Definite causes for several pathologies of pregnancy remain unknown. In light of several recent studies, however, diminished or aberrant HLA-G expression may be associated with certain complication of pregnancy and be linked to HLA-G polymorphism. We analyzed DNA from 60 normal placentas (controls), 140 placentas from miscarriage, 36 placentas from preeclampsia, 76 placentas from fetal hypotrophy, and 34 placentas with hypoxia for variations in coding regions (allelic groups G*0101 to G*0107) and the 14-bp deletion/insertion into the 3′-untranslated region. No statistically significant differences were observed in the distribution of allelic group between pathological placentas and controls with the exception of G*0106 allele frequency in preeclamptic compared with control placentas (21.2% and 6.6%, respectively). A greater frequency of this allele also was observed in the two subgroups of miscarriage and hypoxia compared with that in controls. In addition, presence of the 14-bp sequence was prominent in preeclampsia compared with controls (60.8% vs. 35%, respectively), and homozygotes with deletion were not detected in the pathology. The results suggest that the G*0106 allele, which is coupled with the presence of the 14-bp sequence, contributes and/or is a relevant marker in some specific complications of pregnancy, especially preeclampsia.

Hypoxia inducible factor-1 mediates the expression of the immune checkpoint HLA-G in glioma cells through hypoxia response element located in exon 2

Human leukocyte antigen-G (HLA-G) is a nonclassical major histocompatibility complex (MHC) class I molecule involved in immune tolerance processes, playing an important role in the maintenance of the semi-allogeneic fetus. Although HLA-G expression is restricted in normal tissues, it is broadly expressed in malignant tumors and may favor tumor immune escape. We analyzed HLA-G protein and mRNA expression in tumor samples from patients with glioblastoma collected in France, Denmark, and Brazil. We found HLA-G protein expression in 65 of 108 samples and mRNA in 20 of 21 samples. The absence of HLA-G protein expression was associated with a better long-term survival rate. The mechanisms underlying HLA-G gene expression were investigated in glioma cell lines U251MG, D247MG, and U138MG. Induction of HLA-G transcriptional activity was dependent of 5-aza-2'-deoxycytidine treatment and enhanced by interferon-γ. HLA-G protein expression was observed in U251MG cells only. These cells exhibited a permissive chromatin state at the HLA-G gene promoter and the highest levels of induced HLA-G transcriptional activity following 5-aza-2'-deoxycytidine treatment. Several antigen-presenting machinery components were up-regulated in U251MG cells after demethylating and IFN-γ treatments, suggesting an effect on the up-regulation of HLA-G cell surface expression. Therefore, because of its role in tumor tolerance, HLA-G found to be expressed in glioblastoma samples should be taken into consideration in clinical studies on the pathology and in the design of therapeutic strategies to prevent its expression in HLA-G-negative tumors.