ABSTRACT: Hematopoiesis- lipids in Maternal-Fetal immune interactions
Elevated levels of beta-glucosylceramides (bGlcCers) have been found in allergic mouse mothers. These bGlcCers are necessary and sufficient to induce allergy predisposition the offspring of allergic mothers. bGlcCers increase certain subsets of IRF4+ dendritic cell (DC) numbers in the fetal liver and pup lungs. I hypothesize that these DCs are elevated in the lungs of pups born to allergic mothers and that these DCs predispose offspring to allergic lung responses.
To test this hypothesis, pregnant mice were injected with a mixture of bGlcCers that predispose the offspring to allergic inflammation. DCs were assayed by flow cytometry. Also, lung DCs were isolated from pups born to non-allergic mothers or allergy predisposed pups born to allergic mothers. These DCs were transferred to the lungs of pups of non-allergic dams. All recipient pups were sub optimally sensitized and allergen challenged.
IRF4+ DC numbers were increased in fetal livers when dams received bGlcCers compared to fetal livers from vehicle-injected dams. IRF4+ DC numbers were increased in the lungs of pups born to allergic dams compared to pups born to non-allergic dams. Lung DCs transferred from pups born to allergic dams to the lungs of pups born to non allergic dams induced allergic inflammation in the recipients compared to lung DC transfers from pups born to non allergic dams. Elevated numbers of endogenous CD45.2 IRF4+ lung DCs were observed in allergen-challenged pups that received lung DCs from pups born to allergic dams. These results suggest that bGlcCer induces increased numbers of pro-allergy IRF4+ DCs during fetal hematopoiesis.
These results further suggest that lung DCs from pups born to allergic dams are induce allergen responsiveness and higher lung IRF4+ DC numbers.
When a new baby enters the world, he or she must be prepared to encounter pathogens and fight off infection. The mother helps her baby in this regard. By passing antibodies through the placenta and milk, the mother gives her baby protection against pathogens at the moment of birth, but reliance on the mother cannot last a lifetime. Development of a baby’s own immune system begins well before birth. Immune cells develop through a process called hematopoiesis.
In the fetus, hematopoiesis takes place in the liver. Just after a baby is born, hematopoietic cells migrate to the bone marrow where hematopoiesis will take place for the rest of that individual’s life. Interactions between the mother and the fetus shape immune system development in the baby. Evidence is suggesting that immune perturbations like infections in the mother during pregnancy increase risk of developing leukemia in her children. Similar effects have been seen in allergy as well because children whose mothers have allergies are more likely to have allergies themselves. Of course, genetics and sharing the same environment likely has a role in explaining this observation. However, laboratory studies using mice that are genetically very similar and that all have the same environmental conditions also show this allergy predisposition effect. This suggests that something non-genetic and inherent to the mother’s allergy state is contributing to the offspring’s development of allergy. Our lab has found that lipids elevated in allergic mothers are passed across the placenta and through the milk. These lipids skew immune cells in fetal and newborn mice in ways that could explain the
allergy predisposition phenomenon.