Prenatal environmental tobacco smoke exposure increases allergic asthma risk with methylation changes in mice

Allergic asthma remains an inadequately understood disease. In utero exposure to environmental tobacco smoke (ETS) has been identified as an environmental exposure that can increase an individual's asthma risk. To improve our understanding of asthma onset and development, we examined the effect of in utero ETS exposure on allergic disease susceptibility in an asthmatic phenotype using a house dust mite (HDM) allergen‐induced murine model. Pregnant C57BL/6 mice were exposed to either filtered air or ETS during gestation, and their offspring were further exposed to HDM at 6–7 weeks old to induce allergic inflammation. Methylation in the promoter regions of allergic inflammation‐related genes and genomic DNA was quantified. Exposure to HDM resulted in the onset of allergic lung inflammation, with an increased presence of inflammatory cells, Th2 cytokines (IL‐4, IL‐5, and IL‐13), and airway remodeling. These asthmatic phenotypes were significantly enhanced when the mice had been exposed to in utero ETS. Furthermore, prenatal ETS exposure and subsequent HDM (ETS/HDM)‐induced asthmatic phenotypes agree with methylation changes in the selected asthma‐related genes, including IL‐4, IL‐5, IL‐13, INF‐γ, and FOXP3. Global DNA methylation was significantly lower in ETS/HDM‐exposed mice than that of controls, which coincides with the results observed in lung, spleen, and blood DNAs. Prenatal ETS exposure resulted in a severe increase in allergic inflammatory responses after an HDM challenge, with corresponding methylation changes. Prenatal ETS exposure may influence developmental plasticity and result in altered epigenetic programming, leading to an increased susceptibility to asthma. Environ. Mol. Mutagen. 58:423–433, 2017. © 2017 Wiley Periodicals, Inc.     

Influenza A facilitates sensitization to house dust mite in infant mice leading to an asthma phenotype in adulthood

The origins of allergic asthma, particularly in infancy, remain obscure. Respiratory viral infections and allergen sensitization in early life have been associated with asthma in young children. However, a causal link has not been established. We investigated whether an influenza A infection in early life alters immune responses to house dust mite (HDM) and promotes an asthmatic phenotype later in life. Neonatal (8-day-old) mice were infected with influenza virus and 7 days later, exposed to HDM for 3 weeks. Unlike adults, neonatal mice exposed to HDM exhibited negligible immune responsiveness to HDM, but not to influenza A. HDM responsiveness in adults was associated with distinct Ly6c+ CD11b+ inflammatory dendritic cell and CD8α+ plasmacytoid (pDC) populations that were absent in HDM-exposed infant mice, suggesting an important role in HDM-mediated inflammation. Remarkably, HDM hyporesponsiveness was overcome when exposure occurred concurrently with an acute influenza infection; young mice now displayed robust allergen-specific immunity, allergic inflammation, and lung remodeling. Remodeling persisted into early adulthood, even after prolonged discontinuation of allergen exposure and was associated with marked impairment of lung function. Our data demonstrate that allergen exposure coincident with acute viral infection in early life subverts constitutive allergen hyporesponsiveness and imprints an asthmatic phenotype in adulthood.     

IL-5 T-cell responses to house dust mite are associated with the development of allergen-specific IgE responses and asthma in the first 5 years of life

BACKGROUND: Allergen-specific T(H)2-like cytokine responses are considered to be important in sensitization and allergic diseases. OBJECTIVE: To examine the profile of house dust mite (HDM) stimulated T-cell cytokines and their relationship to allergic disease in children over the period of the first 5 years of life. METHODS: Subjects with a family history of asthma who were enrolled antenatally in the Childhood Asthma Prevention Study and had skin prick tests, clinical evaluation for asthma and eczema, and in vitro assessment of lymphocyte cytokine responses to HDM extract performed at ages 18 months (n = 281), 3 years (n = 349), and 5 years (n = 370). IL-13 at 3 and 5 years and IL-5, IL-10, and IFN- gamma at 18 months, 3 years, and 5 years were measured by ELISA. RESULTS: House dust mite-specific cytokine responses increased with age for all cytokines except IFN-gamma. HDM-specific IL-5 responses at 3 years and 5 years were significantly positively related to skin prick test positivity at 5 years. IL-5 responses at 5 years were also significantly related to asthma at 5 years. Other HDM-specific cytokine responses were not related to asthma or eczema at 5 years. Responses were not altered by a HDM avoidance intervention. CONCLUSION: IL-5 responses to HDM, the dominant local inhalant allergen, are related to the expression of clinical illness at age 5 years. CLINICAL IMPLICATIONS: The T-cell response to HDM, as reflected in IL-5 production, is acquired over the first years of life and may play a role in the expression of allergic airways disease.     

Activin‐A: a novel critical regulator of allergic asthma

Activin‐A is a pleiotropic cytokine that belongs to the TGF‐β superfamily and plays an important role in fundamental biological processes, such as development and tissue repair. Growing evidence proposes a crucial role for activin‐A in immune‐mediated responses and associated diseases, with both enhancing and suppressive effects depending on the cell type, the cytokine micromilieu and the context of the response. Several recent studies have demonstrated a striking increase in activin‐A expression in experimental models of asthma, as well as, in the asthmatic airway in humans. Importantly, a strong immunoregulatory role for activin‐A in allergic airway disease, with suppression of T helper (Th) type 2 cell‐driven allergic responses and protection against the development of cardinal features of the asthmatic phenotype was revealed by in vivo functional studies. Activin‐A‐mediated immunosuppression is associated with induction of functional allergen‐specific regulatory T cells. In human asthma, although activin‐A levels are increased in the airway epithelium and submucosal cells, the expression of its signalling components is markedly decreased, pointing to decreased regulation. Nevertheless, a rapid activation of the activin‐A signalling pathway is observed in the airway of individuals with asthma following inhalational allergen challenge, suggestive of an inherent protective mechanism to control disease. In support, in vitro studies using human airway epithelial cells have demonstrated that endogenous activin‐A suppresses the release of inflammatory mediators, while it induces epithelial repair. Collectively, compelling evidence suggests that activin‐A orchestrates the regulation of key events involved in the pathogenesis of allergic asthma. The critical role of activin‐A in allergic airway responses places this cytokine as an exciting new therapeutic target for asthma. Cite this as: H. H. Kariyawasam, M. Semitekolou, D. S. Robinson and G. Xanthou, Clinical & Experimental Allergy, 2011 (41) 1505–1514.     

The Innate Immune Response in House Dust Mite-Induced Allergic Inflammation

Hypersensitivity to house dust mite (HDM; Dermatophagoides sp.) allergens is one of the most common allergic responses, affecting up to 85% of asthmatics. Sensitization to indoor allergens is the strongest independent risk factor associated with asthma. Additionally, >50% of children and adolescents with asthma are sensitized to HDM. Although allergen-specific CD4⁺ Th2 cells orchestrate the HDM allergic response through induction of IgE directed toward mite allergens, activation of innate immunity also plays a critical role in HDM-induced allergic inflammation. This review highlights the HDM components that lead to activation of the innate immune response. Activation may due to HDM proteases. Proteases may be recognized by protease-activation receptors (PARs), Toll-like receptors (TLRs), or C-type lectin receptors (CTRs), or act as a molecular mimic for PAMP activation signaling pathways. Understanding the role of mite allergen-induced innate immunity will facilitate the development of therapeutic strategies that exploit innate immunity receptors and associated signaling pathways for the treatment of allergic asthma.     

Effect of specific immunotherapy added to pharmacologic treatment and allergen avoidance in asthmatic patients allergic to house dust mite

BACKGROUND: Although several studies support the efficacy of specific immunotherapy in allergic asthma, its benefit compared with that of standardized pharmacologic intervention remains unknown. OBJECTIVE: A double-blind, placebo-controlled trial in 72 patients with mild-to-moderate asthma and allergy to house dust mite (HDM; Dermatophagoides species) was conducted to assess the effects of specific immunotherapy added to guideline-adjusted pharmacologic treatment and allergen avoidance. METHODS: After 1 observational year of pharmacologic treatment and standard measures of HDM avoidance, 2 groups of asthmatic subjects were randomly assigned to receive specific immunotherapy consisting of subcutaneous injections of either a mixture of Dermatophagoides pteronyssinus and Dermatophagoides farinae vaccine (n=41) or placebo (n=31) for 3 years. Medications were adjusted every 3 months according to the Global Initiative for Asthma guidelines. RESULTS: The adjustment of treatment was associated with a reduction in asthma symptom scores in all subjects. The addition of specific immunotherapy was associated with a decrease in the number of subjects requiring rescue bronchodilators, an increase in morning and evening peak expiratory flow, and a reduced skin sensitivity to HDM extracts. The addition of specific immunotherapy had no significant effects on the cumulative dose of inhaled corticosteroids, asthma symptoms, lung volumes, or bronchial responsiveness to methacholine. CONCLUSION: These results suggest that specific immunotherapy added to pharmacologic treatment and HDM avoidance provides marginal but statistically significant clinical benefits, possibly by reducing the allergic response of asthmatic patients sensitized to HDM.     

Modification of the late asthmatic reaction by hyposensitization in asthmatic children allergic to house dust mite (Dermatophagoides pteronyssinus) or grass pollen

The frequency and severity of the late asthmatic reaction (LAR) was studied in asthmatic children allergic to house dust mite (HDM) or grass pollen (GP) with and without hyposensitization (HS). The four groups were comparable according to their severity of asthma. All children were allergic to HDM (Dermatophagoides pteronyssinus) or GP according to history, skin testing and specific IgE determination via the RAST. The LAR occurred less frequently (29% versus 73%) (P less than 0.001) and was less severe in children receiving HS. The difference was significant between the children allergic to HDM as well as between children allergic to GP. The immediate asthmatic reaction (IAR) was also less severe in children allergic to HDM who received HS, compared to those who never received HS, (P = 0.033) although the PD20 of the HDM challenge (PD20HDM) was not different between the two groups. In children allergic to GP, there was no difference in PD20 of the GP challenge (PD20GP) or in severity of the IAR, whether the children received HS or not. There was no difference between the PD20HDM in patients who developed a LAR and in patients who did not. There was no relation between the type of asthmatic reaction following the allergen provocation test and the level of circulating immune complexes (CIC) and the level of house dust mite-specific IgG (IgGHDM) or grass pollen-specific IgE (IgGGP) in the different groups, determined before the challenge. There was a decrease in the level of IgG containing CIC (IgGCIC) during the LAR. It is concluded that the LAR occurs less frequently and is less severe in asthmatic children who receive HS.     

EAACI Guidelines on Allergen Immunotherapy: House dust mite‐driven allergic asthma

Allergen immunotherapy (AIT) has been in use for the treatment of allergic disease for more than 100 years. Asthma treatment relies mainly on corticosteroids and other controllers recommended to achieve and maintain asthma control, prevent exacerbations, and improve quality of life. AIT is underused in asthma, both in children and in adults. Notably, patients with allergic asthma not adequately controlled on pharmacotherapy (including biologics) represent an unmet health need. The European Academy of Allergy and Clinical Immunology has developed a clinical practice guideline providing evidence‐based recommendations for the use of house dust mites (HDM) AIT as add‐on treatment for HDM‐driven allergic asthma. This guideline was developed by a multi‐disciplinary working group using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. HDM AIT was separately evaluated by route of administration and children and adults: subcutaneous (SCIT) and sublingual AIT (SLIT), drops, and tablets. Recommendations were formulated for each. The important prerequisites for successful treatment with HDM AIT are (a) selection of patients most likely to respond to AIT and (b) use of allergen extracts and desensitization protocols of proven efficacy. To date, only AIT with HDM SLIT‐tablet has demonstrated a robust effect in adults for critical end points (exacerbations, asthma control, and safety). Thus, it is recommended as an add‐on to regular asthma therapy for adults with controlled or partially controlled HDM‐driven allergic asthma (conditional recommendation, moderate‐quality evidence). HDM SCIT is recommended for adults and children, and SLIT drops are recommended for children with controlled HDM‐driven allergic asthma as the add‐on to regular asthma therapy to decrease symptoms and medication needs (conditional recommendation, low‐quality evidence).     

T cells are necessary for ILC2 activation in house dust mite‐induced allergic airway inflammation in mice

Allergic asthma is a chronic inflammation of the airways mediated by an adaptive type 2 immune response. Upon allergen exposure, group 2 innate lymphoid cells (ILC2s) can be rapidly activated and represent an early innate source of IL‐5 and IL‐13. Here, we used a house dust mite (HDM)‐driven asthma mouse model to study the induction of ILC2s in allergic airway inflammation. In BALF, lungs, and lymph nodes, ILC2 activation is critically dependent on prior sensitization with HDM. Importantly, T cells are required for ILC2 induction, whereby T‐cell activation precedes ILC2 induction. During HDM‐driven allergic airway inflammation the accumulation of ILC2s in BALF is IL‐33 independent, although infiltrating ILC2s produce less cytokines in Il33^?/? mice. Transfer of in vitro polarized OVA‐specific OT‐II Th2 cells alone or in combination with Th17 cells followed by OVA and HDM challenge is not sufficient to induce ILC2, despite significant eosinophilic inflammation and T‐cell activation. In this asthma model, ILC2s are therefore not an early source of Th2 cytokines, but rather contribute to type 2 inflammation in which Th2 cells play a key role. Taken together, ILC2 induction in HDM‐mediated allergic airway inflammation in mice critically depends on activation of T cells.     

The role of macrophage IL‐10/innate IFN interplay during virus‐induced asthma

Activation through different signaling pathways results in two functionally different types of macrophages, the pro‐inflammatory (M1) and the anti‐inflammatory (M2). The polarization of macrophages toward the pro‐inflammatory M1 phenotype is considered to be critical for efficient antiviral immune responses in the lung. Among the various cell types that are present in the asthmatic airways, macrophages have emerged as significant participants in disease pathogenesis, because of their activation during both the inflammatory and resolution phases, with an impact on disease progression. Polarized M1 and M2 macrophages are able to reversibly undergo functional redifferentiation into anti‐inflammatory or pro‐inflammatory macrophages, respectively, and therefore, macrophages mediate both processes. Recent studies have indicated a predominance of M2 macrophages in asthmatic airways. During a virus infection, it is likely that M2 macrophages would secrete higher amounts of the suppressor cytokine IL‐10, and less innate IFNs. However, the interactions between IL‐10 and innate IFNs during virus‐induced exacerbations of asthma have not been well studied. The possible role of IL‐10 as a therapy in allergic asthma has already been suggested, but the divergent roles of this suppressor molecule in the antiviral immune response raise concerns. This review attempts to shed light on macrophage IL‐10–IFNs interactions and discusses the role of IL‐10 in virus‐induced asthma exacerbations. Whereas IL‐10 is important in terminating pro‐inflammatory and antiviral immune responses, the presence of this immune regulatory cytokine at the beginning of virus infection could impair the response to viruses and play a role in virus‐induced asthma exacerbations. © 2014 The Authors. Reviews in Medical Virology published by John Wiley & Sons Ltd.     

Allergic asthma: a tale of many T cells

Asthma is a common immune‐mediated disorder characterized by reversible airway inflammation, mucus production, and variable airflow obstruction with airways hyperresponsiveness (AHR). In most cases the airway inflammation characteristic of asthma is thought to result from an allergic‐type reaction to an inhaled substance from the environment (so‐called allergic asthma). In allergic asthma, allergen exposure stimulates eosinophilic inflammation of the airways associated with infiltration of T cells. Although the recruitment of eosinophils into the airways is an important component in the pathogenesis of asthma, the trafficking of T lymphocytes into the airways is now believed to establish and orchestrate the asthmatic inflammatory response. This review explores the roles of various T cell subsets in the pathogenesis of allergic airway inflammation and highlights the contributions of these cells in regulating asthma.     

Severity of Allergic Airway Disease Due to House Dust Mite Allergen Is Not Increased after Clinical Recovery of Lung Infection with Chlamydia pneumoniae in Mice

Chlamydia pneumoniae is associated with chronic inflammatory lung diseases like bronchial asthma and chronic obstructive pulmonary disease. The existence of a causal link between allergic airway disease and C. pneumoniae is controversial. A mouse model was used to address the question of whether preceding C. pneumoniae lung infection and recovery modifies the outcome of experimental allergic asthma after subsequent sensitization with house dust mite (HDM) allergen. After intranasal infection, BALB/c mice suffered from pneumonia characterized by an increased clinical score, reduction of body weight, histopathology, and a bacterial load in the lungs. After 4 weeks, when infection had almost resolved clinically, HDM allergen sensitization was performed for another 4 weeks. Subsequently, mice were subjected to a methacholine hyperresponsiveness test and sacrificed for further analyses. As expected, after 8 weeks, C. pneumoniae-specific antibodies were detectable only in infected mice and the titer was significantly higher in the C. pneumoniae/HDM allergen-treated group than in the C. pneumoniae/NaCl group. Intriguingly, airway hyperresponsiveness and eosinophilia in bronchoalveolar lavage fluid were significantly lower in the C. pneumoniae/HDM allergen-treated group than in the mock/HDM allergen-treated group. We did observe a relationship between experimental asthma and chlamydial infection. Our results demonstrate an influence of sensitization to HDM allergen on the development of a humoral antibacterial response. However, our model demonstrates no increase in the severity of experimental asthma to HDM allergen as a physiological allergen after clinically resolved severe chlamydial lung infection. Our results rather suggest that allergic airway disease and concomitant cellular changes in mice are decreased following C. pneumoniae lung infection in this setting.     

General,but not myeloid or type II lung epithelial cell,myeloid differentiation factor 88 deficiency abrogates house dust mite induced allergic lung inflammation

Asthma is a highly prevalent chronic allergic inflammatory disease of the airways affecting people worldwide. House dust mite (HDM) is the most common allergen implicated in human allergic asthma. HDM‐induced allergic responses are thought to depend upon activation of pathways involving Toll‐like receptors and their adaptor protein myeloid differentiation factor 88 (MyD88). We sought here to determine the role of MyD88 in myeloid and type II lung epithelial cells in the development of asthma‐like allergic disease using a mouse model. Repeated exposure to HDM caused allergic responses in control mice characterized by influx of eosinophils into the bronchoalveolar space and lung tissue, lung pathology and mucus production and protein leak into bronchoalveolar lavage fluid. All these responses were abrogated in mice with a general deficiency of MyD88 but unaltered in mice with MyD88 deficiency, specifically in myeloid or type II lung epithelial cells. We conclude that cells other than myeloid or type II lung epithelial cells are responsible for MyD88‐dependent HDM‐induced allergic airway inflammation.     

Prevalence and severity of allergic rhinitis in house dust mite-allergic patients with bronchial asthma or atopic dermatitis

BACKGROUND: Allergic rhinitis, asthma and atopic dermatitis are closely associated. Although population-based studies report a high prevalence of rhinitis among asthma patients, less is known of the association between rhinitis and atopic dermatitis and the severity of concomitant rhinitis. OBJECTIVES: We aimed to determine the prevalence and severity of allergic rhinitis among asthmatics and patients with atopic dermatitis and assessed whether age and comorbidity influence the severity of rhinitis signs and symptoms. METHODS: Three hundred and twenty-five patients recruited for a multicentre trial to study the effect of encasings of mattresses, pillows and duvets on signs and symptoms of allergic rhinitis and/or asthma and/or atopic dermatitis recorded visual analogue scores (VAS) and daily symptom scores and underwent nasal challenge tests with house dust mite (HDM). RESULTS: Based on history and clinical symptoms 92% of the 164 asthmatic patients and 85% of the 86 patients with atopic dermatitis could be diagnosed as having rhinitis. Inclusion of a positive provocation to HDM did not result in a substantial lower prevalence of rhinitis. Subjects reported moderate symptoms, with mean rhinitis VAS scores ranging from 40.0 to 55.0. Presence of atopic dermatitis was associated with lower rhinitis VAS and symptoms scores, whereas in multivariate analysis the presence of asthma was positively associated with nasal responsiveness to HDM. CONCLUSION: The prevalence of nasal symptoms in patients with bronchial asthma or atopic dermatitis and sensitized to house dust mites is high. Although the majority of patients experience mild to moderate symptoms, the presence of nasal disease needs to be examined in all patients with atopic disorders.     

Variation in the TEK gene is not associated with asthma but with allergic conjunctivitis

The Tie2 receptor is an important player in angiogenesis. The Tie2 mRNA and protein are abundantly expressed in the lungs and the associated pathway also has an important role in the development and function of the eye. Tie2 is encoded by the TEK gene in humans. Recently, variations in the TEK gene have been found associated with asthma. The objective of the present study was to investigate whether variations in the TEK gene influenced the susceptibility to pediatric asthma and/or associated phenotypes like GINA status, viral‐ or exercise‐induced asthma, allergic asthma, indoor, outdoor, inhalative allergies, IgE and eosonophil levels, allergic rhinitis and allergic conjunctivitis. Three single nucleotide polymorphisms (SNPs, rs3780315, rs581724 and rs7876024) in the TEK gene were genotyped in 1189 unrelated individuals, out of which 435 were asthmatic children and 754 healthy controls. Different types of asthma, allergies and co‐morbidities were defined in 320 patients. Among the fully phenotyped 320 asthmatic patients 178 (55.6%) also had allergic rhinitis and 100 (31.3%) had conjunctivitis. Among the rhinitis patients 98 (55.1%) also had conjunctivitis. Two patients had conjunctivitis without rhinitis. The genotyped SNPs showed no association with asthma. However, SNP rs581724 was significantly associated with allergic conjunctivitis in a recessive way (p=0.007; OR=2.3 (1.3‐4.4)) within the asthmatic population. The risk remained significant when the whole population (asthmatics and healthy controls) was included in the calculation (p = 0.003; OR = 2.1 (1.3‐3.6)). The minor allele of the rs581724 SNP which is associated with the increased risk to conjunctivitis is also associated with reduced Tie2 expression. There was a significant association between SNP rs581724 and the occurrence of allergic conjunctivitis in asthmatic children. If additional studies can confirm the role of the Tie2 pathway in allergic conjunctivitis, it can be a potential novel therapeutic target in the disease.     

Novel T‐cell epitopes on Schistosoma japonicum SjP40 protein and their preventive effect on allergic asthma in mice

Allergic asthma is a chronic inflammatory disease mediated by Th2 cell immune responses. Currently, immunotherapies based on immune deviation are attractive, preventive, and therapeutic strategies for asthma. Many studies have shown that intracellular bacterial infections such as mycobacteria and their components can suppress asthmatic reactions by enhancing Th1 responses, while helminth infections and their proteins can inhibit allergic asthma via immune regulation. However, some helminth proteins such as SmP40, the major egg antigen of Schistosoma mansoni, are found as Th1 type antigens. Using a panel of overlapping peptides, we identified T‐cell epitopes on SjP40 protein of Schistosoma japonicum, which can induce Th1 cytokine and inhibit the production of Th2 cytokines and airway inflammation in a mouse model of allergic asthma. These results reveal a novel form of immune protective mechanism, which may play an important role in the modulating effect of helminth infection on allergic asthmatic reactions.     

Blockade of CCR4 in a humanized model of asthma reveals a critical role for DC-derived CCL17 and CCL22 in attracting Th2 cells and inducing airway inflammation

Background:  As Th2 type lymphocytes orchestrate the cardinal features of allergic asthma, inhibiting their recruitment to the lungs could be of therapeutic benefit. Although human Th2 cells express the CCR4 chemokine receptor and increased production of CCR4 ligands has been found in asthmatic airways, studies in animals have reached contradictory conclusions on whether blocking this pathway would be beneficial.
Objective:  As a lack of efficacy might be due to differences between mouse and man, we readdressed this question using a humanized severe combined immunodeficiency model of asthma.
Methods:  Mice received peripheral blood mononuclear cells from house dust mite (HDM) allergic asthmatic patients and then underwent bronchial challenge with HDM.
Results:  This resulted in marked allergic inflammation and bronchial hyper-reactivity. Administration of CCR4 blocking antibody abolished the airway eosinophilia, goblet cell hyperplasia, IgE synthesis and bronchial hyperreactivity. In this chimeric system, human CD11c+ dendritic cells (DCs) were the predominant source of CCR4 ligands, suggesting that DC-derived chemokines attract Th2 cells. In separate experiments using human DCs, in vitro exposure to HDM of DCs from HDM allergic patients but not healthy controls caused CCL17 and CCL22 release that resulted in chemoattraction of polarized human Th2 cells in a CCR4-dependent way.
Conclusions:  Taken together, our data provide proof of concept that CCR4 blockade inhibits the salient features of asthma and justify further clinical development of CCR4 antagonists for this disease.     

Influence of a positive family history and associated allergic diseases on the natural course of asthma

The outcome of childhood asthma was studied in a cohort of 406 asthmatic children, with emphasis on the influence of family history for allergic disease, as well as the influence of associated allergic diseases on prognosis. Sixty-two per cent had a positive family history for atopy. In young adulthood no differences, either in symptoms or lung function were demonstrated in comparison to subjects with a negative family history. Fifty-two per cent of the children had no other allergic disease, 48% had either eczema or hay fever or both. When subjects were stratified based on associated allergic disease, no differences in outcome in adulthood were revealed either. It is concluded that neither a positive family history, nor concurrent associated allergic diseases in the child contribute to the prognosis of asthma from childhood to young adulthood. Therefore, environmental factors as well as patient characteristics (including lung function level, level of bronchial responsiveness) are likely to be more important for the prognosis.     

Der p 1 and Der p 2 induce less severe late asthmatic responses than native Dermatophagoides pteronyssinus extract after a similar early asthmatic response

Background The models for exposure to house dust in research and clinical practice are selected with respect to their role in IgE‐mediated immediate hypersensitivity. The use of isolated major allergens instead of complex allergen extracts is becoming increasingly popular as it offers some important advantages for quantitative measures in diagnosis and research. Objective To compare house dust mite extract and isolated mite major allergens with respect to their ability to induce early and late asthmatic responses and bronchial hyperreactivity. Methods Bronchial responses to house dust mite (HDM, Dermatophagoides pteronyssinus) extract and isolated major allergens from HDM (Der p 1 and Der p 2) were compared in a double‐blind, randomized, cross‐over study in 20 patients with mild to moderate asthma who were allergic to HDM. Allergen was titrated to a standardized early asthmatic response. Bronchial hyper‐responsiveness to histamine (PC₂₀histamine) was determined before and after allergen inhalation to assess allergen‐induced bronchial hyper‐responsiveness and IL‐5 was measured in serum. In addition, the allergens were applied in intracutaneous skin tests and activation of basophil leucocytes and proliferation of peripheral blood mononuclear cells was tested in vitro. Results After a similar early asthmatic response (mean Δforced expiratory volume in 1 s (FEV₁)_,max?29.4 (SD 7.2) vs. ?33.1 (8.6) %; mean difference 3.6 (95% CI ?0.9 to 8.2) %), the late asthmatic response (mean ΔFEV_1,max?45.9 (21.9) vs. ?32.7 (22.3) %; mean difference 13.2 (3.8–22.3) %), the degree of allergen‐induced bronchial hyper‐responsiveness (mean ΔPC₂₀histamine, 1.8 (1.0) vs. 1.2 (0.9) doubling dose; mean difference 0.6 (0.2–1.1) doubling dose) and serum IL‐5 at 6 h were found to be significantly higher after bronchial challenge with HDM extract than after challenge with an isolated HDM major allergen. Likewise, there was an increased late skin reaction with HDM compared with isolated major allergen after a similar early skin reaction. Conclusion Constituents of HDM extract, other than Der p 1 or Der p 2, with no significant influence on the IgE‐mediated early asthmatic response contribute significantly to the allergen‐induced late asthmatic response and bronchial hyper‐reactivity.     

Influences of environmental bacteria and their metabolites on allergies,asthma, and host microbiota

The prevalence of allergic diseases and asthma has dramatically increased over the last decades, resulting in a high burden for patients and healthcare systems. Thus, there is an unmet need to develop preventative strategies for these diseases. Epidemiological studies show that reduced exposure to environmental bacteria in early life (eg, birth by cesarean section, being formula‐fed, growing up in an urban environment or with less contact to various persons) is associated with an increased risk to develop allergies and asthma later in life. Conversely, a reduced risk for asthma is consistently found in children growing up on traditional farms, thereby being exposed to a wide spectrum of microbes. However, clinical studies with bacteria to prevent allergic diseases are still rare and to some extent contradicting. A detailed mechanistic understanding of how environmental microbes influence the development of the human microbiome and the immune system is important to enable the development of novel preventative approaches that are based on the early modulation of the host microbiota and immunity. In this mini‐review, we summarize current knowledge and experimental evidence for the potential of bacteria and their metabolites to be used for the prevention of asthma and allergic diseases.