A single base-pair mutation in the 3'-untranslated region of HLA-G mRNA is associated with pre-eclampsia.

Human leukocyte antigen-G (HLA-G) is a non-classical class I HLA molecule that is expressed by extravillous cytotrophoblast cells. This protein may play a critical role in the protection of cytotrophoblasts from maternal immune response, allowing these semi-allogeneic cells to invade the uterus unimpeded. We have demonstrated that diminished placental HLA-G expression is associated with pre-eclampsia. In order to explore fundamental mechanisms underlying this reduced HLA-G expression in pre-eclampsia, we looked for, and found by sequences analysis, a single base-pair mutation in the HLA-G gene 3'-untranslated region (3'UTR) adjacent to an AUUUA motif. This mutation is significantly associated with pre-eclampsia, the severe form being more strongly associated with homozygosity for this mutation than the mild form. Since the null allele was discovered in the HLA-G mRNA 3'UTR adjacent to an AUUUA motif, we also examined the effect of this mutation on HLA-G mRNA stability, and found that half-lives of HLA-G mRNA with the mutation were significantly shorter than without the mutation. These data provide evidence that this mutation could be one of the fundamental mechanisms for lower levels of placental HLA-G protein expression in patients with pre-eclampsia.

Progesterone enhances HLA-G gene expression in JEG-3 choriocarcinoma cells and human cytotrophoblasts in vitro.

BACKGROUND: Evidence suggests that HLA-G plays a critical role in maternal immune tolerance to the fetus. However, regulation of HLA-G gene expression is not well understood. Many studies have suggested that progesterone may also be important in suppressing maternal immune response to the fetus. Therefore, we hypothesized that this steroid hormone may play a role in regulating HLA-G gene expression. The objective of the study was to explore potential effects of progesterone on HLA-G gene expression in vitro. METHODS: Cultured first trimester trophoblasts and JEG-3 choriocarcinoma cells were treated with progesterone and its antagonist RU486. HLA-G gene transcription was determined by real-time PCR while HLA-G translation was investigated by a specific enzyme-linked immunosorbent assay for HLA-G and western blot analysis. RESULTS: HLA-G mRNA and protein expression in trophoblasts and JEG-3 cells were elevated by progesterone in dose- and time-dependent manners. The effect of progesterone can be completely inhibited by co-incubation with RU486 at the same concentrations. CONCLUSION: Progesterone has an up-regulatory effect on HLA-G gene expression in first trimester trophoblasts and JEG-3 cells in vitro.

HLA-G protein concentrations in maternal serum and placental tissue are decreased in preeclampsia.

OBJECTIVE: The aim of this study were to determine whether soluble human leukocyte antigen-G protein levels in serum and/or human leukocyte antigen protein in placental tissues differ between women with preeclampsia versus uncomplicated pregnancies. Study design human leukocyte antigen-G levels were determined with the use of a specific enzyme-linked immunosorbent assay in 20 subjects with preeclampsia and 14 normal control subjects. RESULTS: Both serum and placental human leukocyte antigen-G levels were decreased significantly in the preeclampsia group (median, 0.026 microg/mL in serum; median, 0.026 microg/mg protein in placenta), in comparison with normal pregnant women (median, 0.093 microg/mL in serum; median, 0.088 microg/mg protein in placenta; P=.0112 and P=.0406, respectively). There was a significant correlation between serum and placental human leukocyte antigen-G levels (r=0.603; P=0.0002). CONCLUSION: The reduced expression of placental human leukocyte antigen-G and reduced release of this protein into the maternal circulation in preeclampsia may alter the maternal-fetal immune relationship and thus be involved in the cause of this disorder.