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Dad’s genes direct mum’s cells to nourish baby during pregnancy

16 February 2011

A new study in mice reveals how a mother’s immune system helps to nourish her growing fetus, with help from the father’s genes. The findings may provide insights into pregnancy disorders in humans, such as pre-eclampsia and recurrent miscarriage.

The relationship between a mother's immune system and her growing fetus is complex and remains one of human biology's greatest mysteries. The fetus, having genes from both mother and father, has a different tissue type to the mother. It should therefore appear 'foreign' to the mother's immune system and trigger an immune response, in much the same way as a non-matched kidney transplant would be rejected.

Researchers at the University of Cambridge and the Babraham Institute have now shown that, rather than triggering rejection, genes from the father that are expressed in the placenta actually help to guide the maternal immune system in remodelling the blood supply in the womb. This helps to provide optimal nourishment for the growing fetus and is associated with a healthy pregnancy.

The team looked specifically at the MHC genes, which encode proteins that are expressed on the surface of all cells in the body and help the immune system to discriminate 'foreign' from 'self' tissues so that it knows when to attack. Everybody has different combinations of MHC genes, which determine our 'tissue type'.

A type of maternal immune cells known as uterine NK (uNK) cells are known to be important for adapting the blood supply in the womb to maximise fetal nourishment. By mating mice whose only genetic difference was in the MHC genes of the mother and father, the researchers found that these cells sense the difference in MHC, and this interaction instructs the uNK cells to encourage the development of the blood supply. This, in turn, correlates with a healthier pregnancy overall and a growth advantage for the pups.

Until now, it was not clear which paternal MHC genes were expressed by mouse placentae. This has made studying pregnancy disorders in mice difficult and has held back research in the field of reproductive biology.

Francesco Colucci, from the University of Cambridge Department of Obstetrics and Gynaecology and co-author on the paper, explains: "What is most exciting is that by revealing the similarities between human and mouse immunology of pregnancy, the research lays new foundations for using mouse genetics to test new ideas and hypotheses informed by human genetics data."

In humans, the importance of the interaction between the mother's uNK cells and the placenta is underlined by the finding that certain combinations of MHC expression are associated with pregnancy disorders. However, how these maternal-fetal immunological interactions dictate the outcome of pregnancy remains unknown.

Colucci describes where this research is leading, saying: "We are now well positioned to explore how the inherent variability of these immune system genes affects reproductive success by comparing NK receptors and MHC in normal pregnancy, to those with disorders."

In future, researchers will be able to mimic the 'good' and 'bad' combinations of uNK cells and MHC genes to examine uterine blood vessels and fetal growth, with a view to understanding how to prevent pregnancy disorders in humans.

Pre-eclampsia is a major cause of poor pregnancy outcome and affects around 1 in 200 pregnancies in the UK.

The study was published online this month in the 'Proceedings of the National Academy of Sciences of the United States of America'. The work was funded by the Wellcome Trust, BBSRC, Centre for Trophoblast Research, Medical Research Council and NIHR Cambridge Biomedical Research Centre.

Image credit: Wellcome Library, London.

References

Madeja Z et al. Paternal MHC expression on mouse trophoblast affects uterine vascularization and fetal growth. PNAS, 2011. [Epub ahead of print]

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