Maternal Systemic Inflammation Research Articles

A mouse model of prenatal exposure to Interleukin-6 to study the developmental origin of health and disease

Systemic inflammation in pregnant obese women is associated with 1.5- to 2-fold increase in serum Interleukin-6 (IL-6) and newborns with lower kidney/body weight ratio but the role of IL-6 in increased susceptibility to chronic kidney (CKD) in adult progeny is not known. Since IL-6 crosses the placental barrier, we administered recombinant IL-6 (10 pg/g) to pregnant mice starting at mid-gestation yielded newborns with lower body (p < 0.001) and kidney (p < 0.001) weights. Histomorphometry indicated decreased nephrogenic zone width (p = 0.039) with increased numbers of mature glomeruli (p = 0.002) and pre-tubular aggregates (p = 0.041). Accelerated maturation in IL-6 newborns was suggested by early expression of podocyte-specific protein podocin in glomeruli, increased 5-methyl-cytosine (LC–MS analysis for CpG DNA methylation) and altered expression of certain genes of cell-cycle and apoptosis (RT-qPCR array-analysis). Western blotting showed upregulated pJAK2/pSTAT3. Thus, treating dams with IL-6 as a surrogate provides newborns to study effects of maternal systemic inflammation on future susceptibility to CKD in adulthood.

Systemic Inflammation among Pregnant African American Women Is Related to Depressive Symptoms and Intimate Partner Violence

Systemic inflammation (e.g., higher levels of pro-inflammatory cytokine interleukin [IL]-6 and C-reactive protein [CRP]) during pregnancy increases risk for both the mother and the infant. For the mother, systemic inflammation is associated with an increased risk of pregnancy complications (e.g., preeclampsia). For the infant, cytokine dysregulation may lead to long term immune dysregulation and susceptibility to metabolic diseases. Pregnant African American women are more likely to have greater systemic inflammation compared with pregnant non-Hispanic White women. They also experience a higher prevalence of chronic conditions (e.g., asthma), have higher levels of depressive symptoms, and report more incidents of intimate partner violence (IPV). We hypothesize that maternal systemic inflammation is related to chronic disease, depressive symptoms, and IPV among pregnant African American women. Pregnant African American women (n=180) were recruited at prenatal clinics in the Midwest. Women completed a questionnaire and had blood drawn at a prenatal visit. Plasma cytokine levels (interferon [IFN]-γ, tumor necrosis factor [TNF]-α, IL-6, IL8 and IL10) were measured by multiplex array and CRP was measured by ELISA. Data were log (x+1) transformed and analyzed using descriptive statistics and correlational analysis (Pearson and point-biserial correlations). Women had a mean age of 27±5.5 years (range 18-41) and a mean gestational age at data collection of 16±5.8 weeks (range 8-29). Fifty-five percent of women were employed, 42% had annual household income < $10,000, and 16% smoked cigarettes during pregnancy. Twenty-five percent of women reported asthma, 8% hypertension, 6% diabetes, and 4% thyroid disease. Twenty-seven percent of women had Center for Epidemiological Studies-Depression (CES-D) scores ≥ 23, which have been correlated with depression diagnosis. IPV during the year before pregnancy was more frequent (8%) than IPV during pregnancy (5.1%). Women who reported hypertension had higher levels of TNF-α (r= 0.151, p< 0.05); and women with asthma had higher levels of CRP (r= 0.20, p< 0.01). Women who reported higher CES-D scores (r= 0.19, p< 0.05) had higher CRP levels. Women who reported IPV during pregnancy had higher IL-8 levels (r= 0.17, p< 0.05). Women who were employed had lower levels of IL-6 compared to women who were not employed (r= -0.180, p< 0.05). These results indicate that systemic inflammation is related to chronic health conditions (hypertension, asthma), depressive symptoms, IPV and employment status in pregnant African American women. The relationships between systemic inflammation, depressive symptoms and IPV, with a focus on metabolic and molecular pathways should be investigated to better understand the mechanisms by which maternal and fetal health are affected.

Maternal allergic inflammation in rats impacts the offspring perinatal neuroimmune milieu and the development of social play, locomotor behavior, and cognitive flexibility

Maternal systemic inflammation increases risk for neurodevelopmental disorders like autism, ADHD, and schizophrenia in offspring. Notably, these disorders are male-biased. Studies have implicated immune system dysfunction in the etiology of these disorders, and rodent models of maternal immune activation provide useful tools to examine mechanisms of sex-dependent effects on brain development, immunity, and behavior. Here, we employed an allergen-induced model of maternal inflammation in rats to characterize levels of mast cells and microglia in the perinatal period in male and female offspring, as well as social, emotional, and cognitive behaviors throughout the lifespan. Adult female rats were sensitized to ovalbumin (OVA), bred, and challenged intranasally on gestational day 15 of pregnancy with OVA or saline. Allergic inflammation upregulated microglia in the fetal brain, increased mast cell number in the hippocampus on the day of birth, and conferred region-, time- and sex- specific changes in microglia measures. Additionally, offspring of OVA-exposed mothers subsequently exhibited abnormal social behavior, hyperlocomotion, and reduced cognitive flexibility. These data demonstrate the long-term effects of maternal allergic challenge on offspring development and provide a basis for understanding neurodevelopmental disorders linked to maternal systemic inflammation in humans.

Associations between maternal obesity, gestational cytokine levels and child obesity in the NEST cohort.

Although maternal systemic inflammation is hypothesized to link maternal pre-pregnancy obesity to offspring metabolic dysfunction, patient empirical data are limited. In this study, we hypothesized that pre-pregnancy obesity alters systemic chemo/cytokines concentrations in pregnancy, and this alteration contributes to obesity in children. In a multi-ethnic cohort of 361 mother-child pairs, we measured prenatal concentrations of plasma TNF-α, IL-6, IL-8, IL-1β, IL-4, IFN-γ, IL-12 p70 subunit, and IL-17A using a multiplex ELISA and examined associations of pre-pregnancy obesity on maternal chemo/cytokine levels, and associations of these cytokine levels with offspring body mass index z score (BMI-z) at age 2-6 years using linear regression. After adjusting for maternal smoking, ethnicity, age, and education, pre-pregnancy obesity was associated with increased concentrations of TNF-α (P=.026) and IFN-γ (P=.06). While we found no evidence for associations between TNF-α concentrations and offspring BMI-z, increased IFN-γ concentrations were associated with decreased BMI-z (P=.0002), primarily in Whites (P=.0011). In addition, increased maternal IL-17A concentrations were associated with increased BMI-z in offspring (P=.0005) with stronger associations in African Americans (P=.0042) than Whites (P=.24). Data from this study are consistent with maternal obesity-related inflammation during pregnancy, increasing the risk of childhood obesity in an ethnic-specific manner.

Iron-Dependent Apoptosis Causes Embryotoxicity in Inflamed and Obese Pregnancy

Since iron is essential for pregnancy, iron supplements are routinely prescribed to pregnant women without screening for iron deficiency. Most women in developed countries have sufficient iron stores, prompting concerns of the potential risks of iron supplementation in iron-replete women. A signal of potential harm of this practice is the association of maternal iron marker ferritin and pregnancy complications. Since ferritin is also induced by inflammation, it is unclear whether iron excess, inflammation, or their interaction cause fetal injury. We used mouse models to address this question. Two mouse models of maternal iron excess were used and compared to mice with normal iron status. To model dietary iron supplementation, C57BL/6 females were fed high-iron diet (2500-5000ppm iron) for 1 week prior to and during pregnancy. To model genetic iron loading, hepcidin knockout females were used and fed standard chow (185ppm iron). Two models of maternal inflammation were used. Acute systemic maternal inflammation was induced by a single subcutaneous injection of LPS on E8.5 or 15.5. Obesity was used as a model of mild chronic systemic maternal inflammation and was induced by feeding female mice Western diet. We evaluated the maternal, placental, and embryo response to iron excess in LPS- and obesity-induced inflammation at various time points. In the model of acute inflammation, we observed an adverse synergistic effect on embryo development when dams were both iron-loaded and LPS-injected, but not with either condition alone. On E8.5, LPS injection in iron-loaded dams caused embryo loss and encephalic malformations (Fig 1a) and on E15.5, LPS injection in iron-loaded dams caused embryo demise and resorption (Fig 1b). Western blotting and immunostaining showed increased apoptotic marker cleaved caspase-3 protein localized to endothelia in placentas and embryos, only when the dam was both iron-loaded and LPS-injected. Cytokine screen in vitro identified TNFα as the signal that synergized with iron to potentiate apoptosis of endothelial cells. Treatment of iron-loaded dams with TNFα-neutralizing antibody protected embryos from LPS-induced death, demonstrating the embryotoxic role of maternal TNFα in iron-loaded dams. Furthermore, RNA-Seq analysis of placental endothelial cells showed enrichment in oxidative stress pathways with maternal iron loading. Treatment of iron-loaded dams with antioxidant α-tocopherol protected against LPS-induced embryo death, attenuated placental inflammation and cleaved caspase-3 expression, and prevented endothelial apoptosis in the placenta and embryo. These data show that iron loading causes endothelial oxidative stress, which sensitizes endothelial cells to inflammation-induced apoptosis. In the obesity model, iron loading worsened embryotoxicity, causing subcutaneous hemorrhaging and eye malformations (Fig 1c), and potentiated placental cleaved caspase-3 expression. Iron loading increased TNFα levels in maternal serum. Importantly, treatment of obese iron-loaded dams with neutralizing TNFα antibody throughout pregnancy reduced the incidence of embryo eye malformations, confirming the role of TNFα in causing embryo injury in iron-loaded obese pregnancy. In summary, maternal iron excess worsened inflammation-induced embryo injury. Iron-dependent embryotoxicity was mediated by TNFα causing lethal apoptotic damage to embryo and placental endothelium which was prevented by antioxidant therapy. Our models raise the possibility that women exposed to both excessive iron and inflammation could be at risk for preventable pregnancy complications. Figure 1. Embryo outcomes in mouse pregnancies with maternal iron loading and inflammation. Figure 1 Disclosures Ganz: Akebia: Consultancy; Vifor: Consultancy; Ionis Pharmaceuticals: Consultancy; Silarus Therapeutics: Current equity holder in private company; Intrinsic LifeSciences: Current equity holder in private company; Global Blood Therapeutics: Consultancy; Ambys: Consultancy; Gossamer Bio: Consultancy; Astellas: Consultancy; Rockwell: Consultancy; Sierra Oncology: Consultancy; Disc Medicine: Consultancy; American Regent: Consultancy. Nemeth:Intrinsic LifeSciences: Current equity holder in private company; Vifor: Consultancy; Protagonist: Consultancy; Silarus Therapeutics: Current equity holder in private company; Ionis Pharmaceuticals: Consultancy.

Fetal growth restriction is a host specific response to infection with an impaired spiral artery remodeling-inducing strain of Porphyromonas gingivalis

Porphyromonas gingivalis is a periodontal pathogen implicated in a range of pregnancy disorders that involve impaired spiral artery remodeling (ISAR) with or without fetal growth restriction (FGR). Using a rodent periodontitis model, we assessed the ability of P. gingivalis to produce ISAR and FGR in Sprague Dawley (SD) and Wistar (WIS) rats. Both infected SD and WIS rats developed ISAR, but only WIS rats developed FGR despite both rat strains having equivalent microbial loads within the placenta. Neither maternal systemic inflammation nor placental (fetal) inflammation was a feature of FGR in WIS rats. Unique to infected WIS rats, was loss of trophoblast cell density within the junctional zone of the placenta that was not present in SD tissues. In addition, infected WIS rats had a higher proportion of junctional zone trophoblast cells positive for cytoplasmic high temperature requirement A1 (Htra1), a marker of cellular oxidative stress. Our results show a novel phenomenon present in P. gingivalis-induced FGR, with relevance to human disease since dysregulation of placental Htra1 and placental oxidative stress are features of preeclamptic placentas and preeclampsia with FGR.

Sex Bias in Maternal Immune Activation-Induced Neurodevelopmental Disorder Begins at the Placenta

Systemic maternal inflammation during pregnancy is increasingly thought to be a risk factor for development of autism spectrum disorder (ASD), which is diagnosed at a rate 4-fold higher in males than in females. Administration of the viral mimic polyI:C to pregnant mice at mid-gestation leads to ASD-related phenotypes in offspring, consisting of deficits in communication and socialization, as well as repetitive behaviors. In this model of maternal immune activation (MIA), elevated production of maternal serum cytokines is known to promote alterations in fetal neurodevelopment. Although male and female littermates are exposed to the same maternal inflammation, we show that behavioral deficits can be elicited preferentially in the male offspring, mirroring the sex bias observed in human ASD. Because the placenta is partially derived from fetal cells and is the first site of fetal exposure to hematogenous maternal inflammation, we hypothesized that sex-specific reactions to MIA may originate at the placenta and that characterization of these sex differences may offer new insights into the orgins of neurodevelopmental disorders. To characterize responses to MIA at the maternal-fetal interface, we conducted bulk RNA sequencing of the placenta from polyI:C- and saline-treated embryos at several time points post-injection. We identified male-biased elevation in the expression of inflammatory signatures involving neutrophils, innate immune signaling, and antigen presentation. Placental transcriptomics analysis also identified male-specific downregulation of cholesterol and fatty acid synthesis as well as a gene signature suggesting failing placental health. Interestingly, we found that MIA induced the differential expression of a large percentage of high-risk autism genes at the placenta. These findings shed new light on how sex and maternal inflammation interface to shape placental responses and may help to reveal new molecular players underpinning sex differences in neurodevelopmental disorders.

Systemic Maternal Inflammation and Postnatal Hyperoxia Induce Early Life Cardiovascular Contractile Abnormalities in Mice

BACKGROUND: Young adults who were born prematurely have higher rates of heart failure, cardiac hypertrophy, and systolic dysfunction than those born full term. The mechanism underlying these abnormalities likely include changes in the contractile machinery of the heart, including α myosin heavy chain (αMHC) and β myosin heavy chain (βMHC). microRNA-208a and microRNA-208b play key roles in the regulation of myosin heavy chain expression. In adult mice, previous exposure to perinatal inflammation and postnatal …

Systemic Maternal Inflammation and Postnatal Hyperoxia Induce Early Life Cardiovascular Contractile Abnormalities in Mice

Systemic Maternal Inflammation and Postnatal Hyperoxia Induce Early Life Cardiovascular Contractile Abnormalities in Mice

Regulatory T Cells Play a Role in a Subset of Idiopathic Preterm Labor/Birth and Adverse Neonatal Outcomes

SUMMARYRegulatory T cells (Tregs) have been exhaustively investigated during early pregnancy; however, their role later in gestation is poorly understood. Herein, we report that functional Tregs are reduced at the maternal-fetal interface in a subset of women with idiopathic preterm labor/birth, which is accompanied by a concomitant increase in Tc17 cells. In mice, depletion of functional Tregs during late gestation induces preterm birth and adverse neonatal outcomes, which are rescued by the adoptive transfer of such cells. Treg depletion does not alter obstetrical parameters in the mother, yet it increases susceptibility to endotoxin-induced preterm birth. The mechanisms whereby depletion of Tregs induces adverse perinatal outcomes involve tissue-specific immune responses and mild systemic maternal inflammation, together with dysregulation of developmental and cellular processes in the placenta, in the absence of intra-amniotic inflammation. These findings provide mechanistic evidence supporting a role for Tregs in the pathophysiology of idiopathic preterm labor/birth and adverse neonatal outcomes.

Dose-dependent structural and immunological changes in the placenta and fetal brain in response to systemic inflammation during pregnancy.

Systemic maternal inflammation is associated with adverse neonatal sequelae. We tested the hypothesis that IL-1β is a key inflammatory regulator of adverse pregnancy outcomes. Pregnant mice were treated with intraperitoneal injections of IL-1β (0, 0.1, 0.5, or 1μg) from embryonic day (E)14 to E17. Placenta and fetal brains were harvested and analyzed for morphologic changes and IL-1β signaling markers. As compared with non-treated dams, maternal injections with IL-1β resulted in increased p-NF-κB and caspase-1 in placentas and fetal brains, but not consistently in spleens, suggesting induction of intrinsic IL-1β production. These findings were confirmed by increased levels of IL-1β in the placentas of the IL-1β-treated dams. Systemic treatment of dams with IL-1β suppressed Stat1 signaling. Maternal inflammation caused by IL-1β treatment reduced fetal viability to 80.6% and 58.9%, in dams treated with either 0.5 or 1μg of IL-1β, respectively. In the placentas, there was an IL-1β dose-dependent distortion of the labyrinth structure, decreased numbers of mononuclear trophoblast giant cells, and reduced proportions of endothelial cells as compared to placentas from control dams. In fetal brains collected at E17, there was an IL-1β dose-dependent reduction in cortical neuronal morphology. This work demonstrates that systemic IL-1β injection causes dose-dependent structural and functional changes in the placenta and fetal brain.

The Impact of Perinatal Exposure to Inflammation and Hyperoxia on the MicroRNA Profile of the Developing Heart

BackgroundSeveral cardiac‐specific microRNAs (miRs) are involved in the embryonic and postnatal development of the heart, with alterations in normal expression implicated in multiple disease states. This research aims to understand the impact of exposure to maternal systemic inflammation and/or postnatal hyperoxia on the microRNA profile of the developing heart using a murine model. MiRs‐1 and ‐133 are involved early in cardiac embryogenesis and regulate the transformation of mesoderm into cardiomyocytes. MiR‐195 regulates the cell cycle and proliferation of cardiomyocytes. MiRs‐208a, ‐208b, and ‐499 regulate the differential expression of myosin heavy chain isoforms, which contribute to myocardial contractile strength and energy consumption.MethodsPregnant C3H/HeN mice were injected on embryonic day 16 (E16) intraperitoneal lipopolysaccharide (LPS) to induce maternal inflammation or saline. Offspring were euthanized on E18 or postnatal day 1 (P1). Other offspring were placed into room air or 85% oxygen for 7 days after birth before euthanizing on P7. RT‐PCR was used to analyze expression of microRNA‐1, ‐133, ‐195, ‐208a, ‐208b, and ‐499. Results were normalized to expression of U6.ResultsAt E18 with exposure to LPS, no differences in expression were detected for miR‐1, ‐ 133, ‐195, ‐208, or 499. Exposure to LPS at P1 led to upregulation of miR‐208a (3‐fold; p=0.032) and miR‐208b (10‐fold; p=0.032), but no differences in expression of miR‐1, ‐133, ‐ 195, or ‐499. Upregulation of miR‐208a (4‐fold; p=0.006) and miR‐208b (7‐fold; p=0.047) persisted in hearts exposed to LPS/O2 at P7. No changes in expression of miR‐1, ‐133, ‐195, or ‐ 499 were detected in samples exposed to LPS and/or hyperoxia at P7.ConclusionsPerinatal exposure to inflammation and hyperoxia led to upregulation of miR‐208a and miR‐208b expression in heart tissue from samples at P1 and P7. No changes in expression of miR‐208a and ‐208b were detected in embryonic heart samples. Perinatal exposure to inflammation and hyperoxia did not alter expression of miR‐1, ‐133, ‐195, or ‐499 at any timepoint.Support or Funding InformationAmerican Academy of Pediatrics Marshall Klaus Perinatal Research Award (Pavlek)

Fetal and amniotic fluid iron homeostasis in healthy and complicated murine, macaque, and human pregnancy.

Adequate iron supply during pregnancy is essential for fetal development. However, how fetal or amniotic fluid iron levels are regulated during healthy pregnancy, or pregnancies complicated by intraamniotic infection or inflammation (IAI), is unknown. We evaluated amniotic fluid and fetal iron homeostasis in normal and complicated murine, macaque, and human pregnancy. In mice, fetal iron endowment was affected by maternal iron status, but amniotic fluid iron concentrations changed little during maternal iron deficiency or excess. In murine and macaque models of inflamed pregnancy, the fetus responded to maternal systemic inflammation or IAI by rapidly upregulating hepcidin and lowering iron in fetal blood, without altering amniotic fluid iron. In humans, elevated cord blood hepcidin with accompanying hypoferremia was observed in pregnancies with antenatal exposure to IAI compared with those that were nonexposed. Hepcidin was also elevated in human amniotic fluid from pregnancies with IAI compared with those without IAI, but amniotic fluid iron levels did not differ between the groups. Our studies in mice, macaques, and humans demonstrate that amniotic fluid iron is largely unregulated but that the rapid induction of fetal hepcidin by inflammation and consequent fetal hypoferremia are conserved mechanisms that may be important in fetal host defense.

Maternal Noninfectious Fever Enhances Cell Proliferation and Microglial Activation in the Neonatal Rat Dentate Gyrus

(Anesth Analg. 2019;128(6):1190–1198) Maternal fever during labor is a complication that poses many risks for the infant being delivered, and is frequently associated with epidural analgesia. Elevated levels of a proinflammatory cytokine called interleukin-6 (IL-6) are found in the maternal serum and umbilical cord blood of patients with fevers who received an epidural. These investigators have demonstrated through previous studies that higher IL-6 levels can cause temperature increases in rats, and are also connected with microglial activation and subventricular inflammation. In addition, the authors have conducted prior research that connected a higher IL-6 measurement to maternal systemic and fetal brain inflammation. This current study aimed to examine the effect of maternally administered IL-6 on neonatal brain development.

In utero Exposure to Maternal Chronic Inflammation Transfers a Pro-Inflammatory Profile to Generation F2 via Sex-Specific Mechanisms.

Generational transfer of maladaptations in offspring have been reported to persist for multiple generations in conditions of chronic inflammation, metabolic and psychological stress. Thus, the current study aimed to expand our understanding of the nature, potential sex specificity, and transgenerational plasticity of inflammatory maladaptations resulting from maternal chronic inflammation. Briefly, F1 and F2 generations of offspring from C57/BL/6 dams exposed to a modified maternal periconception systemic inflammation (MSPI) protocol were profiled in terms of leukocyte and splenocyte counts and cytokine responses, as well as glucocorticoid sensitivity. Overall, F1 male and female LPS groups presented with glucocorticoid hypersensitivity (with elevated corticosterone and increased leukocyte glucocorticoid receptor levels) along with a pro-inflammatory phenotype, which carried over to the F2 generation. The transfer of inflammatory and glucocorticoid responsiveness from F1 to F2 is evident, with heritability of this phenotype in F2. The findings suggest that maternal (F0) perinatal chronic inflammation resulted in glucocorticoid dysregulation and a resultant pro-inflammatory phenotype, which is transferred in the maternal lineage but seems to affect male offspring to a greater extent. Of further interest, upregulation of IL-1β cytokine responses is reported in female offspring only. The cumulative maladaptation reported in F2 offspring when both F1 parents were affected by maternal LPS exposure is suggestive of immune senescence. Given the potential impact of current results and the lack of sex-specific investigations, more research in this context is urgently required.

The Impact of Infection in Pregnancy on Placental Vascular Development and Adverse Birth Outcomes.

Healthy fetal development is dependent on nutrient and oxygen transfer via the placenta. Optimal growth and function of placental vasculature is therefore essential to support in utero development. Vasculogenesis, the de novo formation of blood vessels, and angiogenesis, the branching and remodeling of existing vasculature, mediate the development and maturation of placental villi, which form the materno-fetal interface. Several lines of evidence indicate that systemic maternal infection and consequent inflammation can disrupt placental vasculogenesis and angiogenesis. The resulting alterations in placental hemodynamics impact fetal growth and contribute to poor birth outcomes including preterm delivery, small-for-gestational age (SGA), stillbirth, and low birth weight (LBW). Furthermore, pathways involved in maternal immune activation and placental vascularization parallel those involved in normal fetal development, notably neurovascular development. Therefore, immune-mediated disruption of angiogenic pathways at the materno-fetal interface may also have long-term neurological consequences for offspring. Here, we review current literature evaluating the influence of maternal infection and immune activation at the materno-fetal interface and the subsequent impact on placental vascular function and birth outcome. Immunomodulatory pathways, including chemokines and cytokines released in response to maternal infection, interact closely with the principal pathways regulating placental vascular development, including the angiopoietin-Tie-2, vascular endothelial growth factor (VEGF), and placental growth factor (PlGF) pathways. A detailed mechanistic understanding of how maternal infections impact placental and fetal development is critical to the design of effective interventions to promote placental growth and function and thereby reduce adverse birth outcomes.

Exposure to systemic and intrauterine inflammation leads to decreased pup survival via different placental mechanisms

ProblemExposure to systemic maternal inflammation (i.e., maternal sepsis, influenza, human immunodeficiency virus, or pyelonephritis) and intrauterine (IU) inflammation (i.e., chorioamnionitis or preterm labor) have been associated with adverse perinatal sequelae. Whether systemic and localized inflammation leading to adverse outcomes have similar placental mechanisms remain unclear. Method of StudyWe conducted a study by murine modeling systemic and localized IU inflammation with injections of either intraperitoneal (IP) or IU interleukin-1β (IL-1β) and compared fetoplacental hemodynamic changes, cytokine/chemokine expression, and fetal loss. ResultsIU IL-1β exposure reduced offspring survival by 31.1% and IP IL-1β exposure by 34.5% when compared with control pups. Despite this similar outcome in offspring survival, Doppler analysis revealed a stark difference: IU group displayed worsened fetoplacental hemodynamic changes while no differences were found between IP and control groups. While both IU and IP groups had increases in pro-inflammatory cytokines and chemokines, specific gene expression trends differed between the two groups, once again highlighting their mechanistic differences. ConclusionWhile both IP and IU IL-1β exposure similarly affected pup survival, only IU inflammation resulted in fetoplacental hemodynamic changes. We speculate that exposure to maternal systemic and IU inflammation plays a key role in fetal injury by utilizing different placental inflammatory pathways and mechanisms.

Beyond the brain: A multi-system inflammatory subtype of autism spectrum disorder.

An immune-mediated subtype of autism spectrum disorder (ASD) has long been hypothesized. This article reviews evidence from family history studies of autoimmunity, immunogenetics, maternal immune activation, neuroinflammation, and systemic inflammation, which suggests immune dysfunction in ASD. Individuals with ASD have higher rates of co-morbid medical illness than the general population. Major medical co-morbidities associated with ASD are discussed by body system. Mechanisms by which FDA-approved and emerging treatments for ASD act upon the immune system are then reviewed. We conclude by proposing the hypothesis of an immune-mediated subtype of ASD which is characterized by systemic, multi-organ inflammation or immune dysregulation with shared mechanisms that drive both the behavioral and physical illnesses associated with ASD. Although gaps in evidence supporting this hypothesis remain, benefits of this conceptualization include framing future research questions that will help define a clinically meaningful subset of patients and focusing clinical interactions on early detection and treatment of high-risk medical illnesses as well as interfering behavioral signs and symptoms across the lifespan.

P58: Changes in mTOR activity in fetal brain after exposure to intrauterine and systemic maternal inflammation

P58: Changes in mTOR activity in fetal brain after exposure to intrauterine and systemic maternal inflammation

Maternal Inflammation and Urogenital Microbial Profiling as Predictors of Preterm Birth [26C

INTRODUCTION: Preterm birth (PTB) is defined as delivery prior to 37 weeks gestation. Maternal immune dysregulation is thought to play a major role in the development of PTB. We hypothesize that systemic maternal inflammation during pregnancy alters the urogenital microbiome and decreases immune suppression by reducing circulating and placental regulatory T cells (Tregs), the immune cells primarily responsible for maternal immune suppression. METHODS: Patients considered high risk for PTB were recruited from the Department of Ob/Gyn at SIU School of Medicine. Following exclusion for non-compliance and intrauterine fetal demise, 18 term and 6 preterm deliveries were assessed (25% preterm rate). Peripheral blood and urine were collected at various timepoints during gestation (8-12 weeks, 20-24 weeks and 32-36 weeks), delivery and 6 weeks postpartum. Lymphocyte buffy coats were extracted and flow cytometry analyses identified specific immune populations. Urinary microbial analyses were performed by miSeq amplicon sequencing using the V4 region of the bacterial 16S rRNA gene. RESULTS: Higher levels of peripheral Treg populations, corresponding with immune tolerance for the fetal alloantigen, were found in patients with term deliveries. Reduced levels of peripheral Tregs were found in patients with subsequent preterm deliveries. This group also had a higher ratio of Th17/Treg cells, corresponding with increased inflammation, and altered urinary microbial profiles at each gestational timepoint. CONCLUSION: We found atypical shifts in immune and urinary microbial profiles from women with another PTB as compared to women with term deliveries. Our results demonstrate a potential novel screening modality for PTB utilizing the mother's immunological and urinary microbial profiles.