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HLA-G histocompatibility antigen, class I, G, also known as human leukocyte antigen G (HLA-G), is a protein that in humans is encoded by the HLA-G gene.[1]

HLA-G belongs to the HLA nonclassical class I heavy chain paralogues. This class I molecule is a heterodimer consisting of a heavy chain and a light chain (beta-2 microglobulin). The heavy chain is anchored in the membrane. HLA-G is expressed on fetal derived placental cells. The heavy chain is approximately 45 kDa and its gene contains 8 exons. Exon one encodes the leader peptide, exons 2 and 3 encode the alpha1 and alpha2 domain, which both bind the peptide, exon 4 encodes the alpha3 domain, exon 5 encodes the transmembrane region, and exon 6 encodes the cytoplasmic tail.[1] Exon 7 and 8 are not translated due to a stop codon present in exon 6.[2]


HLA-G may play a role in immune tolerance in pregnancy, being expressed in the placenta by extravillous trophoblast cells (EVT), while the classical MHC class I genes (HLA-A and HLA-B) are not.[3] As HLA-G was first identified in placenta samples, many studies have evaluated its role in pregnancy disorders, such as preeclampsia and recurrent pregnancy loss.[4] its downregulation is related to HLA-A and -B downregulation results in protection from cytotoxic T cell responses, but would in theory result in a missing self response by natural killer cells. HLA-G is a ligand for NK cell inhibitory receptor KIR2DL4, and therefore expression of this HLA by the trophoblast defends it against NK cell-mediated death.[5]

However, a large family with several members bearing only "null" HLA-G alleles has been found. None of these homozygous subjects have pregnancy or birth difficulties; nor do they present immunodeficiencies, autoimmune diseases, or tumors.[6][7] It is striking that this "null" allele (HLA-G*01:05N), while it is quite frequent in some populations, like in Iranians, it is almost absent in some Amerindian populations.[8] Also, some higher primates do not show all MHC-G isoforms.[9] In addition, Cercopithecinae middle-sized Old World monkeys do not bear full MHC-G molecules since all of these monkeys present stop codons at MHC-G DNA.[10] All of these anomalies must be studied.

The presence of soluble HLA-G (sHLA-G) in embryos is associated with better pregnancy rates. In order to optimize pregnancy rates, there is significant evidence that a morphological scoring system is the best strategy for the selection of embryos.[11] However, presence of soluble HLA-G might be considered as a second parameter if a choice has to be made between embryos of morphologically equal quality.[11]


HLA-G has been shown to interact with CD8A.[12][13]


  1. 1.0 1.1 "Entrez Gene: HLA-G HLA-G histocompatibility antigen, class I, G".
  2. Castelli, Erick C.; Mendes-Junior, Celso T.; Veiga-Castelli, Luciana C.; Roger, Michel; Moreau, Philippe; Donadi, Eduardo A. (2011-11-01). "A Comprehensive Study of Polymorphic Sites along the HLA-G Gene: Implication for Gene Regulation and Evolution". Molecular Biology and Evolution. 28 (11): 3069–3086. doi:10.1093/molbev/msr138. ISSN 0737-4038. PMID 21622995.
  3. Jay Iams; Creasy, Robert K.; Resnik, Robert; Robert Reznik (2004). Maternal-fetal medicine. Philadelphia: W.B. Saunders Co. pp. 31–32. ISBN 0-7216-0004-2.
  4. Michita, Rafael Tomoya; Zambra, Francis Maria Báo; Fraga, Lucas Rosa; Sanseverino, Maria Teresa Vieira; Callegari-Jacques, Sidia Maria; Vianna, Priscila; Chies, José Artur Bogo. "A tug-of-war between tolerance and rejection – New evidence for 3′UTR HLA-G haplotypes influence in recurrent pregnancy loss". Human Immunology. 77 (10): 892–897. doi:10.1016/j.humimm.2016.07.004.
  5. Lash, G, Robson, S, Bulmer, J. (2010). "Review: Functional role of uterine natural killer (uNK) cells in human early pregnancy decidua". Placenta. 31 (S): 87–92. doi:10.1016/j.placenta.2009.12.022. PMID 20061017.
  6. Suárez MB, Morales P, Castro MJ, Fernández V, Varela P, Alvarez M, Martínez-Laso J, Arnaiz-Villena A (1997). "A new HLA-G allele (HLA-G*0105N) and its distribution in the Spanish population". Immunogenetics. 45 (6): 464–5. doi:10.1007/s002510050235. PMID 9089111.
  7. Casro MJ, Morales P, Rojo-Amigo R, Martinez-Laso J, Allende L, Varela P, Garcia-Berciano M, Guillen-Perales J, Arnaiz-Villena A (September 2000). "Homozygous HLA-G*0105N healthy individuals indicate that membrane-anchored HLA-G1 molecule is not necessary for survival". Tissue Antigens. 56 (3): 232–9. doi:10.1034/j.1399-0039.2000.560305.x. PMID 11034559.
  8. Arnaiz-Villena A, Enriquez-de-Salamanca M, Areces C, Alonso-Rubio J, Abd-El-Fatah-Khalil S, Fernandez-Honrado M, Rey D (April 2013). "HLA-G(∗)01:05N null allele in Mayans (Guatemala) and Uros (Titikaka Lake, Peru): Evolution and population genetics". Hum. Immunol. 74 (4): 478–82. doi:10.1016/j.humimm.2012.12.013. PMID 23261410.
  9. Castro MJ, Morales P, Martinez-Laso J, Allende L, Rojo-Amigo R, Gonzalez-Hevilla M, Varela P, Moscoso J, Garcia-Berciano M, Arnaiz-Villena A (November 2000). "Lack of MHC-G4 and soluble (G5, G6) isoforms in the higher primates, Pongidae". Hum. Immunol. 61 (11): 1164–8. doi:10.1016/s0198-8859(00)00189-0. PMID 11137222.
  10. Castro MJ, Morales P, Fernández-Soria V, Suarez B, Recio MJ, Alvarez M, Martín-Villa M, Arnaiz-Villena A (1996). "Allelic diversity at the primate Mhc-G locus: exon 3 bears stop codons in all Cercopithecinae sequences". Immunogenetics. 43 (6): 327–36. doi:10.1007/bf02199801. PMID 8606053.
  11. 11.0 11.1 Rebmann V, Switala M, Eue I, Grosse-Wilde H (May 2010). "Soluble HLA-G is an independent factor for the prediction of pregnancy outcome after ART: a German multi-centre study". Hum Reprod. 25 (7): 1691–8. doi:10.1093/humrep/deq120. PMID 20488801.
  12. Gao GF, Willcox BE, Wyer JR, Boulter JM, O'Callaghan CA, Maenaka K, Stuart DI, Jones EY, Van Der Merwe PA, Bell JI, Jakobsen BK (May 2000). "Classical and nonclassical class I major histocompatibility complex molecules exhibit subtle conformational differences that affect binding to CD8alphaalpha". J. Biol. Chem. 275 (20): 15232–8. doi:10.1074/jbc.275.20.15232. PMID 10809759.
  13. Sanders SK, Giblin PA, Kavathas P (September 1991). "Cell-cell adhesion mediated by CD8 and human histocompatibility leukocyte antigen G, a nonclassical major histocompatibility complex class 1 molecule on cytotrophoblasts". J. Exp. Med. 174 (3): 737–40. doi:10.1084/jem.174.3.737. PMC 2118947. PMID 1908512.

Further reading