The role of HLA-G in human pregnancy

Abstract

Pregnancy in mammals featuring hemochorial placentation introduces a major conflict with the mother's immune system, which is dedicated to repelling invaders bearing foreign DNA and RNA. Numerous and highly sophisticated strategies for preventing mothers from rejecting their genetically different fetus(es) have now been identified. These involve production of novel soluble and membrane-bound molecules by uterine and placental cells. In humans, the placenta-derived molecules include glycoproteins derived from the HLA class Ib gene, HLA-G. Isoforms of HLA-G saturate the maternal-fetal interface and circulate in mothers throughout pregnancy. Uteroplacental immune privilege for the fetus and its associated tissues is believed to result when immune cells encounter HLA-G. Unequivocally demonstration of this concept requires experiments in animal models. Both the monkey and the baboon express molecules that are similar but not identical to HLA-G, and may comprise suitable animal models for establishing a central role for these proteins in pregnancy.

Figure 1

Exposure of term cytotrophoblast cells to low oxygen increases steady state levels of HLA-G mRNAs. Cytotrophoblast cells harvested from a term placenta using gradient centrifugation and purified by magnetic bead technology were >98% cytokeratin-7 positive. The cells were cultured for 72 hr under ambient (20% O₂) and two hypoxic (8%, 2%) conditions. RT-PCR experiments were conducted using mRNA-specific primers. The results were analyzed using scanning densitometer against a stable message (β2m). Note that the abundance of transcripts encoding HLA-G1, -G2, -G5 (sHLA-G1), and -G6 (sHLA-G2) were inversely related to levels of O₂. Under 2% O₂, mRNAs encoding HLA-G1 and -G5 were more profoundly enhanced (×7, ×4, respectively) than those encoding HLA-G2 and -G6 (×2, ×2, respectively).