β-Glucosylceramide From Allergic Mothers Enhances Offspring Responsiveness to Allergen

Abstract

In animals and humans, offspring of allergic mothers have increased responsiveness to allergen and the allergen-specificity of the offspring can be different than that of the mother. In our preclinical models, the mother's allergic responses influence development of the fetus and offspring by elevating numbers of cells in dendritic cell subsets. A major question is the identity of maternal factors of allergic mothers that alter offspring development of responsiveness to allergen. Lipids are altered during allergic responses and lipids are transported to the fetus for growth and formation of fetal membranes. We hypothesized that pro-inflammatory lipids, that are elevated in allergic mothers, are transported to the fetus and regulate fetal immune development. We demonstrate in this report that there was a significant 2-fold increase in β-glucosylceramides (βGlcCer) in allergic mothers, the fetal liver and her offspring. The βGlcCer were transported from mother's plasma, across the placenta, to the fetus and in breastmilk to the offspring. Administration of βGlcCer to non-allergic mothers was sufficient for offspring responses to allergen. Importantly, maternal administration of a clinically relevant pharmacological inhibitor of βGlcCer synthase returned βGlcCer to normal levels in the allergic mothers and her offspring and blocked the offspring increase in dendritic cell subsets and offspring allergen responsiveness. In summary, allergic mothers had increased βGlcCer that was transported to offspring and mediated increases in offspring DCs and responsiveness to allergen. These data have a significant impact on our understanding of mechanisms for development of allergies in offspring of allergic mothers and have the potential to lead to novel interventions that significantly impact risk for allergic disease early in life.

Cord blood sphingolipids are associated with atopic dermatitis and wheeze in the first year of life

“…Briefly, internal lipid standards were added to the samples and the lipids were extracted and analyzed by mass spectrometry as previously described. 7 Because bGlcCer and b-galactosylceramide (bGalCer) are coeluted by the UHPLC-MS/MS method, biologic samples containing both were separated with an LC-Si column and then analyzed by mass spectrometry, as described in detail in the Supplementary Methods.…”

“…[21][22][23][24]42 The P value cutoffs for significant lipids were adjusted for FDR as in the volcano plot analysis in comparison with cluster 6. The proinflammatory lipid index for each cluster or for each infant was based a priori on preclinical data and studies in humans for proinflammatory functions of sphingolipids 7,15 and the anti-inflammatory functions reported for lipoxin A4 and resolvins 11,43 ; the index was generated by using the lipids that had significant increases in the volcano plots for the clusters compared with cluster 6. The means for the lipids in cluster 6 were used as reference values (see Table E3 in the Online Repository at www.jaci-global.org) to calculate the log 2 FC for lipids in clusters or for each infant.…”

“…In the analysis of lipids, the mean log 2 FC is used instead of absolute lipid concentrations because the lipids occur at different magnitudes and because absolute plasma or tissue concentrations for sphingolipid chain lengths do not reflect proinflammatory and anti-inflammatory potency. 7,44 The statistical analyses for outcomes were based on the biologic function of lipids and preclinical data in mice and associations in humans. 7,15,45,46 Boxplots for the immune cell phenotypes of each of the clusters were generated by ggplot2, and the statistical significance of proportions of each of the phenotypes among clusters was calculated by using wilcox.test in the rstatix package.…”

“…4 In humans and animals, offspring of mothers with allergy have increased responsiveness to allergens. [5][6][7] In mechanistic murine studies addressing why maternal atopy is a strong risk factor, 7 we demonstrated that lipid changes in mothers with allergy and the transfer of these lipids to offspring enhance development of allergic disease and increase the numbers of subsets of proinflammatory dendritic cells (DCs) in the fetal liver and offspring. 4,8 Also, DCs from pups of mothers with allergy have enhanced allergen presentation function.…”

“…4,[18][19][20] We reported that elevated plasma sphingosine-1-phosphate of mothers with allergy is catabolized in the placenta and is not elevated in the fetus, whereas maternal b-glucosylceramides (bGlcCers) are transported to the fetal liver and enhance the numbers of offspring DCs. 7 It is not known whether these preclinical observations for sphingolipid regulation of offspring development of allergy extend to humans or whether early-life changes in the anti-inflammatory lipids resolvins and lipoxins influence the development of wheeze early in life. Lipids have different classes, have several chain lengths, and are present at different concentrations in vivo for regulation of biologic functions.…”