar 

  • Wiendl H, Behrens L, Maier S, Johnson MA, Weiss EH, Hohlfeld R (2000) Muscle fibers in inflammatory myopathies and cultured myoblasts express the nonclassical major histocompatibility antigen HLA-G. Ann Neurol 48:679–684

    Article  CAS  PubMed  Google Scholar 

  • Yamashita T, Fujii T, Tokunaga K, Tadokoro K, Hamai Y, Miki A, Kozuma S, Juji T, Taketani Y (1999) Analysis of human leukocyte antigen-G polymorphism including intron 4 in Japanese couples with habitual abortion. Am J Reprod Immunol 41:159–163

    Article  CAS  PubMed  Google Scholar 

  • Yan WH, Fan LA, Yang JQ, Xu LD, Ge Y, Yao FJ (2006) HLA-G polymorphism in a Chinese Han population with recurrent spontaneous abortion. Int J Immunogenet 33:55–58

  • Yie SM, Li LH, Li YM, Librach C (2004) HLA-G protein concentrations in maternal serum and placental tissue are decreased in preeclampsia. Am J Obstet Gynecol 191:525–529

    Article  CAS  PubMed  Google Scholar 

  • Yie SM, Li LH, Xiao R, Librach CL (2008) A single base-pair mutation in the 3′-untranslated region of HLA-G mRNA is associated with pre-eclampsia. Mol Hum Reprod 14:649–653

    Article  CAS  PubMed  Google Scholar 

  • Zhang Z, Li Y, Zhang LL, Jia LT, Yang XQ (2012) Association of 14 bp insertion/deletion polymorphism of the HLA-G gene in father with severe preeclampsia in Chinese. Tissue Antigens 80:158–164

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

Support for this work was generously provided by The Region Zealand Health Sciences Research Foundation.

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Authors and Affiliations

  1. Department of Clinical Biochemistry, Centre for Immune Regulation and Reproductive Immunology (CIRRI), Zealand University Hospital, 10 Sygehusvej, 4000, Roskilde, Denmark

    Gry Persson, Wenna Nascimento Melsted, Line Lynge Nilsson & Thomas Vauvert F. Hviid

  2. Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark

    Gry Persson, Wenna Nascimento Melsted, Line Lynge Nilsson & Thomas Vauvert F. Hviid

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  1. Gry Persson
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This article is published in the Special Issue MHC Genes and Their Ligands in Health and Disease with Editor Prof. Ronald Bontrop.

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Persson, G., Melsted, W.N., Nilsson, L.L. et al. HLA class Ib in pregnancy and pregnancy-related disorders. Immunogenetics 69, 581–595 (2017). https://doi.org/10.1007/s00251-017-0988-4

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