An international research team led by the University of British Columbia (UBC) has for the first time discovered the importance of a small gland behind the breastbone in preventing miscarriage and diabetes in pregnant women.
The organ in question is the thymus, which was identified in a study published in the journal today nature as a significant role in both metabolic control and immunity during pregnancy.
How the immune system adapts to the mother and fetus has puzzled researchers for decades. The study, which was carried out by an international research team including Dr. Josef Penninger owned by UBC gives an answer. The researchers found that female sex hormones direct important changes in the thymus, a central organ of the immune system, to produce specialized cells called Tregs to deal with physiological changes that occur during pregnancy.
The researchers also identified RANK, a receptor expressed in part of the thymus called the epithelium, as the key molecule behind this mechanism.
We knew that RANK was expressed in the thymus, but its role in pregnancy was unknown. “
Dr. Josef Penninger, Senior Author and Professor of Studies, Department of Medical Genetics and Director of the Life Sciences Institute, University of British Columbia
For a better understanding, the authors examined mice in which RANK had been removed from the thymus.
“The absence of RANK prevented the production of Tregs in the thymus during pregnancy. This resulted in fewer Tregs in the placenta, which led to increased miscarriage rates,” says lead author of the study, Dr. Magdalena Paolino, assistant professor in the medical department at Karolinska Institutet.
The results also provide new molecular insights into the development of diabetes during pregnancy, known as gestational diabetes, a disease that affects around 15 percent of women around the world during pregnancy that scientists still know little about.
In healthy pregnancies, the researchers found that Tregs migrated into the mother’s adipose tissue to help prevent inflammation and control glucose levels in the body. Pregnant mice without RANK had high levels of glucose and insulin in the blood and many other indicators of gestational diabetes, including above-average young people.
“Similar to babies of women with diabetes during pregnancy, the newborn pups were much heavier than average,” says Dr. Paolino.
The lack of Tregs during pregnancy also resulted in long-lasting, cross-generational effects on the offspring. The puppies were prone to diabetes and obesity throughout their lifespan. Administration of Thregus-derived Tregs from RANK-deficient mice isolated from normal pregnancies reversed all health problems, including miscarriages and maternal glucose levels, and normalized the puppies’ body weights.
The researchers also analyzed women with diabetes during pregnancy and found a reduced number of Tregs in their placenta, similar to the study in mice.
“The discovery of this new mechanism that underlies gestational diabetes may offer new therapeutic targets for the mother and fetus in the future,” says co-author Dr. Alexandra Kautzky-Willer, a clinician and researcher based at the Medical University of Vienna.
“The thymus changes massively during pregnancy and how rewiring of entire tissue like this contributes to a healthy pregnancy has been one of the remaining puzzles in immunology,” adds Dr. Penninger added. “Our many years of work have not only solved this mystery – pregnancy hormones rewire the thymus via RANK – but also uncovered a new paradigm for its function: The thymus not only changes the mother’s immune system so that it does not reject the fetus. The thymus controls but also the mother’s metabolic health.
“This research is changing our view of the thymus as an active and dynamic organ needed to ensure pregnancy,” says Dr. Penninger.
University of British Columbia
Paolino, M., et al. (2020) RANK links thymic regulatory T cells to fetal loss and gestational diabetes in pregnancy. nature. doi.org/10.1038/s41586-020-03071-0.