Developmental origin and sex-specific risk for infections and immune diseases later in life.

The intrauterine environment is an important determinant of immunity later in life of the offspring. An altered prenatal immune development can result in a high postnatal risk for infections, chronic immune diseases, and autoimmunity. Many of these immune diseases show a strong sex bias, such as a high incidence of autoimmune diseases and allergies in adult females or a high risk for infections in males. Here, we comprehensively review established pathways and propose novel concepts modulating the risk for such poor immunity during childhood and throughout life. Moreover, we highlight how an adverse fetal environment may affect or aggravate the risk for poor immunity in a sex-specific manner. An improved understanding of a sex-specific susceptibility to poor immunity along with insights on how such risk can be modulated before or around birth will allow the development of tailored prevention strategies.

Prenatal maternal stress exposure and immune function in the offspring.

The intra-uterine environment provides the first regulatory connection for the developing fetus and shapes its physiological responses in preparation for postnatal life. Psychological stress acts as a programming determinant by setting functional parameters to abnormal levels, thus inducing postnatal maladaptation. The effects of prenatal maternal stress (PNMS) on the developing immune system have been documented mostly through animal studies, but inconsistent results and methodological differences have hampered the complete understanding of these findings. As the immune system follows a similar ontogenic pattern in all mammals, a translational framework based on the developmental windows of vulnerability proposed by immunotoxicology studies was created to integrate these findings. The objective of this review is to examine the available literature on PNMS and immune function in the offspring through the above framework and gain a better understanding of these results by elucidating the moderating influence of the stressor type, timing and duration, and the offspring species, sex and age at assessment. The evaluation of the literature through this framework showed that the effects of PNMS are parameter specific: the moderating effects of timing in gestation were relevant for lymphocyte population numbers, Natural Killer cell function and mitogen-induced proliferation. The presence of an important and directional sexual dimorphism was evident and the influence of the type or duration of PNMS paralleled that of stress in non-pregnant animals. In conclusion, PNMS is a relevant factor in the programming of immune function. Its consequences may be related to disorders with an important immune component such as allergies.

Role of the Mac-1 and VLA-4 integrins, and concomitant Th2-cytokine production, in nitric oxide modulated eosinophil migration from bone marrow to lungs in allergic mice.

Although numerous studies demonstrate the participation of nitric oxide (NO) in various inflammatory diseases, the precise function of NO in allergic asthma remains unclear. We investigated whether iNOS inhibition could interfere with the kinetics of VLA-4 and Mac-1 expression and adhesion properties of bone marrow and peripheral blood eosinophils of sensitized mice after antigen exposure. Treatment of allergic mice with 1400 W (iNOS inhibitor) increased the adhesion of bone marrow eosinophils to ICAM-1, but not blood eosinophils, at 24h and 48 h after OVA-challenge. Conversely, adhesion of blood eosinophils from 1400 W-treated mice to VCAM-1 diminished at 24h and was almost completely blocked at 48 h. 1400 W did not induce any change in the adhesion of bone marrow eosinophils to VCAM-1, at 24h, but cells collected 48 h after challenge showed significantly lower adherence. Flow cytometry demonstrated that 1400 W resulted in a significantly increased Mac-1 expression on bone marrow eosinophils at 24h, as compared to control mice. However, at 24h, 1400 W significantly decreased Mac-1 and VLA-4 expressions on blood eosinophils. At 48 h, the expressions of both Mac-1 and VLA-4 returned to previous levels. Results show a temporal effect of iNOS upon Mac-1 expression and function, the chief adhesion molecule involved in the eosinophil efflux from the bone marrow at 24h. In contrast, Mac-1 and VLA-4 were involved in eosinophil mobilization from blood to lungs at 48 h after antigen challenge. Data suggest an important role of the Mac-1 and VLA-4 in the iNOS-modulated migration of eosinophils to the lungs of allergic mice.

Fetal and early postnatal life roots of asthma.

The origins of asthma might be traced back to events occurring during fetal life. Reduced lung development has been shown to be a risk factor both for viral induced wheeze and allergic asthma. The evidence for a causal relationship between exposure to environmental tobacco smoke, chemical domestic products for cleaning, outdoor pollutants, and reduction in lung function is quite strong. Reduced maternal intake of vitamin E, vitamin D, and zinc, or increased use of paracetamol during pregnancy is associated with increased wheezing outcomes in children. The odds ratio for asthma onset is also increased in infants born from mothers with oligohydramnios, chorioamnionitis, hypertension, preeclampsia, diabetes and exposed to stressful events. The risk of developing allergic asthma is increased if the child is exposed in the first months of life to synthetic bedding and is enhanced by allergen exposure and an inadequate barrier function of the skin. In conclusion, several lines of evidence support the concept of fetal programming and very early life events in the development of the different phenotypes of asthma. Since some environmental triggers can be easily avoided and some protective factors can be easily implemented all efforts should be made to prevent intrauterine insults and early sensitization.

Prenatal and childhood Mediterranean diet and the development of asthma and allergies in children.

OBJECTIVE: To discuss current evidence about the relation between prenatal and childhood Mediterranean diet, and the development of asthma and allergies in children. DESIGN: Review of the literature. SETTING AND RESULTS: Four recent studies conducted in Mediterranean countries (Spain, Greece) and one conducted in Mexico evaluated the association between childhood Mediterranean diet and asthma outcomes in children. All of the studies reported beneficial associations between a high level of adherence to the Mediterranean diet during childhood and symptoms of asthma or allergic rhinitis. Individual foods or food groups contributing to the protective effect of Mediterranean diet included fish, fruits, vegetables, legumes, nuts and cereals, while detrimental components included red meat, margarine and junk food intake. Two studies focused on prenatal Mediterranean diet: the first is a birth cohort in Spain that showed a protective effect of a high adherence to the Mediterranean diet during pregnancy on persistent wheeze, atopic wheeze and atopy at the age of 6.5 years; while the second is a cross-sectional study in Mexico, collecting information more than 6 years after pregnancy, that showed no associations between maternal Mediterranean diet during pregnancy and allergic symptoms in childhood except for current sneezing. CONCLUSIONS: Findings from recent studies suggest that a high level of adherence to the Mediterranean diet early in life protects against the development of asthma and atopy in children. Further studies are needed to better understand the mechanisms of this protective effect, to evaluate the most relevant window of exposure, and to address specific components of diet in relation to disease.

Impact of PUFA on early immune and fetal development.

It has recently been reported that the increased prevalence in childhood allergy may be linked to deviations in fetal immune development. One reason may be impaired nutrient supply. Hence, a well-differentiated placenta together with an optimal fetal nutrition via the mother are important prerequisites for the establishment of a functional immune system with normal immune responses. Fatty acids and their derivatives can influence both the early immune development and immune maturation by regulating numerous metabolic processes and the gene expression of important proteins such as enzymes and cytokines. The present review summarises the impact of nutritional fatty acids on the development of the immune system as well as the fetal development. It describes the mechanisms of action of PUFA, trans fatty acids and conjugated linoleic acids in programming the fetus with regard to its risk of acquiring atopic diseases in childhood.

Perinatal characteristics and obstetric complications as risk factors for asthma, allergy and eczema at the age of 6 years.

BACKGROUND: Considerable effort has been put into identifying early determinants for atopic disorders. Many studies have evaluated the role of fetal development and obstetric complications. However, the results are not unequivocal. STUDY OBJECTIVE: To assess the relationship between perinatal characteristics and obstetric complications, and the presence of reported current asthma, allergy and eczema at the age of 6 years in the framework of a previously conducted study. METHOD: Seven hundred families in the Netherlands with index children born in 1988-1990 were retrospectively selected. Data were extracted from the Municipal Health Service's records of health examinations of these children and their siblings. These examinations were carried out at the age of 6 years. The records contained data on reported atopic disorders and perinatal characteristics. RESULTS: Gestational age was inversely related to the risk of asthma (P for trend: 0.03). Children with low birth weight tended to have a lower risk of any allergy, albeit not significant (P=0.07). However, no link was found between neonatal head circumference and atopic disorders. The ratio of neonatal head circumference to birth weight was positively associated with the risk of atopic disorders, especially with the risk of asthma (odds ratio (OR)=1.87; 95% confidence interval (CI(95%))=[1.11, 3.15]). Vacuum extraction was a risk factor for allergy (OR=1.84, CI(95%)=[1.03, 3.28]), but not for asthma. Induced labour was positively associated with the risk of inhalant allergy (OR=2.22, CI(95%)=[1.09, 4.51]) and, to a lesser extent, asthma (OR=1.72, CI(95%)=[0.95, 3.10]). For caesarean section and forcipal extraction there were no such relationships. CONCLUSIONS: Prematurity is a risk factor for asthma reported at 6 years. A high ratio of head circumference to birth weight is a risk factor for any atopic disorder. Vacuum extraction was associated with a higher risk of allergy, and induced labour is a risk factor for inhalant allergy. All results should be viewed with the possibility of residual confounding.

Prenatal paracetamol exposure and risk of asthma and elevated immunoglobulin E in childhood.

BACKGROUND: We recently found that paracetamol (acetaminophen) use in late pregnancy was associated with an increased risk of early wheezing in the offspring. OBJECTIVE: To see whether use of paracetamol in late pregnancy is associated with an increased risk of asthma, wheezing and other atopic outcomes in the child at school age. METHODS: In the population-based Avon Longitudinal Study of Parents and Children, we measured associations of paracetamol and aspirin use in late pregnancy (20-32 weeks) with asthma, hayfever, eczema (n = 8511) and wheezing (8381) in the offspring at 69-81 months, and with atopy (positive skin prick test to Dermatophagoides pteronyssinus, cat or grass, n = 6527) and blood total IgE (n = 5148) at 7 years. We used logistic and linear regression to analyse binary outcomes and log-transformed IgE, respectively, controlling for potential confounders. RESULTS: Use of paracetamol, but not aspirin, in late pregnancy was positively associated with asthma (odds ratios (ORs), comparing children whose mothers took paracetamol 'sometimes' and 'most days/daily' with those whose mothers never took it, 1.22 (95% confidence interval (CI): 1.06-1.41) and 1.62 (95% CI: 0.86-3.04), respectively; P trend = 0.0037), wheezing (ORs 1.20 (95% CI: 1.02-1.40) and 1.86 (95% CI: 0.98-3.55), respectively; P trend = 0.011), and total IgE (geometric mean ratios 1.14 (95% CI: 1.03-1.26) and 1.52 (95% CI: 0.98-2.38), respectively; P trend = 0.0034), but not hayfever, eczema or skin test positivity. The proportion of asthma attributable to paracetamol use in late pregnancy, assuming a causal relation, was 7%. CONCLUSION: Paracetamol exposure in late gestation may cause asthma, wheezing and elevated IgE in children of school age.

The relation of markers of fetal growth with asthma, allergies and serum immunoglobulin E levels in children at age 5-7 years.

BACKGROUND: It has been suggested that fetal growth and maturation have an impact on the development of allergic diseases later in life. OBJECTIVE: To examine the association between measures of fetal growth and allergic disease in children at age 5-7 years. METHODS: As part of the German International Study of Asthma and Allergies in Childhood phase II surveys, a random sample of school beginners (n=1138) was examined in 1995. Data on anthropometric measures at birth and gestational age were obtained from maternal copies of birth records. Data on symptoms and doctor-diagnosed asthma, atopic dermatitis and hayfever were gathered by parental questionnaires. Atopic sensitization was assessed by serum IgE and skin prick tests to common aeroallergens. Children (741) had complete data for the explanatory variables of interest and were thus eligible for this analysis. Confounder-adjusted prevalence odds ratios (PORs) and means ratios with 95% confidence intervals (CI) were calculated using multiple logistic and linear regression. RESULTS: Birth weight and gestational age were positively associated with atopic sensitization (Ptrend=0.025 and 0.035, respectively). Children with a low birth weight relative to head circumference had a decreased risk of sensitization (POR 0.44, 95% CI 0.21-0.91; Ptrend=0.020). Moreover, total serum IgE increased with increasing birth weight (Ptrend=0.042). No consistent relationship was observed between markers of fetal growth and wheezing, doctor-diagnosed asthma, atopic dermatitis and hayfever. CONCLUSION: These data suggest that fetal growth and maturity are associated with atopic sensitization and total serum IgE levels in childhood.

Prenatal origins of allergic disease.

The prevalence of asthma and related allergic disorders has increased considerably over the last 25 years. Because genetic stock has not changed, environmental factors must have influenced the phenotype. Infants who experience the development of allergy already have an altered immune response at birth. We have investigated the development of immune responses during gestation and the effect of maternal allergen exposure during pregnancy and infant exposure in the first month of life on the development of allergy and disease. There was higher specific peripheral blood mononuclear cell proliferation to house dust mite and birch pollen in the third trimester compared with the second trimester, with the first positive responses seen at 22 weeks gestation. Maternal exposure to birch pollen after 22 weeks resulted in higher infant peripheral blood mononuclear cell responses to birch pollen at birth. Infants born at term, with at least 1 atopic parent with asthma, who experienced the development of allergic symptoms and positive skin prick test by 1 year of age had raised proliferative responses to house dust mite at birth compared with those infants with no symptoms. In genetically predisposed individuals, antenatal factors including maternal and thereby fetal exposure to allergens and materno-placental-fetal immunologic interactions are active in determining whether an allergic predisposition is manifested as disease.

Experimental intestinal hypersensitivity. Effect of four anti-allergic drugs on protein uptake, permeability to sugars and mucosal mast-cell activation.

The ability of four drugs with anti-allergic action to modulate the uptake of bystander protein, lactulose/rhamnose permeability ratios and mast cell activation was studied in rats presensitized with egg albumin in alum and challenged intraduodenally with the same antigen. Beclomethasone dipropionate (BDP) and nedocromil both significantly reduced the uptake of the bystander protein, bovine serum albumin (P < 0.002 and P > 0.02 respectively). BDP also significantly reduced sugar permeability (P < 0.01). In animals with elevated lactulose/rhamnose permeability ratios we confirmed our earlier observation of a significant correlation between levels of the specific mucosal mast cell protease Rat Chymase II (RChyII-previously known as RMCPII) and the sugar ratios. None of the drugs had any influence on the levels of mast cell protease II released following challenge and there was no correlation between the histological light microscopic appearance of the mast cells and the experimental treatment administered. Our results suggest that in the gut the pharmacological effect of anti-allergic drugs may be complex. Some, such as nedocromil, appear to act only on the mechanisms underlying increased protein uptake whereas others, such as BDP, appear to abrogate both increased protein uptake and increased sugar permeability.