The effects of pregnancy on the exacerbation and development of maternal allergic respiratory disease

The T-helper 2 (T_H2) bias associated with pregnancy may predispose the pregnant mother to the development or exacerbation of allergic disease. To determine the effects of pregnancy on pre-existing maternal sensitization, we sensitized BALB/c mice before breeding by two intratracheal aspiration (IA) exposures to the fungal allergen, Metarhizium anisopliae crude antigen (MACA). Some mice also received three IA exposures to MACA on gestational days 11, 15, and 19. After weaning, all mice were challenged IA with MACA before killing. To determine the effects of pregnancy on susceptibility to future sensitization, naïve parous and nulliparous BALB/c mice were sensitized by three IA exposures to MACA or to Hank’s buffered salt solution vehicle control. Pregnancy did not have a significant effect on individual inflammatory parameters (airway responsiveness to methacholine, total serum and bronchoalveolar lavage fluid (BALF) IgE, BALF total protein, lactate dehydrogenase activity, and total and differential cell counts) following allergen challenge in sensitized mice, regardless of post-breeding allergen exposure. In conclusion there was a weak inhibition of the overall response in mice exposed to allergen during pregnancy compared to identically treated nulliparous mice. In contrast, parous mice that did not encounter allergen post-breeding tended to have exacerbated responses. Parity had no significant impact on future susceptibility to sensitization.     

Allergic sensitization and allergen exposure during pregnancy favor the development of atopy in the neonate

BACKGROUND: Several studies have considered that the in utero environment plays an important role in the onset of the allergic phenotype. We assessed whether allergic sensitization and allergen exposure during pregnancy favor the postnatal onset of allergy in the neonate. METHODS: BALB/c mice were sensitized to ovalbumin (OVA) before mating followed by allergen aerosol exposure during pregnancy. T and B cell responses in offspring were followed up until day 60 postpartum. At the age of 4 weeks offspring were exposed to a heterologous antigen, beta-lactoglobulin (BLG). RESULTS: Pregnant mice developed immediate hypersensitivity responses and Th-2/ Th-0 immunity following allergen aerosol exposure. At birth, T cells from offspring of nonsensitized BALB/c mice were characterized by an impaired IFN-gamma production, which was lowered even further in offspring of OVA-sensitized BALB/c mice. Offspring of OVA-sensitized BALB/c mice responded with immediate-type cutaneous hypersensitivity reactions to OVA which could be related to the pre- and postnatal transfer of maternal OVA-specific IgG1 antibodies. After exposure to BLG, offspring of OVA-sensitized BALB/c mice developed an accelerated Th-2-driven immune response compared to offspring from nonsensitized BALB/c mice as indicated by enhanced anti-BLG IgG1 antibody production and increased numbers of positive immediate-type cutaneous hypersensitivity reactions to BLG. CONCLUSION: Our data suggest that Th-2/Th-0 immunity present during pregnancy has a decisive impact on shaping the Th-1/Th-2 T cell profile in response to postnatal allergen exposure.     

Maternal allergy acts synergistically with cigarette smoke exposure during pregnancy to induce hepatic fibrosis in adult male offspring

Maternal environmental exposures during pregnancy are known to affect disease onset in adult offspring. For example, maternal asthma exacerbations during pregnancy can worsen adult asthma in the offspring. Cigarette smoking during pregnancy is associated with future onset of cardiovascular disease, obesity and diabetes. However, little is known about the effect of maternal environmental exposures on offspring susceptibility to liver disease. This pilot study examined the long-term effect of maternal allergen challenge and/or cigarette smoking during pregnancy on hepatic inflammation and fibrosis in adult mouse offspring. Ovalbumin (OVA) or phosphate-buffered saline (PBS)-sensitized/challenged CD-1 dams were exposed to mainstream cigarette smoke (MCS) or filtered air from gestational day 4 until parturition. Eight weeks postnatally, offspring were sacrificed for comparison of hepatic histology and mRNA expression. Adult male offspring of OVA-sensitized/challenged dams exposed to MCS (OSM) displayed significantly increased liver fibrosis (9.2% collagen content vs. <4% for all other treatment groups). These mice also had 1.8-fold greater collagen 1A1 mRNA levels. From the results here, we concluded that maternal allergen challenge in combination with cigarette smoke exposure during pregnancy may be an important risk factor for liver disease in adult male offspring.     

Maternal allergy acts synergistically with cigarette smoke exposure during pregnancy to induce hepatic fibrosis in adult male offspring

Maternal environmental exposures during pregnancy are known to affect disease onset in adult offspring. For example, maternal asthma exacerbations during pregnancy can worsen adult asthma in the offspring. Cigarette smoking during pregnancy is associated with future onset of cardiovascular disease, obesity and diabetes. However, little is known about the effect of maternal environmental exposures on offspring susceptibility to liver disease. This pilot study examined the long-term effect of maternal allergen challenge and/or cigarette smoking during pregnancy on hepatic inflammation and fibrosis in adult mouse offspring. Ovalbumin (OVA) or phosphate-buffered saline (PBS)-sensitized/challenged CD-1 dams were exposed to mainstream cigarette smoke (MCS) or filtered air from gestational day 4 until parturition. Eight weeks postnatally, offspring were sacrificed for comparison of hepatic histology and mRNA expression. Adult male offspring of OVA-sensitized/challenged dams exposed to MCS (OSM) displayed significantly increased liver fibrosis (9.2% collagen content vs. <4% for all other treatment groups). These mice also had 1.8-fold greater collagen 1A1 mRNA levels. From the results here, we concluded that maternal allergen challenge in combination with cigarette smoke exposure during pregnancy may be an important risk factor for liver disease in adult male offspring.     

Lymphoproliferative responses in cord blood and at one year: no evidence for the effect of in utero exposure to dust mite allergens

BACKGROUND: Maternal allergen exposure beyond the 22nd week of pregnancy may be important in foetal T cell priming. Allergen-specific cord blood mononuclear cell (CBMC) immunoproliferative responses without corresponding bacterial antigen responses (tetanus toxoid), have been suggested as evidence of in utero sensitization. OBJECTIVES: To investigate the relationship between lymphoproliferative responses at birth and at 1 year with maternal and 1-year infants house dust mite allergen exposure. METHODS: Home visits and dust sampling were performed by the 20th week of pregnancy, immediately after birth, and then at 1 years of age. Der p 1 was assayed using a two-site immunometric ELISA. CBMC immunoproliferative responses (AIM V serum-free medium; 1 x 105 cells/well) were measured for 225 neonates (171 had a high risk of atopy (HR)--both parents skin test positive; 59 had a low risk of atopy (LR) - both parents skin test negative, no history of atopy) by 3H-Thymidine (1microCi/well) incorporation after stimulation in primary culture with phytohaemagglutinin (PHA) (1 microg/mL), house dust mite [HDM] extract (30 microg/mL), immunopurified Der p 1 (30 microg/mL), Tetanus toxoid (TT) (aluma free, 30 Lf/mL) or vehicle. Blood was collected from 144 infants at the age of 1 years and stimulated proliferative responses were assessed using the same procedure. RESULTS: PHA-stimulated lymphoproliferative response was significantly lower in HR compared to LR neonates (mean difference 38%, 95% CI 15%-54%; P = 0.003); significantly lower proportion of positive CBMC responses to HDM occurred in LR than in HR neonates (30.4% vs. 46.6%; P = 0.034). There was no relationship between Der p 1 levels in maternal bed and CBMC immunoproliferative responses, despite the 21 000-fold range of maternal Der p 1 exposure. No significant differences in magnitude, or in proportion of positive responses to any stimulant were observed between the neonates at low, medium or high tertile of allergen exposure. Immunoproliferative responses at birth were not predictive of 1-year PBMC responses. There was no relationship between maternal allergen exposure in pregnancy and 1-year PBMC proliferative responses. However, the proportion of positive proliferative responses at 1 years significantly increased with increasing infant Der p 1 exposure at 1 years. CONCLUSION: These results indicate that the magnitude of immunoproliferative responses are unrelated to maternal mite allergen exposure and cannot be used as evidence for in utero sensitization to inhalant allergens. The immunoproliferative responses at 1 year seem to shift away from the genetically influenced responses at birth towards responses to specific stimulants which correlate with environmental exposure to those specific stimulants. These data support the concept of sensitization to inhalant allergens occurring in early life, but not in utero.     

Associations of allergic sensitization and clinical phenotypes with innate immune response genes polymorphisms are modified by house dust mite allergen exposure

Introduction

Polymorphisms within innate immunity genes are associated with allergic phenotypes but results are variable. These associations were not analyzed with respect to allergen exposure. We investigated associations of TLR and CD14 polymorphisms with allergy phenotypes in the context of house dust mite (HDM) exposure.

Material and methods

Children, aged 12-16 years (n=326), were recruited from downtown and rural locations and assessed by allergist. Skin prick tests, total and HDM-specific sIgE measurements were done. HDM allergen concentrations in dust were measured. Genetic polymorphisms were identified using restriction fragment length polymorphism (RFLP).

Results

Allergic rhinitis, asthma and atopy were more prevalent in urban area. Although HDM allergen concentrations were higher in rural households, sIgE were present more frequently in urban children. In the whole population no association was found between HDM exposure and sensitization. In children with CD14/−159CC, CD14/−159TT and TLR9/2848GA genotypes increased exposure to HDM was associated with reduced incidence of allergic rhinitis. Significant associations of increased HDM exposure with reduced incidence of atopy were found for the whole population and subjects with CD14/−159CC, CD14/−1359GT, TLR4/896AA and TLR9/2848GA genotypes. Among children with CD14/−159CC and CD14/−1359GG significant positive correlation between HDM allergen concentrations in household and sensitization to HDM was observed. In contrast, protective effect of high HDM allergen exposure against specific sensitization was seen in subjects with TLR4/896 AG.

Conclusions

Development of specific sensitization and allergy may be associated with innate immune response genes polymorphisms and is modified by allergen exposure.     

Suppression of Allergen‐Specific IgE in Offspring After Preconceptional Immunisation: Maternal,Paternal and Genetic Influences

Immunisation of female mice with the allergen ovalbumin (OVA) during pregnancy reduces the OVA‐specific IgE response in adult offspring. To approach primary prevention strategies for allergy, we investigated to what extent genetic, paternal and maternal factors influence this suppressive effect on allergic sensitisation in offspring and investigated the possibility of pregestational immunisation. Maternal allergen immunisation reduced OVA‐specific IgE levels in immunised offspring, even after maternal immunisation up to 8 weeks before conception without further allergen exposure. Immunisation of immunodeficient BALB/c severe combined immune deficiency (SCID) dams mated with wild type males did not lead to IgE suppression in offspring, indicating the importance of a functional maternal immune system. Immunisation of male mice before the relevant spermatogenesis did not cause antibody suppression in offspring. OVA‐specific IgG1, presumably of maternal origin, was present in naïve offspring only from immunised dams and was associated with suppressed IgE responses after offspring immunisation. The IgE‐suppressive effect of maternal immunisation was demonstrated in all three immunocompetent strains tested (NIH/OlaHsd, BALB/cA and C57BL/6 mice). In conclusion, suppression of allergen‐specific IgE production in offspring could not be induced by paternal immunisation, and genetic factors were of minor importance. In contrast, we demonstrate the necessity of maternal factors, possibly allergen‐specific IgG1, resulting from a functional adaptive immune response, for the IgE‐suppressive effect in offspring. These maternal factors could be induced by immunisation of female mice even before conception.     

Prevention of allergic disease during childhood by allergen avoidance: the Isle of Wight prevention study

BACKGROUND: Early life allergen exposure may increase the risk of childhood allergy, but the protective effect of reduction in allergen exposure remains uncertain. OBJECTIVE: To evaluate the effect of reduction in food and house dust mite (HDM) allergen exposure in infancy in preventing asthma and allergy. METHODS: Infants, at higher risk because of family predisposition, were recruited prenatally and randomized to prophylactic (n = 58) and control (n = 62) groups. Prophylactic group infants were either breast-fed with mother on a low allergen diet or given an extensively hydrolyzed formula. Exposure to HDM was reduced by the use of an acaricide and mattress covers. The control group followed standard advice. Development of allergic diseases and sensitization to common allergens (atopy) was assessed blindly at ages 1, 2, 4, and 8 years in all 120 children. RESULTS: Repeated measurement analysis, adjusted for all relevant confounding variables, confirmed a preventive effect on asthma: adjusted odds ratio (OR), 0.24; 95% CI, 0.09-0.66; P = .005; atopic dermatitis, OR, 0.23; CI, 0.08-0.64; P = .005; rhinitis, OR, 0.42; CI, 0.19-0.92; P = .03; and atopy, OR, 0.13; CI, 0.05-0.32; P < .001. The protective effect was primarily observed in the subgroup of children with persistent disease (symptoms at all visits) and in those with evidence of allergic sensitization. CONCLUSION: Allergic diseases can be reduced, for at least the first 8 years of life, by combined food and HDM allergen avoidance in infancy. CLINICAL IMPLICATIONS: Strict food and HDM allergen avoidance should be considered for prevention of allergy in high-risk infants.     

Exposure to endotoxin and allergen in early life and its effect on allergen sensitization in mice

BACKGROUND: Exposure to endotoxins, allergens, or both in early life might regulate the development of tolerance to allergens later in life. OBJECTIVE: We investigated whether continuous exposure of infant mice to aerosolized endotoxin, allergen, or both inhibits subsequent allergen-induced immune and inflammatory responses. METHODS: Infant BALB/c mice were pre-exposed to aerosolized endotoxin, ovalbumin (OVA), or both (3 times a week for the first 4 weeks of life) before systemic sensitization (days 1-14) and repeated airway challenge (days 28-30) with OVA. RESULTS: Compared with that seen in negative control animals, systemic sensitization and airway allergen challenges induced high serum levels of allergen-specific IgE (0.7 +/- 0.09 vs 0.02 +/- 0.01 OD units), predominant T(H)2-type cytokine production (IL-5 by splenic mononuclear cells in vitro, 1.2 +/- 0.2 vs 0.04 +/- 0.06 ng/mL), airway inflammation (bronchoalveolar lavage fluid leukocytes, 125 +/- 15 vs 64 +/- 7/microL; eosinophils, 28 +/- 5 vs 1 +/- 0/microL) and development of in vivo airway hyperreactivity (maximal enhanced pause, 11 +/- 1.9 vs 4 +/- 0.2). Pre-exposure with LPS before sensitization increased production of specific IgG2a (67 +/- 10 vs 32 +/- 5 U/mL) but failed to prevent T(H)2-mediated immune responses. Pre-exposure with OVA or with OVA plus LPS completely suppressed allergen sensitization, airway inflammation, and development of in vivo airway hyperreactivity; values were similar to those of negative control animals. Inhibition was due to allergen-specific T-cell anergy indicated by omitted allergen-specific T(H)2 and T(H)1 immune responses. In addition, combined exposure to endotoxin and allergen induced a general shift toward an unspecific T(H)1 immune response. CONCLUSION: Exposure with endotoxins before allergen sensitization is not able to induce unresponsiveness but might decrease the susceptibility for sensitization to a variety of common allergens.     

Maternal Transmission of Asthma Risk

Maternal asthma significantly increases the risk of asthma in offspring, but the mechanisms remain poorly defined. We review animal models used to study the maternal effect, focusing on a murine model developed in our laboratory. Mother mice rendered allergic to ovalbumin produce offspring that are more susceptible to allergic sensitization, seen as airway hyperresponsiveness and allergic airway inflammation after a sensitization protocol, which has minimal effects on newborns from normal mothers. Mechanistic analyses identify a role for interleukin-4 (based on pre-mating injection of neutralizing antibodies), dendritic cells and allergen-specific T cells (based on adoptive transfer experiments). Other maternal exposures (e.g. pollutant exposure and non-pulmonary allergy) can increase asthma susceptibility in offspring. This observation implies that the maternal transmission of asthma represents a final common pathway to various types of inflammatory stimuli. Identification of the shared molecular mechanisms in these models may allow better prevention and therapy. Current knowledge, gaps in knowledge and future directions are discussed.     

Maternal-fetal interaction: preconception immunization in mice prevents neonatal sensitization induced by allergen exposure during pregnancy and breastfeeding

Allergen exclusion measures during pregnancy and lactation have been given consideration in studies of primary allergy prevention but complete avoidance of mother/neonatal allergen exposure has proven to be a difficult procedure. To evaluate a strategy to prevent allergen sensitization in early life in mice, we first established a neonatal model with ovalbumin sensitization through maternal allergen exposure during pregnancy or breastfeeding. The modulatory potential of preconception immunization was investigated on the neonatal development of subsequent allergic responses to maternal allergen exposure. Herein, we demonstrate that immunized mothers exposed to antigen during pregnancy or breastfeeding underwent intense vertical transmission of antibodies, including immunoglobulin G (IgG) in complex with ovalbumin and IgG1 antibody with anaphylactic function. It was further shown that maternal immunization efficiently decreased the passage of free antigens through breastfeeding and inhibited the enhanced IgE antibody response after postnatal antigen exposure. In addition, antenatal immunization decreased the antigen-specific proliferative response of immunized neonates, in parallel with profound downmodulatory effects on both the activation and differentiation of T and B cells after a non-specific stimulus and cytokine production. These findings showed that early life sensitization, subsequent to maternal allergen exposure during both the prenatal and postnatal periods, could be avoided by preventive vaccination of the mother.     

Cord blood mononuclear cell cytokine responses in relation to maternal house dust mite allergen exposure

BACKGROUND: Cord blood mononuclear cells have demonstrated specific immune responses to environmental allergens. OBJECTIVE: To establish whether the nature of this response is related to the level of maternal antenatal exposure to house dust mite (HDM) allergen and, hence, whether antenatal allergen avoidance may have a role in the prevention of allergic sensitization in children. METHODS: Children with a family history of asthma were recruited antenatally as subjects in a randomised controlled trial: the Childhood Asthma Prevention Study. HDM allergen (Der p 1) concentrations were measured in dust collected from the maternal bed at 36 weeks gestation. Cord blood mononuclear cells were stimulated in culture, separately, with phytohaemaglutinin (PHA) and HDM extract. Cytokine IL-4, IL-5, IL-10 and IFN-gamma concentrations in supernatant were measured by ELISA. mRNA signals for these cytokines were measured using RT-PCR. RESULTS: The median concentration of HDM allergen was 18.4 microg/g (interquartile range 7.3-35.3 microg/g). Median concentrations of IL-4, IL-5, IL-10 and IFN-gamma, after PHA stimulation were 4, 19, 401 and 1781 pg/mL, respectively. After HDM allergen stimulation the median concentrations were 0, 0, 20 and 14 pg/mL, respectively. The distribution of mRNA cytokine signals was similar. Neither cytokine protein concentrations nor cytokine mRNA signal levels were correlated with the concentration of HDM allergen in the mothers' beds at 36 weeks gestation. CONCLUSION: These findings do not support the view that the prevention of allergic disease in children requires the institution of HDM avoidance interventions during pregnancy.     

Maternal allergen immunization during pregnancy in a mouse model reduces adult allergy-related antibody responses in the offspring

BACKGROUND: The immune status and allergen exposure of the mother may influence the immune response in the offspring after birth. This relationship may be important both for allergen avoidance strategies and, alternatively, for allergy prophylaxis by allergen exposure of the mother. OBJECTIVE: The aim of the present study was to investigate the effect of allergen immunization of the mother during pregnancy and postpartum, in relation to the allergy-related immune response (IgE) and the non-allergy-related (IgG2a) response in the offspring. METHODS: Pregnant NIH/OlaHsd females were immunized three times during pregnancy and one time postpartum with ovalbumin and the adjuvant Al(OH)3, and the offspring's ovalbumin-specific IgE, IgG1 and IgG2a responses were measured after challenge with the same allergen as young adults. Ovalbumin-specific IgE, IgG1 and IgG2a responses were also analysed in offspring of NIH/OlaHsd females immunized once at different times during pregnancy: about 3 days into pregnancy, mid-pregnancy (10 days into pregnancy) and about 4 days before giving birth (17 days into pregnancy). RESULTS: Allergen immunization of mother during pregnancy and postpartum significantly reduced the IgE response in the progenies, whereas the IgG2a response to the same allergen was increased. Allergen immunization of the mother 3 days into pregnancy resulted in a significantly lower IgE response in offspring compared with the response in offspring of non-immunized mothers and in offspring of mothers immunized 17 days into pregnancy. CONCLUSIONS: Maternal allergen immunization might favour selection for an allergen-specific Th1-dependent antibody response in the offspring. Our results indicate that IgE suppression is stronger after maternal allergen exposure during early pregnancy than after exposure in late pregnancy.     

Prenatal farm exposure is related to the expression of receptors of the innate immunity and to atopic sensitization in school-age children

BACKGROUND: There is increasing evidence that environmental exposures determining childhood illnesses operate early in life. Prenatal exposure to a farming environment through the mother might also play an important role. OBJECTIVE: We sought to investigate the role of maternal exposures to environments rich in microbial compounds for the development of atopic sensitization, asthma, and corresponding alterations in the innate immune system in offspring. METHODS: In the children of the cross-sectional Prevention of Allergy Risk Factors for Sensitization in Children Related to Farming and Anthroposophic Life Style study, asthma and atopy were assessed by means of standardized questionnaires (n = 8263) and serum IgE measurements (n = 2086). In a subsample (n = 322) gene expression of Toll-like receptors (TLR2 and TLR4) and CD14 was assessed. Maternal exposures were defined through questionnaire information. RESULTS: Both atopic sensitization (adjusted odds ratio, 0.58; 95% CI, 0.39-0.86) and the gene expression of receptors of innate immunity were strongly determined by maternal exposure to stables during pregnancy, whereas current exposures had much weaker or no effects. A dose-response relation was found between the extent of upregulation of these genes and the number of different farm animal species the mother had encountered in her pregnancy. Each additional farm animal species increased the expression of TLR2, TLR4, and CD14 by a factor of 1.16 (95% CI, 1.07-1.26), 1.12 (95% CI, 1.04-1.2), and 1.10 (95% CI, 1.03-1.23), respectively. CONCLUSION: Maternal exposure to an environment rich in microbial compounds might protect against the development of atopic sensitization and lead to upregulation of receptors of the innate immune system. The underlying mechanisms potentially operating through the intrauterine milieu or epigenetic inheritance await further elucidation. CLINICAL IMPLICATIONS: When assessing risk factors of allergies in an infant's medical history, attention must also be paid to environmental exposures affecting the mother.     

Influence of the early-life gut microbiota on the immune responses to an inhaled allergen

Antibiotics, among the most used medications in children, affect gut microbiome communities and metabolic functions. These changes in microbiota structure can impact host immunity. We hypothesized that early-life microbiome alterations would lead to increased susceptibility to allergy and asthma. To test this, mouse pups between postnatal days 5–9 were orally exposed to water (control) or to therapeutic doses of azithromycin or amoxicillin. Later in life, these mice were sensitized and challenged with a model allergen, house dust mite (HDM), or saline. Mice with early-life azithromycin exposure that were challenged with HDM had increased IgE and IL-13 production by CD4⁺ T cells compared to unexposed mice; early-life amoxicillin exposure led to fewer abnormalities. To test that the microbiota contained the immunological cues to alter IgE and cytokine production after HDM challenge, germ-free mice were gavaged with fecal samples of the antibiotic-perturbed microbiota. Gavage of adult germ-free mice did not result in altered HDM responses, however, their offspring, which acquired the antibiotic-perturbed microbiota at birth showed elevated IgE levels and CD4⁺ cytokines in response to HDM, and altered airway reactivity. These studies indicate that early-life microbiota composition can heighten allergen-driven Th2/Th17 immune pathways and airway responses in an age-dependent manner.     

Pulmonary exposure to particles during pregnancy causes increased neonatal asthma susceptibility

Maternal immune responses can promote allergy development in offspring, as shown in a model of increased susceptibility to asthma in babies of ovalbumin (OVA)-sensitized and -challenged mother mice. We investigated whether inflammatory responses to air pollution particles (diesel exhaust particles, DEP) or control "inert" titanium dioxide (TiO(2)) particles are enhanced during pregnancy and whether exposure to particles can cause increased neonatal susceptibility to asthma. Pregnant BALB/c mice (or nonpregnant controls) received particle suspensions intranasally at Day 14 of pregnancy. Lung inflammatory responses were evaluated 48 hours after exposure. Offspring of particle- or buffer-treated mothers were sensitized and aerosolized with OVA, followed by assays of airway hyperresponsiveness (AHR) and allergic inflammation (AI). Nonpregnant females had the expected minimal response to "inert" TiO(2). In contrast, pregnant mice showed robust and persistent acute inflammation after both TiO(2) and DEP. Genomic profiling identified genes differentially expressed in pregnant lungs exposed to TiO(2). Neonates of mothers exposed to TiO(2) (and DEP, but not PBS) developed AHR and AI, indicating that pregnancy exposure to both "inert" TiO(2) and DEP caused increased asthma susceptibility in offspring. We conclude that (1) pregnancy enhances lung inflammatory responses to otherwise relatively innocuous inert particles; and (2) exposures of nonallergic pregnant females to inert or toxic environmental air particles can cause increased allergic susceptibility in offspring.     

Maternal allergen immunisation to prevent sensitisation in offspring: Th2-polarising adjuvants are more efficient than a Th1-polarising adjuvant in mice

Background

Preconception allergen immunization prevents neonatal allergen sensitization in mice by a complex interaction between regulatory cells/factors and antibodies. The present study assessed the influence of maternal immunization with ovalbumin (OVA) on the immune response of 3 day-old and 3 week-old offspring immunized or non-immunized with OVA and evaluated the effect of IgG treatment during fetal development or neonatal period.

Results

Maternal immunization with OVA showed increased levels of FcγRIIb expression in splenic B cells of neonates, which were maintained for up to 3 weeks and not affected by additional postnatal OVA immunization. Maternal immunization also exerted a down-modulatory effect on both IL-4 and IFN-γ-secreting T cells and IL-4 and IL-12- secreting B cells. Furthermore, immunized neonates from immunized mothers showed a marked inhibition of antigen-specifc IgE Ab production and lowered Th2/Th1 cytokine levels, whereas displaying enhanced FcγRIIb expression on B cells. These offspring also showed reduced antigen-specific proliferative response and lowered B cell responsiveness. Moreover, in vitro evaluation revealed an impairment of B cell activation upon engagement of B cell antigen receptor by IgG from OVA-immunized mice. Finally, in vivo IgG transference during pregnancy or breastfeeding revealed that maternal Ab transference was able to increase regulatory cytokines, such as IL-10, in the prenatal stage; yet only the postnatal treatment prevented neonatal sensitization. None of the IgG treatments induced immunological changes in the offspring, as it was observed for those from OVA-immunized mothers.

Conclusion

Maternal immunization upregulates the inhibitory FcγRIIb expression on offspring B cells, avoiding skewed Th2 response and development of allergy. These findings contribute to the advancement of prophylactic strategies to prevent allergic diseases in early life.     

Prenatal lipopolysaccharide-exposure prevents allergic sensitization and airway inflammation, but not airway responsiveness in a murine model of experimental asthma

BACKGROUND: Epidemiological evidence underlines the impact of prenatal environmental factors on the development of postnatal allergies. In this regard an inverse correlation between lipopolysaccharide (LPS) exposure and development of childhood allergy has been found. OBJECTIVE: To assess the impact of prenatal LPS exposure on the development of postnatal respiratory allergies in a mouse model of experimental asthma. METHODS: Female BALB/c mice were exposed to LPS before conception and during pregnancy. Several weeks after birth offspring were sensitized to ovalbumin (OVA) followed by aerosol allergen challenges. RESULTS: Prenatal, maternal LPS-exposure enhanced neonatal IFN-gamma, but not IL-4 and IL-2 production. OVA sensitization of prenatally LPS-exposed mice was accompanied by a marked suppression in anti-OVA IgG1 and IgE as well as unchanged IgG2a antibody responses, paralleled by a significant reduction in IL-5 and IL-13 levels following mitogenic stimulation of splenic leucocytes. Assessment of bronchoalveolar lavage fluids following allergen challenges revealed a marked reduction in eosinophils and macrophages in these mice. Surprisingly, development of airway hyper-responsiveness, a hallmark of bronchial asthma, was not affected. CONCLUSION: This study provides first experimental evidence that LPS may already operate in prenatal life in order to modulate the development of allergies in the offspring.     

Effects of established allergen sensitization on immune and airway responses after secondary allergen sensitization

BACKGROUND: Spreading of sensitization with clinical manifestation of allergy is often observed in atopic individuals. OBJECTIVE: To investigate the effects of an established primary allergen sensitization on immune responses and airway inflammation/reactivity on secondary allergen sensitization and airway challenges in a murine model. METHODS: Balb/c mice were primarily sensitized intraperitoneally with ovalbumin or PBS, followed by systemic sensitization and airway challenges with latex extract as a secondary, unrelated allergen. Purely sham-sensitized animals were included as controls. In a second set of experiments, the primary and secondary allergens were switched. RESULTS: Sensitization with ovalbumin before sensitization with latex resulted in increased production of total and latex-specific (Hev b 3-specific) IgE and IgG(1), and enhanced secretion of T(H)2-cytokines by spleen mononuclear cells cultured with mitogen compared with single latex-sensitized mice. Furthermore, airway challenges of double-sensitized mice (ovalbumin + latex) with latex caused a significant increase in airway reactivity compared with purely latex-sensitized and challenged animals. These effects were dependent on dosing and timing of the primary sensitization in relation to the secondary sensitization and independent of the primary allergen used. CONCLUSION: Primary sensitization boosted systemic T(H)2 immune responses and enhanced the development of airway reactivity after sensitization and airway challenges with a secondary, unrelated allergen. This effect of consecutive priming was dependent on the strength of the primary sensitization but independent of the allergen used. The results explain the increased susceptibility toward sensitization spreading in atopic individuals. CLINICAL IMPLICATIONS: Because sensitization spreading is facilitated by primary sensitization, early prevention measurements or immunotherapy should be considered at this stage of monosensitization.     

House dust mite sensitivity: interaction of genetics and allergen dosage

Pairwise analysis of siblings from 21 families showed that house dust mite (HDM) sensitive children were exposed to higher concentrations of Der p I allergen in their mattress (P = 0.005) and bedding (P = 0.04), but not bedroom floor (P = 0.33), than their atopic sibling who was not sensitive to HDM antigens. There was no difference in the exposure to HDM numbers/100 mg of dust in the mattress (P = 0.61) or bedroom floors (P = 0.09). In contrast, pairwise analysis of siblings from 15 families showed that HDM sensitive children were not exposed to significantly different concentrations of Der p I in the mattress (P = 0.96), bedding (P = 0.11) or bedroom floor (P = 0.70) nor HDM numbers/100 mg of dust in the mattress (P = 0.12) and bedroom floor (P = 0.98) than their non-atopic siblings. These findings were identical when absolute allergen load was compared in these pairs. Genetic linkage studies in these families suggest the tendency to atopic IgE responses is conferred by a putative atopy locus on chromosome 11q. These results together suggest that differences in allergen levels in beds, among siblings with a comparable genetic tendency to atopy, play a significant role in determining the development of HDM allergy.