, Volume 56, Issue 3, pp 135–141 | Cite as

HLA-G and IL-10 in serum in relation to HLA-G genotype and polymorphisms

  • Thomas Vauvert F. HviidEmail author
  • Roberta Rizzo
  • Ole B. Christiansen
  • Loredana Melchiorri
  • Anette Lindhard
  • Olavio R. Baricordi
Original Paper


The expression and importance of the non-classical human leukocyte antigen (HLA) class Ib gene, HLA-G, at the feto-maternal interface have been recognized. The HLA-G molecule is almost monomorphic and expressed in both membrane-bound and soluble isoforms. It has been shown to inhibit NK-mediated cell lysis and influence cytokine expression. Recently, a possible boarder immunoregulatory function of HLA-G also in adult life has been recognized. HLA-G gene polymorphism has been linked to differences in gene expression profile of alternatively spliced HLA-G transcripts and levels of specific HLA-G mRNA isoforms. On this background it is of general interest to further elucidate any associations between HLA-G polymorphism and protein expression. We have HLA-G genotyped 85 individuals attending IVF treatment, and further studied sHLA-G1/HLA-G5 and interleukin-10 (IL-10) in serum samples. In 21% of the serum samples sHLA-G1/HLA-G5 could be detected. There was no correlation between sHLA-G1/HLA-G5 and IL-10 concentrations in serum. Soluble HLA-G1/HLA-G5 was not detected in any samples homozygous for a 14-bp insertion polymorphism in exon 8 of the 3′-untranslated region (3′UTR) of the HLA-G gene (P=0.03; Fisher’s exact test). Polymorphisms in the 5′-upstream regulatory region (5′URR) of the HLA-G gene were also studied. In conclusion, this study indicates that polymorphisms in the 3′UTR and the 5′URR of the HLA-G gene may influence the expression of sHLA-G of possible importance in pathological pregnancies and also in organ transplantation.


Soluble HLA-G MHC Polymorphism IL-10 Immunoregulation 



This study was supported by The Pharmacy Foundation of 1991, The Copenhagen Hospital Corporation, The A.P. Møller Foundation for the Advancement of Medical Science, The Plasmid Foundation and The Danish Medical Association Research Fund.


  1. 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 33:125–134CrossRefPubMedGoogle Scholar
  2. Creput C, Durrbach A, Menier C, Guettier C, Samuel D, Dausset J, Charpentier B, Carosella ED, Rouas-Freiss N (2003) Human leukocyte antigen-G (HLA-G) expression in biliary epithelial cells is associated with allograft acceptance in liver-kidney transplantation. J Hepatol 39:587–594CrossRefPubMedGoogle Scholar
  3. Emmer PM, Steegers EA, Kerstens HM, Bulten J, Nelen WL, Boer K, Joosten I (2002) Altered phenotype of HLA-G expressing trophoblast and decidual natural killer cells in pathological pregnancies. Hum Reprod 17:1072–1080Google Scholar
  4. Fainardi E, Rizzo R, Melchiorri L, Vaghi L, Castellazzi M, Marzola A, Govoni V, Paolino E, Tola MR, Granieri E, Baricordi OR (2003) Presence of detectable levels of soluble HLA-G molecules in CSF of relapsing-remitting multiple sclerosis: relationship with CSF soluble HLA-I and IL-10 concentrations and MRI findings. J Neuroimmunol 142:149–158CrossRefPubMedGoogle Scholar
  5. Fournel S, Aguerre-Girr M, Huc X, Lenfant F, Alam A, Toubert A, Bensussan A, Le Bouteiller P (2000) Cutting edge: soluble HLA-G1 triggers CD95/CD95 ligand-mediated apoptosis in activated CD8+ cells by interacting with CD8. J Immunol 164:6100–6104PubMedGoogle Scholar
  6. Fujii T, Ishitani A, Geraghty DE (1994) A soluble form of the HLA-G antigen is encoded by a messenger ribonucleic acid containing intron 4. J Immunol 153:5516–5524PubMedGoogle Scholar
  7. 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 32:311–315CrossRefPubMedGoogle Scholar
  8. 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 6:88–95CrossRefPubMedGoogle Scholar
  9. 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 36:349–358PubMedGoogle Scholar
  10. Hunt JS, Jadhav L, Chu W, Geraghty DE, Ober C (2000) Soluble HLA-G circulates in maternal blood during pregnancy. Am J Obstet Gynecol 183:682–688Google Scholar
  11. Hviid TV, Møller C, Sørensen S, Morling N (1998) Co-dominant expression of the HLA-G gene and various forms of alternatively spliced HLA-G mRNA in human first trimester trophoblast. Hum Immunol 59:87–98CrossRefPubMedGoogle Scholar
  12. Hviid TV, Sorensen S, Morling N (1999) Polymorphism in the regulatory region located more than 1.1 kilobases 5′ to the start site of transcription, the promoter region, and exon 1 of the HLA-G gene. Hum Immunol 60:1237–1244CrossRefPubMedGoogle Scholar
  13. Hviid TV, Hylenius S, Hoegh AM, Kruse C, Christiansen OB (2002) HLA-G polymorphisms in couples with recurrent spontaneous abortions. Tissue Antigens 60:122–132CrossRefPubMedGoogle Scholar
  14. 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 55:63–79PubMedGoogle Scholar
  15. Jurisicova A, Casper RF, MacLusky NJ, Mills GB, Librach CL (1996) HLA-G expression during preimplantation human embryo development. Proc Natl Acad Sci USA 93:161–165CrossRefPubMedGoogle Scholar
  16. Kanai T, Fujii T, Kozuma S, Yamashita T, Miki A, Kikuchi A, Taketani Y (2001) Soluble HLA-G influences the release of cytokines from allogeneic peripheral blood mononuclear cells in culture. Mol Hum Reprod 7:195–200PubMedGoogle Scholar
  17. 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 101:191–200CrossRefPubMedGoogle Scholar
  18. Kirszenbaum M, Moreau P, Gluckman E, Dausset J, Carosella E (1994) An alternatively spliced form of HLA-G mRNA in human trophoblasts and evidence for the presence of HLA-G transcript in adult lymphocytes. Proc Natl Acad Sci USA 91:4209–4213PubMedGoogle Scholar
  19. Kovats S, Main EK, Librach C, Stubblebine M, Fisher SJ, DeMars R (1990) A class I antigen, HLA-G, expressed in human trophoblasts. Science 248:220–223PubMedGoogle Scholar
  20. Le Bouteiller P, Blaschitz A (1999) The functionality of HLA-G is emerging. Immunol Rev 167:233–244PubMedGoogle Scholar
  21. LeMaoult J, Le Discorde M, Rouas-Freiss N, Moreau P, Menier C, McCluskey J, Carosella ED (2003) Biology and functions of human leukocyte antigen-G in health and sickness. Tissue Antigens 62:273–284CrossRefPubMedGoogle Scholar
  22. Lila N, Rouas-Freiss N, Dausset J, Carpentier A, Carosella ED (2001) Soluble HLA-G protein secreted by allo-specific CD4+ T cells suppresses the allo-proliferative response: a CD4+ T cell regulatory mechanism. Proc Natl Acad Sci USA 98:12150–12155PubMedGoogle Scholar
  23. Lila N, Amrein C, Guillemain R, Chevalier P, Latremouille C, Fabiani JN, Dausset J, Carosella ED, Carpentier A (2002) Human leukocyte antigen-G expression after heart transplantation is associated with a reduced incidence of rejection. Circulation 105:1949–1954CrossRefPubMedGoogle Scholar
  24. Lim KH, Zhou Y, Janatpour M, McMaster M, Bass K, Chun SH, Fisher SJ (1997) Human cytotrophoblast differentiation/invasion is abnormal in pre-eclampsia. Am J Pathol 151:1809–1818PubMedGoogle Scholar
  25. Menier C, Saez B, Horejsi V, Martinozzi S, Krawice-Radanne I, Bruel S, Le Danff C, Reboul M, Hilgert I, Rabreau M, Larrad ML, Pla M, Carosella ED, Rouas-Freiss N (2003) Characterization of monoclonal antibodies recognizing HLA-G or HLA-E: new tools to analyze the expression of nonclassical HLA class I molecules. Hum Immunol 64:315–326CrossRefPubMedGoogle Scholar
  26. Miller SA, Dykes DD, Polesky HF (1988) A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res 16:1215PubMedGoogle Scholar
  27. 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 11:803–811PubMedGoogle Scholar
  28. 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 58:1943–1949PubMedGoogle Scholar
  29. 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 72:1425–1435CrossRefPubMedGoogle Scholar
  30. Pfeiffer KA, Rebmann V, van der Ven K (2000) Soluble histocompatibility antigen levels in early pregnancy after IVF. Hum Immunol 61:559–564CrossRefPubMedGoogle Scholar
  31. Pfeiffer KA, Fimmers R, Engels G, van der Ven, van der Ven (2001) The HLA-G genotype is potentially associated with idiopathic recurrent spontaneous abortion. Mol Hum Reprod 7:373–378Google Scholar
  32. 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 USA 96:5674–5679CrossRefPubMedGoogle Scholar
  33. 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 53:14–22CrossRefPubMedGoogle Scholar
  34. Rebmann V, van der Ven K, Passler M, Pfeiffer K, Krebs D, Grosse-Wilde H (2001) Association of soluble HLA-G plasma levels with HLA-G alleles. Tissue Antigens 57:15–21CrossRefPubMedGoogle Scholar
  35. Rebmann V, Busemann A, Lindemann M, Grosse-Wilde H (2003) Detection of HLA-G5 secreting cells. Hum Immunol 64:1017–1024CrossRefPubMedGoogle Scholar
  36. Rieger L, Hofmeister V, Probe C, Dietl J, Weiss EH, Steck T, Kammerer U (2002) Th1- and Th2-like cytokine production by first trimester decidual large granular lymphocytes is influenced by HLA-G and HLA-E. Mol. Hum Reprod 8:255–261CrossRefGoogle Scholar
  37. 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 USA 94:11520–11525CrossRefPubMedGoogle Scholar
  38. 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 64:1005–1010CrossRefPubMedGoogle Scholar
  39. Solier C, Aguerre-Girr M, Lenfant F, Campan A, Berrebi A, Rebmann V, Grosse-Wilde H, Le Bouteiller P (2002) Secretion of pro-apoptotic intron 4-retaining soluble HLA-G1 by human villous trophoblast. Eur J Immunol 32:3576–3586CrossRefPubMedGoogle Scholar
  40. Steinborn A, Rebmann V, Scharf A, Sohn C, Grosse-Wilde H (2003) Placental abruption is associated with decreased maternal plasma levels of soluble HLA-G. J Clin Immunol 23:307–314CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2004

Authors and Affiliations

  • Thomas Vauvert F. Hviid
    • 1
    Email author
  • Roberta Rizzo
    • 2
  • Ole B. Christiansen
    • 3
  • Loredana Melchiorri
    • 2
  • Anette Lindhard
    • 3
  • Olavio R. Baricordi
    • 2
    • 4
  1. 1.Department of Clinical BiochemistryCopenhagen University Hospital, RigshospitaletCopenhagen ØDenmark
  2. 2.Department of Experimental and Diagnostic Medicine, Section of Medical GeneticsUniversity of FerraraFerraraItaly
  3. 3.Fertility Clinic 4071The Juliane Marie Centre, RigshospitaletCopenhagen ØDenmark
  4. 4.Department of Experimental and Diagnostic Medicine, Biotechnology CenterUniversity of FerraraFerraraItaly

Personalised recommendations