Allelic imbalance modulates surface expression of the tolerance-inducing HLA-G molecule on primary trophoblast cells

S Djurisic, S Teiblum, Cæcilie Krogsgaard Tolstrup, O B Christiansen, T V F Hviid

25 Citations (Scopus)

Abstract

The HLA-G molecule is expressed on trophoblast cells at the feto-maternal interface, where it interacts with local immune cells, and upholds tolerance against the semi-allogeneic fetus. Aberrant HLA-G expression in the placenta and reduced soluble HLA-G levels are observed in pregnancy complications, partly explained by HLA-G polymorphisms which are associated with differences in the alternative splicing pattern and of the stability of HLA-G mRNA. Of special importance is a 14 bp insertion/deletion polymorphism located in the 3'-untranslated region of the HLA-G gene. In the current study, we present novel evidence for allelic imbalance of the 14 bp insertion/deletion polymorphism, using a very accurate and sensitive Digital droplet PCR technique. Allelic imbalance in heterozygous samples was observed as differential expression levels of 14 bp insertion/deletion allele-specific mRNA transcripts, which was further associated with low levels of HLA-G surface expression on primary trophoblast cells. Full gene sequencing of HLA-G allowed us to study correlations between HLA-G extended haplotypes and single-nucleotide polymorphisms and HLA-G surface expression. We found that a 1:1 expression (allelic balance) of the 14 bp insertion/deletion mRNA alleles was associated with high surface expression of HLA-G and with a specific HLA-G extended haplotype. The 14 bp del/del genotype was associated with a significantly lower abundance of the G1 mRNA isoform, and a higher abundance of the G3 mRNA isoform. Overall, the present study provides original evidence for allelic imbalance of the 14 bp insertion/deletion polymorphism, which influences HLA-G surface expression on primary trophoblast cells, considered to be important in the pathogenesis of pre-eclampsia and other pregnancy complications.

Original languageEnglish
JournalMolecular Human Reproduction
Volume21
Issue number3
Pages (from-to)281-95
Number of pages15
ISSN1360-9947
DOIs
Publication statusPublished - Mar 2015

Keywords

  • 3' Untranslated Regions
  • Abortion, Legal
  • Alleles
  • Allelic Imbalance
  • Alternative Splicing
  • Base Sequence
  • Female
  • HLA-G Antigens
  • Haplotypes
  • Heterozygote
  • Humans
  • INDEL Mutation
  • Immune Tolerance
  • Molecular Sequence Data
  • Polymerase Chain Reaction
  • Polymorphism, Genetic
  • Pregnancy
  • Pregnancy Trimester, First
  • Primary Cell Culture
  • Sequence Analysis, DNA
  • Trophoblasts

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