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1.
Gut ; 69(1): 42-51, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31036757

RESUMO

BACKGROUND AND AIMS: Prenatal and early life bacterial colonisation is thought to play a major role in shaping the immune system. Furthermore, accumulating evidence links early life exposures to the risk of developing IBD later in life. We aimed to assess the effect of maternal IBD on the composition of the microbiome during pregnancy and on the offspring's microbiome. METHODS: We prospectively examined the diversity and taxonomy of the microbiome of pregnant women with and without IBD and their babies at multiple time points. We evaluated the role of maternal IBD diagnosis, the mode of delivery, antibiotic use and feeding behaviour on the microbiome composition during early life. To assess the effects of IBD-associated maternal and infant microbiota on the enteric immune system, we inoculated germ-free mice (GFM) with the respective stool and profiled adaptive and innate immune cell populations in the murine intestines. RESULTS: Pregnant women with IBD and their offspring presented with lower bacterial diversity and altered bacterial composition compared with control women and their babies. Maternal IBD was the main predictor of the microbiota diversity in the infant gut at 7, 14, 30, 60 and 90 days of life. Babies born to mothers with IBD demonstrated enrichment in Gammaproteobacteria and depletion in Bifidobacteria. Finally, GFM inoculated with third trimester IBD mother and 90-day infant stools showed significantly reduced microbial diversity and fewer class-switched memory B cells and regulatory T cells in the colon. CONCLUSION: Aberrant gut microbiota composition persists during pregnancy with IBD and alters the bacterial diversity and abundance in the infant stool. The dysbiotic microbiota triggered abnormal imprinting of the intestinal immune system in GFM.


Assuntos
Microbioma Gastrointestinal/imunologia , Doenças Inflamatórias Intestinais/microbiologia , Complicações na Gravidez/microbiologia , Efeitos Tardios da Exposição Pré-Natal/microbiologia , Imunidade Adaptativa , Adulto , Animais , Bactérias/classificação , Bactérias/isolamento & purificação , Disbiose/imunologia , Disbiose/microbiologia , Transplante de Microbiota Fecal/métodos , Fezes/microbiologia , Feminino , Seguimentos , Trato Gastrointestinal/imunologia , Trato Gastrointestinal/microbiologia , Vida Livre de Germes , Humanos , Recém-Nascido , Doenças Inflamatórias Intestinais/imunologia , Masculino , Troca Materno-Fetal , Gravidez , Complicações na Gravidez/imunologia , Efeitos Tardios da Exposição Pré-Natal/imunologia , Estudos Prospectivos
2.
Ecotoxicol Environ Saf ; 188: 109867, 2020 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-31689658

RESUMO

BACKGROUND: Accumulating epidemiological studies showed that prenatal and early life exposure to ambient air pollution was important contributor to the development of childhood asthma. However, the effects and mechanisms of prenatal exposure to ozone (O3), a type of ambient air pollution, on the progression of asthma in offspring remain unclear. OBJECTIVE: This study aimed to determine the effects and mechanism of asthma in offspring after prenatal O3 exposure. METHODS: Pregnant BALB/c mice were exposed to O3 or air on gestational days (GDs) 13-18. Their offspring were sensitized and challenged to ovalbumin (OVA) to establish asthma model, and the asthma features were evaluated. The splenic natural killer (NK) cells in the offspring were measured to explore the mechanism on the effects of asthma in the offspring. The responses of the pregnant mice and dams after O3 exposure were evaluated. RESULTS: Airway inflammation, mucus secretion, OVA-specific immunoglobulin (Ig) E, T helper (Th) 2-skewed response, the frequency of CD3ε-CD49b+ splenic NK cells, the expression of tumor necrosis factor (TNF)-α, and IL (interleukin)-17 were significantly exacerbated in the OVA-induced asthma offspring after prenatal O3 exposure. In addition, airway inflammation, a lower number of CD3ε-CD49b+ splenic NK cells, and systemic oxidative stress were caused at the end of pregnancy after O3 exposure, which did not recover at the end of lactation for the first two responses. CONCLUSIONS: Prenatal O3 exposure increased the severity of OVA-induced asthma in the offspring, which might be directly induced by CD3ε-CD49b+ splenic NK cells in the offspring and indirectly related to the damaged maternal immune system.


Assuntos
Poluentes Atmosféricos/toxicidade , Asma/induzido quimicamente , Asma/patologia , Ovalbumina , Ozônio/toxicidade , Efeitos Tardios da Exposição Pré-Natal/patologia , Animais , Asma/imunologia , Feminino , Células Matadoras Naturais/imunologia , Masculino , Camundongos Endogâmicos BALB C , Gravidez , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Efeitos Tardios da Exposição Pré-Natal/imunologia , Equilíbrio Th1-Th2
3.
Rev Chil Pediatr ; 90(5): 555-558, 2019 Oct.
Artigo em Espanhol | MEDLINE | ID: mdl-31859740

RESUMO

Autism Spectrum Disorder (ASD) etiology has been related whit complex interaction between ge netic and environmental factors. In the last years, numerous studies have suggested that maternal immune activation during pregnancy could be related to ASD in the offspring. This relation could be explained by the effects of pro-inflammatory cytokines, autoantibodies and microglial synap tic pruning during early embryonic development. Better understanding of Neurodevelopmental Disorders risk factors will support appropriate strategies of screening and management of risk population.


Assuntos
Transtorno do Espectro Autista/imunologia , Complicações na Gravidez/imunologia , Efeitos Tardios da Exposição Pré-Natal/imunologia , Transtorno do Espectro Autista/etiologia , Autoanticorpos/imunologia , Citocinas/imunologia , Feminino , Humanos , Microglia/imunologia , Gravidez , Fatores de Risco
4.
PLoS Med ; 16(8): e1002854, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31386660

RESUMO

BACKGROUND: Exposure to a nutritionally deficient environment during fetal life and early infancy may adversely alter the ontogeny of the immune system and affect an infant's ability to mount an optimal immune response to vaccination. We examined the effects of maternal nutritional supplementation during pregnancy on infants' antibody responses to the diphtheria-tetanus-pertussis (DTP) vaccine included in the Expanded Programme on Immunisation (EPI). METHODS AND FINDINGS: The Early Nutrition and Immune Development (ENID) trial was a randomised, partially blinded trial conducted between April 2010 and February 2015 in the rural West Kiang region of The Gambia, a resource-poor region affected by chronic undernutrition. Pregnant women (<20 weeks' gestation) with a singleton pregnancy (n = 875) were randomised to receive one of four supplements: iron-folic acid (FeFol; standard of care), multiple micronutrient (MMN), protein-energy (PE), or PE + MMN daily from enrolment (mean [SD] 13.7 [3.3] weeks' gestation) until delivery. Infants were administered the DTP vaccine at 8, 12, and 16 weeks of age according to the Gambian Government protocol. Results for the primary outcome of the trial (infant thymic size) were described previously; here, we report on a secondary outcome, infant antibody response to vaccination. The effects of supplementation on mean DTP antibody titres measured in blood samples collected from infants at 12 weeks (n = 710) and 24 weeks (n = 662) were analysed with adjustment for confounders including maternal age, compliance to supplement, and infant sex and season. At 12 weeks, following a single dose of the vaccine, compared with FeFol (mean 95% confidence interval [CI]; 0.11 IU/mL, 0.09-0.12), antenatal supplementation with MMN or MMN + PE resulted in 42.4% (95% CI 20.1-64.6; p < 0.001) and 29.4% (6.4-52.5; p = 0.012) higher mean anti-diphtheria titres, respectively. Mean anti-tetanus titres were higher by 9.0% (5.5-12.5), 7.8% (4.3-11.4), and 7.3% (4.0-10.7) in MMN, PE, and PE + MMN groups (all, p < 0.001), respectively, than in the FeFol group (0.55 IU/mL, 0.52-0.58). Mean anti-pertussis titres were not significantly different in the FeFol, MMN, and PE + MNN groups but were all higher than in the PE group (all, p < 0.001). At 24 weeks, following all three doses, no significant differences in mean anti-diphtheria titres were detected across the supplement groups. Mean anti-tetanus titres were 3.4% (0.19-6.5; p = 0.038) higher in the PE + MMN group than in the FeFol group (3.47 IU/mL, 3.29-3.66). Mean anti-pertussis titres were higher by 9.4% (3.3-15.5; p = 0.004) and 15.4% (9.6-21.2; p < 0.001) in PE and PE + MMN groups, compared with the FeFol group (74.9 IU/mL, 67.8-82.8). Limitations of the study included the lack of maternal antibody status (breast milk or plasma) or prevaccination antibody measurements in the infants. CONCLUSION: According to our results from rural Gambia, maternal supplementation with MMN combined with PE during pregnancy enhanced antibody responses to the DTP vaccine in early infancy. Provision of nutritional supplements to pregnant women in food insecure settings may improve infant immune development and responses to EPI vaccines. TRIAL REGISTRATION: ISRCTN49285450.


Assuntos
Suplementos Nutricionais , Vacina contra Difteria, Tétano e Coqueluche/imunologia , Imunidade Humoral/efeitos dos fármacos , Efeitos Tardios da Exposição Pré-Natal/imunologia , Adolescente , Adulto , Vacina contra Difteria, Tétano e Coqueluche/farmacologia , Feminino , Gâmbia , Humanos , Imunidade Humoral/imunologia , Fenômenos Fisiológicos da Nutrição Materna/efeitos dos fármacos , Fenômenos Fisiológicos da Nutrição Materna/imunologia , Pessoa de Meia-Idade , Estado Nutricional , Gravidez , Adulto Jovem
5.
Nat Commun ; 10(1): 3031, 2019 07 10.
Artigo em Inglês | MEDLINE | ID: mdl-31292453

RESUMO

Maternal immune dysregulation seems to affect fetal or postnatal immune development. Preeclampsia is a pregnancy-associated disorder with an immune basis and is linked to atopic disorders in offspring. Here we show reduction of fetal thymic size, altered thymic architecture and reduced fetal thymic regulatory T (Treg) cell output in preeclamptic pregnancies, which persists up to 4 years of age in human offspring. In germ-free mice, fetal thymic CD4+ T cell and Treg cell development are compromised, but rescued by maternal supplementation with the intestinal bacterial metabolite short chain fatty acid (SCFA) acetate, which induces upregulation of the autoimmune regulator (AIRE), known to contribute to Treg cell generation. In our human cohorts, low maternal serum acetate is associated with subsequent preeclampsia, and correlates with serum acetate in the fetus. These findings suggest a potential role of acetate in the pathogenesis of preeclampsia and immune development in offspring.


Assuntos
Acetatos/sangue , Feto/imunologia , Pré-Eclâmpsia/imunologia , Efeitos Tardios da Exposição Pré-Natal/imunologia , Linfócitos T Reguladores/imunologia , Acetatos/administração & dosagem , Acetatos/imunologia , Acetatos/metabolismo , Adulto , Animais , Animais Recém-Nascidos , Estudos de Casos e Controles , Desenvolvimento Infantil , Pré-Escolar , Suplementos Nutricionais , Feminino , Feto/citologia , Feto/diagnóstico por imagem , Microbioma Gastrointestinal/imunologia , Vida Livre de Germes/imunologia , Humanos , Tolerância Imunológica/imunologia , Lactente , Recém-Nascido , Estudos Longitudinais , Troca Materno-Fetal/imunologia , Camundongos , Tamanho do Órgão/imunologia , Pré-Eclâmpsia/sangue , Pré-Eclâmpsia/diagnóstico , Gravidez , Efeitos Tardios da Exposição Pré-Natal/patologia , Efeitos Tardios da Exposição Pré-Natal/prevenção & controle , Estudos Prospectivos , Timo/citologia , Timo/diagnóstico por imagem , Timo/crescimento & desenvolvimento , Timo/imunologia , Fatores de Transcrição/imunologia , Fatores de Transcrição/metabolismo , Ultrassonografia Pré-Natal , Adulto Jovem
6.
PLoS One ; 14(7): e0218198, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31291264

RESUMO

Bisphenol A (BPA) is an endocrine disruptor compound with estrogenic activity, possessing affinity for both nuclear (ERα and ERß) and membrane estrogen receptors. The main source of BPA exposure comes from the contamination of food and water by plastic storage containers or disposable bottles, among others, in which case BPA is easily ingested. Exposure to BPA during early pregnancy leads to lifelong effects; however, its effect on the immune system has not been fully studied. Since endocrine and immune systems interact in a bidirectional manner, the disruption of the former may cause permanent alterations of the latter, thus affecting a future anti-parasitic response. In this study, neonate BALB/c mice were exposed to a single dose of BPA (250 µg/kg); once sexual maturity was reached, they were orally infected with Trichinella spiralis (T. spiralis). The analyses performed after 5 days of infection revealed a decreased parasitic load in the duodenum of mice in the BPA-treated group. Flow cytometry analyses also revealed changes in the immune cell subpopulations of the infected animals when compared to the BPA-treated group. RT-PCR analyses of duodenum samples showed an increased expression of TNF-α, IFN-γ, IL-4, IL-5, and IL-9 in the BPA-treated group. These findings show a new aspect whereby early-life exposure to BPA contributes to the protection against T. spiralis by modulating the anti-parasitic immune response.


Assuntos
Compostos Benzidrílicos/imunologia , Disruptores Endócrinos/imunologia , Fenóis/imunologia , Efeitos Tardios da Exposição Pré-Natal/imunologia , Trichinella spiralis/imunologia , Triquinelose/imunologia , Animais , Feminino , Imunidade/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Gravidez , Fatores de Proteção , Triquinelose/prevenção & controle
7.
Pediatr Rheumatol Online J ; 17(1): 33, 2019 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-31266504

RESUMO

BACKGROUND: The etiology of Juvenile Idiopathic Arthritis (JIA) is poorly understood. The purpose of this study was to examine the possible influence of early nutrition on later development of JIA. METHODS: In a population-based prospective birth cohort of 15,740 children we collected nutritional data, including fish consumption, and biological samples during pregnancy, at birth and at different ages. 16 years after study inclusion we identified 42 children with JIA, of whom 11 were positive for Antinuclear Antibodies (ANA). Heavy metals were analysed in cord blood of all 42 JIA patients and 40 age and sex-matched controls. A multivariable logistic regression model, adjusted for relevant factors, was used as well as Mann-Whitney U-test. RESULTS: Fish consumption more than once a week during pregnancy as well as during the child's first year of life was associated with an increased risk of JIA (aOR 4.5 (1.95-10.4); p < 0.001 and aOR 5.1 (2.1-12.4) p < 0.001) and of ANA-positivity (aOR 2.2 (1.4-3.6); p = 0.002 and p < 0.001). Concentrations of Al, Cd, Hg and Li in cord blood were significantly higher in the JIA-group than in controls. The ANA-positive, all of whom had consumed fish >once/week their first year, had significantly higher concentrations of Al (p < 0.001), Cd (p = 0.003), and Li (p < 0.001) in cord blood than controls. Frequency of fish consumption correlated with concentrations of Cd (p = 0.003), Li (p = 0.015) and Hg (p = 0.011). CONCLUSIONS: Moderate exposure to heavy metals, associated with fish consumption, during pregnancy and early childhood may cause effects on the immune system of the offspring, resulting in ANA positivity and JIA.


Assuntos
Artrite Juvenil/imunologia , Autoimunidade/fisiologia , Metais Pesados/efeitos adversos , Adolescente , Animais , Anticorpos Antinucleares/metabolismo , Criança , Pré-Escolar , Dieta/efeitos adversos , Feminino , Sangue Fetal/química , Peixes/imunologia , Peixes/metabolismo , Humanos , Lactente , Recém-Nascido , Masculino , Metais Pesados/metabolismo , Linhagem , Gravidez , Efeitos Tardios da Exposição Pré-Natal/imunologia , Estudos Prospectivos , Fatores de Risco
8.
Food Funct ; 10(8): 5018-5031, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31355385

RESUMO

Maternal restriction of dietary proteins during pregnancy and lactation is known to induce renal disease in later life. High fructose intake causes metabolic syndrome, which results in an increased risk of chronic kidney disease development. We investigated whether quercetin intake during lactation affects high-fructose-diet-induced inflammation and autophagy flux in the kidneys of high-fructose-diet-fed adult female offspring exposed to maternal normal-protein (NP) or low-protein (LP) diets. Pregnant Wistar rats received diets containing 20% (NP) or 8% (LP) casein, and 0 or 0.2% quercetin containing NP diets (NP/NP or NP/NPQ) in experiment (Expt.) 1 and 0 or 0.2% quercetin containing LP diets (LP/LP or LP/LPQ) in Expt. 2 during lactation. At weaning, pups that received a diet of distilled water (Wa) or 10% fructose solution (Fr) were divided into six groups: NP/NP/Wa, NP/NP/Fr, NP/NPQ/Fr in Expt. 1, and LP/LP/Wa, LP/LP/Fr, LP/LPQ/Fr in Expt. 2. At week 12, macrophage infiltration, mRNA levels of TNF-α and IL-6, and markers of autophagy flux in the kidneys of male offspring were examined. We found that macrophage number and, TNF-α and IL-6 mRNA levels increased in the kidneys of the NP/NP/Fr or LP/LP/Fr, respectively. Conversely, macrophage number and IL-6 levels in the NP/NPQ/Fr or LP/LPQ/Fr decreased. LC3B-II levels were downregulated in the NP/NP/Fr or LP/LP/Fr rats. In contrast, LC3B-II levels were upregulated, while p62 levels were downregulated in the NP/NPQ/Fr and LP/LPQ/Fr rats. In conclusion, maternal quercetin intake during lactation may cause long-term alterations in inflammation and autophagy flux in the kidneys of high-fructose-diet-fed adult female offspring.


Assuntos
Autofagia/efeitos dos fármacos , Frutose/efeitos adversos , Nefropatias/prevenção & controle , Desnutrição/complicações , Efeitos Tardios da Exposição Pré-Natal/prevenção & controle , Quercetina/administração & dosagem , Animais , Feminino , Frutose/metabolismo , Humanos , Interleucina-6/genética , Interleucina-6/imunologia , Rim/efeitos dos fármacos , Rim/imunologia , Rim/fisiopatologia , Nefropatias/etiologia , Nefropatias/imunologia , Nefropatias/fisiopatologia , Lactação , Masculino , Desnutrição/metabolismo , Fenômenos Fisiológicos da Nutrição Materna , Gravidez , Efeitos Tardios da Exposição Pré-Natal/etiologia , Efeitos Tardios da Exposição Pré-Natal/imunologia , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Ratos , Ratos Wistar , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia
10.
Transl Psychiatry ; 9(1): 135, 2019 04 12.
Artigo em Inglês | MEDLINE | ID: mdl-30979867

RESUMO

Women exposed to a variety of viral and bacterial infections during pregnancy have an increased risk of giving birth to a child with autism, schizophrenia or other neurodevelopmental disorders. Preclinical maternal immune activation (MIA) models are powerful translational tools to investigate mechanisms underlying epidemiological links between infection during pregnancy and offspring neurodevelopmental disorders. Our previous studies documenting the emergence of aberrant behavior in rhesus monkey offspring born to MIA-treated dams extends the rodent MIA model into a species more closely related to humans. Here we present novel neuroimaging data from these animals to further explore the translational potential of the nonhuman primate MIA model. Nine male MIA-treated offspring and 4 controls from our original cohort underwent in vivo positron emission tomography (PET) scanning at approximately 3.5-years of age using [18F] fluoro-l-m-tyrosine (FMT) to measure presynaptic dopamine levels in the striatum, which are consistently elevated in individuals with schizophrenia. Analysis of [18F]FMT signal in the striatum of these nonhuman primates showed that MIA animals had significantly higher [18F]FMT index of influx compared to control animals. In spite of the modest sample size, this group difference reflects a large effect size (Cohen's d = 0.998). Nonhuman primates born to MIA-treated dams exhibited increased striatal dopamine in late adolescence-a hallmark molecular biomarker of schizophrenia. These results validate the MIA model in a species more closely related to humans and open up new avenues for understanding the neurodevelopmental biology of schizophrenia and other neurodevelopmental disorders associated with prenatal immune challenge.


Assuntos
Comportamento Animal/efeitos dos fármacos , Corpo Estriado/fisiologia , Dopamina/fisiologia , Neostriado/patologia , Animais , Corpo Estriado/diagnóstico por imagem , Modelos Animais de Doenças , Feminino , Macaca mulatta , Masculino , Neostriado/imunologia , Poli I-C/farmacologia , Tomografia por Emissão de Pósitrons , Gravidez , Efeitos Tardios da Exposição Pré-Natal/imunologia , Efeitos Tardios da Exposição Pré-Natal/patologia , Esquizofrenia/imunologia , Comportamento Estereotipado
12.
Biochim Biophys Acta Mol Basis Dis ; 1865(6): 1477-1489, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-30826466

RESUMO

BACKGROUND: Maternal immune activation (MIA) is an independent risk factor for psychiatric disorders including depression spectrum in the offsprings, but the molecular mechanism is unclear. Recent studies show that interferon-stimulated gene-15 (ISG15) is involved in inflammation and neuronal dendrite development; here we studied the role of ISG15 in MIA-induced depression and the underlying mechanisms. METHODS: By vena caudalis injecting polyinosinic: polycytidylic acid (poly I:C) into the pregnant rats to mimic MIA, we used AAV or lentivirus to introduce or silence ISG15 expression. Synaptic plasticity was detected by confocal microscope and Golgi staining. Cognitive performances of the offspring were measured by Open field, Forced swimming and Sucrose preference test. RESULTS: We found that MIA induced depression-like behaviors with dendrite impairments in the offspring with ISG15 level increased in the offsprings' brain. Overexpressing ISG15 in the prefrontal cortex of neonatal cubs (P0) could mimic dendritic pathology and depressive like behaviors, while downregulating ISG15 rescued these abnormalities in the offsprings. Further studies demonstrated that MIA-induced upregulation of inflammatory cytokines promoted ISG15 expression in the offspring' brain which suppressed Rap2A ubiquitination via NEDD4 and thus induced Rap2A accumulation, while upregulating NEDD4 abolished ISG15-induced dendrite impairments. CONCLUSIONS: These data reveal that MIA impedes offsprings' dendrite development and causes depressive like behaviors by upregulating ISG15 and suppressing NEDD4/Rap2A signaling. The current findings suggest that inhibiting ISG15 may be a promising intervention of MIA-induced psychiatric disorders in the offsprings.


Assuntos
Citocinas/genética , Dendritos/metabolismo , Proteínas de Ligação ao GTP/genética , Ubiquitina-Proteína Ligases Nedd4/genética , Efeitos Tardios da Exposição Pré-Natal/genética , Ubiquitinas/genética , Animais , Escala de Avaliação Comportamental , Citocinas/antagonistas & inibidores , Citocinas/imunologia , Dendritos/imunologia , Dendritos/patologia , Depressão , Modelos Animais de Doenças , Feminino , Proteínas de Ligação ao GTP/antagonistas & inibidores , Proteínas de Ligação ao GTP/imunologia , Regulação da Expressão Gênica , Imunidade Inata/efeitos dos fármacos , Inflamação , Injeções Intravenosas , Ubiquitina-Proteína Ligases Nedd4/antagonistas & inibidores , Ubiquitina-Proteína Ligases Nedd4/imunologia , Neurogênese/efeitos dos fármacos , Neurogênese/genética , Neurogênese/imunologia , Plasticidade Neuronal/efeitos dos fármacos , Plasticidade Neuronal/genética , Plasticidade Neuronal/imunologia , Poli I-C/administração & dosagem , Córtex Pré-Frontal/imunologia , Córtex Pré-Frontal/metabolismo , Córtex Pré-Frontal/patologia , Gravidez , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Efeitos Tardios da Exposição Pré-Natal/imunologia , Efeitos Tardios da Exposição Pré-Natal/patologia , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Ratos , Ratos Sprague-Dawley , Transdução de Sinais , Ubiquitinas/antagonistas & inibidores , Ubiquitinas/imunologia
13.
PLoS Negl Trop Dis ; 13(2): e0007172, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30818339

RESUMO

BACKGROUND: Globally, vaccine-preventable diseases remain a significant cause of early childhood mortality despite concerted efforts to improve vaccine coverage. One reason for impaired protection may be the influence of prenatal exposure to parasitic antigens on the developing immune system. Prior research had shown a decrease in infant vaccine response after in utero parasite exposure among a maternal cohort without aggressive preventive treatment. This study investigated the effect of maternal parasitic infections on infant vaccination in a more recent setting of active anti-parasitic therapy. METHODOLOGY/PRINCIPAL FINDINGS: From 2013-2015, 576 Kenyan women were tested in pregnancy for malaria, soil-transmitted helminths, filaria, and S. haematobium, with both acute and prophylactic antiparasitic therapies given. After birth, 567 infants received 10-valent S. pneumoniae conjugate vaccine and pentavalent vaccine for hepatitis B, pertussis, tetanus, H. influenzae type B (Hib) and C. diphtheriae toxoid (Dp-t) at 6, 10, and 14 weeks. Infant serum samples from birth, 10 and 14 weeks, and every six months until age three years, were analyzed using a multiplex bead assay to quantify IgG for Hib, Dp-t, and the ten pneumococcal serotypes. Antenatal parasitic prevalence was high; 461 women (80%) had at least one and 252 (43.6%) had two or more infections during their pregnancy, with the most common being malaria (44.6%), S. haematobium (43.9%), and hookworm (29.2%). Mixed models comparing influence of infection on antibody concentration revealed no effect of prenatal infection status for most vaccine outcomes. Prevalences of protective antibody concentrations after vaccination were similar among the prenatal exposure groups. CONCLUSIONS/SIGNIFICANCE: These findings are in contrast with results from our prior cohort study performed when preventive anti-parasite treatment was less frequently given. The results suggest that the treatment of maternal infections in pregnancy may be able to moderate the previously observed effect of antenatal maternal infections on infant vaccine responses.


Assuntos
Anticorpos Antibacterianos/sangue , Doenças Parasitárias/imunologia , Complicações Parasitárias na Gravidez/patologia , Efeitos Tardios da Exposição Pré-Natal/imunologia , Adulto , Formação de Anticorpos , Antígenos de Bactérias/imunologia , Estudos de Coortes , Difteria/prevenção & controle , Vacina contra Difteria, Tétano e Coqueluche/uso terapêutico , Feminino , Vacinas Anti-Haemophilus/uso terapêutico , Haemophilus influenzae tipo b , Vacinas contra Hepatite B/uso terapêutico , Humanos , Lactente , Doenças Parasitárias/tratamento farmacológico , Vacinas Pneumocócicas/uso terapêutico , Gravidez , Complicações Parasitárias na Gravidez/tratamento farmacológico , Efeitos Tardios da Exposição Pré-Natal/parasitologia , Estudos Prospectivos , Streptococcus pneumoniae , Tétano/prevenção & controle , Vacinação , Coqueluche/prevenção & controle , Adulto Jovem
14.
Neurochem Int ; 126: 109-117, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30880046

RESUMO

Autism spectrum disorder (ASD) is a complex neurodevelopmental disease which involves functional and structural defects in selective central nervous system (CNS) regions harming capability to process and respond to external stimuli. In addition to genetic background, etiological causes of ASD have not been fully clarified. Maternal immune activation (MIA) during pregnancy have been proposed as a potential etiological cause leading to aberrant synaptic pruning and microglia-mediated neurogenesis impairment. Several clinical studies suggest that pro-inflammatory profile during maternal obesity associates with a higher risk of having a child with autism. In this context, the effect of maternal programing by high fat diet overconsumption during pregnancy sets a pro-inflammatory profile partly dependent on an epigenetic program of immunity which promotes brain micro and macrostructural abnormalities in the offspring that might last through adulthood accompanied by phenotypic changes in ASD subjects. Of note, maternal programming of inflammation during development seems to integrate the CNS and peripheral immune system cross-talk which arrays central inflammatory domains coordinating ASD behavior. In this review, we discuss basic and clinical studies regarding the effects of obesity-induced MIA on peripheral immune cells and microglia priming and their relationship with brain structural alterations in ASD models. Also, we show supportive evidence stating the role of maternal programming on epigenetic gene activation in immune cells of ASD subjects. We suggest that maternal programming by hypercaloric diets during development sets a central and peripheral immune cross-talk which potentially might modulate brain macro and microstructural defects leading to autism susceptibility.


Assuntos
Transtorno do Espectro Autista/metabolismo , Dieta Hiperlipídica/efeitos adversos , Suscetibilidade a Doenças/metabolismo , Mediadores da Inflamação/metabolismo , Hipernutrição/metabolismo , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Animais , Transtorno do Espectro Autista/induzido quimicamente , Transtorno do Espectro Autista/imunologia , Suscetibilidade a Doenças/induzido quimicamente , Suscetibilidade a Doenças/imunologia , Epigênese Genética/fisiologia , Feminino , Humanos , Mediadores da Inflamação/imunologia , Saúde Materna , Obesidade/complicações , Obesidade/imunologia , Obesidade/metabolismo , Hipernutrição/complicações , Hipernutrição/imunologia , Gravidez , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Efeitos Tardios da Exposição Pré-Natal/imunologia
15.
Birth Defects Res ; 111(4): 178-196, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30708400

RESUMO

In human studies, it is well established that exposures during embryonic and fetal development periods can influence immune health. Coupled with genetic predisposition, these exposures can alter lifetime chronic and infectious disease trajectory, and, ultimately, life expectancy. Fortunately, as research advances, mechanisms governing long-term effects of prenatal exposures are coming to light and providing the opportunity for intervention and risk reduction. For instance, human association studies have provided a foundation for the association of prenatal exposure to particulate matter with early immunosuppression and later allergic disease in the offspring. Only recently, the mechanisms mediating this response have been revealed and there is much we have yet to discover. Although cellular immune response is understood for many exposure scenarios, molecular pathways are still unidentified. This review will provide commentary and synthesis of the current literature regarding environmental exposures during pregnancy and mechanisms determining immune outcomes. Shared mechanistic features and current gaps in the state of the science are identified and discussed. To such purpose, we address exposures by their immune effect type: immunosuppression, autoimmunity, inflammation and tissue damage, hypersensitivity, and general immunomodulation.


Assuntos
Exposição Ambiental/efeitos adversos , Desenvolvimento Fetal/imunologia , Predisposição Genética para Doença , Exposição Materna/efeitos adversos , Material Particulado/efeitos adversos , Efeitos Tardios da Exposição Pré-Natal/imunologia , Animais , Feminino , Humanos , Gravidez , Efeitos Tardios da Exposição Pré-Natal/patologia
16.
Immunopharmacol Immunotoxicol ; 41(1): 40-47, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30706732

RESUMO

Aim: Aluminum (Al) is a ubiquitous element extensively utilized in many products like food additives, pharmaceuticals, and vaccines, but its hematotoxic and immunotoxic effects are not entirely clarified. The present study explored the developmental hematotoxic and immunotoxic properties of aluminum sulfate (AS) in rats' offspring. Methods: Forty female offspring (10 rats each) were given three incremental AS doses plus a control group, from conception through lactation and after weaning until reached eight weeks old (near adults). Spleen relative weights along with total and differential blood counts were evaluated. Spectroscopic Al levels in spleen and brain were analyzed. Three immunoglobulins (IgG, IgM, and IgE) and two cytokines, interferon-γ and tumor necrosis factor-α, were measured through the ELISA technique. Results: The results revealed a significant relative increase in splenic weights mostly observed in the highest AS dose treated group. Reduction in the total leukocytic count was noticed in the three AS treated groups with relative lymphocytosis. Additionally, a significant decline in RBCs counts and hemoglobin concentrations were recorded. Tumor necrosis factor-α was significantly elevated in the three Al treated groups, while, interferon- γ showed a non-significant reduction compared to the control group. A significant increment in IgG and decline in IgE concentrations with no change in IgM level among groups were observed. Conclusion: Perinatal AS exposure caused mostly non-linear dose-dependent hematotoxicity and immunological impairment especially for the acquired immunity either cellular or humoral. Further studies can examine the immunotoxic effect of Al on male offspring during different stages of immune development.


Assuntos
Compostos de Alúmen/toxicidade , Exposição Materna/efeitos adversos , Efeitos Tardios da Exposição Pré-Natal/sangue , Efeitos Tardios da Exposição Pré-Natal/imunologia , Baço/efeitos dos fármacos , Animais , Animais Recém-Nascidos , Contagem de Células Sanguíneas , Relação Dose-Resposta a Droga , Feminino , Imunidade Celular/efeitos dos fármacos , Imunidade Humoral/efeitos dos fármacos , Imunoglobulina E/sangue , Imunoglobulina G/sangue , Masculino , Tamanho do Órgão/efeitos dos fármacos , Gravidez , Ratos , Fatores Sexuais , Baço/crescimento & desenvolvimento
17.
J Vet Med Sci ; 81(4): 541-544, 2019 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-30773519

RESUMO

The aim of this study is to identify the combined effect of multiple chemicals to the development of allergy. In this study, the effect of prenatal exposure to an organochlorine agent methoxychlor (MXC) and/or an organophosphate agent parathion (PARA) on trimellitic anhydride-induced allergic airway inflammation was examined in mice. Eosinophil infiltration in the bronchoalveolar lavage fluid (BALF) was significantly enhanced by MXC + PARA exposure compared to that of the control, MXC, and PARA groups. In the hilar lymph node, only slight increases in B-cell infiltration, as well as IL-6 and IL-9 secretions were observed in MXC + PARA group, and no effect was observed in the individual treatment groups. Our findings imply that prenatal exposure to some combinations of multiple chemicals may exacerbate the allergic inflammatory responses including eosinophils and cytokine production.


Assuntos
Imunossupressores/toxicidade , Metoxicloro/toxicidade , Paration/toxicidade , Efeitos Tardios da Exposição Pré-Natal/imunologia , Hipersensibilidade Respiratória/induzido quimicamente , Animais , Líquido da Lavagem Broncoalveolar/citologia , Líquido da Lavagem Broncoalveolar/imunologia , Citocinas , Sinergismo Farmacológico , Eosinófilos , Feminino , Linfonodos/citologia , Linfonodos/imunologia , Metoxicloro/administração & dosagem , Camundongos Endogâmicos BALB C , Paration/administração & dosagem , Anidridos Ftálicos/imunologia , Gravidez , Hipersensibilidade Respiratória/imunologia
18.
Ann Rheum Dis ; 78(5): 696-703, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30808622

RESUMO

OBJECTIVE: Congenital heart block (CHB) may develop in fetuses of Ro/SSA autoantibody-positive women. Given the rarity of CHB, information on comorbidity and complications later in life is difficult to systematically collect for large groups of patients. We therefore used nation-wide healthcare registers to investigate comorbidity and outcomes in patients with CHB and their siblings. METHODS: Data from patients with CHB (n= 119) and their siblings (n= 128), all born to anti-Ro/SSA-positive mothers, and from matched healthy controls (n= 1,190) and their siblings (n= 1,071), were retrieved from the Swedish National Patient Register. Analyses were performed by Cox proportional hazard modelling. RESULTS: Individuals with CHB had a significantly increased risk of cardiovascular comorbidity, with cardiomyopathy and/or heart failure observed in 20 (16.8%) patients versus 3 (0.3%) controls, yielding a HR of 70.0 (95% CI 20.8 to 235.4), and with a HR for cerebral infarction of 39.9 (95% CI 4.5 to 357.3). Patients with CHB also had a higher risk of infections. Pacemaker treatment was associated with a decreased risk of cerebral infarction but increased risks of cardiomyopathy/heart failure and infection. The risk of systemic connective tissue disorder was also increased in patients with CHB (HR 11.8, 95% CI 4.0 to 11.8), and both patients with CHB and their siblings had an increased risk to develop any of 15 common autoimmune conditions (HR 5.7, 95% CI 2.83 to 11.69 and 3.6, 95% CI 1.7 to 8.0, respectively). CONCLUSIONS: The data indicate an increased risk of several cardiovascular, infectious and autoimmune diseases in patients with CHB, with the latter risk shared by their siblings.


Assuntos
Anticorpos Antinucleares/imunologia , Autoanticorpos/imunologia , Bloqueio Cardíaco/congênito , Exposição Materna/efeitos adversos , Efeitos Tardios da Exposição Pré-Natal/imunologia , Adolescente , Adulto , Doenças Autoimunes/imunologia , Criança , Pré-Escolar , Comorbidade , Feminino , Bloqueio Cardíaco/imunologia , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Linhagem , Gravidez , Complicações na Gravidez/imunologia , Sistema de Registros , Irmãos , Suécia , Adulto Jovem
19.
Proc Natl Acad Sci U S A ; 116(9): 3443-3448, 2019 02 26.
Artigo em Inglês | MEDLINE | ID: mdl-30808738

RESUMO

Early life exposure to fine particulate matter (PM) in air is associated with infant respiratory disease and childhood asthma, but limited epidemiological data exist concerning the impacts of ultrafine particles (UFPs) on the etiology of childhood respiratory disease. Specifically, the role of UFPs in amplifying Th2- and/or Th17-driven inflammation (asthma promotion) or suppressing effector T cells (increased susceptibility to respiratory infection) remains unclear. Using a mouse model of in utero UFP exposure, we determined early immunological responses to house dust mite (HDM) allergen in offspring challenged from 0 to 4 wk of age. Two mice strains were exposed throughout gestation: C57BL/6 (sensitive to oxidative stress) and BALB/C (sensitive to allergen exposure). Offspring exposed to UFPs in utero exhibited reduced inflammatory response to HDM. Compared with filtered air (FA)-exposed/HDM-challenged mice, UFP-exposed offspring had lower white blood cell counts in bronchoalveolar lavage fluid and less pronounced peribronchiolar inflammation in both strains, albeit more apparent in C57BL/6 mice. In the C57BL/6 strain, offspring exposed in utero to FA and challenged with HDM exhibited a robust response in inflammatory cytokines IL-13 and Il-17. In contrast, this response was lost in offspring exposed in utero to UFPs. Circulating IL-10 was significantly up-regulated in C57BL/6 offspring exposed to UFPs, suggesting increased regulatory T cell expression and suppressed Th2/Th17 response. Our results reveal that in utero UFP exposure at a level close to the WHO recommended PM guideline suppresses an early immune response to HDM allergen, likely predisposing neonates to respiratory infection and altering long-term pulmonary health.


Assuntos
Asma/imunologia , Hipersensibilidade/imunologia , Material Particulado/efeitos adversos , Efeitos Tardios da Exposição Pré-Natal/imunologia , Alérgenos/química , Alérgenos/toxicidade , Animais , Asma/induzido quimicamente , Asma/genética , Asma/patologia , Líquido da Lavagem Broncoalveolar/imunologia , Citocinas/genética , Feminino , Hipersensibilidade/genética , Hipersensibilidade/patologia , Imunossupressão , Pulmão/efeitos dos fármacos , Pulmão/patologia , Camundongos , Gravidez , Efeitos Tardios da Exposição Pré-Natal/patologia , Pyroglyphidae/química , Células Th17/imunologia , Células Th2/imunologia
20.
Transl Psychiatry ; 9(1): 90, 2019 02 14.
Artigo em Inglês | MEDLINE | ID: mdl-30765690

RESUMO

Recent and rapidly developing movements relating to the increasing awareness and reports of gender bias, discrimination, and abuse have reached the academic environments. The consideration that negative attitudes toward women and abuse of power creates a hostile environment for female scientists, facilitating sexual harassment and driving women out of science, can be easily related to. Rationally inaccessible gender biases are not only evident at the level of the researchers, but are also paralleled by a corresponding imbalance at the level of the research subjects. Here, we focus on the maternal immune activation (MIA) animal model to illustrate exemplarily the current state of ex-/inclusion of female research subjects and the consideration of sex as biological variable in the basic neurosciences. We demonstrate a strong sex disparity with a major emphasis on male animals in studies examining behavioral and neurochemical alterations in MIA offspring. We put forward the hypothesis that this neglect of female subjects in basic research may stem from a hard-wired sex/gender bias, which may also be reflected in a similar attitude toward female scientists. We suggest exploring the possibility that by dismantling sex bias and male dominance in basic research one would get an additional handle on favorably modifying the perception and appreciation for women in science.


Assuntos
Modelos Animais , Neurociências , Efeitos Tardios da Exposição Pré-Natal/imunologia , Sexismo , Animais , Atitude , Feminino , Humanos , Masculino , Gravidez , Assédio Sexual
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