The interleukin 4 receptor gene and its role in recurrent airway obstruction in Swiss Warmblood horses

Recurrent airway obstruction (RAO) in horses is the result of an interaction of genetic and environmental factors and shares many characteristics with human asthma. Many studies have suggested that the interleukin-4 receptor gene (IL4R) is associated with this disease, and a QTL region on chromosome 13 containing IL4R was previously detected in one of the two Swiss Warmblood families. We sequenced the entire IL4R gene in this family and detected 93 variants including five non-synonymous protein-coding variants. The allele distribution at these SNPs supported the previously detected QTL signal. Subsequently, we investigated IL4R mRNA expression in bronchoalveolar lavage fluid cells. During exacerbation, IL4R expression was increased in RAO-affected offspring in the implicated family, but not in the other family. These findings support that IL4R plays a role in some cases of RAO.

Molecular cloning and characterization of equine thymic stromal lymphopoietin

Thymic stromal lymphopoietin (TSLP) is a novel cytokine that plays a central role in T helper 2 (Th2) cell differentiation and allergic inflammation. It is predominantly expressed by epithelial cells, and its expression is increased in patients with atopic dermatitis and asthma. Mice overexpressing TSLP in the skin develop allergic dermatitis and mice overexpressing TSLP in lungs develop asthma-like disease. However, it is not known whether TSLP plays an important role in equine allergies. Therefore, we cloned and sequenced the complete translated region of equine TSLP gene and measured its expression in various tissues. The equine TSLP gene is organized in 4 exons and encodes a protein of 143 amino acids, which has 62% amino acid identity with human TSLP.

Novel insights into mechanisms of food allergy and allergic airway inflammation using experimental mouse models

Over the last decades, considerable efforts have been undertaken in the development of animal models mimicking the pathogenesis of allergic diseases occurring in humans. The mouse has rapidly emerged as the animal model of choice, due to considerations of handling and costs and, importantly, due to the availability of a large and increasing arsenal of genetically modified mouse strains and molecular tools facilitating the analysis of complex disease models. Here, we review latest developments in allergy research that have arisen from in vivo experimentation in the mouse, with a focus on models of food allergy and allergic asthma, which constitute major health problems with increasing incidence in industrialized countries. We highlight recent novel findings and controversies in the field, most of which were obtained through the use of gene-deficient or germ-free mice, and discuss new potential therapeutic approaches that have emerged from animal studies and that aim at attenuating allergic reactions in human patients.

Pediatric and adult eosinophilic esophagitis: similarities and differences

Early in the 1990s, several case series described adults suffering from dysphagia and children with refractory reflux symptoms, both accompanied by an eosinophil-predominant infiltration, thereby conclusively distinguishing it from gastroesophageal reflux disease. Eosinophilic esophagitis (EoE) was recognized as its own entity in the adult and in the pediatric literature. In the last decade, evidence has accumulated that EoE represents a T-helper (Th)2-type inflammatory disease. Remodeling of the esophagus is a hallmark of EoE, leading to esophageal dysfunction and bolus impaction. Familial occurrence and disease association with single-nucleotide polymorphisms underscore the influence of genetics in this disease. Eosinophilic esophagitis may affect individuals at any age, although the clinical presentation is highly age dependent. There is a significant allergic bias in the EoE population, with the majority of patients having concurrent allergic rhinitis, asthma, eczema, and/or a history of atopy. One noteworthy difference is that in children, EoE seems to be primarily a food antigen-driven disease, whereas in adults, mainly aeroallergen sensitization has been observed. Treatment modalities for EoE include the 3Ds: drugs, diet, and dilation. The crucial question of whether adult and pediatric EoE are different phenotypes of one single entity or whether we are confronted with two different diseases is still open. Here, we review similarities and differences between EoE in adults and children.

Increased parasite resistance and recurrent airway obstruction in horses of a high-prevalence family

BACKGROUND: Equine recurrent airway obstruction (RAO) shares many characteristics with human asthma. In humans, an inverse relationship between susceptibility to asthma and resistance to parasites is suspected. HYPOTHESIS/OBJECTIVES: Members of a high-incidence RAO half-sibling family (F) shed fewer strongylid eggs compared with RAO-unaffected pasture mates (PM) and that RAO-affected horses shed fewer eggs than RAO-unaffected half-siblings. ANIMALS: Seventy-three F and 73 unrelated, age matched PM. METHODS: Cases and controls kept under the same management and deworming regime were examined. Each individual was classified as RAO affected or RAO unaffected and fecal samples were collected before and 1-3 weeks and 3 months after deworming. Samples were analyzed by combined sedimentation-flotation and modified McMaster methods and classified into 3 categories of 0 eggs per gram of feces (EpG), 1-100 EpG, and > 100 EpG, respectively. RESULTS: PM compared with RAO-affected F had a 16.7 (95% confidence interval [CI]: 2.0-136.3) times higher risk for shedding > 100 EpG compared with 0 EpG and a 5.3 (95% CI: 1.0-27.4) times higher risk for shedding > 100 EpG compared with 0 EpG. There was no significant effect when RAO-unaffected F were compared with their PM. RAO-unaffected compared with RAO-affected offspring had a 5.8 (95% CI: 0.0-1.0) times higher risk for shedding 1-100 EpG. Age, sex, breed, and sharing pastures with other species had no significant confounding effects. CONCLUSION AND CLINICAL IMPORTANCE: RAO is associated with resistance against strongylid parasites in a high-prevalence family.

Accelerated disassembly of IgE-receptor complexes by a disruptive macromolecular inhibitor

IgE antibodies bind the high-affinity IgE Fc receptor (FcεRI), found primarily on mast cells and basophils, and trigger inflammatory cascades of the allergic response. Inhibitors of IgE-FcεRI binding have been identified and an anti-IgE therapeutic antibody (omalizumab) is used to treat severe allergic asthma. However, preformed IgE-FcεRI complexes that prime cells before allergen exposure dissociate extremely slowly and cannot be disrupted by strictly competitive inhibitors. IgE-Fc conformational flexibility indicated that inhibition could be mediated by allosteric or other non-classical mechanisms. Here we demonstrate that an engineered protein inhibitor, DARPin E2_79 (refs 9, 10, 11), acts through a non-classical inhibition mechanism, not only blocking IgE-FcεRI interactions, but actively stimulating the dissociation of preformed ligand-receptor complexes. The structure of the E2_79-IgE-Fc(3-4) complex predicts the presence of two non-equivalent E2_79 sites in the asymmetric IgE-FcεRI complex, with site 1 distant from the receptor and site 2 exhibiting partial steric overlap. Although the structure is indicative of an allosteric inhibition mechanism, mutational studies and quantitative kinetic modelling indicate that E2_79 acts through a facilitated dissociation mechanism at site 2 alone. These results demonstrate that high-affinity IgE-FcεRI complexes can be actively dissociated to block the allergic response and suggest that protein-protein complexes may be more generally amenable to active disruption by macromolecular inhibitors.

An integrated nano-scale approach to profile miRNAs in limited clinical samples

Profiling miRNA expression in cells that directly contribute to human disease pathogenesis is likely to aid the discovery of novel drug targets and biomarkers. However, tissue heterogeneity and the limited amount of human diseased tissue available for research purposes present fundamental difficulties that often constrain the scope and potential of such studies. We established a flow cytometry-based method for isolating pure populations of pathogenic T cells from bronchial biopsy samples of asthma patients, and optimized a high-throughput nano-scale qRT-PCR method capable of accurately measuring 96 miRNAs in as little as 100 cells. Comparison of circulating and airway T cells from healthy and asthmatic subjects revealed asthma-associated and tissue-specific miRNA expression patterns. These results establish the feasibility and utility of investigating miRNA expression in small populations of cells involved in asthma pathogenesis, and set a precedent for application of our nano-scale approach in other human diseases. The microarray data from this study (Figure 7) has been submitted to the NCBI Gene Expression Omnibus (GEO; http://ncbi.nlm.nih.gov/geo) under accession no. GSE31030.

Guidelines for treatment of atopic eczema (atopic dermatitis) Part II

The existing evidence for treatment of atopic eczema (atopic dermatitis, AE) is evaluated using the national standard Appraisal of Guidelines Research and Evaluation. The consensus process consisted of a nominal group process and a DELPHI procedure. Management of AE must consider the individual symptomatic variability of the disease. Basic therapy is focused on hydrating topical treatment, and avoidance of specific and unspecific provocation factors. Anti-inflammatory treatment based on topical glucocorticosteroids and topical calcineurin inhibitors (TCI) is used for exacerbation management and more recently for proactive therapy in selected cases. Topical corticosteroids remain the mainstay of therapy, but the TCI tacrolimus and pimecrolimus are preferred in certain locations. Systemic immune-suppressive treatment is an option for severe refractory cases. Microbial colonization and superinfection may induce disease exacerbation and can justify additional antimicrobial treatment. Adjuvant therapy includes UV irradiation preferably with UVA1 wavelength or UVB 311 nm. Dietary recommendations should be specific and given only in diagnosed individual food allergy. Allergen-specific immunotherapy to aeroallergens may be useful in selected cases. Stress-induced exacerbations may make psychosomatic counselling recommendable. 'Eczema school' educational programs have been proven to be helpful. Pruritus is targeted with the majority of the recommended therapies, but some patients need additional antipruritic therapies.

Guidelines for treatment of atopic eczema (atopic dermatitis) part I

The existing evidence for treatment of atopic eczema (atopic dermatitis, AE) is evaluated using the national standard Appraisal of Guidelines Research and Evaluation. The consensus process consisted of a nominal group process and a DELPHI procedure. Management of AE must consider the individual symptomatic variability of the disease. Basic therapy is focused on hydrating topical treatment, and avoidance of specific and unspecific provocation factors. Anti-inflammatory treatment based on topical glucocorticosteroids and topical calcineurin inhibitors (TCI) is used for exacerbation management and more recently for proactive therapy in selected cases. Topical corticosteroids remain the mainstay of therapy, but the TCI tacrolimus and pimecrolimus are preferred in certain locations. Systemic immune-suppressive treatment is an option for severe refractory cases. Microbial colonization and superinfection may induce disease exacerbation and can justify additional antimicrobial treatment. Adjuvant therapy includes UV irradiation preferably with UVA1 wavelength or UVB 311 nm. Dietary recommendations should be specific and given only in diagnosed individual food allergy. Allergen-specific immunotherapy to aeroallergens may be useful in selected cases. Stress-induced exacerbations may make psychosomatic counselling recommendable. 'Eczema school' educational programs have been proven to be helpful. Pruritus is targeted with the majority of the recommended therapies, but some patients need additional antipruritic therapies.

Atemwegserkrankungen und Allergien

Aufgrund ihrer großen Oberfläche und des dort stattfindenden Gasaustauschs ist die Lunge den zahlreichen Luftschadstoffen unmittelbar ausgesetzt. Besonders empfindlich hierfür ist die noch wachsende Lunge. Atemwegserkrankungen und Allergien können dann die Folge sein. Sowohl in Mitteleuropa wie auch in den sog. Entwicklungsländern sind Atemwegserkrankungen eine bedeutende Ursache der Krankheitslast (Burden of Disease). Betroffen sind vorwiegend Kinder und ältere Menschen. In Entwicklungsländern tragen Lungenentzündung und Tuberkulose signifikant zur Gesamtmortalität bei, in den westlichen Industrienationen sind chronische Atemwegserkrankungen wie COPD und Asthma für einen erheblichen Teil der Gesamtmorbidität verantwortlich. In diesem Abschnitt betrachten wir die Entwicklung der Lungenfunktion im Laufe des Lebens, die unterschiedliche Vulnerabilität der Lunge gegenüber Umwelteinflüssen in den verschiedenen Entwicklungsstadien sowie die globale Krankheitslast als Folge von respiratorischen Erkrankungen. Anschließend beschreiben wir das Asthma und die COPD hinsichtlich ihrer Risikofaktoren und erörtern, mit welchen präventiven Maßnahmen diese Erkrankungen zu verhindern wären. Schweizerische Lernziele: CPH 40

[Allergies to animals and fungi]

Allergies to animals are behind the house-dust mite allergy the most frequent cause for indoor allergic respiratory symptoms. In case of persistent allergen exposure symptoms like rhinitis, itch of the skin or asthma are usually not perceived intensively and, thus, can not assigned to an animal or an animal source. In many cases animal allergies are based on a perennial allergen exposure. Although most likely all animals may be the cause of a respiratory allergy, cats, dogs, and horses are the most frequent elicitors. The diagnosis of an allergy to an animal needs to be set with due care, since it often causes emotional reactions, diverse conflicts, but also lack of understanding. Rarer are allergies to fungi even though fungi as allergen sources since decades belong to the differential diagnosis in respiratory allergies particularly in case of late summer asthma. Fungi are ubiquitous and present indoors as well as outdoors. Unfortunately the field of fungal allergy is not well explored and diagnostic possibilities are limited. The most promising therapy in both allergy to animals and fungi would be complete avoiding of contact with the respective allergen source. Indeed many preventive recommendations are given; however, realization is often not successful. In selected cases specific immunotherapy for both animal and fungal allergies is a potential therapeutic option.

[House dust mite allergy]

House dust mites can be found all over the world where human beings live independent from the climate. Proteins from the gastrointestinal tract- almost all known as enzymes - are the allergens which induce chronic allergic diseases. The inhalation of small amounts of allergens on a regular base all night leads to a slow beginning of the disease with chronically stuffed nose and an exercise induced asthma which later on persists. House dust mites grow well in a humid climate - this can be in well isolated dwellings or in the tropical climate - and nourish from human skin dander. Scales are found in mattresses, upholstered furniture and carpets. The clinical picture with slowly aggravating complaints leads quite often to a delayed diagnosis, which is accidently done on the occasion of a wider spectrum of allergy skin testing. The beginning of a medical therapy with topical steroids as nasal spray or inhalation leads to a fast relief of the complaints. Although discussed in extensive controversies in the literature - at least in Switzerland with the cold winter and dry climate - the recommendation of house dust mite avoidance measures is given to patients with good clinical results. The frequent ventilation of the dwelling with cold air in winter time cause a lower indoor humidity. Covering encasings on mattresses, pillow, and duvets reduces the possibility of chronic contact with mite allergens as well as the weekly changing the bed linen. Another option of therapy is the specific immunotherapy with extracts of house dust mites showing good results in children and adults. Using recombinant allergens will show a better quality in diagnostic as well as in therapeutic specific immunotherapy.

Farming environments and childhood atopy, wheeze, lung function, and exhaled nitric oxide

Previous studies have demonstrated that children raised on farms are protected from asthma and allergies. It is unknown whether the farming effect is solely mediated by atopy or also affects nonatopic wheeze phenotypes.

Rhinovirus infections in infancy and early childhood

Rhinovirus (RV) infections occur early and recurrently in life, imposing a significant burden of disease on infants and young children. They are the most frequent causative agents of both upper and lower respiratory tract infections in this age group and are associated with a broad variety of clinical outcomes, ranging from asymptomatic infections to severe respiratory disease requiring hospitalisation. In addition to their impact on short-term morbidity, RVs are also debated as important pathogens in the development of recurrent wheeze and/or asthma. Several studies in infants at high-risk for atopy and asthma and in hospitalised children have demonstrated that recurrent wheezing illnesses induced by RVs early in life are a risk factor for the development of asthma later in childhood. However, underlying mechanisms are poorly understood. The question whether RVs are directly involved in the development of childhood wheeze and asthma, or whether symptomatic RV infections only represent a proxy for infants prone to develop obstructive lung diseases, is still open. In this review we provide an overview on the role of RVs as important disease-causing agents from infancy to early childhood and discuss their contribution to the subsequent development of childhood wheeze and/or asthma.

Impaired innate interferon induction in severe therapy resistant atopic asthmatic children

Deficient type I interferon-β and type III interferon-λ induction by rhinoviruses has previously been reported in mild/moderate atopic asthmatic adults. No studies have yet investigated if this occurs in severe therapy resistant asthma (STRA). Here, we show that compared with non-allergic healthy control children, bronchial epithelial cells cultured ex vivo from severe therapy resistant atopic asthmatic children have profoundly impaired interferon-β and interferon-λ mRNA and protein in response to rhinovirus (RV) and polyIC stimulation. Severe treatment resistant asthmatics also exhibited increased virus load, which negatively correlated with interferon mRNA levels. Furthermore, uninfected cells from severe therapy resistant asthmatic children showed lower levels of Toll-like receptor-3 mRNA and reduced retinoic acid inducible gene and melanoma differentiation-associated gene 5 mRNA after RV stimulation. These data expand on the original work, suggesting that the innate anti-viral response to RVs is impaired in asthmatic tissues and demonstrate that this is a feature of STRA.