How the immune system adapts to pregnancy has puzzled scientists for decades. Now an international team of researchers has discovered that important changes in the thymus occur to prevent miscarriages and gestational diabetes and published their results in the journal Nature.
The scientists found that female sex hormones tell the thymus, a central organ of the immune system, to produce specialized cells called “tregs” to deal with physiological changes that occur during pregnancy. They also found that RANK, a receptor expressed in part of the thymus called the epithelium, was the key molecule behind this mechanism.
“We knew that RANK was expressed in the thymus, but its role in pregnancy was unknown,” said senior author Dr. Josef Penninger, founding director of the Institute for Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), who is now director of the Life Sciences Institute at the University of British Columbia. To gain a deeper insight, 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, ”said lead author Magdalena Paolino, a former postdoctoral fellow at IMBA who now runs her own laboratory at Karolinska Institutet.
The results also offer new molecular insights into the development of gestational diabetes, a disease that affects around 15% of pregnant women worldwide and which continues to confuse scientists to this day. In healthy pregnancies, the researchers found that Tregs migrated into the mother’s adipose tissue to help prevent inflammation and help 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.
“Much like babies of women with gestational diabetes, the newborn pups were much heavier than average,” said Paolino.
The lack of Tregs during pregnancy in mothers also resulted in long-lasting intergenerational effects on the offspring, who were prone to diabetes and obesity throughout their lifespan. Interestingly, administration of thymus-derived Tregs isolated from normal pregnancies to RANK-deficient mice reversed all of the mice’s health problems, including maternal miscarriages and glucose levels, and also normalized the puppy’s body weight.
The researchers also analyzed women with gestational diabetes and found a decreased number of Tregs in their placenta, similar to the study in mice. According to co-author Dr. Alexandra Kautzky-Willer from the Medical University of Vienna, the discovery of this new mechanism underlying gestational diabetes may offer new therapeutic goals for mother and fetus in the future.
Dr. Penninger concluded, “The thymus changes massively during pregnancy, and how such rewiring of entire tissue contributes to a healthy pregnancy has been one of the remaining puzzles in immunology. Our long-term work has now not only solved this riddle – 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, but also The thymus also controls the mother’s metabolic health.
“This research is changing our view of the thymus as an active and dynamic organ needed to protect pregnancies.”
Photo credit: © IMBA / Kulcsar
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