It has long been known that mothers greatly influence the development of the growing fetus by not only providing nutrients through the placenta, but also a growing list of biological elements including beneficial antibodies, gut bacteria and now, allergies.
New research from Duke University-NUS shows that allergen-primed antibodies may be passed to offspring in utero. This means that mothers may be able to transmit allergies to their babies prenatally, helping explain why some infants display them very early on in life. The findings may allow for the identification of potential therapeutic targets for early intervention.
Researchers from the Agency for Science, Technology and Research (A*STAR), KK Women’s and Children’s Hospital (KKH) and Duke-NUS Medical School in Singapore conducted preclinical studies in an animal model in which they showed that specific antibodies that trigger allergic reactions can cross the placenta. They reported their findings last week in the journal Science.
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“Allergies begin very early in life,” said Associate Professor Ashley St. John, an immunologist at Duke-NUS’ Emerging Infectious Diseases Program and a senior co-author on the study. “Infants experience allergic responses closely linked with the mother’s allergic response in ways that cannot only be explained by genetics. This work emphasizes one way that allergic responses can pass from the mother to the developing fetus, and shows how allergies can then persist after birth.”
The researchers used an animal model to show that immunoglobulin E (IgE) — the key antibody responsible for triggering allergic reactions — can cross the placenta and enter the fetus. In the fetus, the antibody binds to fetal mast cells, a type of allergen-responsive immune cell that contains granules rich in histamine and heparin; these are released (in a process called degranulation) when the cells are stimulated by an allergen, triggering an allergic reaction. Mast cells play important roles in inflammatory and allergic reactions in a wide range of conditions, including asthma and a simple runny nose.
Both mast cells and IgE are detectable in fetuses, explaining why allergies can appear early in infants.
Results from the study showed that newborn mice develop allergic reactions to the same type of allergen as their mothers at the time of first exposure. This is in contrast to adult mice, which need two exposures. Additionally, the researchers showed that maternal IgE from the mice could bind to human fetal mast cells, suggesting they might cross the placenta in humans in a similar way.
As part of the study, researchers exposed mice to ragweed pollen, a common allergen, before pregnancy. The researchers reported that mice that developed a sensitivity to the pollen had offspring that also showed an allergic reaction to ragweed. They found that the sensitivity was allergen-specific as the offspring did not react to dust mites, which is another common allergen.
Interestingly, the sensitivity transfer appears to wane with time. While the allergen-sensitive newborn mice displayed allergic reactions at four weeks, they were diminished, or completely absent, at six weeks.
IgE Sensitizes Mast Cells to Trigger Allergic Reactions
In the study, IgE was found to cross the placenta via the fetal neonatal Fc-receptor (FcRN), sensitizing fetal mast cells to induction of allergen-specific degranulation. In mice that had FcRN knocked out, maternal IgE was unable to attach to fetal mast cells and offspring did not develop allergies after birth.
In vitro cellular assays and imaging confirmed binding of maternal IgE to fetal mast cells, triggering the cells to release chemicals in reaction to an allergen.
The study also demonstrated that human and mouse fetal mast cells phenotypically mature through pregnancy and can be sensitized by maternal IgE. According to the research, both passive and active prenatal sensitization conferred allergen sensitivity, leading to postnatal skin and airway inflammation after the first allergen encounter. The authors, therefore, report “a role for mast cells within the developing fetus and demonstrate that fetal mast cells may contribute to antigen-specific vertical transmission of allergic disease.”
In a news release from Duke-NUS, Dr. Florent Ginhoux, senior principal investigator at A*STAR’s Singapore Immunology Network (SIgN), and a senior co-author on the study, said, “There is currently a significant lack of knowledge on mast cells that are present early on in the developing fetus. Here, we discovered that fetal mast cells phenotypically mature through the course of pregnancy, and can be sensitized by IgE of maternal origin that cross the placental barrier.
“The study suggests that a highly allergic pregnant mother may potentially transfer her IgE to her baby that consequently develop allergic reactions when exposed to the first time to the allergen.”
Implications: From Nasal to Skin Allergies
Approximately ten to 30 percent of the world’s population is affected by allergies. The numbers are expected to rise, and thus interventions to prevent allergies from being passed from mother to child could help reduce the number of allergy sufferers. The research could help identify new therapeutic targets that could aid in the development of interventions to reduce the occurrence and/or impact of neonatal allergies, as well as other ailments, including skin conditions such as eczema.
“Our research has really exciting findings that may explain the high incidence of early onset atopic dermatitis (eczema) in children of mothers with clinically proven eczema, which parallel findings in our local birth cohort findings,” said Professor Jerry Chan, senior consultant, Department of Reproductive Medicine at KKH, and vice chair of research with the Obstetrics and Gynaecology Academic Clinical Program at the SingHealth Duke-NUS Academic Medical Centre. “From a clinical point of view, developing a further understanding in placental transfer of IgE, and the mechanism of fetal mast cell activation, would be key to developing strategies to reduce the chance of eczema or other allergies from being transferred from mother to baby.”
The authors say they are now aiming to better understand the mechanism of IgE transfer via the placenta, as well as how IgE can modulate the function of mast cells in fetal skin to affect skin physiology at birth.
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