RESUMO
Maternal immune activation (MIA) is reported to increase the risk of psychiatric disorders in the offspring. However, the underlying mechanism remains unclear. Methods: We constructed a MIA mouse model by intraperitoneal injection of LPS into pregnant mice and evaluated the behaviors and gene expression profiles in the brains of the female and male offspring, respectively. Results: We found that the MIA female offspring exhibited increased anxiety and a large number of differentially expressed genes (DEGs) in the brain, which were enriched with candidate gene sets of psychiatric disorders and immune functions. In contrast, the MIA male offspring exhibited no significant abnormal behaviors and only a small number of DEGs that were not enriched with disease genes and immune functions. Therefore, we further pursued the downstream study on the molecular mechanism underlying the increased anxiety in the female offspring. We identified the lncRNA AU020206-IRFs-STAT1-cytokine axis by integrating lncRNA-protein interaction data and TF-promoter interaction data, and verified the axis in vitro and in vivo. Conclusion: This study illustrates that MIA upregulates the AU020206-IRFs-STAT1 axis in controlling the brain immunity linked to abnormal behaviors, providing a basis for understanding the role of MIA in psychiatric disorders.
Assuntos
Encéfalo , Citocinas , Modelos Animais de Doenças , Fator de Transcrição STAT1 , Animais , Feminino , Fator de Transcrição STAT1/metabolismo , Fator de Transcrição STAT1/genética , Camundongos , Encéfalo/metabolismo , Encéfalo/imunologia , Gravidez , Citocinas/metabolismo , Masculino , Regulação para Cima , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Fatores Reguladores de Interferon/metabolismo , Fatores Reguladores de Interferon/genética , Lipopolissacarídeos , Efeitos Tardios da Exposição Pré-Natal/imunologia , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Ansiedade/imunologia , Ansiedade/metabolismo , Camundongos Endogâmicos C57BL , Transdução de SinaisRESUMO
Dietary factors have been associated with an increased prevalence of food allergy (FA). However, little is known about how an unhealthy diet in early life affects FA reactions in offspring. The objective of this study is to provide a scientific foundation for developing and promoting healthy dietary patterns in early life. In this study, we found that maternal high-fat diet (HFD) during pregnancy and lactation exacerbates FA (HFD-FA) in offspring mice, leading to increased serum levels of mast cell protease 1. First, we studied the systemic immunity of the HFD-FA mice and observed elevated levels of proinflammatory cytokines (IL-4, IL-6, and IL-1ß) and a reduced frequency of Treg cells in splenocytes. Additionally, the HFD-FA mice showed increased gut permeability, accumulation of intestinal mast cells, and a decrease in the Treg cell frequency in the mesenteric lymph nodes. Furthermore, our findings also indicated a reduction in gut microbial diversity and abundance in HFD-FA mice. Importantly, lipid metabolism profiling revealed unique lipid profiles in the HFD-FA mice, with significant upregulation of triglycerides and downregulation of sphingolipids. Taken together, our results suggest that maternal HFD alters intestinal homeostasis and increases FA susceptibility in offspring mice.
Assuntos
Dieta Hiperlipídica , Hipersensibilidade Alimentar , Ovalbumina , Linfócitos T Reguladores , Animais , Dieta Hiperlipídica/efeitos adversos , Feminino , Camundongos , Gravidez , Hipersensibilidade Alimentar/imunologia , Ovalbumina/imunologia , Linfócitos T Reguladores/imunologia , Masculino , Humanos , Microbioma Gastrointestinal , Efeitos Tardios da Exposição Pré-Natal/imunologia , Camundongos Endogâmicos C57BL , Citocinas/metabolismo , Citocinas/imunologiaRESUMO
BACKGROUND: Association of early pregnancy body mass index (BMI) and maternal gestational weight gain (GWG), and asthma and allergic disease in children is unclear. METHODS: We analyzed data from 3176 mother-child pairs in a prospective birth cohort study. Maternal anthropometric measurements in the first and last antenatal clinic visits were obtained through post-delivery questionnaires to calculate early pregnancy BMI and maternal GWG. Asthma and allergic diseases in children by the age of 5 years was assessed using a validated questionnaire. Furthermore, serum samples were analyzed for IgE antibodies to eight allergens. We applied Cox proportional hazards and logistic regression analyses to estimate the association of early pregnancy BMI and maternal GWG (as continuous variables and categorized into quarters), and asthma, atopic eczema, atopic sensitization, and allergic rhinitis in children. RESULTS: Neither early pregnancy BMI nor maternal GWG was associated with asthma and allergic disease in children when analyzed as continuous variables. However, compared to the first quarter of GWG (a rate <0.32 kg/week), mothers in the third quarter (rate 0.42-0.52 kg/week) had children with significantly higher odds of developing atopic eczema (adjusted OR 1.49, 95% CI [1.13-1.96]) by 5 years of age. CONCLUSION: Association of early pregnancy BMI and maternal GWG, and asthma and allergic disease in children, is inconsistent. High maternal GWG may be associated with increased odds of atopic eczema.
Assuntos
Asma , Índice de Massa Corporal , Ganho de Peso na Gestação , Hipersensibilidade , Humanos , Gravidez , Feminino , Asma/epidemiologia , Asma/imunologia , Pré-Escolar , Masculino , Estudos Prospectivos , Hipersensibilidade/epidemiologia , Hipersensibilidade/imunologia , Adulto , Imunoglobulina E/sangue , Lactente , Dermatite Atópica/epidemiologia , Dermatite Atópica/imunologia , Efeitos Tardios da Exposição Pré-Natal/epidemiologia , Efeitos Tardios da Exposição Pré-Natal/imunologia , Inquéritos e Questionários , Estudos de Coortes , Coorte de Nascimento , Recém-NascidoRESUMO
The prevalence of allergies has been globally escalating. While allergies could appear at any age, they often develop in early life. However, the significant knowledge gap in the field is the mechanisms by which allergies affect certain people but not others. Investigating early factors and events in neonatal life that have a lasting impact on determining the susceptibilities of children to develop allergies is a significant area of the investigation as it promotes the understanding of neonatal immune system that mediates tolerance versus allergies. This review focuses on the research over the recent 10 years regarding the potential maternal factors that influence offspring allergies with a view to food allergy, a potentially life-threatening cause of anaphylaxis. The role of breast milk, maternal diet, maternal antibodies, and microbiota that have been suggested as key maternal factors regulating offspring allergies are discussed here. We also suggest future research area to expand our knowledge of maternal-offspring interactions on the pathogenesis of food allergy.
Assuntos
Hipersensibilidade Alimentar , Humanos , Hipersensibilidade Alimentar/imunologia , Feminino , Gravidez , Animais , Leite Humano/imunologia , Efeitos Tardios da Exposição Pré-Natal/imunologia , Tolerância Imunológica , Microbiota/imunologia , Anafilaxia/imunologia , Anafilaxia/etiologia , Exposição Materna/efeitos adversos , Recém-Nascido , Alérgenos/imunologiaRESUMO
Changes in maternal gut microbiota due to stress and/or ethanol exposure can have lasting effects on offspring's health, particularly regarding immunity, inflammation response, and susceptibility to psychiatric disorders. The literature search for this review was conducted using PubMed and Scopus, employing keywords and phrases related to maternal stress, ethanol exposure, gut microbiota, microbiome, gut-brain axis, diet, dysbiosis, progesterone, placenta, prenatal development, immunity, inflammation, and depression to identify relevant studies in both preclinical and human research. Only a limited number of reviews were included to support the arguments. The search encompassed studies from the 1990s to the present. This review begins by exploring the role of microbiota in modulating host health and disease. It then examines how disturbances in maternal microbiota can affect the offspring's immune system. The analysis continues by investigating the interplay between stress and dysbiosis, focusing on how prenatal maternal stress influences both maternal and offspring microbiota and its implications for susceptibility to depression. The review also considers the impact of ethanol consumption on gut dysbiosis, with an emphasis on the effects of prenatal ethanol exposure on both maternal and offspring microbiota. Finally, it is suggested that maternal gut microbiota dysbiosis may be significantly exacerbated by the combined effects of stress and ethanol exposure, leading to immune system dysfunction and chronic inflammation, which could increase the risk of depression in the offspring. These interactions underscore the potential for novel mental health interventions that address the gut-brain axis, especially in relation to maternal and offspring health.
Assuntos
Disbiose , Etanol , Microbioma Gastrointestinal , Efeitos Tardios da Exposição Pré-Natal , Estresse Psicológico , Humanos , Gravidez , Feminino , Efeitos Tardios da Exposição Pré-Natal/imunologia , Microbioma Gastrointestinal/efeitos dos fármacos , Microbioma Gastrointestinal/imunologia , Etanol/efeitos adversos , Animais , Estresse Psicológico/imunologia , Estresse Psicológico/complicações , Disbiose/imunologia , Transtornos Mentais/etiologia , Transtornos Mentais/imunologia , Transtornos Mentais/microbiologia , Eixo Encéfalo-IntestinoRESUMO
Maternal immune activation (MIA) during pregnancy has been increasingly recognized as a critical factor in the development of neurodevelopmental disorders, with potential sex-specific impacts that are not yet fully understood. In this study, we utilized a murine model to explore the behavioral and molecular consequences of MIA induced by lipopolysaccharide (LPS) administration on embryonic day 12.5. Our findings indicate that male offspring exposed to LPS exhibited significant increases in anxiety-like and depression-like behaviors, while female offspring did not show comparable changes. Molecular analyses revealed alterations in pro-inflammatory cytokine levels and synaptic gene expression in male offspring, suggesting that these molecular disruptions may underlie the observed behavioral differences. These results emphasize the importance of considering sex as a biological variable in studies of neurodevelopmental disorders and highlight the need for further molecular investigations to understand the mechanisms driving these sex-specific outcomes. Our study contributes to the growing evidence that prenatal immune challenges play a pivotal role in the etiology of neurodevelopmental disorders and underscores the potential for sex-specific preventative approaches of MIA.
Assuntos
Comportamento Animal , Modelos Animais de Doenças , Lipopolissacarídeos , Transtornos do Neurodesenvolvimento , Efeitos Tardios da Exposição Pré-Natal , Animais , Feminino , Gravidez , Camundongos , Masculino , Transtornos do Neurodesenvolvimento/imunologia , Transtornos do Neurodesenvolvimento/etiologia , Transtornos do Neurodesenvolvimento/induzido quimicamente , Efeitos Tardios da Exposição Pré-Natal/imunologia , Comportamento Animal/efeitos dos fármacos , Citocinas/metabolismo , Ansiedade/imunologia , Fatores Sexuais , Depressão/imunologia , Caracteres Sexuais , Camundongos Endogâmicos C57BLRESUMO
Vitamin D deficiency is a common deficiency worldwide, particularly among women of reproductive age. During pregnancy, it increases the risk of immune-related diseases in offspring later in life. However, how the body remembers exposure to an adverse environment during development is poorly understood. Herein, we explore the effects of prenatal vitamin D deficiency on immune cell proportions in offspring using vitamin D deficient mice established by dietary manipulation. We found that prenatal vitamin D deficiency alters immune cell proportions in offspring by changing the transcriptional properties of genes downstream of vitamin D receptor signaling in hematopoietic stem and progenitor cells of both the fetus and adults. Moreover, further investigations of the associations between maternal vitamin D levels and cord blood immune cell profiles from 75 healthy pregnant women and their term offspring also confirm that maternal vitamin D levels in the second trimester significantly affect immune cell proportions in the offspring. These findings imply that the differentiation properties of hematopoiesis act as long-term memories of prenatal vitamin D deficiency exposure in later life.
Assuntos
Efeitos Tardios da Exposição Pré-Natal , Deficiência de Vitamina D , Vitamina D , Deficiência de Vitamina D/imunologia , Feminino , Gravidez , Animais , Humanos , Efeitos Tardios da Exposição Pré-Natal/imunologia , Camundongos , Vitamina D/sangue , Sangue Fetal/citologia , Adulto , Receptores de Calcitriol/genética , Receptores de Calcitriol/metabolismo , Células-Tronco Hematopoéticas/metabolismo , MasculinoRESUMO
The first 1000 days of life is a critical period of development in which adverse circumstances can have long-term consequences for the child's health. Maternal immune activation is associated with increased risk of neurodevelopmental disorders in the child. Aberrant immune responses have been reported in individuals with neurodevelopmental disorders. Moreover, lasting effects of maternal immune activation on the offspring's immune system have been reported. Taken together, this indicates that the effect of maternal immune activation is not limited to the central nervous system. Here, we explore the impact of maternal immune activation on the immune system of the offspring. We first describe the development of the immune system and provide an overview of reported alterations in the cytokine profiles, immune cell profiles, immune cell function, and immune induction in pre-clinical models. Additionally, we highlight recent research on the impact of maternal COVID-19 exposure on the neonatal immune system and the potential health consequences for the child. Our review shows that maternal immune activation alters the offspring's immune system under certain conditions, but the reported effects are conflicting and inconsistent. In general, epigenetic modifications are considered the mechanism for fetal programming. The available data was insufficient to identify specific pathways that may contribute to immune programming. As a consequence of the COVID-19 pandemic, more research now focuses on the possible health effects of maternal immune activation on the offspring. Future research addressing the offspring's immune response to maternal immune activation can elucidate specific pathways that contribute to fetal immune programming and the long-term health effects for the offspring.
Assuntos
COVID-19 , Desenvolvimento Fetal , Sistema Imunitário , Efeitos Tardios da Exposição Pré-Natal , Humanos , Gravidez , Feminino , Efeitos Tardios da Exposição Pré-Natal/imunologia , Sistema Imunitário/imunologia , Sistema Imunitário/metabolismo , Desenvolvimento Fetal/imunologia , COVID-19/imunologia , Animais , SARS-CoV-2/imunologia , Epigênese Genética , Citocinas/metabolismo , Transtornos do Neurodesenvolvimento/imunologia , Transtornos do Neurodesenvolvimento/etiologia , Exposição Materna/efeitos adversos , Recém-NascidoRESUMO
This systematic review explored the impact of maternal immune activation (MIA) on learning and memory behavior in offspring, with a particular focus on sexual dimorphism. We analyzed 20 experimental studies involving rodent models (rats and mice) exposed to either lipopolysaccharide (LPS) or POLY I:C during gestation following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Our findings reveal that most studies report a detrimental impact of MIA on the learning and memory performance of offspring, highlighting the significant role of prenatal environmental factors in neurodevelopment. Furthermore, this review underscores the complex effects of sex, with males often exhibiting more pronounced cognitive impairment compared to females. Notably, a small subset of studies report enhanced cognitive function following MIA, suggesting complex, context-dependent outcomes of prenatal immune challenges. This review also highlights sex differences caused by the effects of MIA in terms of cytokine responses, alterations in gene expression, and differences in microglial responses as factors that contribute to the cognitive outcomes observed.
Assuntos
Aprendizagem , Memória , Efeitos Tardios da Exposição Pré-Natal , Animais , Feminino , Gravidez , Efeitos Tardios da Exposição Pré-Natal/imunologia , Aprendizagem/fisiologia , Memória/fisiologia , Caracteres Sexuais , Camundongos , Lipopolissacarídeos/farmacologia , Poli I-C/farmacologia , Ratos , MasculinoRESUMO
Few human studies have assessed the association of prenatal maternal immune activation (MIA) with measures of brain development and psychiatric risk in newborn offspring. Our goal was to identify the effects of MIA during the 2nd and 3rd trimesters of pregnancy on newborn measures of brain metabolite concentrations, tissue microstructure, and motor development. This was a prospective longitudinal cohort study conducted with nulliparous pregnant women who were aged 14 to 19 years and recruited in their 2nd trimester, as well as their children who were followed through 14 months of age. MIA was indexed by maternal interleukin-6 (IL-6) and C-reactive protein (CRP) in both trimesters of pregnancy. Primary outcomes included: (1) newborn brain metabolite concentrations as ratios to creatine (N-acetylaspartate (NAA)/creatine (Cr) and choline (Cho)/Cr) measured using Magnetic Resonance Spectroscopy; (2) newborn fractional anisotropy and mean diffusivity, measured using Diffusion Tensor Imaging; and (3) indices of motor development, assessed prenatally and postnatally at ages 4- and 14-months. Maternal IL-6 and CRP levels associated significantly with both metabolites in the putamen, thalamus, insula, and the internal capsule. Maternal IL-6 associated significantly with fractional anisotropy in the putamen, caudate, thalamus, insula, and precuneus, and with mean diffusivity in the inferior parietal and middle temporal gyrus. CRP associated significantly with fractional anisotropy in the thalamus, insula, and putamen. Significant associations were found in common regions across imaging modalities, though the direction of associations differed by immune marker. In addition, both maternal IL-6 and CRP (in both trimesters) prenatally associated significantly with offspring motor development at 4- and 14-months of age. The left thalamus mediated effects of IL-6 on postnatal motor development. These findings demonstrate that levels of MIA in mid- to late pregnancy in a generally healthy sample associate with tissue characteristics in newborn brain regions that primarily support motor integration and coordination, as well as behavioral regulation. Those brain effects may contribute to differences in motor development.
Assuntos
Encéfalo , Proteína C-Reativa , Interleucina-6 , Humanos , Feminino , Gravidez , Encéfalo/metabolismo , Recém-Nascido , Interleucina-6/metabolismo , Adolescente , Estudos Longitudinais , Proteína C-Reativa/metabolismo , Proteína C-Reativa/análise , Adulto Jovem , Estudos Prospectivos , Adulto , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Efeitos Tardios da Exposição Pré-Natal/imunologia , Creatina/metabolismo , Masculino , Lactente , Colina/metabolismo , Ácido Aspártico/metabolismo , Ácido Aspártico/análogos & derivados , Imagem de Tensor de Difusão , Espectroscopia de Ressonância Magnética , Desenvolvimento Infantil/fisiologiaRESUMO
PURPOSE: Few longitudinal studies have investigated the mediating role of inflammation during childhood in associations between prenatal maternal stress and adolescent mental health. The objective of this study was to examine the associations between prenatal maternal stress, concentrations of immune markers at age 9, and symptoms of generalized anxiety disorder (GAD) and depression during adolescence. METHODS: This study included 3723 mother-child pairs from the Avon Longitudinal Study of Parents and Children (ALSPAC). Prenatal maternal stress was examined using 55 items measured during pregnancy. Inflammation was assessed using serum concentrations of interleukin-6 (IL-6) and C-reactive protein (CRP) when children were 9 years old. GAD and depression were assessed when children were 16 and 18 years of age, respectively. Analyses comprised of structural equation models. RESULTS: Prenatal maternal stress was associated with higher concentrations of IL-6 in childhood, and with greater symptoms of depression and GAD in adolescence. However, we did not observe associations between prenatal maternal stress and CRP; also, CRP and IL-6 were not associated with depression and GAD. There was no evidence that CRP and IL-6 mediated the associations between prenatal maternal stress and either GAD or depression. CONCLUSIONS: Prenatal maternal stress is associated with IL-6 levels in childhood, and with GAD and depression during adolescence. Future studies should examine immune activity at multiple points during development in relation to mental health into adulthood to determine whether inflammation at different points during development could increase risk for mental health problems among children whose mothers experienced significant stressors during pregnancy.
Assuntos
Transtornos de Ansiedade , Ansiedade , Proteína C-Reativa , Depressão , Inflamação , Interleucina-6 , Efeitos Tardios da Exposição Pré-Natal , Estresse Psicológico , Humanos , Feminino , Gravidez , Efeitos Tardios da Exposição Pré-Natal/imunologia , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Criança , Estresse Psicológico/sangue , Estresse Psicológico/metabolismo , Estresse Psicológico/imunologia , Inflamação/sangue , Adolescente , Interleucina-6/sangue , Estudos Longitudinais , Proteína C-Reativa/análise , Proteína C-Reativa/metabolismo , Depressão/sangue , Masculino , Transtornos de Ansiedade/sangue , Transtornos de Ansiedade/epidemiologia , Adulto , Complicações na Gravidez/psicologia , Complicações na Gravidez/sangue , Complicações na Gravidez/imunologiaRESUMO
Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder caused by the interaction of multiple pathogenic factors. Epidemiological studies and animal experiments indicate that maternal immune activation (MIA) is closely related to the development of ASD in offspring. A large number of pro-inflammatory cytokines are transferred from the placenta to the fetal brain during MIA, which impedes fetal neurodevelopment and is accompanied by activation of immune cells and microglia. Programmed cell death protein 1 (PD-1) can be highly expressed on the surface of various activated immune cells, when combined with programmed cell death-ligand 1 (PD-L1), it can activate the PD-1/PD-L1 pathway and exert powerful immunosuppressive effects, suggesting that this immune checkpoint may have the potential to treat MIA-induced ASD. This study combined bioinformatics analysis and experimental validation to explore the efficacy of Fc-fused PD-L1 (PD-L1-Fc) in treating MIA-induced ASD. Bioinformatics analysis results showed that in human placental inflammation, IL-6 was upregulated, T cells proliferated significantly, and the PD-1/PD-L1 pathway was significantly enriched. The experimental results showed that intraperitoneal injection of poly(I:C) induced MIA in pregnant mice resulted in significant expression of IL-6 in their serum, placenta, and fetal brain. At the same time, the expression of PD-1 and PD-L1 in the placenta and fetal brain increased, CD4+ T cells in the spleen were significantly activated, and PD-1 expression increased. Their offspring mice exhibited typical ASD-like behaviors. In vitro experiments on primary microglia of offspring mice have confirmed that the expression of IL-6, PD-1, and PD-L1 is significantly increased, and PD-L1-Fc effectively reduced their expression levels. In the prefrontal cortex of MIA offspring mice, there was an increase in the expression of IL-6, PD-1, and PD-L1; activation of microglial cells, and colocalization with PD-1. Then we administered brain stereotaxic injections of PD-L1-Fc to MIA offspring mice and intraperitoneal injections to MIA pregnant mice. The results indicated that PD-L1-Fc effectively suppressed neuroinflammation in the frontal cortex of offspring mice and partially ameliorated ASD-like behaviors; MIA in pregnant mice was significantly alleviated, and the offspring mice they produced did not exhibit neuroinflammation or ASD-like behaviors. In summary, we have demonstrated the therapeutic ability of PD-L1-Fc for MIA-induced ASD, aiming to provide new strategies and insights for the treatment of ASD.
Assuntos
Transtorno do Espectro Autista , Antígeno B7-H1 , Placenta , Receptor de Morte Celular Programada 1 , Animais , Feminino , Antígeno B7-H1/metabolismo , Gravidez , Receptor de Morte Celular Programada 1/metabolismo , Camundongos , Masculino , Transtorno do Espectro Autista/metabolismo , Transtorno do Espectro Autista/prevenção & controle , Humanos , Placenta/metabolismo , Modelos Animais de Doenças , Efeitos Tardios da Exposição Pré-Natal/imunologia , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Comportamento Animal , Camundongos Endogâmicos C57BL , Transtorno Autístico/metabolismo , Transtorno Autístico/imunologia , Inflamação/metabolismo , Interleucina-6/metabolismo , Encéfalo/metabolismo , Encéfalo/efeitos dos fármacosRESUMO
BACKGROUND: Maternal immune activation (MIA) triggers neurobiological changes in offspring, potentially reshaping the molecular synaptic landscape, with the hippocampus being particularly vulnerable. However, critical details regarding developmental timing of these changes and whether they differ between males and females remain unclear. METHODS: We induced MIA in C57BL/6J mice on gestational day nine using the viral mimetic poly(I:C) and performed mass spectrometry-based proteomic analyses on hippocampal synaptoneurosomes of embryonic (E18) and adult (20 ± 1 weeks) MIA offspring. RESULTS: In the embryonic synaptoneurosomes, MIA led to lipid, polysaccharide, and glycoprotein metabolism pathway disruptions. In the adult synaptic proteome, we observed a dynamic shift toward transmembrane trafficking, intracellular signalling cascades, including cell death and growth, and cytoskeletal organisation. In adults, many associated pathways overlapped between males and females. However, we found distinct sex-specific enrichment of dopaminergic and glutamatergic pathways. We identified 50 proteins altered by MIA in both embryonic and adult samples (28 with the same directionality), mainly involved in presynaptic structure and synaptic vesicle function. We probed human phenome-wide association study data in the cognitive and psychiatric domains, and 49 of the 50 genes encoding these proteins were significantly associated with the investigated phenotypes. CONCLUSIONS: Our data emphasise the dynamic effects of viral-like MIA on developing and mature hippocampi and provide novel targets for study following prenatal immune challenges. The 22 proteins that changed directionality from the embryonic to adult hippocampus, suggestive of compensatory over-adaptions, are particularly attractive for future investigations.
Assuntos
Hipocampo , Camundongos Endogâmicos C57BL , Efeitos Tardios da Exposição Pré-Natal , Proteoma , Sinapses , Animais , Hipocampo/metabolismo , Feminino , Proteoma/metabolismo , Gravidez , Masculino , Camundongos , Efeitos Tardios da Exposição Pré-Natal/imunologia , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Sinapses/metabolismo , Poli I-C/farmacologia , Proteômica/métodos , HumanosRESUMO
Mother and child are immunologically interconnected by mechanisms that we are only beginning to understand. During pregnancy, multiple molecular and cellular factors of maternal origin are transferred across the placenta and influence the development and function of the fetal and newborn immune system. Altered maternal immune states arising from pregnancy-associated infections or immunizations have the potential to program offspring immune function in ways that may have long-term health consequences. In this study, we review current literature on the impact of prenatal infection and vaccination on the developing immune system, highlight knowledge gaps, and look to the horizon to envision maternal interventions that could benefit both the mother and her child.
Assuntos
Vacinação , Humanos , Gravidez , Feminino , Recém-Nascido , Placenta/imunologia , Sistema Imunitário/imunologia , Complicações Infecciosas na Gravidez/imunologia , Troca Materno-Fetal/imunologia , Mães , Criança , Feto/imunologia , Efeitos Tardios da Exposição Pré-Natal/imunologiaRESUMO
OBJECTIVE: To explore the association between maternal thyroid peroxidase antibody (TPOAb) exposure and 5- to 6-year-old children's cardiometabolic risk (CMR). METHODS: A total of 2129 mother-child pairs were recruited from the Ma'anshan Birth Cohort (MABC) study. Serum TPOAb was retrospectively measured in pregnant women using an electrochemiluminescence immunoassay. CMR score was evaluated by the serum glycolipids, blood pressure, and waist circumference for children aged 5-6 years. Growth mixture modelling was used to fit trajectories of TPOAb levels throughout pregnancy. Multiple linear regression models and logistic regression models were used for statistical analyses. RESULTS: Two thousand one hundred twenty-nine mother-child pairs (mean [SD] age, 26.6 [3.6] years) were enrolled for the final study. Maternal TPOAb exposure in the first trimester increased children's overall CMR, glucose level, HOMA-IR, triglyceride level, boys' overall CMR, boys' glucose level, and girls' glucose level. TPOAb exposure in the first trimester was also associated with lower boys' high-density lipoprotein cholesterol (HDL-C) level. In the second trimester, maternal TPOAb exposure was positively associated with children's triglyceride level. Compared with low TPOAb trajectory, children with high maternal TPOAb trajectory had an increased risk of developing high CMR (OR = 3.40; 95% CI, 1.30-8.90), hyperglycemia (OR = 5.20; 95% CI, 2.20-12.28), insulin-resistance (adjusted OR = 2.12; 95% CI, 1.10-4.07), and hypertriglyceridemia (OR = 2.55; 95% CI, 1.06-6.14). CONCLUSIONS: The first trimester of pregnancy is a critical period for maternal TPOAb exposure to affect CMR in children, with some sex specificity, mainly to the detriment of boys.
Assuntos
Autoanticorpos , Iodeto Peroxidase , Efeitos Tardios da Exposição Pré-Natal , Humanos , Feminino , Gravidez , Masculino , Pré-Escolar , Criança , Efeitos Tardios da Exposição Pré-Natal/sangue , Efeitos Tardios da Exposição Pré-Natal/imunologia , Iodeto Peroxidase/imunologia , Adulto , Autoanticorpos/sangue , Coorte de Nascimento , Estudos de Coortes , Fatores Sexuais , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/sangue , Fatores de Risco Cardiometabólico , Estudos Retrospectivos , Fatores de RiscoRESUMO
Exposure to infectious or non-infectious immune activation during early development is a serious risk factor for long-term behavioural dysfunctions. Mouse models of maternal immune activation (MIA) have increasingly been used to address neuronal and behavioural dysfunctions in response to prenatal infections. One commonly employed MIA model involves administering poly(I:C) (polyriboinosinic-polyribocytdilic acid), a synthetic analogue of double-stranded RNA, during gestation, which robustly induces an acute viral-like inflammatory response. Using electroencephalography (EEG) and infrared (IR) activity recordings, we explored alterations in sleep/wake, circadian and locomotor activity patterns on the adult male offspring of poly(I:C)-treated mothers. Our findings demonstrate that these offspring displayed reduced home cage activity during the (subjective) night under both light/dark or constant darkness conditions. In line with this finding, these mice exhibited an increase in non-rapid eye movement (NREM) sleep duration as well as an increase in sleep spindles density. Following sleep deprivation, poly(I:C)-exposed offspring extended NREM sleep duration and prolonged NREM sleep bouts during the dark phase as compared with non-exposed mice. Additionally, these mice exhibited a significant alteration in NREM sleep EEG spectral power under heightened sleep pressure. Together, our study highlights the lasting effects of infection and/or immune activation during pregnancy on circadian activity and sleep/wake patterns in the offspring.
Assuntos
Poli I-C , Efeitos Tardios da Exposição Pré-Natal , Sono , Animais , Feminino , Masculino , Poli I-C/farmacologia , Efeitos Tardios da Exposição Pré-Natal/imunologia , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Gravidez , Camundongos , Sono/fisiologia , Sono/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Ritmo Circadiano/fisiologia , Ritmo Circadiano/efeitos dos fármacos , Eletroencefalografia , Atividade Motora/efeitos dos fármacos , Atividade Motora/fisiologia , Privação do Sono/imunologia , Privação do Sono/fisiopatologiaRESUMO
Introduction: Latent tuberculosis infection (LTBI) is a common coinfection in people living with HIV (PWH). How LTBI and HIV exposure in utero influence the development of infant humoral immunity is not well characterized. To address this question, we assessed the relationship between maternal humoral responses in pregnant women with HIV or with HIV/LTBI on humoral responses in infants to BCG vaccination and TB acquisition. Methods: Plasma samples were obtained from mother infant pairs during pregnancy (14-34 wks gestation) and in infants at 12 and 44 wks of age from the IMPAACT P1078 clinical trial. LTBI was established by Interferon gamma release assay (IGRA). Progression to active TB (ATB) disease was observed in 5 women at various times after giving birth. All infants were BCG vaccinated at birth and tested for IGRA at 44 weeks. Mtb (PPD, ESAT6/CFP10, Ag85A, LAM), HIV (GP120), and Influenza (HA) specific IgG, IgM, and IgA were measured in plasma samples using a bead based Luminex assay with Flexmap 3D. Results: In maternal plasma there were no differences in Mtb-specific antibodies or viral antibodies in relation to maternal IGRA status. ATB progressors showed increases in Mtb-specific antibodies at diagnosis compared to study entry. However, when compared to the non-progressors at entry, progressors had higher levels of Ag85A IgG and reduced ESAT6/CFP10 IgG and LAM IgG, IgM, and IgA1. All infants showed a decrease in IgG to viral antigens (HIV GP120 and HA) from 12 to 44 weeks attributed to waning of maternally transferred antibody titers. However, Mtb-specific (PPD, ESAT6/CFP10, Ag85A, and LAM) IgG and IgM increased from 12 to 44 weeks. HIV and HA IgG levels in maternal and 12-week infant plasma were highly correlated, and ESAT6/CFP10 IgG and LAM IgG showed a relationship between maternal and infant Abs. Finally, in the subset of infants that tested IGRA positive at 44 weeks, we observed a trend for lower LAM IgM compared to IGRA- infants at 44 weeks. Discussion: The results from our study raise the possibility that antibodies to LAM are associated with protection from progression to ATB and support further research into the development of humoral immunity against TB through infection or vaccination.
Assuntos
Anticorpos Antibacterianos , Infecções por HIV , Imunidade Humoral , Tuberculose Latente , Humanos , Feminino , Tuberculose Latente/imunologia , Infecções por HIV/imunologia , Gravidez , Lactente , Anticorpos Antibacterianos/sangue , Anticorpos Antibacterianos/imunologia , Adulto , Mycobacterium tuberculosis/imunologia , Complicações Infecciosas na Gravidez/imunologia , Complicações Infecciosas na Gravidez/sangue , Vacina BCG/imunologia , Recém-Nascido , Coinfecção/imunologia , Masculino , Efeitos Tardios da Exposição Pré-Natal/imunologiaRESUMO
Converging data show that exposure to maternal immune activation (MIA) in utero alters brain development in animals and increases the risk of neurodevelopmental disorders in humans. A recently developed non-human primate MIA model affords opportunities for studies with uniquely strong translational relevance to human neurodevelopment. The current longitudinal study used 1H-MRS to investigate the developmental trajectory of prefrontal cortex metabolites in male rhesus monkey offspring of dams (n = 14) exposed to a modified form of the inflammatory viral mimic, polyinosinic:polycytidylic acid (Poly IC), in the late first trimester. Brain metabolites in these animals were compared to offspring of dams that received saline (n = 10) or no injection (n = 4). N-acetylaspartate (NAA), glutamate, creatine, choline, myo-inositol, taurine, and glutathione were estimated from PRESS and MEGA-PRESS acquisitions obtained at 6, 12, 24, 36, and 45 months of age. Prior investigations of this cohort reported reduced frontal cortical gray and white matter and subtle cognitive impairments in MIA offspring. We hypothesized that the MIA-induced neurodevelopmental changes would extend to abnormal brain metabolite levels, which would be associated with the observed cognitive impairments. Prefrontal NAA was significantly higher in the MIA offspring across all ages (p < 0.001) and was associated with better performance on the two cognitive measures most sensitive to impairment in the MIA animals (both p < 0.05). Myo-inositol was significantly lower across all ages in MIA offspring but was not associated with cognitive performance. Taurine was elevated in MIA offspring at 36 and 45 months. Glutathione did not differ between groups. MIA exposure in male non-human primates is associated with altered prefrontal cortex metabolites during childhood and adolescence. A positive association between elevated NAA and cognitive performance suggests the hypothesis that elevated NAA throughout these developmental stages reflects a protective or resilience-related process in MIA-exposed offspring. The potential relevance of these findings to human neurodevelopmental disorders is discussed.
Assuntos
Encéfalo , Macaca mulatta , Poli I-C , Córtex Pré-Frontal , Efeitos Tardios da Exposição Pré-Natal , Animais , Masculino , Feminino , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Efeitos Tardios da Exposição Pré-Natal/imunologia , Gravidez , Encéfalo/metabolismo , Poli I-C/farmacologia , Córtex Pré-Frontal/metabolismo , Inositol/metabolismo , Ácido Aspártico/metabolismo , Ácido Aspártico/análogos & derivados , Creatina/metabolismo , Taurina/metabolismo , Colina/metabolismo , Modelos Animais de Doenças , Ácido Glutâmico/metabolismo , Glutationa/metabolismo , Estudos LongitudinaisRESUMO
BACKGROUND: Many studies have reported that prenatal exposure to Per- and Polyfluoroalkyl Substances (PFASs) can disrupt immune function. However, little is known about the effects of PFASs on immune molecules. The study analyzed the association between prenatal exposure to mixed and single PFASs and plasma immune molecules in three-year-old children. METHODS: Ten PFASs were measured in umbilical cord serum, while peripheral blood samples were collected at age three to measure immune molecules. Associations between exposure to individual and combined PFASs and immune molecules were analyzed using Generalized Linear Models and Weighted Quantile Sum (WQS) regression. RESULTS: (1) Interleukin-4 (IL-4) increased by 23.85% (95% CI:2.99,48.94) with each doubling of Perfluorooctanoic Acid (PFOA), and Interleukin-6 (IL-6) increased by 39.07% (95%CI:4.06,85.86) with Perfluorotridecanoic Acid (PFTrDA). Elevated PFOA and Perfluorononanoic Acid (PFNA) were correlated with increases of 34.06% (95% CI: 6.41, 70.28) and 24.41% (95% CI: 0.99, 53.27) in Eotaxin-3, respectively. Additionally, the doubling of Perfluorohexane Sulfonic Acid (PFHxS) was associated with a 9.51% decrease in Periostin (95% CI: -17.84, -0.33). (2) The WQS analysis revealed that mixed PFASs were associated with increased IL-6 (ß = 0.37, 95%CI:0.04,0.69), mainly driven by PFTrDA, PFNA, and 8:2 Chlorinated Perfluoroethyl Sulfonamide (8:2 Cl-PFESA). Moreover, mixed PFASs were linked to an increase in Eotaxin-3 (ß = 0.32, 95% CI: 0.09,0.55), primarily influenced by PFOA, PFTrDA, and Perfluorododecanoic Acid (PFDoDA). CONCLUSIONS: Prenatal PFASs exposure significantly alters the levels of immune molecules in three-year-old children, highlighting the importance of understanding environmental impacts on early immune development.