Singapore study sheds new light on fetal immune system

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Zain and parents (Image: Stacey Lee Robson)

Questions of birth and death have mystified humans for centuries. For centuries, the period before the birth of a child, known as the gestation period was shrouded in mystery. With the advent of ultrasound imaging, parents are intimately aware of their developing child and keep track of every milestone.

Scientists, however, are a completely different species. Even as the rest of us cast adoring glances at babies, scientists are out to understand ever more about how fetuses develop.

Now a new study by scientists from A*STAR’s Singapore Immunology Network (SIgN) and KK Women’s and Children’s Hospital (KKH) in Singapore breaks long held myths to show that a fetus’s immune system is established as early as the first 13 weeks of the pregnancy. Interestingly, this fetal immune system is also able to initiate immune responses that are independent of the mother’s immune system and significantly different in nature.

In adults, the immune system comprises of many different types of cells. In addition to the T-cells and B-cells, the cells involved in attack and formation of immune memory, the dendritic cells play a major role.

Section of skin showing large numbers of dendritic (Langerhans) cells in the epidermis. A new blueprint defines subpopulations of dendritic cells across tissues and across species. Pic Credit: Wikimedia commons

The dendritic cells are often the first line of defense which comes in contact with foreign agents known as antigens. Often called antigen processing cells, the Dendritic cells process the antigen in a form that can be recognized by T-cells and help bolster a strong immune response and memory.

Interestingly, during pregnancy, despite the constant exposure to foreign proteins, both the mother and baby are restrained from launching a full immune attack on each other. This suggested that there were mechanisms in place in both mother and baby to keep the powers (of the immune system) that be, in check.Understanding the mechanisms that maintain this balance between the immune systems of two different individuals also held potential for organ transplants, pre-eclampsia, cell therapy and gene therapy.

“We have known for a long time that maternal cells cross into the baby’s bloodstream, but are not rejected by the fetal immune system. It had been long thought that the fetal immune system does not reject these semi-foreign cells due to its immaturity” said Associate Professor Jerry Chan, Senior Consultant, Department of Reproductive Medicine, at KK Women’s and Children’s Hospital, Singapore, and joint senior author of the study

This exciting new study finds that an unborn baby’s immune system contains a unique mechanism to prevent rejection of the mother’s cells, even as it develops independently. In contrast, to the dendritic cells in adults which mount a strong response to foreign proteins, fetal dendritic cells expressing Arginase-2 dampen the immune response. This makes sure that fetal immune system does not react strongly to proteins or cells of the mother that it encounters through the placenta.

Furthermore, Arginase-2 regulates the ability of immune cells to secrete a key inflammatory signaling protein called TNFα. This prevents the fetus’s immune system from overreacting and initiating unwanted inflammatory immune responses that could impact the baby’s ongoing development in the womb. Increased TNFα signaling has also been implicated in gestational diabetes and recurrent miscarriages.

The study provides a fresh insight into the nuanced functions of the fetal immune system and its role in mediating fetal development and growth.

Dr. Florent Ginhoux, Senior Principal Investigator at SIgN, A*STAR, and joint senior author of the study further said:

“We are excited by the prospects this discovery holds for the growing field of research into fetal immunity, and the insights it provides into the very beginnings of the human immune system. Our eventual goal is to build an atlas of the fetal immune system.Hopefully, this will allow us to discover additional mechanisms of fetal tolerance, and
identify gene signatures so that we can better evaluate fetal fitness and immunity.”

Dr.Chan further said, “This new insight lays the foundation for future immune-directed therapies, and contributes to our knowledge of the fetal origins of certain pregnancy-associated conditions, such as pre-eclampsia.”

The journal article can be accessed at Nature.