Nicole Blümer

Maternal TLR signaling is required for prenatal asthma protection by the nonpathogenic microbe Acinetobacter lwoffii F78

The pre- and postnatal environment may represent a window of opportunity for allergy and asthma prevention, and the hygiene hypothesis implies that microbial agents may play an important role in this regard. Using the cowshed-derived bacterium Acinetobacter lwoffii F78 together with a mouse model of experimental allergic airway inflammation, this study investigated the hygiene hypothesis, maternal (prenatal) microbial exposure, and the involvement of Toll-like receptor (TLR) signaling in prenatal protection from asthma. Maternal intranasal exposure to A. lwoffii F78 protected against the development of experimental asthma in the progeny. Maternally, A. lwoffii F78 exposure resulted in a transient increase in lung and serum proinflammatory cytokine production and up-regulation of lung TLR messenger RNA. Conversely, suppression of TLRs was observed in placental tissue. To investigate further, the functional relevance of maternal TLR signaling was tested in TLR2/3/4/7/9−/− knockout mice. The asthma-preventive effect was completely abolished in heterozygous offspring from A. lwoffii F78–treated TLR2/3/4/7/9−/− homozygous mother mice. Furthermore, the mild local and systemic inflammatory response was also absent in these A. lwoffii F78–exposed mothers. These data establish a direct relationship between maternal bacterial exposures, functional maternal TLR signaling, and asthma protection in the progeny.

Cord blood cytokines are modulated by maternal farming activities and consumption of farm dairy products during pregnancy: The PASTURE Study

BACKGROUND Traditional farming represents a unique model situation to investigate the relationship of early-life farm-related exposure and allergy protection. OBJECTIVES To investigate associations between maternal farm exposures and cytokine production in cord blood (CB) mononuclear cells in a prospective multinational birth cohort of 299 farm and 326 nonfarm children and their families. METHODS Supernatants from phorbol 12-myristate 13-acetate/ionomycin-stimulated CB mononuclear cells were assessed for the production of IFN-gamma, TNF-alpha, IL-5, IL-10, and IL-12. RESULTS Significantly higher levels of IFN-gamma and TNF-alpha in farm compared with nonfarm children were found, whereas IL-5, IL-10, and IL-12 levels did not differ between study groups. Maternal contact with different farm animal species and barns and consumption of farm-produced butter during pregnancy enhanced the production of proinflammatory CB cytokines, whereas maternal consumption of farm-produced yogurt resulted in significant lower levels of IFN-gamma and TNF-alpha in umbilical blood. CONCLUSION Maternal exposure to farming activities and farm dairy products during pregnancy modulated cytokine production patterns of offspring at birth.

The Drosophila don juan (dj) gene encodes a novel sperm specific protein component characterized by an unusual domain of a repetitive amino acid motif

We identified and characterized the don juan gene (dj) of Drosophila melanogaster. The don juan gene codes for a sperm specific protein component with an unusual repetitive six amino acid motif (DPCKKK) in the carboxy-terminal part of the protein. The expression of Don Juan is limited to male germ cells where transcription of the dj gene is initiated during meiotic prophase. But Western blot experiments indicate that DJ protein occurs just postmeiotically. Examination of transgenic flies bearing a dj-promoter-lacZ reporter construct revealed lacZ mRNA distribution resembling the expression pattern of the endogenous dj mRNA in the adult testes, whereas beta-galactosidase expression is exclusively present in postmeiotic germ cells. Thus, these observations strongly suggest that dj transcripts are under translational repression until in spermiogenesis. To study the function and subcellular distribution of DJ in spermiogenesis we expressed a chimaeric dj-GFP fusion gene in the male germline exhibiting strong GFP fluorescence in the liver testes, where only elongated spermatids are decorated. With regard to the characteristic expression pattern of DJ protein and its conspicuous repeat units possible functional roles are discussed.

Anti-ulcer treatment during pregnancy induces food allergy in mouse mothers and a Th2-bias in their offspring

The treatment of dyspeptic disorders with anti‐acids leads to an increased risk of sensitization against food allergens. As these drugs are taken by 30–50% of pregnant women due to reflux and heartburn, we aimed here to investigate the impact of maternal therapy with anti‐acids on the immune response in the offspring in a murine model. Codfish extract as model allergen was fed with or without sucralfate, an anti‐acid drug, to pregnant BALB/c mice during pregnancy and lactation. These mothers developed a codfish‐specific allergic response shown as high IgG1 and IgE antibody levels and positive skin tests. In the next step we analyzed whether this maternal sensi‐tization impacts a subsequent sensitization in the offspring. Indeed, in stimulated splenocytes of these off‐spring we found a relative Th2‐dominance, because the Thl‐ and T‐regulatory cytokines were significantly sup‐pressed. Our data provide evidence that the anti‐acid drug sucralfate supports sensitization against food in pregnant mice and favors a Th2‐milieu in their offspring. From these results we propose that anti‐acid treatment during pregnancy could be responsible for the increasing number of sensitizations against food allergens in young infants.—Schöll, I., Ackermann, U., Özdemir, C., Blümer, N., Dicke, T., Sel, S., Sel, S., Wegmann, M., Szalai, K., Knittelfelder, R., Untersmayr, E., Scheiner, O., Garn, H., Jensen‐Jarolim, E., Renz, H. Anti‐ulcer treatment during pregnancy induces food allergy in mouse mothers and a Th2‐bias in their offspring. FASEB J. 21, 1264–1270 (2007)

Animal shed Bacillus licheniformis spores possess allergy-protective as well as inflammatory properties

BACKGROUND Numerous epidemiologic studies have demonstrated an allergy-protective effect of farm life early in childhood. It has been hypothesized that environmental exposure to microbes may contribute to this effect. Because of their small size and thereby their potential for deposition in lower airways of small children, bacterial spores may be candidates for such allergy-protective effects. OBJECTIVE To investigate immune responses elicited by exposure to Bacillus spores in experimental settings. METHODS Animal shed and mattress dusts were analyzed for bacteria and fungi by aerobic and anaerobic growth. Bacillus licheniformis, the most prominent microorganism found in these samples, was investigated with respect to spore specific stimulation of pattern recognition receptors, monocyte-derived dendritic cells and T(H)-cell polarization in vitro as well as to the prevention of asthma development in a mouse model of allergic asthma. RESULTS In vitro, B. licheniformis spores activated a T(H)1 cytokine expression profile. In vivo application of these spores resulted in less spore-specific but long-lasting immune activation preventing eosinophilia and goblet cell hyperplasia; however, they provoked an influx of neutrophils in lung tissue of asthmatic mice. CONCLUSION Bacterial spores may contribute to the allergy-protective properties of farming environments, but their persistence in the lung causes ongoing immune activation in mouse experiments.

Consumption of ω3-fatty acids during perinatal life: role in immuno-modulation and allergy prevention

Abstract Epidemiological data suggest that dietary factors may have a role in recent increases of the prevalence of allergic diseases. One food-related component might be the reduced consumption of ω3-polyunsaturated fatty acids observed especially in the Western societies; yet, clinical trials supplementing ω3-fatty acids to adults with established allergies and bronchial asthma have generally been disappointing. However, it is known that the immature immune system is highly susceptible to immuno-modulatory environmental conditions particularly in the pre- and postnatal period. This review discusses the immuno-modulatory effects of ω3-fatty acids supplementation in the perinatal life phase on the immune system of the child. Evidence exists that perinatal ω3-fatty acid exposure affects T-cells and antigen presenting cells of the neonates likely due to altered eicosanoid metabolism. Although animal experiments strongly suggest a role of maternal ω3-fatty acid intake on allergic immune responses in the offspring, the beneficial effect of ω3-fatty acid supplementation has been studied in a small number of clinical trials. In these studies perinatal supplementation had some positive effects on distinct clinical phenotypes of the atopic syndrome. However, more studies are needed to fully explore the opportunity of perinatal immuno-modulation.

Diagnostic and analytical performance of a screening panel for allergy.

Abstract Worldwide, allergic diseases are increasing in prevalence and incidence. Early assessment of the immunoglobulin E (IgE) sensitisation status has a major impact on clinical outcome and selection of therapeutic options. Recently, a number of new IgE-detecting test systems have entered the market, including screening tests allowing identification of a wide spectrum of sensitising allergens. We evaluated the analytical and diagnostic performance of the newly developed Allergy Screen test panel for atopy (Mediwiss Analytic, Moers, Germany). The evaluation was performed for four major respiratory and four major nutritional allergens in 142 patients with clinical suspicion of respiratory and/or food allergies. For all allergens, the test showed acceptable concordance to the skin-prick test and the in vitro IgE CAP system (Pharmacia, Freiburg, Germany). The analytical performance was acceptable, with CVs between 2 and 8% in the positive range and good dilution linearity (R=0.9735). Imprecision in the low IgE concentration range dramatically improved by lowering the cut-off value to 0.2IU/mL IgE. In conclusion, the Allergy Screen panel yields reliable results in the detection of allergic sensitisation to common allergens.

Development of mucosal immune function in the intrauterine and early postnatal environment.

Purpose of review There is recent evidence that immunological priming can start prenatally or in the very early life phase. This review summarizes recent progress in the field of early gut immunology with special attention to factors contributing to the intrauterine and early postnatal development of mucosal immune responses in the gut. Recent findings Development and maturation of the fetal gut immune system occurs under close control of the maternal environment. Examples include maternal antibodies, cytokines, sCD14 molecules and bacterial antigens. Mouse experiments reveal that activated T cells can be detected already at birth in the fetal gut, which are supposed to be activated by signals from the maternal microbial gut flora. Human milk sCD14 is involved in the immunological priming of the developing gut immune system to Gram-negative bacteria and modulates the microbial recognition system of the gut. The development of food allergies is associated with consumption of food components like polyunsaturated fatty acids acting prenatally or in the early postnatal life span as immunomodulators. Summary The new findings highlight the importance of very early life factors for the development of the mucosal immune functions of the gut. Therefore, the gut might be a new target to establish preventive strategies with regard to different immunologic disorders.

Latent class analysis reveals clinically relevant atopy phenotypes in 2 birth cohorts

Background Phenotypes of childhood‐onset asthma are characterized by distinct trajectories and functional features. For atopy, definition of phenotypes during childhood is less clear. Objective We sought to define phenotypes of atopic sensitization over the first 6 years of life using a latent class analysis (LCA) integrating 3 dimensions of atopy: allergen specificity, time course, and levels of specific IgE (sIgE). Methods Phenotypes were defined by means of LCA in 680 children of the Multizentrische Allergiestudie (MAS) and 766 children of the Protection against allergy: Study in Rural Environments (PASTURE) birth cohorts and compared with classical nondisjunctive definitions of seasonal, perennial, and food sensitization with respect to atopic diseases and lung function. Cytokine levels were measured in the PASTURE cohort. Results The LCA classified predominantly by type and multiplicity of sensitization (food vs inhalant), allergen combinations, and sIgE levels. Latent classes were related to atopic disease manifestations with higher sensitivity and specificity than the classical definitions. LCA detected consistently in both cohorts a distinct group of children with severe atopy characterized by high seasonal sIgE levels and a strong propensity for asthma; hay fever; eczema; and impaired lung function, also in children without an established asthma diagnosis. Severe atopy was associated with an increased IL‐5/IFN‐&ggr; ratio. A path analysis among sensitized children revealed that among all features of severe atopy, only excessive sIgE production early in life affected asthma risk. Conclusions LCA revealed a set of benign, symptomatic, and severe atopy phenotypes. The severe phenotype emerged as a latent condition with signs of a dysbalanced immune response. It determined high asthma risk through excessive sIgE production and directly affected impaired lung function. Graphical abstract Figure. No caption available.