The potential role of HLA-G polymorphism in maternal tolerance to the developing fetus

The mechanism by which the developing fetus survives the maternal immunity has eluded investigators and remains a central paradox in the field of stem cell research. If the mechanism can be defined, allogenic stem cells may find increased utility after transplantation. While several theories have been advanced, the differential expression of HLA antigens on trophoblasts has been the focus of many studies. Interestingly, an inverse relationship between HLA-G (nonclassical class I molecules) and class I MHC gene expression exists early in pregnancy. HLA-G transcripts are present in quite significant amounts in first-trimester placental tissue, particularly in the extravillous membranes, while the opposite occurs at term. This kind of expression is consistent with the theory that HLA-G might play a role in fetal protection. This could be consequent to either nonimmune (structural) or immune functions at the maternal-fetal interface. Current evidence suggest an immune function wherein HLA-G protects fetal cells from maternal uterine natural killer (NK) cells, which are found in large numbers within cells invading the trophoblasts. This effect has been attributed to maternal NK receptor alterations as well as inhibition of maternal NK cell traffic across the placenta. The recent identification of HLA-G polymorphism brings into play the potential role of these isoforms in fetal protection. Polymorphism may be associated with differential function or may effect linkage disequilibria with other HLA variants, providing fetal protection.