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Early life events in allergic sensitisation

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Abstract

The timing of events leading to allergic sensitisation has become a very important area in the attempt to halt the dramatic increase in the prevalence of diseases such as asthma, eczema and hay fever. Recent research has demonstrated that events taking place during the gestational period may well play a role in determining whether or not a genetic susceptibility becomes translated into disease processes. Maternal atopy seems to have an important effect on the developing immune response of the infant and increases the chances of the child developing allergy in later life. Maternal IgE, IgG and amniotic fluid cytokines, combined with the presence of allergen in the feto–maternal environment are all possible factors involved in the ultimate outcome in terms of infants Th-1/Th-2 responses to common environmental antigens. Immune modulation at this stage of development may, in the future, be a way forward in the prevention of allergy.

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... Immunoglobulin E (IgE)-a central mediator for type I hypersensitivity-contributes to the pathogenesis of a wide range of childhood-onset allergic diseases, including asthma, allergic rhinitis, atopic dermatitis, and food allergy [1][2][3][4]. IgE-mediated allergic sensitization has its roots very early in life and is likely impacted by the in utero environment [5,6]. The manifestation of IgE-mediated responses often involves childhood re-exposures to antigens in sensitized individuals, with subsequent IgE-dependent release of inflammatory mediators that give rise to allergic symptoms [3,4]. ...
... It is now recognized that allergic sensitization may occur as early as in utero [5,6]. Factors such as genetic predisposition [25,26], parental atopic status [27][28][29], and aspects of the intrauterine environment [30][31][32][33] including exposures to allergens in amniotic fluid [6] may impact the development of fetal immune responses and Th2 immune responses postnatally. ...
... It is now recognized that allergic sensitization may occur as early as in utero [5,6]. Factors such as genetic predisposition [25,26], parental atopic status [27][28][29], and aspects of the intrauterine environment [30][31][32][33] including exposures to allergens in amniotic fluid [6] may impact the development of fetal immune responses and Th2 immune responses postnatally. We identified multiple differentially methylated immuno-regulatory loci in cord blood associated with total serum IgE measured in midchildhood. ...
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Background: IgE-mediated sensitization may be epigenetically programmed in utero, but early childhood environment may further alter complex traits and disease phenotypes through epigenetic plasticity. However, the epigenomic footprint underpinning IgE-mediated type-I hypersensitivity has not been well-understood, especially under a longitudinal early-childhood life-course framework. Methods: We used epigenome-wide DNA methylation (IlluminaHumanMethylation450 BeadChip) in cord blood and mid-childhood peripheral blood to investigate pre- and post-natal methylation marks associated with mid-childhood (age 6.7-10.2) total serum IgE levels in 217 mother-child pairs in Project Viva-a prospective longitudinal pre-birth cohort in eastern Massachusetts, USA. We identified methylation sites associated with IgE using covariate-adjusted robust linear regressions. Results: Nineteen methylation marks in cord blood were associated with IgE in mid-childhood (FDR < 0.05) in genes implicated in cell signaling, growth, and development. Among these, two methylation sites (C7orf50, ZAR1) remained robust after the adjustment for the change in DNA methylation from birth to mid-childhood (FDR < 0.05). An analysis of the change in methylation between cord blood and mid-childhood DNA (Δ-DNAm) identified 395 methylation marks in 272 genes associated with mid-childhood IgE (FDR < 0.05), with multiple sites located within ACOT7 (4 sites), EPX (5 sites), EVL (3 sites), KSR1 (4 sites), ZFPM1 (3 sites), and ZNF862 (3 sites). Several of these methylation loci were previously associated with asthma (ADAM19, EPX, IL4, IL5RA, and PRG2). Conclusion: This study identified fetally programmed and mid-childhood methylation signals associated with mid-childhood IgE. Epigenetic priming during fetal development and early childhood likely plays an important role in IgE-mediated type-I hypersensitivity.
... [6][7][8] Experimental studies have suggested that stress-induced production of proallergic cytokines during pregnancy, possibly associated with transplacental passage to the fetus, may operate as an underlying mechanism that promotes T H 2 proinflammation. [9][10][11][12][13][14] To date, the association between maternal mental health, specifically during pregnancy, and childhood seroatopy has not been determined. ...
... A binary (yes/no) variable was derived from the question, "In the last 3 months has your child had wheezing or whistling in the chest?" The outcome, wheeze, was determined at 14 time points (3,6,9,12,15,18,21,24,30,36,42,48,54, and 60 months). ...
Article
Prior research has linked maternal prenatal and postnatal mental health with the subsequent development of asthma in children. However, this relationship has not been examined in inner-city African Americans and Hispanics, populations at high risk for asthma. To determine the relationship of maternal demoralization with wheeze, specific wheeze phenotypes, and seroatopy among children living in a low-income, urban community. African American and Dominican women aged 18 to 35 years residing in New York City (the Bronx and Northern Manhattan) were recruited during pregnancy (n = 279). Maternal demoralization (ie, psychological distress) was measured both prenatally and postnatally by validated questionnaire. Outcomes included wheeze, transient (birth to 2.5 years of age), late onset (3-5 years), and persistent (birth to 5 years of age), evaluated via questionnaire and total and indoor allergen specific IgE (at birth and ages 2, 3, and 5 years). Logistic regression with generalized estimating equations assessed the association of demoralization with wheeze and atopy. Multinomial regression explored associations between demoralization and specific wheeze phenotypes. Prenatal demoralization significantly predicted overall wheeze (adjusted odds ratio OR, 1.66; 95% confidence interval [CI], 1.29-2.14), transient wheeze (OR, 2.25; 95% CI, 1.34-3.76), and persistent wheeze (OR, 2.69; 95% CI, 1.52-4.77). No association was found between demoralization and IgE after adjustment (total IgE: OR, 1.04; 95% CI, 0.74-1.45; any specific IgE: OR, 0.96; 95% CI, 0.57-1.60). In this inner-city cohort, prenatal demoralization was associated with transient and persistent wheeze. Understanding how maternal demoralization influences children's respiratory health may be important for developing effective interventions among disadvantaged populations.
... In addition, the structure and function of various other organs are controlled by the brain [50]. Alteration in brain development is well known to result in multiple signals that lead to APO [19,59]. Beginning early on in the second week of gestation in rodents (GD7 in mouse) and first month of gestation in humans, specific areas of the CNS begin to form in the forebrain, midbrain, and hindbrain [50]. ...
... Individual measures of consumption of known DBP concentrations have not been considered [61,62]. Laboratory studies on most DBP have generally focused on their acute maternal, embryonic, and fetal toxicity and teratogenicity [15,29,42,51,55,58,59]. The molecular and mechanistic events that occur in response to doses of DBP below those causing such adverse endpoints are not known. ...
Article
Epidemiological studies indicate a relationship between water disinfectant by-products (DBP) and adverse pregnancy outcomes (APO) including neural tube defects. These studies suggest that fetal brain may be vulnerable to DBP during early stages of development. Therefore, we examined several molecular markers commonly known to indicate chemical-induced neurotoxicity during fetal brain development following prenatal exposure to the DBP; chloroacetonitrile (CAN). Pregnant mice, at gestation day 6 (GD6), were treated with a daily oral dose of CAN (25 mg/kg). At GD12, two groups of animals were treated with an i.v. tracer dose of [2-14C]-CAN. These animals were sacrificed at 1 and 24 h after treatment and processed for quantitative in situ micro-whole-body autoradiography. The remaining groups of animals continued to receive CAN. At GD18, control and treated animals were weighed, anesthetized, and fetuses were obtained and their brains were removed for biochemical and immunohistochemical analyses. Whole-body autoradiography studies indicate a significant uptake and retention of [2-14C]-CAN/metabolites (M) in fetal brain (cerebral cortex, hippocampus, cerebellum) at 1 and 24 h. There was a 20% reduction in body weight and a 22% reduction in brain weight of fetuses exposed to CAN compared to controls. A significant increase in oxidative stress markers was observed in various fetal brain regions in animals exposed to CAN compared to controls. This was indicated by a 3- to 4-fold decrease in the ratio of the reduced to oxidized form of glutathione (GSH/GSSG), increased lipid peroxidation (1.3-fold), and increased 8-hydroxy-2-deoxyguanosine levels (1.4-fold). Cupric silver staining indicated a significant increase in the number of degenerating neurons in cortical regions in exposed animals. In animals exposed to CAN there was increase in nuclear DNA fragmentation (TUNEL staining) detected in the cerebral cortex and cerebellum (2-fold increase in apoptotic indices). Caspase-3 activity in cerebral cortex and cerebellum of treated animals were also increased (1.7- and 1.5-fold, respectively). In conclusion, this study indicates that CAN/M crossed the placenta and accumulated in fetal brain tissues where it caused oxidative stress and neuronal apoptosis. These events could predispose the fetus to altered brain development leading to APO as well as behavioral and learning and memory deficits.
... In addition, the structure and function of various other organs are controlled by the brain [50]. Alteration in brain development is well known to result in multiple signals that lead to APO [19,59]. Beginning early on in the second week of gestation in rodents (GD7 in mouse) and first month of gestation in humans, specific areas of the CNS begin to form in the forebrain, midbrain, and hindbrain [50]. ...
... Individual measures of consumption of known DBP concentrations have not been considered [61,62]. Laboratory studies on most DBP have generally focused on their acute maternal, embryonic, and fetal toxicity and teratogenicity [15,29,42,51,55,58,59]. The molecular and mechanistic events that occur in response to doses of DBP below those causing such adverse endpoints are not known. ...
Article
Developmental exposure to environmental chemicals may have detrimental effects on embryonic brains that could play a major role in the etio-pathology of fetal and adult neurological diseases. The exact mechanism by which prenatal exposures to environmental agents, such as drinking water disinfectant byproducts (DBP), cause neurological impairment in fetus is not known. Our objective is to examine the impact of prenatal exposure to DBP on fetal brain development. Pregnant CD-1 mice, at the sixth day of gestation (GD-6), received a daily (GD-6-GD-18) oral dose of chloroacetonitrile (CAN, 25 ppm), a member of DBP. To assess fetal brain uptake of CAN, several animals were injected with a tracer dose of 2-[(14)C]-CAN (333 microCi/kg, i.v.), at GD-12 and processed for quantitative in situ micro whole-body autoradiography (QIMWBA) at 1 and 24 h after treatment. The remaining animals continued receiving CAN until GD-18 when fetal brains were processed for biochemical determination of oxidative stress (OS) or prepared for histological examinations. The results indicate a rapid placental transfer and fetal brain uptake of 2-[(14)C]-CAN/metabolites in cortical areas and hippocampus. In treated animals 3-fold decrease in glutathione (GSH), 1.3-fold increase in lipid peroxidation and 1.4-fold increase in DNA oxidation were detected as compared to control. DeOlmos cupric silver staining of fetal brains indicated significant increase in cortical neurodegeneration in treated animals. Immunohistochemical labeling (TUNEL) of apoptotic nuclei in the cortices and choroid plexuses were also increased in treated animals as compared to control. In conclusion, CAN crosses the placental and fetal blood-brain barriers and induces OS that triggered apoptotic neurodegenration in fetal brain. Future studies will examine the molecular mechanisms of these events and its impact on neural development of offspring.
... Earlier work by suggested that the infant swallows maternal IgE from amniotic fluid and that IgE does not cross the placenta [78]. Even though IgE does not pass the placenta into the fetal circulation, atopic mothers with higher IgE levels expose their fetuses to higher amounts of IgE through the amniotic fluid. ...
Article
Expression of allergic diseases in very early childhood indicates that early life events play a significant role in childhood allergy development. The developmental origins of allergy hypothesis suggest events initiated in the in-utero period derived from the interaction between maternal, placental, and fetal factors may contribute to childhood allergy susceptibility. Environmental impacts on placental function and fetal programming are imperative in defining illness risk during pregnancy. Fetal programming, a process by which an injury delivered during a critical period of development, causes immediate adaptive responses with long-term consequences on an organism’s structure or function. During pregnancy, the maternal immune response is skewed towards Th2-related humoral responses, hence increasing the susceptibility of childhood allergy development. Maternal atopic phenotype markedly increases the probability of her offspring developing an allergic predisposition. Combination of in utero events – which include maternal asthma or infection, and exposures to maternal allergy which changes the placental function – can alter placental cytokine expression and could predispose offspring to an allergic phenotype. All these events may affect embryology and fetal immune system development. Interestingly, the mechanism and role of the in-utero events on the developmental origins of allergy are not clearly understood; this will be addressed in this review. (199 words)
... Allergic diseases such as atopic dermatitis (AD), eczema, or allergic rhinitis, are inflammatory disorders associated with atopy, that result from both genetic predispositions and environmental exposures [1]. They often occur in patients with a positive family or personal history of atopy and are more frequent among infants [2]. Atopic disorders are public health problems with increased frequency worldwide [3], however, the prevalence and the severity decrease with age. ...
Article
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Objective: To create an allergic disease risk factors scale score that would screen for the risk assessment of asthma, allergic rhinitis and atopic dermatitis in children from 3-17 years. Methods: This case-control study, conducted between December 2015 and April 2016, enrolled 1274 children. The allergic disease risk factors scale was created by combining environmental, exposure to toxics during pregnancy and breastfeeding and parental history of allergic diseases. Results: Playing on carpets, male gender, child’s respiratory problems or history of eczema before the age of 2 years, and humidity significantly increased the odds of allergies in the child. Maternal waterpipe smoking, maternal history of rhinitis, history of asthma in the mother or the father, along with the maternal drug intake or alcohol consumption during pregnancy significantly increased the odds of allergies in the child. There was a significant increase in allergy diseases per category of the allergic disease risk factors scale (p < 0.001 for trend). Scores ≤ 2.60 best represented control individuals, while scores > 5.31 best represented children with allergic diseases. Conclusion: Allergic diseases seem to be linked to several risk factors in our population of school children. Many environmental factors might be incriminated in these allergic diseases.
... Evidence for transplacental priming of fetal B cells has been shown in studies examining cord blood for Ag-specific IgM and IgE, which cannot cross the placenta from the maternal circulation and are therefore of fetal origin (11)(12)(13)(14). Several studies have shown that fetal immune priming might confer postnatal protection against infection (6,15,16), whereas others suggest that this may lead to the development of allergies (17)(18)(19), increased risk of infections (10,(20)(21)(22), and decreased protective immunity to vaccinations (23,24). The biological processes behind the varied consequences of prenatal immune priming are yet to be fully understood. ...
Article
Infections during pregnancy can expose the fetus to microbial Ags, leading to inflammation that affects B cell development. Prenatal fetal immune priming may have an important role in infant acquisition of pathogen-specific immunity. We examined plasma proinflammatory biomarkers, the proportions of various B cell subsets, and fetal priming to tetanus vaccination in cord blood from human United States and Kenyan neonates. United States neonates had no identified prenatal infectious exposures, whereas Kenyan neonates examined had congenital CMV or mothers with prenatal HIV or Plasmodium falciparum or no identified infectious exposures. Kenyan neonates had higher levels of IP-10, TNF-α, CRP, sCD14, and BAFF than United States neonates. Among the Kenyan groups, neonates with prenatal infections/infectious exposures had higher levels of cord blood IFN-γ, IL-7, sTNFR1, and sTNFR2 compared with neonates with no infectious exposures. Kenyan neonates had greater proportions of activated memory B cells (MBC) compared with United States neonates. Among the Kenyan groups, HIV-exposed neonates had greater proportions of atypical MBC compared with the other groups. Although HIV-exposed neonates had altered MBC subset distributions, detection of tetanus-specific MBC from cord blood, indicative of fetal priming with tetanus vaccine given to pregnant women, was comparable in HIV-exposed and non-HIV-exposed neonates. These results indicate that the presence of infections during pregnancy induces fetal immune activation with inflammation and increased activated MBC frequencies in neonates. The immunologic significance and long-term health consequences of these differences warrant further investigation.
... Allergic sensitization starts at the prenatal period (20). The development of allergic diseases has been observed as directly related to certain factors such as the amount of allergens contacted in the first year of life, previous infections, endotoxin exposure, and the bacterial density of intestinal flora (21). Michel et al. (22) showed that asthma symptoms are triggered by endotoxin exposure by inhalation. ...
... Al entrar en contacto con IgE en la superficie de los mastocitos y basófilos, los alérgenos disparan la degranulación, liberando mediadores inmunitarios, responsables de las alteraciones fisiopatológicas y los síntomas inmediatos de la alergia.En la segunda etapa, los órganos afectados sufren un proceso inflamatorio crónico con migración de eosinófilos, basófilos y linfocitos. La patogénesis de las respuestas alérgicas se relaciona estrechamente con la activación preferencial de subpoblaciones específicas de linfocitos T cooperadores, denominados Th2, (en detrimento de las subpoblaciones de Th1), capaces de producir predominantemente interleucinas IL-3, IL-4, IL-5, IL-9 e IL-13, las cuales activan los mastocitos, basófilos y demás células inflamatorias, produciendo las respuestas de los procesos alérgicos inmediatos y retardados[11][12][13] . Las subpoblaciones de linfocitos T cooperadores se relacionan con la respuesta inmunitaria celular aguda, a través de la producción de IL-2, IFN-γ y TNF-β.Después de esta introducción de la fisiopatología de los procesos alérgicos crónicos, discutiremos la evidencia científica actual que indica el desencadenamiento de enfermedades alérgicas crónicas (patrón de respuesta de Th2) cuando las enfermedades inflamatorias agudas (patrón de respuesta de Th1) se han suprimido o tratado inadecuadamente en la niñez, o bien no han logrado seguir su curso natural.La hipótesis de la higieneFormulada inicialmente por Strachan 14 en 1989, la hipótesis de la higiene pretende explicar el hecho observado empíricamente de que los niños que desarrollan enfermedades agudas a temprana edad, incluso si tienen predisposición genética a desarrollar atopia y otras enfermedades crónicas, podrían no presentar tales manifestaciones. ...
Article
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Resumen: La búsqueda de la comprensión del individuo en su totalidad sintomática ha sido uno de los propósitos de la Homeopatía desde sus comienzos. A todo lo largo de su historia, los homeópatas se han interesado por la cuestión de que el tratamiento inadecuado de las enfermedades agudas en la infancia pudiera conducir a enfermedades crónicas futuras. Hahnemann advirtió que tratar las enfermedades agudas con medicina alopática, con fuertes dosis de fármacos, o bien suprimir los síntomas locales de tales enfermedades, incrementaría el riesgo de sufrir enfermedades crónicas futuras. Burnett propuso la teoría de la vacunosis y advirtió de las manifestaciones crónicas subsiguientes a la vacunación contra la viruela. Buscando el origen fisiopatológico de las enfermedades crónicas, homeópatas franceses las correlacionaron con la reacción anormal del sistema reticuloendotelial (RES, por sus siglas en inglés). Estudiando la patología experimental, Maffei atribuyó las manifestaciones sintomáticas al desequilibrio entre los fenómenos inmunológicos de la alergia y la inmunidad. Denominó " meta-alergia " y " para-alergia " a los efectos sensibilizantes y patogénicos de los medicamentos y vacunas, respectivamente. La hipótesis de la higiene se basa en evidencia de que el desequilibrio de la respuesta inmunológica en la niñez, específicamente entre las subpoblaciones de linfocitos Th1 y Th2, es responsable del desarrollo de ciertas enfermedades alérgicas y crónicas en el futuro. El factor perturbador para la predisposición a presentar una respuesta alérgica en el futuro (Th2) es la obstrucción de las manifestaciones naturales de las enfermeda-des infecciosas (respuesta de Th1) en los niños pequeños. El tratamiento homeopático busca equilibrar la reacción vital, correspondiente a una respuesta fisiológica in-tegrativa, con la posibilidad de regular el desequilibrio de Th1/Th2. Sin embargo, se carece de estudios clínicos que sustenten tal hipótesis. Abstract: Seeking to understand the individual in his symptomatic totality has been an aim of homeopathy since its beginning. Throughout its history, homeopaths have been concerned that inadequate treatment of acute diseases in childhood may lead to future chronic diseases. Hahnemann cautioned that by treating acute diseases with allopathic medicine, with strong doses of drugs, or suppressing local symptoms of those diseases, would increase the risk of future chronic diseases. Burnett proposed the theory of vaccinosis and warned of chronic manifestations subsequent to smallpox vaccination. French homeopaths, seeking the physiopathological origin of chronic diseases, correlated it to the abnormal reaction of the reticuloendothelial system (RES). Through the study of experimental pathology, Maffei attributed symptomatic manifestations to the imbalance between the immunological phenomena of allergy and immunity. He termed the sensitizing and pathogenic effects of medications and vaccines, ‘metallergy’ and ‘parallergy’, respectively. The hygiene hypothesis is based on evidence that the imbalance of immunological response in childhood, specifically among the Th1 and Th2 lymphocyte subpopulations, is responsible for the development of some allergic and chronic diseases in the future. The deranging factor for the predisposition to future allergic response (Th2) is the obstruction of natural manifestations of infectious diseases (Th1 response) in young children. Homeopathic treatment aims to equilibrate vital reaction, corresponding to an integrative physiological response, it may regulate Th1/Th2 imbalance. However, clinical trials to support this hypothesis are lacking. Homeopathy (2002) 91, 207–216.
... 13 However, many factors remain unclear, and discerning causal pathways and potential targets for intervention is part of the World Health Organization's strategy for the prevention and control of asthma and allergy. 2 There is evidence that the susceptibility for developing asthma and allergy is established in utero. [14][15][16][17] Certain prenatal exposures are known to influence fetal development, including alcohol, smoking, illicit drugs and teratogenic medications. 18 The concept of fetal programming describes how intrauterine factors can have an impact on subsequent offspring's physiology and development, 19 affecting the risk of chronic diseases later in life. ...
Article
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Background Asthma and allergic disorders are of global concern, with asthma estimated to affect 334 million people and 14% of children worldwide. 1 , 2 Although the prevalence of asthma may have plateaued at ~8–12% in some economically developed countries, the global burden remains substantial.
... Many host and environmental factors that may alter immune expression have been proposed, and recently, there has been a growing interest in the mechanisms linking psychosocial factors to atopic disorders (2). As atopic predisposition is evident already at birth, prenatal factors are thought to have great impact on the development of atopy (3), and it is becoming clear that the in utero environment influences immune development independently of genetic susceptibility (4,5). ...
Article
Full-text available
Background A growing number of studies suggest that maternal stress during pregnancy promotes atopic disorders in the offspring. This is the first systematic review to address prenatal maternal stress (PNMS) and the subsequent risk of atopy‐related outcomes in the child. Methods The review was performed in accordance to the PRISMA criteria. We searched and selected studies in PubMed, Scopus, Embase and PsychINFO until November 2014. Results Sixteen (with 25 analyses) of 426 identified articles met the review criteria. Five main PNMS exposures (negative life events, anxiety/depression, bereavement, distress and job strain) and five main atopic outcomes (asthma, wheeze, atopic dermatitis, allergic rhinitis and IgE) were assessed across the studies. Overall, 21 of the 25 analyses suggested a positive association between PNMS and atopic outcomes. Of the 11 exposure–response analyses reported, six found statistically significant trends. Conclusion This systematic review suggests a relationship between maternal stress during pregnancy and atopic disorders in the child. However, the existing studies are of diverse quality. The wide definitions of often self‐reported stress exposures imply a substantial risk for information bias and false‐positive results. Research comparing objective and subjective measures of PNMS exposure as well as objective measures for atopic outcome is needed.
... With the increase in atopic disorders, such as asthma, food allergies and atopic dermatitis in the Westernized population, it is speculated that genetic predisposition itself cannot be solely responsible, and focus is being placed on in utero events and environmental factors that may be playing a contributing role [11][12][13]. Prenatal stress and the associated rise in glucocorticoids (GCs), as well as the high concentration of pro-inflammatory mediator omega-6 polyunsaturated fatty acid (n-6 PUFA) has been found to be a factor contributing to the susceptibility to atopic diseases by altering the programming of both the immune system and hypothalamic-pituitaryadrenal axis (HPAA) [14,15]. For example, alterations in the HPAA through fetal programming have been shown to increase the occurrence of respiratory, and skin diseases [16][17][18]. ...
Article
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Background Prenatally stressed offspring exhibit increased susceptibility to inflammatory disorders due to in utero programming. Research into the effects of n-3 PUFAs shows promising results for the treatment and prevention of these disorders. The purpose of this study was to investigate whether maternal fishmeal supplementation during pregnancy and lactation protects against programming of the offspring’s immune response following simulated maternal infection. Methods In order to accomplish this, 53 ewes were fed a diet supplemented with fishmeal (FM; rich in n-3 PUFA) or soybean meal (SM; rich in n-6 PUFAs) from day 100 of gestation (gd 100) through lactation. On gd135, half the ewes from each dietary group were challenged with either 1.2 μg/kg Escherichia coli lipopolysaccharide (LPS) endotoxin to simulate a bacterial infection, or saline as the control. At 4.5 months of age the offspring’s dermal immune response was assessed by cutaneous hypersensitivity testing with ovalbumin (OVA) and candida albicans (CAA) 21 days after sensitization. Skinfold measurements were taken and serum blood samples were also collected to assess the primary and secondary antibody immune response. Results Offspring born to SM + LPS mothers had a significantly greater change in skinfold thickness in response to both antigens as well as a greater secondary antibody response to OVA compared to all treatments. Conclusions Supplementation during pregnancy with FM appears to protect against adverse fetal programming that may occur during maternal infection and this may reduce the risk of atopic disease later in life.
... Many host and environmental factors that may alter immune expression have been proposed, and recently, there has been a growing interest in the mechanisms linking psychosocial factors to atopic disorders (2). As atopic predisposition is evident already at birth, prenatal factors are thought to have great impact on the development of atopy (3), and it is becoming clear that the in utero environment influences immune development independently of genetic susceptibility (4,5). ...
Article
Full-text available
BackgroundA growing number of studies suggest that maternal stress during pregnancy promote atopic disorders in the offspring. This is the first systematic review to address prenatal maternal stress (PNMS) and the subsequent risk of atopy related outcomes in the child.Methods The review was performed in accordance to the PRISMA criteria. We searched and selected studies in Pubmed, Scopus, Embase, and PsychINFO until November 2014.ResultsSixteen (with 25 analyses) out of 426 identified articles met the review criteria. Five main PNMS exposures (negative life events, anxiety/depression, bereavement, distress, and job strain) and five main atopic outcomes (asthma, wheeze, atopic dermatitis, allergic rhinitis, and IgE) were assessed across the studies. Overall, 21 of the 25 analyses suggested a positive association between PNMS and atopic outcomes. Of the 11 exposure-response analyses reported, six found statistically significant trends.Conclusion This systematic review suggests a relationship between maternal stress during pregnancy and atopic disorders in the child. However, the existing studies are of diverse quality. The wide definitions of often self-reported stress exposures implies a substantial risk for information bias and false positive results. Research comparing objective and subjective measures of PNMS exposure as well as objective measures for atopic outcome is needed.This article is protected by copyright. All rights reserved.
... The lack of widespread and consistent influences of maternal diet on children's allergies is perhaps not surprising. Although the development of a predisposition toward allergy may be programmed early in the fetus, possibly in the first or second trimester [79], influences early in the neonatal period such as the mode of birth, feeding type, early infections, introduction to solid foods, and exposure to allergens also influence the developing immune system. Parental atopy, epigenetic factors, gut microbiota, dietary, and other environmental influences (such as pollution, tobacco smoke, and alcohol consumption) have potential to affect this programming. ...
... Interestingly, it has been observed that maternal allergy confers a higher risk of allergic disease in the offspring compared with paternal allergy 226 and in general, maternal factors, placental factors or both are frequently discussed in relation to development of allergies [227][228][229] . ...
... The lack of widespread and consistent influences of maternal diet on children's allergies is perhaps not surprising. Although the development of a predisposition toward allergy may be programmed early in the fetus, possibly in the first or second trimester [79], influences early in the neonatal period such as the mode of birth, feeding type, early infections, introduction to solid foods, and exposure to allergens also influence the developing immune system. Parental atopy, epigenetic factors, gut microbiota, dietary, and other environmental influences (such as pollution, tobacco smoke, and alcohol consumption) have potential to affect this programming. ...
Conference Paper
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Objectives To investigate the relationship between maternal diet during pregnancy and lactation and development of atopic disorders in childhood. Methods We included studies published up to August 2011 which either assessed food-based maternal dietary interventions or examined associations between maternal dietary intake during pregnancy and/or lactation and allergic outcomes (eczema, asthma, hay fever and sensitization) in their children. Results We included 43 studies (over 40 000 children): 11 intervention studies (including seven RCTs), 27 prospective cohort studies, four retrospective cohort studies and one case-control study. In the RCTs, no significant difference was noted overall in the prevalence of eczema and asthma in the offspring of women on diets free from common food allergens during pregnancy. The prospective cohorts investigated a large number of potential associations, but reported few significant associations between maternal dietary intake and development of allergy. Maternal diets rich in fruits and vegetables, fish and foods containing vitamin D and ‘Mediterranean’ dietary patterns were among the few consistent associations with lower risk of allergic disease in their children. Foods associated with higher risk included vegetable oils and margarine, nuts and fast food. Conclusion This review did not find widespread or consistent links between mother’s dietary intake and atopic outcomes in their children. However, maternal consumption of ‘Mediterranean’ dietary patterns, diets rich in fruits and vegetables, fish and vitamin D containing foods were suggestive of benefit, requiring further evaluation.
... Earlier studies report immune dysregulation at birth suggesting that prenatal exposures may influence the programming of neonatal immune response [2]. One pathway by which maternal exposure may affect the developing immune response is through direct exposure of the fetus to antigens that cross the placental barrier [3,4]. Alternatively, maternal response to exposure may influence the in-utero environment for the developing fetus [5]. ...
Article
Purpose of review: There is increasing evidence that the prenatal window represents a critical period in which the developing immune system may be primed toward an allergic phenotype. Studies have investigated the role of a number of maternal environmental exposures on subsequent allergic disorders in the offspring. We summarize findings from recent studies on prenatal environmental factors influencing IgE levels, atopy, and early asthma. Recent findings: A building literature supports the influence of maternal exposure to environmental pollutants, such as allergens, traffic-related air pollution, tobacco smoke, and organochlorine compounds and social factors on allergic outcomes. More novel associations have been investigated, such as the effect of prenatal exposures to phthalates, bisphenol A, and magnetic fields. There is also rising interest in epigenetics as a pathway of action by which maternal exposure affect immune health. Summary: Emerging research highlights the challenges of investigating in-utero exposures and of relating exposures to such a heterogeneous and complex outcome as allergic disease. Further research is needed on the mechanisms by which prenatal exposure influences allergic response in childhood and how postnatal, familial and social factors, and sex can modify disease outcomes. Epigenetics is a promising new frontier, and likely one of several explanatory factors.
... It has been considered a long time that the neonate is immunologically naı¨venaı¨ve and the development of specific immune responses is restricted to the period after birth. However, in utero exposure to environmental antigens has been documented in cord blood [6,7,8,9] and amniotic fluid [10] which suggest that an intrauterine sensitization to allergens is possible. An increased proliferation and cytokine production of cord blood mononuclear cells in response to nutritive allergens, when the mother has been exposed, such as bovine beta-lactoglobulin (BLG) and aeroallergens has been described [4,11,12,13]. ...
Article
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Upon antigen exposure, cord blood derived T cells respond to ubiquitous environmental antigens by high proliferation. To date it remains unclear whether these "excessive" responses relate to different regulatory properties of the putative T regulatory cell (Treg) compartment or even expansion of the Treg compartment itself. Cord blood (>37 week of gestation) and peripheral blood (healthy controls) were obtained and different Treg cell subsets were isolated. The suppressive potential of Treg populations after antigen exposure was evaluated via functional inhibition assays ([(3)H]thymidine incorporation assay and CFSE staining) with or without allergen stimulation. The frequency and markers of CD4(+)CD25(high)FoxP3(+) T cells were characterized by mRNA analysis and flow cytometry. Cord blood derived CD4(+)CD25(high) cells did not show substantial suppressor capacity upon TCR activation, in contrast to CD4(+)CD25(high) cells freshly purified from adult blood. This could not be explained by a lower frequency of FoxP3(+)CD4(+)CD25(high)cells or FOXP3 mRNA expression. However, after antigen-specific stimulation in vitro, these cells showed strong proliferation and expansion and gained potent suppressive properties. The efficiency of their suppressive capacity can be enhanced in the presence of endotoxins. If T-cells were sorted according to their CD127 expression, a tiny subset of Treg cells (CD4(+)CD25(+)CD127(low)) is highly suppressive even without prior antigen exposure. Cord blood harbors a very small subset of CD4(+)CD25(high) Treg cells that requires antigen-stimulation to show expansion and become functional suppressive Tregs.
... A high level of total IgE has therefore often been used as a measure of atopic propensity in the newborn. [1][2][3][4][5][6][7] Such early markers of atopy are of major interest in light of the hypothesis of fetal programming of atopic diseases 8 and might help in identification of prenatal risk factors. However, it is essential that such markers are valid to avoid noneffective or harmful recommendations about environmental exposures during pregnancy. ...
Article
IgE in cord blood is thought to be a product of the fetus. A high level of total IgE is therefore used as a measure of atopic propensity in the newborn. We recently found strong evidence that allergen-specific IgE in cord blood was the result of transfer of maternal IgE to fetal blood or cord blood (maternofetal transfer) rather than fetal production. This also suggests that total IgE in cord blood might primarily be a maternal product. We sought to determine to what extent increased levels of total IgE in cord blood is the result of maternofetal transfer of IgE. Total IgE in cord blood was analyzed in a prospective birth cohort study. Maternofetal transfer of IgE was detected by means of high-sensitivity analyses of cord blood IgA and allergen-specific IgE and comparison with parental IgE levels and levels at 6 months of age. Forty-six percent of cord blood samples with increased IgE levels (>or=0.5 IU/mL) showed indication of maternofetal transfer of IgE. Maternal origin of IgE in these samples was validated by showing reduced levels of IgE at 6 months of age compared with samples with no indication of maternofetal transfer (geometric mean, 9.4 vs 5.4 IU/mL; P = .01). Maternofetal transfer was not appropriately accounted for by the conventional method of cord blood IgA measurement. Maternofetal transfer might be a common cause of increased cord blood IgE levels. Future studies should take potential maternofetal transfer into account or use other markers of atopy.
... 1 It has been proposed that individuals with altered immune response at birth have an increased risk of developing allergic diseases. 2 In particular, elevated cord blood IgE has been associated with aeroallergen sensitization and the development of allergic diseases in children, particularly in those with a family history of atopy. [3][4][5] In addition, indoor allergen exposure is considered an important risk factor for both developing and exacerbating asthma in susceptible populations. ...
Article
Whereas some evidence suggests that antigen sensitization may begin prenatally, the influence of maternal allergen exposure during pregnancy has not been fully elucidated. We examined the relationship between prenatal maternal aeroallergen exposure and cord blood total IgE and the potential mediating/indirect effect of maternal immune response. This study was performed in 301 mother-infant pairs enrolled in the Asthma Coalition on Community, Environment, and Social Stress (ACCESS) project, a study examining the effects of prenatal and early life social and physical environmental exposures on urban asthma risk. Dust samples collected prenatally from mothers' bedrooms were analyzed for cockroach and dust mite allergens. Cord blood was analyzed for total IgE, and maternal serum collected during pregnancy for total and specific IgE. We assessed the relationship between prenatal exposure and cord blood total IgE and the potential mediation effect adjusting for maternal age, race, education, smoking status, and dust collection season; and child's sex and season of birth. In multivariate models, elevated prenatal dust mite levels (>0.2 microg/g) increased cord blood IgE concentrations by 29% (P = .08), and continuous dust mite concentration was associated with a significant nonlinear increase in cord blood IgE (P = .02). Elevated prenatal exposure to cockroach allergen (>2 U/g) was not associated with cord blood IgE, but showed a significant indirect relationship through maternal total IgE (beta = 0.23; 95% CI, 0.08-0.41). These results demonstrate that maternal prenatal exposure to household allergens may affect cord blood IgE, albeit the underlying mechanism may be allergen-specific.
... However, the factors that play a crucial role in the development of atopic diseases may act in utero. It has recently been shown that infants are born with the capacity to mount an immune response to environmental antigens: lymphocytes of fetuses were shown to react to allergens as the consequence of fetal sensitization [59][60][61][62]. ...
Article
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The interface between the organism and the outside world, which is the site of exchange of nutrients, export of products and waste components, must be selectively permeable and at the same time, it must constitute a barrier equipped with local defense mechanisms against environmental threats (e.g. invading pathogens). The boundaries with the environment (mucosal and skin surfaces) are therefore covered with special epithelial layers which support this barrier function. The immune system, associated with mucosal surfaces covering the largest area of the body (200-300 m(2)), evolved mechanisms discriminating between harmless antigens and commensal microorganisms and dangerous pathogens. The innate mucosal immune system, represented by epithelial and other mucosal cells and their products, is able to recognize the conserved pathogenic patterns on microbes by pattern recognition receptors such as Toll-like receptors, CD14 and others. As documented in experimental gnotobiotic models, highly protective colonization of mucosal surfaces by commensals has an important stimulatory effect on postnatal development of immune responses, metabolic processes (e.g. nutrition) and other host activities; these local and systemic immune responses are later replaced by inhibition, i.e. by induction of mucosal (oral) tolerance. Characteristic features of mucosal immunity distinguishing it from systemic immunity are: strongly developed mechanisms of innate defense, the existence of characteristic populations of unique types of lymphocytes, colonization of the mucosal and exocrine glands by cells originating from the mucosal organized tissues ('common mucosal system') and preferential induction of inhibition of the responses to nondangerous antigens (mucosal tolerance). Many chronic diseases, including allergy, may occur as a result of genetically based or environmentally induced changes in mechanisms regulating mucosal immunity and tolerance; this leads to impaired mucosal barrier function, disturbed exclusion and increased penetration of microbial, food or airborne antigens into the circulation and consequently to exaggerated and generalized immune responses to mucosally occurring antigens, allergens, superantigens and mitogens.
... The pathogenesis of allergic responses is closely related to the preferential activation of specific T helper lymphocyte subpopulations, called Th2, (to the detriment of Th1 subpopulations), capable of producing predominantly IL-3, IL-4, IL-5, IL-9 and IL-13 interleukins, which activate mastocytes, baso-phils and the other inflammatory cells, producing immediate and delayed allergic process responses. [11][12][13] T helper lymphocyte subpopulations are related to the acute cellular immune response, through IL-2, IFN-g e TNF-b production. ...
Article
Seeking to understand the individual in his symptomatic totality has been an aim of homeopathy since its beginning. Throughout its history, homeopaths have been concerned that inadequate treatment of acute diseases in childhood may lead to future chronic diseases. Hahnemann cautioned that by treating acute diseases with allopathic medicine, with strong doses of drugs, or suppressing local symptoms of those diseases, would increase the risk of future chronic diseases. Burnett proposed the theory of vaccinosis and warned of chronic manifestations subsequent to smallpox vaccination. French homeopaths, seeking the physiopathological origin of chronic diseases, correlated it to the abnormal reaction of the reticuloendothelial system (RES). Through the study of experimental pathology, Maffei attributed symptomatic manifestations to the imbalance between the immunological phenomena of allergy and immunity. He termed the sensitizing and pathogenic effects of medications and vaccines, 'metallergy' and 'parallergy', respectively. The hygiene hypothesis is based on evidence that the imbalance of immunological response in childhood, specifically among the Th1 and Th2 lymphocyte subpopulations, is responsible for the development of some allergic and chronic diseases in the future. The deranging factor for the predisposition to future allergic response (Th2) is the obstruction of natural manifestations of infectious diseases (Th1 response) in young children. Homeopathic treatment aims to equilibrate vital reaction, corresponding to an integrative physiological response, it may regulate Th1/Th2 imbalance. However, clinical trials to support this hypothesis are lacking.
... 4 Childhood infections might have a key role in stimulating the maturation of the immune system away from the T H 2 profile that predominates at birth toward a predominantly T H 1type phenotype. 5 Although biologically plausible, there is a dearth of epidemiologic evidence to support the T H 1/T H 2 model of disease risk. 6,7 The aim of this study was to investigate the relationship between atopic status and allergic diseases and the risk of autoimmune disorders in the American adult population. ...
Article
The findings of an inverse relationship between T(H)1- and T(H)2-mediated disorders would provide strong empiric support to the hygiene hypothesis. We sought to investigate the relationship between T(H)2-mediated atopic allergy and T(H)1-mediated autoimmune conditions in a nationally representative population. We used logistic regression to analyze adult data from the Third National Health and Nutrition Examination Survey. Data on allergic and autoimmune disease history were available for 20,050 subjects, and data on atopy were available for a subsample of 7304 subjects. Atopy was defined by one or more positive skin prick test responses (wheal of > or =3 mm) to 10 common aeroallergens. Allergic disease was defined by patient reports of physician-diagnosed asthma, hay fever, or both. T(H)1-mediated autoimmune disease was defined by patient reports of physician-diagnosed type 1 diabetes mellitus, thyroid disorders, and/or rheumatoid arthritis. Adjusted for age and sex and taking into account the complex survey design, there was no relationship between atopy and a history of autoimmune disorders (adjusted odds ratio, 1.01; 95% CI, 0.61-1.67; P =.97). In contrast, physician diagnosis of allergic disorders was associated with a significant increased risk of physician-diagnosed autoimmune disorders (adjusted odds ratio, 1.67; 95% CI, 1.35-2.07; P <.001). We found no evidence of an inverse relationship between atopy and patient reports of physician-diagnosed common autoimmune disorders in the adult American population. Contrary to our initial hypothesis, reports of physician-diagnosed common allergic disorders are positively associated with reports of physician-diagnosed autoimmune disorders, with this possibly being caused by ascertainment bias. These findings suggest that the T(H)1/T(H)2 paradigm might be an oversimplification.
... So far, a stable association of a distinct infectious disease with a consecutive change in atopic disease manifestation has not been demon- strated. Other environmental modulators, like air pollution, socio-economic status, family size, and passive smoking, as well as genetic parameters, play a role in a complex interaction of allergy promotion [16][17][18][19][20][21]. ...
Article
Atopic diseases develop on a genetic background and are modulated by environmental factors among which some infectious diseases are thought to have a protective influence. The aim of this study was to determine the influence of infectious diseases in younger ages, bacterial and viral, on atopic diseases and sensitization to aero- and food-allergens in adults. A population-based sample of 4262 subjects aged 25-74 years were interviewed concerning their history of infectious disease within the first 18 years of life. Information about allergic disease, including atopic eczema, allergic rhinitis (AR), and asthma was obtained. A blood sample was drawn and analysed for allergen-specific IgE antibodies against food- and aero-allergens. Multiple logistic regression analyses identified viral infection to be associated with AR (adjusted odds ratio (OR) = 1.39; 95% confidence interval (95% CI): 1.13-1.72) and sensitization to aeroallergens (OR = 1.21; 95% CI: 1.05-1.41). Bacterial disease was a negative predictor for atopy development in the subgroup of patients sensitized to nutritional allergens with concomitant atopic eczema (OR = 0.34; 95% CI: 0.11-0.99), AR (OR = 0.67; 95% CI: 0.42-1.07), or asthma (OR = 0.41; 95% CI: 0.19-0.87). Influences of viral and bacterial infection on AR differed with regard to family history of atopic disease. In our study population, history of viral infection was consistently positively associated with AR. Our data suggests that bacterial infections might be preventive for specific subgroups of atopy.
... 5 A number of explanations has been put forward to explain this dysregulation in the immune response, but an interaction between susceptibility genes and fetal programming by the intrauterine environment appears to be important. 6,7 The Th2-type cytokines are especially associated with allergy and parasite immunity because of their actions on some specific cells known to be involved in the allergic inflammatory response. 8 Of particular relevance is the role of IgE, which provides the initial trigger for many allergic responses. ...
Article
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Until recently, the only controller treatment for chronic asthma has been corticosteroids. However, identification of specific effector molecules in asthma has led to targeting of specific pathways by using cytokines and cytokine inhibitors. Administration of a monoclonal blocking antibody against IgE has been shown to be highly efficacious in severe allergic asthma, but blockade of eosinophils using anti-IL-5 monoclonal antibodies has no clinical benefit. In more severe asthma, blockade of TNF-alpha using the decoy etanercept has revealed efficacy in a small open study suggesting that Th-1 in addition to Th-2 pathways are important as the disease adopts a more severe phenotype. It is likely that asthma is not a single disease but a group of disorders which differ in the relative contribution of specific pathophysiological pathways.
Article
The article presents the literature data and the results of own research on the allergic phenotype diagnostics and the prediction capability of IgE level in the cord blood in newborns.
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Background and Objectives Childhood atopy is a complex condition with both a genetic and an environmental component. This systematic review will explore the current understanding of the importance of early life exposures to a farm in the development of atopy measured by objective markers of skin prick testing, and specific IgE measurements in school age children. Methods A systematic review was performed. Results Among 7285 references identified, 14 studies met the inclusion criteria (13 cross-sectional studies and 1 case-control study). The results were fairly consistent in that early farm-related exposures can protect children from becoming atopic at school age. In general, there was heterogeneity in the assessment of outcomes and exposures. Conclusions Early-life farm exposures are associated with a protective effect on childhood atopy as assessed by objective markers. Future work should focus on understanding specific farm exposures that may important in these associations between atopy and farm exposures in children.
Article
Aim To investigate; i) if maternal sensitization to allergens, and lifestyle can influence the risk of acute as well as chronic inflammation of the placenta, in the forms of chorioamnionitis and villitis, respectively, and ii) if these placental inflammations are associated with the outcome of sensitization for the child during preschool age. Methods Placentas from term uncomplicated pregnancies (n = 275) in the ALADDIN study were analysed for the presence of acute chorioamnionitis and chronic villitis. Stepwise logistic regression was performed to estimate the relative risk of placental inflammation in relation to maternal allergic sensitization and lifestyle, and the association between placental inflammation and sensitization of the child up to 5 years of age. Results Parity and delivery at home were independently associated with chorioamnionitis, home delivery only with the low grade. Maternal allergic sensitization was associated with increased risk of villitis in the bivariable model, however, not in the multivariable model. No significant associations were detected between placental inflammation and the outcome of sensitization to allergens at 5 years of age. Conclusion Our data do not support the hypothesis that the increased risk for sensitization of a child when the mother is allergic is mediated via placental inflammation.
Article
Background: Ingestion of food allergens present in maternal milk during breastfeeding has been hypothesized as a gateway to sensitization to food; however, this process could develop during pregnancy, as the maternal-fetal interface develops a Th2- and Treg-mediated environment to protect the fetus. We hypothesized that in these surroundings, unborn children are exposed to food allergens contained in the mother's diet, possibly giving rise to first sensitization. Methods: The presence of allergens in utero was studied by analyzing amniotic fluid (AF) samples in two different stages of pregnancy: at 15-20 weeks and after delivery at term. An antibody microarray was developed to test for the most common food allergens. The array detects the presence of ten allergens from milk, fruit, egg, fish, nuts, and wheat. Results: AF from 20 pregnant women was collected: eight after delivery at term and 12 from women who underwent diagnostic amniocentesis between weeks 15 and 20 of gestation. The presence of allergens was detected in all samples. Samples from amniocentesis had a higher allergen concentration than samples after delivery at term. Conclusions: We demonstrated the presence of intact major food allergens in AF samples. This early contact could explain subsequent sensitization to foods never eaten before. This article is protected by copyright. All rights reserved.
Article
Background: The longitudinal pattern of allergen-specific IgE levels from the prenatal stage to early life has remained largely unexplored. Methods: One hundred and three mother-infant pairs, which were part of an ongoing population-based prospective birth cohort study of early childhood allergic diseases in Tainan, Taiwan, were included in this study. We examined the relationship of 20 allergen-specific IgE levels with blood samples of mothers, cord blood and infants at 12 months of age using Spearman rank correlation, Kenal τ and McNemar test, respectively. Results: Certain degree of IgE sensitization against most 20 examined specific allergens was observed in blood samples of mothers, cord blood and infants at 12 months of age. When we further examined the association between allergic related risk factors and atopy in infants at the first year of life, we found positive association between colic pain and atopy in infants at 12 months of age (adjusted odds ratios (AOR)=3.51; 95% confidence interval (CI): 1.13-10.96; p=0.03), and borderline significance between wheezing and atopy in infants at 12 months of age (AOR=4.58; 95% CI: 0.89-23.50; p=0.07). Conclusion: The findings from this study suggest that influence of maternal allergen-specific IgE levels on infant immune response might occur at birth and then wane in infants at 12 months of age. Positive association of colic pain and wheezing with atopy in infants at 12 months of age provide supportive evidence for the "Allergy March" theory of allergy development in an Asian birth cohort. This article is protected by copyright. All rights reserved.
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Article
There are striking differences between the genders with respect to the onset age and subsequent prevalence of asthma over the human lifespan. Boys appear to have a slight disadvantage in terms of pulmonary mechanics in the early years of life, which may predispose them to higher risks of wheezing and subsequent diagnosis of asthma. In early childhood, boys are more likely to be diagnosed with asthma than girls. As adolescence approaches, there is a noticeable shift, with the female population carrying a larger proportion of asthma, which is a trend that continues into adulthood. The reasons for these changes are certainly a result of a complex combination of factors, including gender-related factors, which are addressed in this chapter. Some of the evidence such as longer hospitalizations for women suggests that asthma might be more severe as well as more prevalent in women.
Chapter
This chapter focuses on development of allergic disease in childhood and the proposed environmental and genetic factors that likely play an important role in this process. Atopy generally refers to development of a specific immune response to non-self antigens characterized by the production of antigen specific IgE. This process is associated with the production of a number of cytokines by T-lymphocytes, generally referred to as "Th2" cytokines, which promote the production of antigen specific-IgE and support growth and differentiation of cells such as eosinophils and mast cells. These cytokines include IL-4, IL-5, and IL-13. There are a number of possible risk factors associated with development of atopy, including family history of atopy, increased IgE in early life, decreased monocyte production of γ -interferon, no (or short duration of) breast feeding, early allergen exposure, and exposure to environmental tobacco smoke.Development of atopy is significantly influenced by the action of cytokines produced by monocytes, T-lymphocytes, and other cells. Certain cytokines promote a "Th1" non-allergic immune response to specific antigens (characterized by antigen specific IgG and neutrophilic inflammation), whereas others promote a "Th2" allergic response. Season of birth has been reported to be an important event in development of atopy, with relationships between early exposure to seasonal airborne allergens and development of TH2 responses to those allergens at an early age being observed. Exposure to environmental tobacco smoke (ETS) may act to enhance atopy by a number of mechanisms such as increased airway mucosal permeability or a direct effect on immune function.
Article
The gut mucosa is exposed to numerous exogenous factors and has differentiated regulatory mechanisms that enable selective permeability for nutrients and certain macromolecules but exclude potentially harmful dietary, environmental or bacterial antigens. The interaction among luminal factors of dietary or bacterial origin and the gut wall is of particular importance. Nutrition has a significant impact on the gastrointestinal tract of young animals and is of special importance for the function of the gut and the associated immune system during the early growth phase and later in adulthood. Proteins are of major importance as nutrients; especially in the young, providing amino acids for protein synthesis and tissue accretion as well as fuel for the gut mucosa. Transport of porcine or human immunoglobulin G across the small intestine of the newborn piglet is mainly related to endocytosis. The lymphatic system is of major importance for the transport and processing of absorbed proteins. The consequence of antigen confrontation can be immune responsiveness or tolerance. Nutritional factors beside protein or peptide intake have been demonstrated to affect the development of oral tolerance. Rats fed a zinc-deficient diet had lower expressions of cytokines involved in oral tolerance. At weaning, dietary and often also environmental changes can stress young animals severely.
Article
Allergic diseases have become a major public health problem in industrialized countries, justifying the development of prevention programs. A review of the literature on allergens and atopic symptoms, age of primary sensitization and other factors associated with allergic diseases development is presented and is followed by a discussion on prevention measures. The most recent physiopathological and immunological data indicate that persistent asthma and allergic diseases in adults may be associated with events in early childhood. The parallel increase in autoimmune and allergic diseases has been correlated with regulatory mechanism defects, contradicting the previous theory that involved a predominantly Th1 or Th2 pathway. The primary prevention of asthma and allergic diseases thus appear to be somewhat utopian. Indeed based on recent results, the risk of developing allergies appears to be related to modern “clean” lyfestyles. Secondary prevention is probably necessary, possibly through specific immunotherapy. Tertiary prevention must also be considered. Passive smoking must be prevented as it can alter the development of the respiratory system and promote allergen sensitization. Randomized, controlled, prospective studies are needed to evaluate the efficacy of the preventive measures.
Article
Epigenetic regulation has been suggested to be a link between environmental intrauterine exposures and development of asthma and allergy. The placenta is an essential part of the intrauterine environment. We have previously found the innate immune receptor CD14 to be differentially expressed on the mRNA level in placentas in relation to lifestyle and parental allergen sensitization. We here hypothesized that the promoter region of CD14 may be subject to differential DNA methylation and therefore a link between intrauterine exposure and mRNA expression. Ninety-four placentas from the ALADDIN (Assessment of Lifestyle and Allergic Disease During Infancy) study were investigated. We used methylation-sensitive high-resolution melting (MS-HRM) analysis to semi-quantitatively analyze the DNA methylation of the promoter region of CD14 in 36 placentas known to have different CD14 mRNA expression. EpiTYPER was used to validate the MS-HRM data and to analyze an additional 58 placentas selected on mothers living on a farm or not. MS-HRM analysis on 36 placenta samples revealed a relation between methylation of the CD14 promoter region with the level of CD14 mRNA expression. The MS-HRM and EpiTYPER data correlated highly significantly. EpiTYPER analysis of the additional 58 placentas demonstrated that DNA methylation in the CD14 promoter was significantly lower in placentas of mothers living on a farm compared with mothers not living on a farm. Our data suggest that epigenetic regulation of CD14 in placenta might be involved in the protective effect of 'living on a farm', with regard to allergy development.
Article
Recently, folic acid supplementation during pregnancy was implicated as a potential risk factor for atopic diseases in childhood. To investigate whether folic acid supplementation and higher intracellular folic acid (ICF) levels during pregnancy increase the risk of childhood atopic diseases. In the KOALA Birth Cohort Study (N=2834), data on eczema and wheeze were collected by using repeated questionnaires at 3, 7, 12, and 24 months, 4 to 5 years, and 6 to 7 years after delivery. Atopic dermatitis and total and specific immunoglobulin E levels were determined at age 2 years and asthma and lung function at age 6 to 7 years. We defined folic acid use as stand-alone and/or multivitamin supplements according to the period of use before and/or during pregnancy. ICF levels were determined in blood samples taken at ∼35 weeks of pregnancy (n=837). Multivariable logistic and linear regression analyses were conducted, with generalized estimating equation models for repeated outcomes. Maternal folic acid supplement use during pregnancy was not associated with increased risk of wheeze, lung function, asthma, or related atopic outcomes in the offspring. Maternal ICF level in late pregnancy was inversely associated with asthma risk at age 6 to 7 years in a dose-dependent manner (P for trend=.05). Our results do not confirm any meaningful association between folic acid supplement use during pregnancy and atopic diseases in the offspring. Higher ICF levels in pregnancy tended, at most, toward a small decreased risk for developing asthma.
Article
Die Fragestellung der vorliegenden Arbeit war, in wieweit die in vitro Zytokinproduktion mononukleärer Nabelschnurblutzellen (CBMC) eine prognostische Aussage über das Risiko eines Kindes geben kann, ein AEDS zu entwickeln. Dazu wurden Nabelschnurblutproben von 50 reif geborenen Kindern direkt nach der Geburt entnommen. CBMC wurden isoliert, mit verschiedenen Antigenen (PHA, Der p 1, BLG) stimuliert und in den Überständen mittels ELISA die Zytokinkonzentrationen (IFN-g, IL-6, IL-10, IL-12, IL-13, IL-18 und TGF-b) quantifiziert. Nach drei Jahren wurden die Eltern mit Hilfe eines standardisierten Fragebogens nach Symptomen eines AEDS bei ihren Kindern befragt (n=40). Dabei zeigte sich, dass die Kinder, die im Alter von drei Jahren ein AEDS entwickelt hatten, zum Zeitpunkt der Geburt signifikant höhere Konzentrationen von IL-13 in den mit PHA stimulierten Zellüberständen aufwiesen (Median 291 pg/ml) verglichen mit Kindern ohne Symptome einer Atopie (Median 149 pg/ml; p=0,021, Wilcoxon-Test). Ebenso verhielt es sich mit den IL-13 Konzentrationen in den Überständen von Der p 1-stimulierten CBMC (symptomatische Kinder: 168,6 pg/ml; gesunde Kinder: 61,6 pg/ml, p=0,0084). Nach Stimulierung mit BLG zeigte sich keine signifikante Änderung der IL-13 Konzentration (Symptomatische Kinder: 287,2 pg/ml, asymptomatische Kinder 123,6 pg/ml; p=0,19). Die Konzentrationen der übrigen Zytokine wiesen keinen signifikanten Unterschied zwischen gesunden und erkrankten Kindern auf. In Übereinstimmung mit den Daten anderer Forschungsgruppen weisen diese Ergeb-nisse darauf hin, dass das Vorhandensein erhöhter IL-13- Konzentrationen bei Geburt einen positiven prädiktiven Parameter für die Entwicklung eines AEDS im Alter von drei Jahren darstellt.
Article
The progression from dermatitis in infancy to asthma and allergy in childhood has been termed the "atopic march". Upper respiratory infections (URIs) in infancy are also linked to allergy and asthma. Human milk feeding and higher intakes of docosahexaenoic acid (DHA) may be protective. For the study, URIs and dermatitis in infancy were recorded and compared to human milk and DHA intake for 50 healthy term infants born to women enrolled in a study of DHA supplementation during pregnancy. All had 24-hour dietary recalls at 6 wk, 4, 6, 9, and 12 months, first year medical records, and information about environmental factors related to allergy/asthma. Forty-one of 50 received at least some human milk. DHA intake was estimated from individual milk (determined by chromatography) and formula DHA concentrations. Most infants had one or more episodes of dermatitis (26/50) and URI (39/50). Duration of human-milk feeding in infancy was associated with fewer dermatitis episodes (R = -0.289, p = 0.044). Breast feeding for >16 wks vs. 16 wks vs. <16 wks appeared to result in later onset but not statistically fewer total first year URIs (p= 0.611). With approximately 25% of the expected final sample complete, we find evidence already that longer human milk feeding may offer some protection against the "atopic march".
Article
There is evidence that stress increases the risk of asthma. Chronic noise exposure is known to act as an unspecific stressor, but little is known about its effect on the risk of asthma in children. The aim of this study was to compare subjectively reported noise annoyance in 12-year-old asthmatic and non-asthmatic children with special regard to sex-specific differences. In a German multi-center birth cohort study we assessed the annoyance by different sources of environmental noise, doctor-diagnosed asthma, and potential confounders by questionnaire. The comparisons between asthmatic and non-asthmatic children were stratified by sex. A total of 336 boys and 316 girls were included in the analysis. Prevalence of doctor-diagnosed asthma was 13% in boys and 5% in girls; 73% of the boys and 74% of the girls reported at least some degree of noise annoyance during the day and night time. In girls, asthma was associated with a significantly increased total noise annoyance at night (adjusted odds ratio aOR 1.5, 95%CI 1.1;2.1), for noise within the home/apartment (aOR 3.5, 95%CI 1.5;8.0), and in or around the house (aOR 3.3, 95%CI 1.7;6.3). No statistical significant effects were seen in boys. Noise annoyance, particularly at night or caused by domestic sources, is associated with increased asthma prevalence in girls but not boys. Further research is needed to identify underlying mechanisms of these sex-specific differences.
Article
Asthma and allergic diseases are disorders with a predominant Th2 immune response and there is some evidence of an inverse correlation between incidence of tuberculosis and prevalence of allergic diseases. Skewing the immune response towards a Th1 phenotype has been shown to suppress allergic inflammation. One of the ways this could be achieved is by administration of BCG vaccination early in life. Unfortunately, studies examining the protective role of BCG vaccination early in life against development of allergic diseases have shown some conflicting results and this article critically discusses the pitfalls in the currently available data. We propose that well controlled double blind placebo-controlled multi-centre study is carried out to address this important question and if this study shows a favourable outcome simple measures such as offering BCG vaccination early in life could help reduce prevalence of allergic diseases.
Article
Research evidence supports a causative relationship between indoor allergen exposure and the development of asthma. Epidemiologic studies demonstrate that exposure to indoor allergens, particularly house-dust mites and cockroaches and, to a lesser extent, animal allergens and mold, is a risk factor for the development of sensitization and perhaps respiratory symptoms. Sensitization to indoor allergen is clearly a major risk factor for the development of asthma and allergy. There is also epidemiologic and experimental evidence that, in sensitized subjects, higher exposure to indoor allergen causes morbidity. Most, but not all, prospective studies support the causative link between allergen exposure and asthma. Additional evidence comes from the prevention studies, in which reduction in indoor allergen exposure may lead to improvement in symptoms, pulmonary function, and bronchial hyperresponsiveness, and, if practiced, in early years of life, perhaps the development of asthma and allergy.
Article
To briefly review some of the factors that have been implicated in the causation of the increased prevalence of allergic disease in children. MEDLINE search of original research and review articles related to the various risk factors considered responsible for the increased prevalence of allergic disease in children. Author selected references. It has been established that there is an increased prevalence of allergic disease, especially in children. Risk factors that are currently under investigation include: genetic atopic predisposition, early childhood allergen exposure and sensitization, occurrence of viral respiratory infections in young children, maternal smoking during pregnancy, poor dietary factors, lack of breast-feeding, childhood obesity, having a certain immunologic predisposition (Th2-prone), air pollution, and frequent immunizations in childhood. It is most likely that the occurrence of allergic disease will be found to be multifactorial.
Article
Prenatal factors have been implicated in childhood eczema, but the relationship between maternal cytokine production during pregnancy and infant eczema is unknown. Non-selected women in their third trimester were enrolled in the Tucson Infant Immune Study. Data from three sources were used to define MD-eczema: parent-completed illness questionnaires at age 2, 3, 4, 6 and 9 months regarding physician-seen eczema, parent-completed questionnaires at 12 months regarding physician-diagnosed eczema, and medical record reviews. Blood samples were taken from mothers during their third trimester and from the umbilical cord at birth. Maternal peripheral blood mononuclear cells and cord blood mononuclear cells were stimulated with ConA/PMA, and supernatants were assayed for IFN-gamma and IL-4, -5, -10, and -13. Of 364 children, 28% were seen by a physician for eczema by 1 yr of age. After adjustment for potential confounders using logistic regression, the odds for development of eczema in infancy were significantly higher when mothers had active eczema in pregnancy (OR, 2.46, CI 1.0-5.8, p <0.042) and when mothers were in the highest tertile of serum IgE production (OR 2.28, CI 1.2-4.4, p <0.013). Colds in the third trimester were associated with lower odds of eczema (OR 0.32, CI 0.16-0.63, p <0.001). Our findings from this cohort study suggest that in utero factors, including maternal IgE, colds, and eczema, may influence the risk of infant eczema.
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Environmental factors are believed to play a role in the development of atopic allergy. This is likely to be important very early in life, at the fetal stage. The in utero environment could be affected by maternal allergy and in turn could influence the immune system of the baby. To investigate how cord blood mononuclear blood cells (CBMCs) from children of women with and without allergy respond to microbial stimuli. PBMCs from women with (n = 9) and without allergy (n = 10) and CBMCs from their newborn babies were stimulated in vitro with LPS and peptidoglycan. Cells were analyzed with flow cytometry for expression of CD14, Toll-like receptor (TLR)-2, and TLR4. The release of cytokines and chemokines (IL-1beta, IL-6, IL-8, IL-10, IL-12p70, TNF-alpha) and soluble CD14 into culture supernatants was measured with Cytometric Bead Array and ELISA, respectively. Cord blood (CB) monocytes from children with mothers with allergy had significantly lower expression of TLR2 and TLR4 compared with maternal monocytes both before and after microbial stimulation, in contrast with CB monocytes from children with mothers without allergy. Further, CBMCs from children with mothers with allergy had a lower ( P = .03) IL-6 response after stimulation with peptidoglycan than CBMCs from children with mothers without allergy. Our results imply that CB monocytes and CBMC immune responses are influenced by maternal allergy. On the basis of these findings, we speculate that monocytes from children with mothers with allergy have a reduced capacity to respond to microbial stimuli.
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To examine differences between virus-associated wheeze and wheeze associated with other triggers (multi-trigger wheeze) in elementary school children, we performed a cross-sectional school-based questionnaire study of 5,998 children mainly 7 to 12 years of age, with outliers 6 and 13 years of age. Using parent-completed questionnaires, we identified 522 children who wheezed only during upper respiratory tract infections (virus-associated wheeze), 1,186 children who wheezed on other occasions (multi-trigger wheeze), and 4,290 children with no wheeze. In comparison with children who had multi-trigger wheeze, children with virus-associated wheeze were more likely to be male, to be younger, and to have less frequent wheezy episodes. They were less likely to have night cough, shortness of breath or chest tightness, to have a personal or parental history of atopic disorders, to have a diagnosis of asthma, or to be receiving asthma treatment. Both types of wheeze were associated with social deprivation, a relationship that persisted after controlling for family smoking. Virus-associated wheeze is a common but diminishing problem in this age group, and the differences between virus-associated wheeze and multi-trigger wheeze already noted in pre-school children persist in this older age group.
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Other factors besides a genetic disposition seem to play a role in the development of allergic disorders. Exposure to risk factors such as indoor air pollution is becoming increasingly interesting, especially during early childhood. Within an epidemiological study (LISS: Leipzig infection, allergy and airway diseases study among school starters, involving 2536 children, birth cohort 1991/92, carried out in 1997/98) the effect of indoor exposure on physician-confirmed eczema and allergic symptoms has been investigated. The exposure situation has been characterized on hand of the redecoration activities (painting, floor covering and new furniture) before birth and in the first years of life. Highly exposed children showed a significant effect on allergic disorders. The lifetime prevalences without any vs. all three redecoration activities were for allergic symptoms 9.3% vs. 17.2% and for eczema 11.5% vs. 20.4%. Adjusted for confounders, the redecoration associated burden led to odds ratios of 1.8 (95% CI: 1.3-2.6) for allergic symptoms and 1.9 (95% CI: 1.4-2.7) for eczema. Exposure emissions due to redecoration activities seem to be associated with the risk of eczema and allergic symptoms. Thus, prevention of allergic disorders should include the avoidance of such activities around birth and in the first year of life.
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