HLA-G histocompatibility antigen, class I, G, also known as human leukocyte antigen G, is a protein that in humans is encoded by the HLA-Ggene. 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. 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. Exon 7 and 8 are not translated due to a stop codon present in exon 6.
Function
HLA-G may play a role in immune tolerance in pregnancy, being expressed in the placenta by extravillous trophoblast cells, while the classical MHC class I genes are not. 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. 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. 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. It is striking that this "null" allele, while it is quite frequent in some populations, like in Iranians, it is almost absent in some Amerindian populations. Also, some higher primates do not show all MHC-G isoforms. 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. All of these anomalies must be studied. The presence of soluble HLA-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. 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.
