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 supported by 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, NIHR Cambridge Biomedical Research Centre and the Wellcome Trust.
Notes to editors
Paternal MHC expression on mouse trophoblast affects uterine vascularization and fetal growth
Zofia Madeja, Hakim Yadi, Richard Apps, Selma Boulenouar, Stephen J. Roper, Lucy Gardner, Ashley Moffett, Francesco Colucci and Myriam Hemberger. www.pnas.org/cgi/doi/10.1073/pnas.1005342108
About the Babraham Institute
The Babraham Institute is an institute supported by the Biotechnology and Biological Sciences Research Council (BBSRC) near Cambridge, undertaking international quality research to generate new knowledge of biological mechanisms underpinning ageing, development and the maintenance of health. The Institute’s research is focused on understanding the biological events that underlie the normal functions of cells and the implication of failure or abnormalities in these processes. Research focuses on signalling and genome regulation, particularly the interplay between the two and how epigenetic signals can influence important physiological adaptations during the lifespan of an organism. By determining how the body reacts to dietary and environmental stimuli and manages microbial and viral interactions, we aim to improve wellbeing and healthier ageing. www.babraham.ac.uk
About 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. www.trophoblast.cam.ac.uk
BBSRC is the UK funding agency for research in the life sciences. Sponsored by Government, BBSRC annually invests around £470M in a wide range of research that makes a significant contribution to the quality of life in the UK and beyond and supports a number of important industrial stakeholders, including the agriculture, food, chemical, healthcare and pharmaceutical sectors.
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