Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology
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Severe asthmatics often exhibit poor control despite high doses of inhaled corticosteroids with or without systemic corticosteroids and suffer from persistent symptoms and/or recurrent exacerbations. Five to ten percentage of the asthmatic population falls within this category. Patients with severe asthma are a heterogeneous group and should be investigated to confirm the diagnosis, identify comorbidities, exclude alternative diagnoses, together with an evaluation of treatment adherence and side-effects from medications. ⋯ Severe asthma consists of different phenotypes that need defining. Investigation of severe asthma should bring into the open the various characteristics of the disease that could point to particular phenotype. Inclusion of investigations based on transcriptomics and proteomics should expand, improve classification and understanding of severe asthma, with the ultimate hope of finding more effective treatments and a step towards personalized medicine.
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Asthma, and severe asthma, in particular, is increasingly recognized as a heterogeneous disease. While traditional views of asthma have centered around a childhood onset disease with an allergic component, several large scale network studies are now confirming that severe asthma can present in multiple different ways, only 30-50% of which meet traditional childhood onset allergic criteria. To understand the different groups better, initial studies have attempted to define phenotypes of severe asthma. ⋯ As biological characteristics are identified, phenotypes should continue to evolve towards asthma endotypes. The identification of these endotypes, either by matching biology, genetics and therapeutic responses to therapy with clinically or statistically defined phenotypes or through unbiased genetic and genomic approaches, remains limited. Moving forward, this integration of genetics, biology and clinical characteristics should substantially enhance our ability to effectively treat complex heterogeneous diseases, such as severe asthma.
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Although immediate-Type I skin reactions to human dander have been described six decades ago, only the recent application of molecular biology to allergology research allowed fast and detailed characterization of IgE-binding autoantigens. These can be functionally subdivided into three classes: (1) self-antigens with sequence homology to environmental allergens belonging to the class of phylogenetically conserved proteins, (2) self-antigens without sequence homology to known environmental allergens, and (3) chemically modified self-antigens deriving from workplace exposure. As environmental allergens, also IgE-binding autoantigens belong to different protein families without common structural features that would explain their IgE-binding capability. ⋯ Well documented is their ability to induce immediate Type I skin reactions in vivo, and to induce mediator release from effector cells of sensitized individuals in vitro. Based on these observations it is reasonable to assume that IgE-mediated cross-linking of FcRIε receptors on effector cells can elicit the same symptoms as those induced by environmental allergens, and this could explain exacerbations of chronic allergic diseases in the absence of external exposure. However, because most of the described IgE-binding self-antigens are intracellular proteins normally not accessible for antigen-antibody interactions, local release of the antigens is required to explain the induction of symptoms.
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Multicenter Study Clinical Trial
Gene-by-environment effect of house dust mite on purinergic receptor P2Y12 (P2RY12) and lung function in children with asthma.
Distinct receptors likely exist for leukotriene (LT)E(4), a potent mediator of airway inflammation. Purinergic receptor P2Y12 is needed for LTE(4)-induced airways inflammation, and P2Y12 antagonism attenuates house dust mite-induced pulmonary eosinophilia in mice. Although experimental data support a role for P2Y12 in airway inflammation, its role in human asthma has never been studied. ⋯ The P2RY12 variants were associated with lung function in a large family-based asthma cohort. House dust mite exposure caused significant gene-by-environment effects. Our findings add the first human evidence to experimental data supporting a role for P2Y12 in lung function. P2Y12 could represent a novel target for asthma treatment.
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The pathophysiology of asthma involves allergic inflammation and remodelling in the airway and airway hyperresponsiveness (AHR) to cholinergic stimuli, but many details of the specific underlying cellular and molecular mechanisms remain unknown. Periostin is a matricellular protein with roles in tissue repair following injury in both the skin and heart. It has recently been shown to be up-regulated in the airway epithelium of asthmatics and to increase active TGF-β. Though one might expect periostin to play a deleterious role in asthma pathogenesis, to date its biological role in the airway is unknown. ⋯ Allergen-induced increases in serum IgE and bronchial hyperresponsiveness are exaggerated in periostin deficient mice challenged with inhaled aeroallergen. The mechanism of periostin's effect as a brake on allergen-induced responses may involve augmentation of TGF-β-induced T regulatory cell differentiation.