Babraham research provides new insights into factors ensuring a healthy pregnancy
Researchers at the Babraham Institute and University of Cambridge have made a breakthrough in understanding how the interplay between the foetus and the maternal immune systems ensures a healthy, successful pregnancy. This new understanding of the fundamental biology behind interactions between the placenta and the immune system may provide insight into the basis of human pregnancy disorders such as recurrent miscarriage, pre-eclampsia and foetal growth restriction, with potential prospects for intervention.
The developmental processes occurring during pregnancy are something of an immunological puzzle. The foetus and the placenta are to some extent considered ‘foreign’ by the mother’s body, as they produce paternal proteins (antigens) that should provoke an immune response by the mother. However, instead of rejecting the foetus, the mother’s immune system recognises and tolerates the paternal antigens, harnessing the immune interaction to promote foetal development.
The research, published today in Proceedings of the National Academy of Sciences of the United States of America (PNAS), reveals that the father’s genes instruct the maternal immune cells on how to build the best resources in the uterus for the developing foetus - remodelling the blood supply to optimise foetal nourishment - and safeguard the foetus from rejection.
“This paradox has puzzled scientists for decades and understanding how the foetus evades rejection, except in severe pregnancy complications, has remained elusive,” said Dr Myriam Hemberger of the Babraham Institute, an institute which receives strategic funding from the Biotechnology and Biological Sciences Research Council (BBSRC), and joint senior author with Dr Francesco Colucci, formerly at Babraham and now at the University of Cambridge. “Our findings show that paternal antigens on foetal trophoblast cells, which form the placenta and are therefore in direct contact with maternal tissue, help to transform the uterus for robust placental and foetal growth. This is essential for reproductive success.”
The research reveals that specific combinations of genes from the father’s immune system, and their target receptors on maternal immune cells, favourably affect blood supply and growth of the foetus. Natural Killer (NK) cells are white blood cells that defend us from tumours, viruses and other assaults on our immune system. However, a specialised set of NK cells in the uterus (uNK), plays a key role at the maternal-foetal boundary when a fertilised embryo implants, adapting the uterine blood vessels to nourish the foetus.
Paternal immune genes (MHC) in the placenta provide information to uNK cells to ensure that the foetus receives enough blood. The mouse model used in this research, which has direct analogy to human pregnancy, will provide better understanding of the precise factors and pathways that are important for a healthy pregnancy and optimal intrauterine development. Pre-eclampsia, a disorder occurring in as many as 5% of pregnancies, is associated with problems with blood vessel development in the uterus.
Certain associations between maternal uterine NK cells and paternal MHC signatures have been linked with a likelihood of developing pre-eclampsia and recurrent miscarriage, as shown by Prof Ashley Moffett at the University of Cambridge who is also a collaborator in this study. Not only is the interaction of specific genes in the immune system key for foetal programming, but also has direct relevance for life-long health and wellbeing since adult diseases like diabetes and hypertension are known to have early developmental origins.
“What is most exciting,” says Dr Colucci now at the University of Cambridge Department of Obstetrics and Gynaecology, “is that by revealing the similarities between human and mouse immunology during pregnancy, the research lays new foundations for using mouse genetics to test new ideas and hypotheses informed by human genetics data.”
The Babraham Institute undertakes world-leading life sciences research to generate new knowledge of biological mechanisms underpinning ageing, development and the maintenance of health. The work was supported by a Babraham Institute Synergy Award to Drs. Colucci and Hemberger, the BBSRC, the Centre for Trophoblast Research at the University of Cambridge, the MRC and the Wellcome Trust.
Publication details: Madeja Z, Yadi H, Apps R, Boulenouar S, Roper SJ, Gardner L, Moffett A, Colucci F, Hemberger M (In press) Paternal MHC expression on mouse trophoblast affects uterine vascularization and fetal growth. Proceedings of the National Academy of Sciences of the United States of America http://dx.doi.org/10.1073/pnas.1005342108
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About the Babraham Institute:
The Babraham Institute undertakes world-class life sciences research to generate new knowledge of biological mechanisms underpinning ageing, development and the maintenance of health. Our research focuses on cellular signalling, gene regulation and the impact of epigenetic regulation at different stages of life. By determining how the body reacts to dietary and environmental stimuli and manages microbial and viral interactions, we aim to improve wellbeing and support healthier ageing. The Institute is strategically funded by the Biotechnology and Biological Sciences Research Council (BBSRC), part of UK Research and Innovation, through an Institute Core Capability Grant and also receives funding from other UK research councils, charitable foundations, the EU and medical charities.
The Biotechnology and Biological Sciences Research Council (BBSRC) is the UK funding agency for research in the life sciences. Sponsored by Government, BBSRC annually invests around £450 million in a wide range of research that makes a significant contribution to the quality of life for UK citizens and supports a number of important industrial stakeholders including the agriculture, food, chemical, health and well-being and pharmaceutical sectors. BBSRC carries out its mission by funding internationally competitive research, providing training in the biosciences, fostering opportunities for knowledge transfer and innovation and promoting interaction with the public and other stakeholders on issues of scientific interest in universities, centres and institutes.
The Centre for Trophoblast Research
The Centre for Trophoblast Research is an inter-departmental initiative that aims to promote the study of placental biology, with special reference to the trophoblast, both within and outside Cambridge. The centre, which draws together researchers from Babraham, The Department of Physiology, Development and Neuroscience, The Gurdon Institute and Addenbrookes Hospital, was officially launched in July 2008 and aims to facilitate interactions and collaborations between established researchers, both nationally and internationally. The Centre aims to promote research and teaching in placental biology and the developmental origins of the trophoblast within the University of Cambridge and affiliated institutes through Next Generation Research Fellowships, Graduate Studentships, seminars, workshops, and infrastructural support. One of the Centre’s principal aims, however, is to encourage young investigators into the field and foster their careers. http://www.trophoblast.cam.ac.uk/