An international research team led by the University of British Columbia (UBC) has for the first time discovered the importance of a small gland retracted behind the sternum that works to prevent abortion and diabetes in pregnant women.
The organ in question is the thymus, identified in a study published today in the journal Nature because it plays a significant role in metabolic control and immunity in pregnancy.
As the immune system adapts to the mother and fetus, it has confused researchers for decades. The study – conducted by an international research team, including others. Josef Penninger from UBC – reveals the answer. The researchers found that female sex hormones point to important changes in the thymus, the central organ of the immune system, to produce specialized cells called Tregs to address the physiological changes that occur in pregnancy.
The researchers also identified RANK, a receptor expressed in a part of the thymus called the epithelium, as a key molecule behind this mechanism.
We knew that RANK was expressed in the thymus, but its role in pregnancy was not known. “
Dr Josef Penninger, Senior Study Author and Professor, Department of Medical Genetics and Director of the Institute of Life Sciences, University of British Columbia
To have a better understanding, the authors studied mice in which RANK was deleted from the thymus.
“The absence of RANK prevented the production of Tregs in the thymus during pregnancy. This resulted in a decrease in the number of Tregs in the placenta, which led to increased abortion rates,” says the lead author of the study, Dr. Magdalena Paolino, assistant professor in the medical department at the Carolingian Institute.
The findings also offer a new molecular insight into the development of diabetes during pregnancy, known as gestational diabetes, a disease that affects approximately 15 percent of pregnant women worldwide and about which scientists still know little.
In a healthy pregnancy, researchers found that Tregs migrated into the mother’s adipose tissue to prevent inflammation and help control glucose levels in the body. Pregnant mice without RANK had high blood glucose and insulin levels and many other indicators of gestational diabetes, including younger than average ones.
“Similar to the babies of women with diabetes in pregnancy, newborn pups were much heavier than average,” says Dr. Paolino.
The lack of Tregs during pregnancy has also resulted in long-lasting, transgenerational effects on offspring. The cubs were prone to diabetes and overweight throughout their lives. Giving mice to Trem performed with RANK-deficient thymus mice was isolated from a normal pregnancy, reversed all of their health issues, including abortion and maternal glucose levels, and also normalized the body weight of the pups.
The researchers also analyzed women with diabetes in pregnancy, finding a reduced number of Tregs in their placenta, similar to a study in mice.
“The discovery of this new mechanism underlying gestational diabetes potentially offers new therapeutic goals for the mother and fetus in the future,” says co-author Dr. Aleksandra Kautzky-Willer, clinician-researcher based at the Medical University of Vienna.
“The thymus changes en masse during pregnancy and how such a pre-fusion of all tissue contributes to a healthy pregnancy is one of the remaining mysteries of immunology,” adds Dr. Penninger. “Our many years of work have not only solved this riddle – pregnancy hormones reshape the thymus via RANK – but have discovered a new paradigm for its function: the thymus not only changes the mother’s immune system, but also does not reject the fetus, but the thymus also controls the mother’s metabolic health. .
“This research changes our view of the thymus as an active and dynamic organ needed to protect pregnancy,” says Dr. Penninger.
University of British Columbia
Paolino, M., and others. (2020) RANK links regulatory thymus T cells with fetal loss and gestational diabetes in pregnancy. Nature. doi.org/10.1038/s41586-020-03071-0.