Abstract
During pregnancy, maternal immune system has to balance tightly between protection against pathogens and tolerance towards a semi-allogeneic organism. Dysfunction of this immune adaptation can lead to severe complications such as pregnancy loss, preeclampsia or fetal growth restriction. In the present study we analyzed the impact of the murine MHC class Ib molecule Qa-2 on pregnancy outcome in vivo. We demonstrate that lack of Qa-2 led to intrauterine growth restriction and increased abortion rates especially in late pregnancy accompanied by a disturbed trophoblast invasion and altered spiral artery remodeling as well as protein aggregation in trophoblast cells indicating a preeclampsia-like phenotype. Furthermore, lack of Qa-2 caused imbalanced immunological adaptation to pregnancy with altered immune cell and especially T-cell homeostasis, reduced Treg numbers and decreased accumulation and functional activation of myeloid-derived suppressor cells. Lastly, we show that application of sHLA-G reduced abortion rates in Qa-2 deficient mice by inducing MDSC. Our results highlight the importance of an interaction between HLA-G and MDSC for pregnancy success and the therapeutic potential of HLA-G for treatment of immunological pregnancy complications.
Highlights
Premature termination of pregnancy either by abortion or by preterm delivery is the most important pregnancy complication
Our data show that the murine MHC-Ib molecule Qa-2 is relevant for pregnancy success and protects from late pregnancy loss by regulating immune adaptation to pregnancy in terms of modulating T-cell homeostasis and promoting Myeloid derived suppressor cells (MDSC) accumulation
We further show that expression of Qa-2 on MDSC is relevant for their functionality and regulated by estrogen via hypoxia-inducible factor 1a (HIF-1a)
Summary
Premature termination of pregnancy either by abortion or by preterm delivery is the most important pregnancy complication. About 15% of clinically recognized pregnancies miscarry, total reproductive losses are closer to 50% [1]. Besides chromosomal or anatomic anomalies and HLA-G and MDSC During Pregnancy endocrinological disorders, immunological factors play an important role in pathogenesis of abortions and preterm delivery [2]. There is a close contact between maternal immune cells and fetal cells. The maternal immune system has to balance tightly between protection against pathogens and tolerance towards the semi-allogeneic fetus. Dysfunction of the immune adaptation to pregnancy can lead to severe complications such as pregnancy loss, preeclampsia, preterm birth or fetal growth restriction. The mechanisms facilitating maternal-fetal tolerance are only incompletely understood and therapeutic options are limited
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