Fetal Immune Development Research Articles

Antibiotic treatment during pregnancy influences placental morphogenesis and fetal immune system development in a murine model

Antibiotic treatment during pregnancy influences placental morphogenesis and fetal immune system development in a murine model

Human erythroid progenitors express antigen presentation machinery.

Early-life immune exposures can profoundly impact lifelong health. However, functional mechanisms underlying fetal immune development remain incomplete. Erythrocytes are not typically considered active immune mediators, primarily because erythroid precursors discard their organelles as they mature, thus losing the ability to alter gene expression in response to stimuli. Erythroid progenitors and precursors circulate in human fetuses and neonates. Although there is limited evidence that erythroid precursors are immunomodulatory, our understanding of the underlying mechanisms remains inadequate. To define the immunobiological role of fetal and perinatal erythroid progenitors and precursors, we analyzed single cell RNA-sequencing data and found that transcriptomics support erythroid progenitors as putative immune mediators. Unexpectedly, we discovered that human erythroid progenitors constitutively express Major Histocompatibility Complex (MHC) class II antigen processing and presentation machinery, which are hallmarks of specialized antigen presenting immune cells. Furthermore, we demonstrate that erythroid progenitors internalize and cleave foreign proteins into peptide antigens. Unlike conventional antigen presenting cells, erythroid progenitors express atypical costimulatory molecules and immunoregulatory cytokines that direct the development of regulatory T cells, which are critical for establishing maternal-fetal tolerance. Expression of MHC II in definitive erythroid progenitors begins during the second trimester, coinciding with the appearance of mature T cells in the fetus, and is absent in primitive progenitors. Lastly, we demonstrate physical and molecular interaction potential of erythroid progenitors and T cells in the fetal liver. Our findings shed light on a unique orchestrator of fetal immunity and provide insight into the mechanisms by which erythroid cells contribute to host defense.

Developmental Programming of the Fetal Immune System by Maternal Western-Style Diet: Mechanisms and Implications for Disease Pathways in the Offspring.

Maternal obesity and over/undernutrition can have a long-lasting impact on offspring health during critical periods in the first 1000 days of life. Children born to mothers with obesity have reduced immune responses to stimuli which increase susceptibility to infections. Recently, maternal western-style diets (WSDs), high in fat and simple sugars, have been associated with skewing neonatal immune cell development, and recent evidence suggests that dysregulation of innate immunity in early life has long-term consequences on metabolic diseases and behavioral disorders in later life. Several factors contribute to abnormal innate immune tolerance or trained immunity, including changes in gut microbiota, metabolites, and epigenetic modifications. Critical knowledge gaps remain regarding the mechanisms whereby these factors impact fetal and postnatal immune cell development, especially in precursor stem cells in bone marrow and fetal liver. Components of the maternal microbiota that are transferred from mothers consuming a WSD to their offspring are understudied and identifying cause and effect on neonatal innate and adaptive immune development needs to be refined. Tools including single-cell RNA-sequencing, epigenetic analysis, and spatial location of specific immune cells in liver and bone marrow are critical for understanding immune system programming. Considering the vital role immune function plays in offspring health, it will be important to understand how maternal diets can control developmental programming of innate and adaptive immunity.

Pregnancy-induced transfer of pathogen-specific Tcells from mother to fetus in mice.

Neonatal health is determined by the transfer of maternal antibodies from the mother to the fetus. Besides antibodies, maternal cells cross the placental barrier and seed into fetal organs. Contrary to maternal antibodies, maternal microchimeric cells (MMc) show a high longevity, as they can persist in the offspring until adulthood. Recent evidence highlights that MMc leukocytes promote neonatal immunity against early-life infections in mice and humans. As shown in mice, this promotion of immunity was attributable to an improved fetal immune development. Besides this indirect effect, MMc may be pathogen-specific and thus, directly clear pathogen threats in the offspring postnatally. By using ovalbumin recombinant Listeria monocytogenes (LmOVA), we here provide evidence that OVA-specific T cells are transferred from the mother to the fetus, which is associated with increased activation of T cells and a milder course of postnatal infection in the offspring. Our data highlight that maternally-derived passive immunity of the neonate is not limited to antibodies, as MMc have the potential to transfer immune memory between generations.

Both maternal IFNγ exposure and acute prenatal infection with Toxoplasma gondii activate fetal hematopoietic stem cells

Infection directly influences adult hematopoietic stem cell (HSC) function and differentiation, but the fetal hematopoietic response to infection during pregnancy is not well‐studied. Here, we investigated the fetal hematopoietic response to maternal infection with Toxoplasma gondii (T. gondii), an intracellular parasite that elicits Type II IFNγ‐mediated maternal immunity. While it is known that maternal infection without direct pathogen transmission can affect fetal immune development, the effects of maternal IFNγ on developing HSCs and the signals that mediate these interactions have not been investigated. Our investigation reveals that the fetal HSCs respond to T. gondii infection with virulence‐dependent changes in proliferation, self‐renewal potential, and lineage output. Furthermore, maternal IFNγ crosses the fetal–maternal interface, where it is perceived by fetal HSCs. By comparing the effects of maternal IFNγ injection with maternal T. gondii infection, we reveal that the effects of IFNγ treatment mimic some aspects of the fetal HSC response to infection. Moreover, our findings illuminate that the fetal HSC response to prenatal infection is distinct from the adult HSC response to IFNγ‐induced inflammation. Altogether, our data disentangle the role of infection‐induced inflammatory cytokines in driving the expansion of downstream hematopoietic progenitors.

Maternal imprinting and determinants of neonates' immune function in the SEPAGES mother-child cohort.

Immune function in pregnancy is influenced by host-specific and environmental factors. This may impact fetal immune development, but the link between maternal and neonatal immune function is still poorly characterized. Here, we investigate the relationship between maternal and neonatal immune function, and identify factors affecting the association between maternal and child cytokine secretion. In the French prospective cohort SEPAGES, blood samples were obtained from pregnant women (n=322) at gestational week 20 ± 4 and from their child at birth (n=156). Maternal and cord blood cytokine and chemokine (CK) levels were measured at baseline in all subjects and after T cell or dendritic cell activation with phytohemagglutinin or R848 (in total 29 and 27 measures in maternal and cord blood samples, respectively). Associations between environmental, individual factors and CK level were estimated by linear regression modeling. The maternal-cord blood CK relations were assessed by Pearson correlation and regression models. We observed that pregnant women and neonates displayed specific CK secretion profiles in the innate and adaptive compartments at baseline and upon activation. Activation of T cells in cord blood induced high levels of IL-2, but low levels of IFNγ, IL-13 or IL-10, in comparison to maternal blood samples. Elsewhere, neonatal innate immune responses were characterized by low production of IFNα, while productions of IL-1β, IL-6, IL-8, IL-10 and TNFα were higher than maternal responses. Strong correlations were observed between most CK after activation in maternal and cord blood samples. Strikingly, a statistical association between global mother and child cytokine profiles was evidenced. Correlations were observed between some individual CK of pregnant women and their children, both at baseline (MCP1, RANTES) and after activation with R848 (IL-6, IL-8 and IL-10). We looked for factors which could influence cytokine secretion in maternal or cord blood, and found that leucocyte counts, maternal age, pre-conception BMI, smoking and season were associated with the levels of several CK in mothers or children. Our study reveals in utero immune imprinting influencing immune responses in infants, opening the way to investigate the mechanisms responsible for this imprinting. Whether such influences have long lasting effects on children health warrants further investigation.

In utero priming of fetal immune activation: Myths and mechanisms

Mechanisms of fetal immune system development in utero remain incompletely elucidated. Protective immunity, the arm of reproductive immunology concerned with the progressive education of the fetal immune system as pregnancy advances, allows for programming of the immune system and immune maturation in utero and provides a responsive system to respond to rapid microbial and other antigenic exposure ex utero. Challenges in studying fetal tissues, immune system development, and the contributions of various endogenous and exogenous factors to this process are difficult to study as a progressive sampling of fetal biological samples is impractical during pregnancy, and animal models are limited. This review provides a summary of mechanisms of protective immunity and how it has been shaped, from transplacental transfer of immunoglobulins, cytokines, metabolites, as well as antigenic microchimeric cells to perhaps more controversial notions of materno-fetal transfer of bacteria that subsequently organize into microbiomes within the fetal tissues. This review will also provide a quick overview of future direction in the area of research on fetal immune system development and discusses methods to visualize fetal immune populations and determine fetal immune functions, as well as a quick look into appropriate models for studying fetal immunity.

Expected impact of immunomodulatory agents during pregnancy: A newborn's perspective.

The neonatal immune ontogeny begins during pregnancy to ensure that the neonate is well-suited for perinatal life. It prioritizes Th2/M2 and regulatory responses over Th/M1 activity to avoid excessive inflammatory responses and to ensure immune tolerance and homeostasis. Newborns also present increased Th17/Th22 responses providing effective anti-fungal immunity and mucosal protection. Intrauterine exposure to immune modulatory drugs with the placental transfer may influence the natural course of the fetal immune development. The vertical transfer of both biological therapy and small molecules begins during the first trimester through neonatal Fc receptor or placental diffusion, respectively, reaching its maximum transfer potential during the third trimester of pregnancy. Most of the biological therapy have a prolonged half-life in newborn's blood, being detectable in infants up to 12 months after birth (usually 6-9 months). The use of immunomodulators during pregnancy is gaining global interest. Current evidence mainly reports birth-related outcomes without exhaustive analysis of the on-target side effect on the perinatal immune system ontogeny, the infection risk, or the immune dysregulation. The present review will focus on: (1) the main characteristics of the perinatal immune system to understand its specific features and vulnerabilities to immune modulation; (2) the mechanisms of placental transfer of immunomodulators; and (3) the immune changes reported to date in newborns exposed to immunomodulators with emphasis on the current concerns and gaps in knowledge.

Oat β-glucan supplementation pre- and during pregnancy alleviates fetal intestinal immunity development damaged by gestational diabetes in rats.

Oat β-glucan (OG) has been shown to improve intestinal microecology in gestational diabetes mellitus (GDM), but the effect on fetal intestine health is unknown. Herein, we aimed to investigate the effects of OG supplementation during gestation in GDM dams on fetal intestinal immune development. OG was supplemented one week before mating until the end of the experiment. GDM rats were made with a high-fat diet (HFD) with a minimal streptozotocin (STZ) dose. The fetal intestines were sampled at gestation day (GD) 19.5, and the intestinal morphology, chemical barrier molecules, intraepithelial immune cell makers, and levels of inflammatory cytokines were investigated. The results showed that OG supplementation alleviated the decrease of the depth of fetal intestinal villi and crypts, the number of goblet cells (GCs), protein expression of mucin-1 (Muc1) and Muc2, the mRNA levels of Gpr41, Gpr43, and T cell markers, and increased the number of paneth cells (PCs), the mRNA levels of defensin-6 (defa6), and macrophage (Mø) marker and the expression of cytokines induced by GDM. In addition, OG supplementation alleviated the function of immune cell self-proliferation, chemotaxis and assembly capabilities, protein, fat, folic acid, and zinc absorption damaged by GDM. As indicated by these findings, OG supplementation before and during pregnancy improved the fetal intestinal chemical barriers, immune cells, cytokines, and the metabolism of nutrients to protect the fetal intestinal immunity.

Hyperemesis gravidarum: does it increase offspring risk for inflammatory bowel disease and failure to thrive?

Hyperemesis gravidarum (HG) affects about 3% of pregnancies and may lead to nutritional deficits and distress. Since maternal malnutrition and stress have been shown to affect fetal intestine and immune system development, we aimed to study the association between HG and the risk for offspring inflammatory bowel disease (IBD) and failure to thrive (FTT).Study Design: A retrospective cohort study was performed comparing incidence of offspring IBD and FTT between mothers with and without HG diagnosis. All singleton deliveries of mothers from the largest HMO in the country between the years 1991-2021 were included. Their offspring were followed until the age of 18 years, and the studied outcomes were based on hospitalization records of the pediatric databases of a large single tertiary center. Multivariable Cox survival models were used to adjust for confounding characteristics.Results: The study population included 232476 pregnancies, of them 3225 (1.4%) were complicated with HG. Mothers with HG were more likely to be smokers, and to deliver preterm and by cesarean delivery (CD). The incidence of FTT was higher among offspring born to mothers with HG (3.4% versus 2.5%, OR=1.36; 1.12-1.65, p=0.002), as well as IBD (13.3% versus 8.1%, OR= 1.74; 1.57-1.93, p< 0.001; Figure, Kaplan-Meier log rank, p< 0.001 for both). In the multivariable Cox model, offspring born following pregnancies complicated with HG were more likely to suffer from IBD (adjusted HR=1.81; 1.64-2.00, p< 0.001), and FTT (adjusted HR=1.49; 1.23-1.80, p< 0.001) while adjusting for gestational age, maternal age, CD and ethnicity.Conclusion: Offspring of pregnancies complicated with HG are at increased risk for FTT and IBD, suggesting this early life exposure may have long-term effects on the offspring, possibly due to maternal stress and malnutrition during critical period of fetal development.View Large Image Figure ViewerDownload Hi-res image Download (PPT)

Gestational Exposure to Ambient Particulate Matter Alters Neonatal Cytokines

The role of maternal exposure to fine particulate matter (PM2.5) in the development of the fetal immune system remains unclear. A total of 482 mother–infant pairs were included in our longitudinal birth cohort study. Maternal PM2.5 exposure during the first trimester was assessed, and 27 neonatal cytokines were detected. This study was designed to evaluate the effects of maternal PM2.5 exposure on fetal immune system development and to identify the most heavily weighted component. Negative associations were observed between maternal PM2.5 exposure and neonatal IL7 [β = −0.05; 95% confidence interval (CI), (−0.07, −0.03); p < 0.001], IL12 [β = −0.04; 95% CI, (−0.06, −0.01); p = 0.05], and IL13 [β = −0.04; 95% CI, (−0.06, −0.02); p = 0.02], while positive associations with neonatal Eotaxin [β = 0.17; 95% CI, (0.09, 0.25); p < 0.001], PDGFbb [β = 0.15; 95% CI, (0.07, 0.23); p = 0.01], MIP1b [β = 0.10; 95% CI, (0.05, 0.15); p < 0.001], and RANTES [β = 0.32; 95% CI, (0.22, 0.41); p < 0.001]. The most heavily weighted component in the three interleukin models was consistently BC (weighted 0.95 for IL7, 0.85 for IL12, and 0.88 for IL13), NH4+ for two chemokines (weighted 0.47 for Eotaxin and 0.32 for RANTES), and SO42– for PDGFbb (0.43) and MIP1b (0.42). Gestational exposure to PM2.5 could alter neonatal cytokine levels, and special attention should be paid to certain components.

Effects of Maternal Diet during Pregnancy or Lactation on the Development or Prevention of Allergic Diseases in Offspring

The increasing prevalence of allergic diseases in the past decades has been caused by environmental rather than genetic factors. Recent research has focused on the relationship between the mother’s environmental exposure, especially during pregnancy, and allergic outcomes in the offspring. Intervention studies to prevent allergic diseases have also been conducted. Environmental factors, such as diet induce changes in the mother's intestinal flora, and the signals generated have a permanent effect on the fetal immune development through an epigenetic mechanism, which may be involved in disease development. This review outlines whether dietary patterns in mothers are related to allergic diseases, and it summarizes whether supplementation with micronutrients, such as omega-3 unsaturated fatty acids, vitamin D, and folic acid can prevent allergic diseases. Studies have found that a westernized diet is associated with an increase in the prevalence of allergic diseases; however, intervention studies conducted with micronutrients or probiotics do not provide clear results regarding its preventive effect. A mother’s diet during pregnancy or lactation may affect the health of the child. Well-designed intervention studies are warranted to attempt to prevent allergic diseases. Consequently, good dietary patterns based on high-quality evidence are recommended for pregnant and lactating mothers.

Maternal obesity, gestational weight gain, and offspring asthma and atopy

BackgroundMaternal obesity may affect offspring asthma and atopic disease risk by altering fetal immune system development. However, few studies evaluate gestational weight gain (GWG). ObjectiveTo evaluate relationships between maternal body mass index (BMI), GWG, and persistent wheeze, eczema, allergy, and asthma risk in offspring through middle childhood. MethodsA total of 5939 children from Upstate KIDS, a population-based longitudinal cohort of children born in upstate New York (2008-2019) were included in the analysis. Persistent wheeze or asthma, eczema, and allergy were maternally reported at multiple study time points throughout early and middle childhood. Poisson regression models with robust SEs were used to estimate adjusted risk ratios (aRRs) and 95% confidence intervals (CIs) for offspring atopic outcomes by maternal prepregnancy BMI and GWG. ResultsPrepregnancy BMI was associated with increased risk of persistent wheeze by 3 years of age even after adjustments for maternal atopy (class I obesity: aRR, 1.58; 95% CI, 1.13-2.20; class II or III obesity: aRR, 1.69; 95% CI, 1.22-2.35). Associations with reported asthma in middle childhood did not reach statistical significance. Furthermore, no associations were found between prepregnancy BMI and atopic outcomes in either early or middle childhood. GWG was not associated with higher risk of early childhood persistent wheeze or middle childhood asthma. ConclusionMaternal prepregnancy BMI was associated with increased risk of offspring wheeze, whereas excessive GWG was generally not associated with childhood asthma or atopy.

Establishment of tissue-resident immune populations in the fetus.

The immune system establishes during the prenatal period from distinct waves of stem and progenitor cells and continuously adapts to the needs and challenges of early postnatal and adult life. Fetal immune development not only lays the foundation for postnatal immunity but establishes functional populations of tissue-resident immune cells that are instrumental for fetal immune responses amidst organ growth and maturation. This review aims to discuss current knowledge about the development and function of tissue-resident immune populations during fetal life, focusing on the brain, lung, and gastrointestinal tract as sites with distinct developmental trajectories. While recent progress using system-level approaches has shed light on the fetal immune landscape, further work is required to describe precise roles of prenatal immune populations and their migration and adaptation to respective organ environments. Defining points of prenatal susceptibility to environmental challenges will support the search for potential therapeutic targets to positively impact postnatal health.

Does the Amniotic Fluid of Mice Contain a Viable Microbiota?

The existence of an amniotic fluid microbiota (i.e., a viable microbial community) in mammals is controversial. Its existence would require a fundamental reconsideration of fetal in utero exposure to and colonization by microorganisms and the role of intra-amniotic microorganisms in fetal immune development as well as in pregnancy outcomes. In this study, we determined whether the amniotic fluid of mice harbors a microbiota in late gestation. The profiles of the amniotic fluids of pups located proximally or distally to the cervix were characterized through quantitative real-time PCR, 16S rRNA gene sequencing, and culture (N = 21 dams). These profiles were compared to those of technical controls for bacterial and DNA contamination. The load of 16S rRNA genes in the amniotic fluid exceeded that in controls. Additionally, the 16S rRNA gene profiles of the amniotic fluid differed from those of controls, with Corynebacterium tuberculostearicum being differentially more abundant in amniotic fluid profiles; however, this bacterium was not cultured from amniotic fluid. Of the 42 attempted bacterial cultures of amniotic fluids, only one yielded bacterial growth – Lactobacillus murinus. The 16S rRNA gene of this common murine-associated bacterium was not detected in any amniotic fluid sample, suggesting it did not originate from the amniotic fluid. No differences in the 16S rRNA gene load, 16S rRNA gene profile, or bacterial culture were observed between the amniotic fluids located Proximally and distally to the cervix. Collectively, these data indicate that, although there is a modest DNA signal of bacteria in murine amniotic fluid, there is no evidence that this signal represents a viable microbiota. While this means that amniotic fluid is not a source of microorganisms for in utero colonization in mice, it may nevertheless contribute to fetal exposure to microbial components. The developmental consequences of this observation warrant further investigation.

Vertically transferred maternal immune cells promote neonatal immunity against early life infections

During mammalian pregnancy, immune cells are vertically transferred from mother to fetus. The functional role of these maternal microchimeric cells (MMc) in the offspring is mostly unknown. Here we show a mouse model in which MMc numbers are either normal or low, which enables functional assessment of MMc. We report a functional role of MMc in promoting fetal immune development. MMc induces preferential differentiation of hematopoietic stem cells in fetal bone marrow towards monocytes within the myeloid compartment. Neonatal mice with higher numbers of MMc and monocytes show enhanced resilience against cytomegalovirus infection. Similarly, higher numbers of MMc in human cord blood are linked to a lower number of respiratory infections during the first year of life. Our data highlight the importance of MMc in promoting fetal immune development, potentially averting the threats caused by early life exposure to pathogens.

Role of maternal tryptophan metabolism in allergic diseases in the offspring.

Nicotinamide (vitamin B3) is a metabolite of tryptophan and dietary precursor of enzymes involved in many regulatory processes, which may influence fetal immune development. We examined whether maternal plasma concentrations of nicotinamide, tryptophan or nine related tryptophan metabolites during pregnancy were associated with the risk of development of infant eczema, wheeze, rhinitis or allergic sensitization. In the Growing Up in Singapore Towards Healthy Outcomes (GUSTO) study, we analysed the associations between maternal plasma levels of nicotinamide, tryptophan and tryptophan metabolites at 26-28weeks of gestation and allergic outcomes collected through interviewer-administered questionnaires at multiple time-points and skin prick testing to egg, milk, peanut and mites at age 18months. Multivariate analysis was undertaken adjusting for all metabolites measured and separately adjusting for relevant demographic and environmental exposures. Analyses were also adjusted for multiple comparisons using the false discovery method. Tryptophan metabolites were evaluated in 976/1247 (78%) women enrolled in GUSTO. In multivariate analysis including all metabolites, maternal plasma 3-hydrokynurenine was associated with increased allergic sensitization at 18months (AdjRR 2.6, 95% CI 1.3-5.2 for highest quartile) but the association with nicotinamide was not significant (AdjRR 1.8, 95% CI 0.9-3.6). In analysis adjusting for other exposures, both 3-hydrokynurenine and nicotinamide were associated with increased allergic sensitization (AdjRR 2.0, 95% CI 1.1-3.6 for both metabolites). High maternal plasma nicotinamide was associated with increased infant eczema diagnosis by 6 and 12months, which was not significant when adjusting for all metabolites measured, but was significant when adjusting for relevant environmental and demographic exposures. Other metabolites measured were not associated with allergic sensitization or eczema, and maternal tryptophan metabolites were not associated with offspring rhinitis and wheeze. Maternal tryptophan metabolism during pregnancy may influence the development of allergic sensitization and eczema in infants.

Maternal heat stress reduces body and organ growth in calves: Relationship to immune status

Late-gestation heat stress of dairy cows reduces fetal growth and influences postnatal performance and immune status of the offspring. Our first objective was to evaluate the effect of in utero heat stress on overall fetal and organ growth, particularly organs associated with immune function. The second objective was to examine the cellular mechanism of altered passive immunity in neonatal bull calves after in utero heat stress. Specifically, we examined the rate of apoptosis of intestinal cells early in life, as it is associated with gut closure. Dams were dried off approximately 45 d before expected calving and randomly assigned to 1 of 2 treatments: heat stress (HT) or cooling (CL). During the dry period all cows were housed under shade in a freestall barn, where the pen for CL cows was equipped with active cooling, including water soakers and fans, whereas the pen for HT cows had no soakers or fans. Using rectal temperature and respiration rate as indicators, heat stress was severe. Average rectal temperature in HT cows was 39.3°C compared with 39.0°C in CL cows, and HT cows had a respiration rate of 66.7 breaths/min compared with 43.2 breaths/min for CL cows. Bull calves (n = 30) were immediately separated from their dams at birth, weighed, and then killed before colostrum feeding (n = 5/treatment; d 0) or at 1 or 2 d of age following colostrum feeding (n = 5/treatment per day). After slaughter, the small intestine was removed and weighed, and samples from the jejunum were fixed for immunohistochemistry. Birth weight of bulls from HT dams was 1.1 kg lower than that of bulls from CL dams. Thymus, spleen, and heart weights of HT bulls were lower relative to those of CL bulls, whereas liver weight of HT bulls tended to be lower relative to that of CL bulls. Jejunal cell apoptosis decreased with age in both HT and CL calves after birth, mirroring gut closure. However, in utero heat stress increased the apoptotic rate in the jejunum, particularly at birth. We conclude that the chronic exposure to heat strain of HT compared with CL dams in late gestation significantly affected fetal growth and immune tissue development, which may be associated with reduced immune function in early life. Also, late-gestation heat stress increased calves' intestinal apoptosis in the first 2 d of life, which might explain the decreased IgG uptake and limited passive immune competence observed in previous studies.

β-Glucosylceramide From Allergic Mothers Enhances Offspring Responsiveness to Allergen.

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.

Microbiota, Epigenetics, and Trained Immunity. Convergent Drivers and Mediators of the Asthma Trajectory from Pregnancy to Childhood.

The prevalence of allergy and asthma has increased significantly over the past several decades, especially in industrialized nations where environmental exposures and lifestyles have rapidly diverged from those with which humans evolved. Developing effective interventions for precision treatment and prevention of allergy and asthma requires a deeper understanding of their origins and underlying mechanisms. This Perspective proposes a trans-generational framework for future studies that integrates microbiome, immunology, genetics and epigenetics research in human populations and model systems. We suggest that environmental exposures during pregnancy shape maternal microbiomes and immune function, which in turn influence fetal immune and microbiome development in the context of the child's genetic makeup. Relying on epigenetic mechanisms, these interacting influences train the neonate's innate immune system and regulate its ability to respond to the stimuli provided by microbes vertically transmitted from the mother that initially colonize neonatal body habitats. Depending on their composition and functional properties, these pioneer microbes shape immune function which controls the rate and types of exogenous microbes accumulated into these body habitats during the first year of life, thereby determining trajectories of microbiota development, innate and adaptive immune development, and ultimately asthma risk. One critical implication of the framework we propose is that hitherto independent research tracks should converge to determine how very early life microbes in the context of extrinsic and intrinsic factors direct the accumulation of environmental microbes in early life, and how the composition and metabolic capacity of the child's microbiome at various body habitats, shaped by these interacting influences, controls immune development and asthma risk.