Maternal Lipid Regulation of the Development of Responsiveness to Allergen in Neonates and Infants

Abstract In animals and humans, offspring of allergic mothers have increased responsiveness to allergen. A major question is what are the maternal factors of allergic mothers that alter offspring responsiveness to allergen? We focused on maternal lipids, because lipids are altered during allergic inflammation and because lipids are transported to the fetal liver and are in the mother’s milk. In our studies, allergic pregnant mice had increased glucosylceramides (GlcCer) in the mother plasma, placenta, and fetal liver as compared to non-allergic mothers. In allergen-challenged pups of allergic mothers, GlcCer was elevated in the pup lung and liver. Maternal GlcCer is directly transported to the placenta, the fetal liver, mother breast tissue and the milk of the pup stomach. Administration of a pharmacolgical inhibitor of GlcCer synthase to allergic mothers reduced GlcCer to the levels of GlcCer in non-allergic mothers and blocked the development of allergic lung inflammation and generation of allergen-specific IgE in allergen-challenged pups of allergic mothers. We also demonstrated that the fetal liver and offspring of allergic mothers have increased numbers of resident dendritic cells (DCs) and that the administration of the GlcCer synthase inhibitor to the allergic mothers blocked the increase in these DCs in the offspring. In summary, allergic mothers had increased GlcCer that is transferred to offspring and mediates changes in offspring DCs and responsiveness to allergen. These data have a significant impact on our understanding of mechanisms of maternal lipid regulation of offspring development of allergies and has the potential to lead to novel interventions that significantly impact risk for allergic disease early in life.