Editorial: The Immunological Implications of the Hygiene Hypothesis

Human beings developed in close vicinity to their natural environment during their long-lasting history

Bioavailability and allergoprotective capacity of milk-associated conjugated linoleic acid in a murine model of allergic airway inflammation

BACKGROUND Cross-sectional epidemiological studies have demonstrated that farm milk from traditional farm settings possesses allergoprotective properties. Up to now, it has not been clarified which milk ingredient is responsible for protection against allergic diseases. As farm milk is rich in conjugated linoleic acids (CLA), it is hypothesized that this n-3 polyunsaturated fatty acid family contributes to the allergoprotective capacity of farm milk. We aim to prove this hypothesis in a murine model of allergic airway inflammation. METHODS To prove the bioavailability and allergoprotective capacity of milk-associated CLA in a standardized protocol, milk batches that differed significantly in terms of their CLA content were spray dried and incorporated into a basic diet by substituting the regular sunflower fat fraction. Initially, the milk CLA uptake from the diet was monitored via measurement of the CLA content in plasma and erythrocyte membranes obtained from supplemented mice. To determine whether a milk CLA-enriched diet possesses allergoprotective properties, female Balb/c mice were fed the milk CLA-enriched diet ahead of sensitization and a challenge with ovalbumin (OVA) and the parameters of airway inflammation and eisosanoid pattern were measured. RESULTS In animals, supplementation with a diet rich in milk CLA resulted in elevated CLA levels in plasma and erythrocyte membranes, indicating bioavailability of milk fatty acids. Though membrane-associated phospholipid patterns were affected by supplementation with milk CLA, this application neither reduced the hallmarks of allergic airway inflammation in sensitized and OVA-challenged mice nor modified the eiconsanoid pattern in the bronchoalveolar lavage fluid of these animals. CONCLUSION Milk-associated CLA was not capable of preventing murine allergic airway inflammation in an animal model of OVA-induced allergic airway inflammation

omega-3 fatty acids contribute to the asthma-protective effect of unprocessed cow's milk

Background: Living on a farm has repeatedly been shown to protect children from asthma and allergies. A major factor involved in this effect is consumption of unprocessed cow's milk obtained directly from a farm. However, this phenomenon has never been shown in a longitudinal design, and the responsible milk components are still unknown. Objectives: We sought to assess the asthma-protective effect of unprocessed cow's milk consumption in a birth cohort and to determine whether the differences in the fatty acid (FA) composition of unprocessed farm milk and industrially processed milk contributed to this effect. Methods: The Protection Against Allergy-Study in Rural Environments (PASTURE) study followed 1133 children living in rural areas in 5 European countries from birth to age 6 years. In 934 children milk consumption was assessed by using yearly questionnaires, and samples of the ``usually'' consumed milk and serum samples of the children were collected at age 4 years. Doctor-diagnosed asthma was parent reported at age 6 years. In a nested case-control study of 35 asthmatic and 49 nonasthmatic children, 42 FAs were quantified in milk samples. Results: The risk of asthma at 6 years of age was reduced by previous consumption of unprocessed farm milk compared with shop milk (adjusted odds ratio for consumption at 4 years, 0.26; 95% CI,0.10-0.67). Part of the effect was explained by the higher fat content of farm milk, particularly the higher levels of omega-3 polyunsaturated FAs (adjusted odds ratio, 0.29; 95% CI,0.11-0.81). Conclusion: Continuous farm milk consumption in childhood protects against asthma at school age partially by means of higher intake of omega-3 polyunsaturated FAs, which are precursors of anti-inflammatory mediators.Peer reviewe

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

Phenotypes of childhood-onset asthma are characterized by distinct trajectories and functional features. For atopy, definition of phenotypes during childhood is less clear.; 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).; 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.; 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-γ 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.; 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

Farm-like indoor microbiota in non-farm homes protects children from asthma development

Asthma prevalence has increased in epidemic proportions with urbanization, but growing up on traditional farms offers protection even today(1). The asthma-protective effect of farms appears to be associated with rich home dust microbiota(2,3), which could be used to model a health-promoting indoor microbiome. Here we show by modeling differences in house dust microbiota composition between farm and non-farm homes of Finnish birth cohorts(4) that in children who grow up in non-farm homes, asthma risk decreases as the similarity of their home bacterial microbiota composition to that of farm homes increases. The protective microbiota had a low abundance of Streptococcaceae relative to outdoor-associated bacterial taxa. The protective effect was independent of richness and total bacterial load and was associated with reduced proinflammatory cytokine responses against bacterial cell wall components ex vivo. We were able to reproduce these findings in a study among rural German children(2) and showed that children living in German non-farm homes with an indoor microbiota more similar to Finnish farm homes have decreased asthma risk. The indoor dust microbiota composition appears to be a definable, reproducible predictor of asthma risk and a potential modifiable target for asthma prevention.Peer reviewe

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-gamma 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.Peer reviewe

Untersuchungen zur Infektionsepidemiologie, Qualität von labordiagnostischen Testsystemen und Disease-Management der Helicobacter pylori-Infektion : Untersuchungen in einer betrieblichen Population und bei niedergelassenen Ärzten

Pfefferle PI. Untersuchungen zur Infektionsepidemiologie, Qualität von labordiagnostischen Testsystemen und Disease-Management der Helicobacter pylori-Infektion : Untersuchungen in einer betrieblichen Population und bei niedergelassenen Ärzten. Bielefeld (Germany): Bielefeld University; 2005.Die hier vorgelegte Studie beschreibt den Spannungsbogen der Helicobacter pylori-Infektion anhand einer betrieblichen Population und das Spektrum von der Übertragung bis hin zur Eradikation, der vollständigen Entfernung des Bakteriums. In der vorliegenden Untersuchung wurden die Faktoren identifiziert und analysiert, die eine Übertragung des Bakteriums in der Kindheit und die Entstehung von Folgeerkrankungen in den mittleren Altersdekaden begünstigen. Außerdem wurden neue Testverfahren evaluiert, die eine größere Aussagekraft bezüglich des Schweregrades der Infektion zulassen oder diese schneller und für den Patienten verträglicher und kostengünstiger nachweisen. Diese Ergebnisse flossen in ein Risikoprofil zur Identifizierung von unter Risiko stehenden Personen ein, welche nach Weiterverweisung an einen niedergelassenen Arzt in bezug auf die darauf folgenden diagnostischen und kurativen Schritte hin beobachtet wurden. Dabei wurden ärztliche Befunde und Befragungen dieser Studienteilnehmer als Datenquellen über die ambulante Weiterbehandlung genutzt. Diese dienten dazu, die derzeitigen Behandlungsszenarien im niedergelassenen Bereich zu erfassen, um sie gemäß Maastricht-Konsensus 2-2000, der qualitätssichernden evidenzbasierten Handlungsempfehlung, zu vergleichen. Die im Rahmen des Surveys erhaltenen Ergebnisse wurden in Hinblick auf die Empfehlungen der Leitlinie diskutiert und in ein erweitertes Behandlungsmodell eingebracht

Helicobacter pylori-infection status and childhood living conditions are associated with signs of allergic diseases in an occupational population

Pfefferle PI, Krämer A. Helicobacter pylori-infection status and childhood living conditions are associated with signs of allergic diseases in an occupational population. EUROPEAN JOURNAL OF EPIDEMIOLOGY. 2008;23(9):635-640.This study assessed the hypothesis that Helicobacter pylori infection and specific living conditions in childhood are associated with allergic outcomes. A cross-sectional survey containing retrospective questions concerning childhood was performed in an occupational population in 2001. This survey included self-administered questionnaire data and stool tests. An inverse association between positive H. pylori infection status and physician diagnosis of allergy/12 month period of anti-allergic medication was observed in a logistic regression model, adjusted for potential confounders (age, sex, nationality, smoking status and education of the participant) (OR 0.26, 95% CI: 0.08-0.84). In addition, childhood living conditions were associated with H. pylori infection status and signs of allergies. In line with the "hygiene hypothesis" our model supports an inverse association between early childhood infection with H. pylori and allergic disease in adulthood

Microbial Exposure and Onset of Allergic Diseases - Potential Prevention Strategies?

Chronic inflammatory diseases are a major health problem with global dimension. Particularly, the incidence of allergic diseases has been increased tremendously within the last decades. This world-wide trend clearly indicates the demand for new approaches in the investigation of early allergy development. Recent studies underlined the basic postulate of the hygiene hypothesis that early exposure to microbial stimuli plays a crucial role in the prevention of chronic inflammatory conditions in adulthood. There is ample evidence that, both, exogenous microbes and endogenous microbial communities, the human microbiota, shape the developing immune system and might be involved in prevention of pathologic pro-inflammatory trails. According to the Barker hypothesis, epidemiological studies pointed to transmaternal transmission from the mother to the offspring already in prenatal life. Experimental data from murine models support these findings. This state of the art review provides an overview on the current literature and presents new experimental concepts that point out to future application in the prevention of allergic diseases

Assoziationen zwischen inflammatorischen Parametern und morphologischen Charakteristika des ZNS bei affektiv erkrankten Patienten – Eine experimentelle Studie im Rahmen der MACS-Kohorte –

Psychiatrische Erkrankungen aus dem affektiven Formenkreis verursachen neben erheblichem individuellem Leid ebenso immense gesamtgesellschaftliche Schäden. Zur weiteren Erforschung dieser multifaktoriell verursachten Störungen werden im Rahmen der DFG geförderten Marburg-Münster Affective Disorder Cohort Studie (MACS) diverse genetische und molekulare Entstehungs- und Aufrechterhaltungsmechanismen untersucht. Zusätzlich zu neuen Behandlungsansätzen verfolgt die Forschungsgemeinschaft die Ziele, messbare Bioparameter als Ansatz für diagnostische Klassifizierungen sowie zur Therapiekontrolle zu entwickeln. Diese Dissertation verfolgt die Ziele, veränderte immunologische Parameter und hirnmorphologische Unterschiede zwischen gesunden und erkrankten Teilnehmern nachzuweisen und diese in einen statistischen Zusammenhang zu bringen. Hierzu wurden bei 609 Teilnehmern der MACS periphervenöse Blutproben mit Lipopolysaccharid (LPS) und anti-CD3/CD28-Antikörpern inkubiert. LPS induziert eine allgemeine proinflammatorische Immunantwort, wohingegen antiCD3/CD28-Antikörper eine T-Zell-spezifische Reaktion hervorrufen. Die ausgeschütteten Zytokine konnten via Durchflusszytometrie (Cytometric Bead Array, CBA) quantifiziert werden und spiegeln die allgemeine Kapazität und Reagibilität des Immunsystems wieder. Zusätzlich wurden Volumendaten diverser Zielstrukturen des zentralen Nervensystems, die mithilfe eines 3-Tesla-Magnetresonanztomographen bestimmt wurden, für diese Dissertation zur Verfügung gestellt. Während gesunde und erkrankte Männer nahezu identische Immunantworten zeigen, exprimieren gesunde Frauen signifikant höhere Konzentrationen der proinflammatorischen Zytokine (IL1-β, TNF-α, IFN-γ, IL17-α und IL12p70) als affektiv erkrankte Frauen. Hirnmorphologische Unterschiede lassen sich in bei den Seitenventrikeln, dem Thalamus und der Amygdala beidseits, dem linken Nucleus caudatus, dem rechten Nucleus accumbens und dem linken Hippocampus berechnen. Bei diesen Regionen stellen sich die Interaktionsfaktoren, die sich aus der Diagnose, dem Alter und/oder dem Geschlecht zusammensetzen, als signifikant dar. Ferner erweisen sich die Zytokine IL10 und TNF-α in der logistischen Regressionsanalyse als signifikante Einflussvariablen im Bezug auf die Zielvolumina: das Putamen beidseits, der linke Nucleus accumbens und der rechte Globus pallidus. Diese Ergebnisse unterstützen die Vermutung einer Schlüsselrolle des Immunsystems in der Ätiopathogenese affektiver Erkrankungen, die von vielen Forschergruppen bereits formuliert wurde. So konnten bereits Ursachen erhöhter Immunparameter, diverse Mechanismen der Interaktion mit dem ZNS und vielseitige Effekte der Zytokine auf die Hirnfunktion und die Hirnstruktur nachgewiesen werden. Diese Arbeit kann bedingt durch ihr Querschnittsdesign zwar keine Kausalbeziehung zwischen Zytokinen und Hirnvolumen nachweisen, liefert durch die signifikanten Assoziationen jedoch deutliche Anhaltspunkte für volumenreduzierende Effekte der Zytokine. Follow-Up-Untersuchungen oder andere longitudinale Studien sollten die immunmodulierenden Effekte der antidepressiven Medikation sowie des Rauchens mitberücksichtigen. Möglicherweise finden die in dieser Arbeit gemessenen Bioparameter zukünftig in Diagnostik und Therapie affektiver Erkrankungen Verwendung. Die heutzutage noch aufwendig zu therapierenden Leiden könnten dadurch effektiver geheilt und somit großer Schaden abgewendet werden