| The survival of the allogeneic fetus in human pregnancy remains a paradox. Studies of the specialized anatomic and molecular environment of the placenta have begun to answer the question of how embryos escape rejection by maternal immune mechanisms. The classical human leukocyte antigens (HLA-A, -B), antigen-presenting molecules that are critical to the adaptive immune response and play a major role in the rejection of foreign tissue, are not expressed in the extravillous cytotrophoblast (EVC), the placental tissue that invades most deeply into maternal decidua and spiral arteries. In place of these classical class I genes, the EVC expresses the non-classical HLA-G gene. Several features of HLA-G suggest that it may aid in establishment and/or maintenance of the conceptus. It exhibits low levels of polymorphism, which has been hypothesized to help fetal tissue avoid recognition as foreign. Notably, HLA-G has also been demonstrated to inhibit NK cells and T cells in vitro. Modulation of these important immune cells may contribute to successful gestation of a ‘non-self’ conceptus. However, the complex nature of HLA-G, including the lack of a murine orthologue, the co-expression of HLA-E and C in the placenta, and differential splicing of message to give several protein isoforms, has prevented the use of traditional techniques such as study of an animal model in understanding the role of HLA-G in pregnancy. The studies undertaken here examine natural genetic variation in HLA-G in human populations and dissect whether different HLA-G alleles or protein isoforms affect interactions at the maternal-fetal interface. Assays of variation around a deletion mutation revealed unusually high linkage disequilibrium, suggestive of positive natural selection on this variant that is a null for the full-length HLA-G1 protein. Another analysis demonstrated significant association between HLA-G exon 3 polymorphisms and recurrent miscarriage. Characterization of variants in the 5′ regulatory region suggests that the association is due to these variants in exon 3 and not to linkage disequilibrium with 5 ′ polymorphisms. Finally, a study of the relationship between the HLA-G deletion polymorphism and two disorders of trophoblast invasion, preeclampsia and intrauterine growth restriction, found little evidence for the involvement of this functional polymorphism. |
