Search

Allergic respiratory diseases, such as allergic dermatitis, food allergy, allergic rhino conjunctivitis and allergic asthma, are chronic inflammatory diseases with increasing prevalence. Symptoms include such as watery or itchy itching of the mouth, skin, or the eyes, swelling of the face or throat, sneezing, congestion or vomiting, wheezing, shortness of breath and coughing. For allergic asthma, additional symptoms include tightness of chest, cough, wheezing, and reversible airflow limitation. These symptoms can be triggered by inhalation of aller -gens such as food allergens or airborne allergens such as those from tree-or grass pollen and house dust mites. Pharmacological intervention in allergic disease includes the use of antihistamines, immune suppressive drugs and in case of asthma, the use of (long acting) beta-agonists for relaxation of the constricted airways. These treat-ment options merely suppress symptoms and do not cure the disease. Allergen immunotherapy (AIT), in con -trast, has the capacity of inducing long-term tolerance, with symptom relief persisting decennia after discontinuation of treatment, despite recurrent re-exposure to the allergen. However, AIT is not effective for all allergic disorders, and treatment for several years is required to obtain long-term protection. Moreover, some forms of AIT have safety concerns, with risk of mild to severe allergic reactions. To improve safety and efficacy of AIT, the underlying mechanisms have been studied extensively in the clinic as well as in experimental models of allergic airway inflammation.Despite more than a century of clinical experience and a vast body of experimental and translational studies into the immunological and cellular mechanisms underpinning its therapeutic potential, AIT is still not implemented in routine clinical care for allergic asthma. This review provides an overview of the substantial developments that contribute to our knowledge of the pathogenesis of allergic airway diseases, the mechanism of action of AIT, its treatment routes and schedules, the standardization of extracts and use of adjuvantia. Moreover, the main con-clusions from experimental models of AIT with regard to the safety and effectiveness of the treatment are summarized, and future directions for further improvements are outlined. AIT urgently requires further improvements in order to increase its efficiency and shorten the treatment duration while remaining safe and costeffective.(c) 2022 Published by Elsevier Inc.

Allergic respiratory diseases, such as allergic dermatitis, food allergy, allergic rhino conjunctivitis and allergic asthma, are chronic inflammatory diseases with increasing prevalence. Symptoms include such as watery or itchy itching of the mouth, skin, or the eyes, swelling of the face or throat, sneezing, congestion or vomiting, wheezing, shortness of breath and coughing. For allergic asthma, additional symptoms include tightness of chest, cough, wheezing, and reversible airflow limitation. These symptoms can be triggered by inhalation of aller -gens such as food allergens or airborne allergens such as those from tree-or grass pollen and house dust mites. Pharmacological intervention in allergic disease includes the use of antihistamines, immune suppressive drugs and in case of asthma, the use of (long acting) beta-agonists for relaxation of the constricted airways. These treat-ment options merely suppress symptoms and do not cure the disease. Allergen immunotherapy (AIT), in con -trast, has the capacity of inducing long-term tolerance, with symptom relief persisting decennia after discontinuation of treatment, despite recurrent re-exposure to the allergen. However, AIT is not effective for all allergic disorders, and treatment for several years is required to obtain long-term protection. Moreover, some forms of AIT have safety concerns, with risk of mild to severe allergic reactions. To improve safety and efficacy of AIT, the underlying mechanisms have been studied extensively in the clinic as well as in experimental models of allergic airway inflammation.Despite more than a century of clinical experience and a vast body of experimental and translational studies into the immunological and cellular mechanisms underpinning its therapeutic potential, AIT is still not implemented in routine clinical care for allergic asthma. This review provides an overview of the substantial developments that contribute to our knowledge of the pathogenesis of allergic airway diseases, the mechanism of action of AIT, its treatment routes and schedules, the standardization of extracts and use of adjuvantia. Moreover, the main con-clusions from experimental models of AIT with regard to the safety and effectiveness of the treatment are summarized, and future directions for further improvements are outlined. AIT urgently requires further improvements in order to increase its efficiency and shorten the treatment duration while remaining safe and costeffective.(c) 2022 Published by Elsevier Inc.

The allergen provocation test is an established model of allergic airway diseases, including asthma and allergic rhinitis, allowing the study of allergen-induced changes in respiratory physiology and inflammatory mechanisms in sensitised individuals as well as their associations. In the upper airways, allergen challenge is focused on the clinical and pathophysiological sequelae of the early allergic response, and is applied both as a diagnostic tool and in research settings. In contrast, bronchial allergen challenge has almost exclusively served as a research tool in specialised research settings with a focus on the late asthmatic response and the underlying type 2 inflammation. The allergen-induced late asthmatic response is also characterised by prolonged airway narrowing, increased nonspecific airway hyperresponsiveness and features of airway remodelling including the small airways, and hence allows the study of several key mechanisms and features of asthma. In line with these characteristics, allergen challenge has served as a valued tool to study the cross-talk of the upper and lower airways and in proof-of-mechanism studies of drug development. In recent years, several new insights into respiratory phenotypes and endotypes including the involvement of the upper and small airways, innovative biomarker sampling methods and detection techniques, refined lung function testing as well as targeted treatment options further shaped the applicability of the allergen provocation test in precision medicine. These topics, along with descriptions of subject populations and safety, in line with the updated Global Initiative for Asthma 2021 document, will be addressed in this review. ispartof: EUROPEAN RESPIRATORY JOURNAL vol:60 issue:2 ispartof: location:England status: published

Background House dust mites (HDMs) are among the most important allergen sources containing many different allergenic molecules. Analysis of patients from a double-blind, placebo-controlled allergen-specific immunotherapy (AIT) study indicated that patients may benefit from AIT to different extents depending on their molecular sensitization profiles. Objective Our aim was to investigate in a real-life setting whether stratification of patients with HDM allergy according to molecular analysis may enhance AIT success. Methods Serum and nasal secretion samples from patients with HDM allergy (n = 24) (at baseline, 7, 15, 33, and 52 weeks) who had received 1 year of treatment with a well-defined subcutaneous AIT form (Alutard SQ 510) were tested for IgE and IgG reactivity to 15 microarrayed HDM allergen molecules with ImmunoCAP Immuno-solid-phase Allergen Chip technology. IgG subclass levels to allergens and peptides were determined by ELISA, and IgG blocking was assessed by basophil activation. In vitro parameters were related to reduction of symptoms determined by combined symptom medication score and visual analog scale score. Results Alutard SQ 510 induced protective IgG mainly against Dermatophagoides pteronyssinus (Der p) 1 and Der p 2 and to a lesser extent to Der p 23, but not to the other important allergens such as Der p 5, Der p 7, and Der p 21, showing better clinical efficacy in patients sensitized only to Der p 1 and/or Der p 2 as compared with patients having additional IgE specificities. Conclusion Stratification of patients with HDM allergy according to molecular sensitization profiles and molecular monitoring of AIT-induced IgG responses may enhance the success of AIT.

Airway epithelial barrier dysfunction is frequently observed in asthma and may have important implications. The physical barrier function of the airway epithelium is tightly interwoven with its immunomodulatory actions, while abnormal epithelial repair responses may contribute to remodelling of the airway wall. We propose that abnormalities in the airway epithelial barrier play a crucial role in the sensitization to allergens and pathogenesis of asthma. Many of the identified susceptibility genes for asthma are expressed in the airway epithelium, supporting the notion that events at the airway epithelial surface are critical for the development of the disease. However, the exact mechanisms by which the expression of epithelial susceptibility genes translates into a functionally altered response to environmental risk factors of asthma are still unknown. Interactions between genetic factors and epigenetic regulatory mechanisms may be crucial for asthma susceptibility. Understanding these mechanisms may lead to identification of novel targets for asthma intervention by targeting the airway epithelium. Moreover, exciting new insights have come from recent studies using single-cell RNA sequencing (scRNA-Seq) to study the airway epithelium in asthma. This review focuses on the role of airway epithelial barrier function in the susceptibility to develop asthma and novel insights in the modulation of epithelial cell dysfunction in asthma.

Eosinophils are typically a minority population of circulating granulocytes being released from the bone-marrow as terminally differentiated cells. Besides their function in the defense against parasites and in promoting allergic airway inflammation, regulatory functions have now been attributed to eosinophils in various organs. Although eosinophils are involved in the inflammatory response to allergens, it remains unclear whether they are drivers of the asthma pathology or merely recruited effector cells. Recent findings highlight the homeostatic and pro-resolving capacity of eosinophils and raise the question at what point in time their function is regulated. Similarly, eosinophils from different physical locations display phenotypic and functional diversity. However, it remains unclear whether eosinophil plasticity remains as they develop and travel from the bone marrow to the tissue, in homeostasis or during inflammation. In the tissue, eosinophils of different ages and origin along the inflammatory trajectory may exhibit functional diversity as circumstances change. Herein, we outline the inflammatory time line of allergic airway inflammation from acute, late, adaptive to chronic processes. We summarize the function of the eosinophils in regards to their resident localization and time of recruitment to the lung, in all stages of the inflammatory response. In all, we argue that immunological differences in eosinophils are a function of time and space as the allergic inflammatory response is initiated and resolved.

Asthma is a chronic respiratory condition, which is highly prevalent worldwide. Although no cure is currently available, it is well recognized that some asthma patients can spontaneously enter remission of the disease later in life. Asthma remission is characterized by absence of symptoms and lack of asthma-medication use. Subjects in asthma remission can be divided into two groups: those in clinical remission and those in complete remission. In clinical asthma remission, subjects still have a degree of lung functional impairment or bronchial hyperresponsiveness, while in complete asthma remission, these features are no longer present. Over longer periods, the latter group is less likely to relapse. This remission group is of great scientific interest due to the higher potential to find biomarkers or biological pathways that elicit or are associated with asthma remission.Despite the fact that the definition of asthma remission varies between studies, some factors are reproducibly observed to be associated with remitted asthma. Among these are lower levels of inflammatory markers, which are lowest in complete remission. Additionally, in both groups some degree of airway remodeling is present. Still, the pathological disease state of asthma remission has been poorly investigated. Future research should focus on at least two aspects: further characterisation of the small airways and airway walls in order to determine histologically true remission, and more thorough biological pathway analyses to explore triggers that elicit this phenomenon. Ultimately, this will result in pharmacological targets that provide the potential to steer the course of asthma towards remission. (C) 2019 Elsevier Inc. All rights reserved.

Dendritic cells (DCs) are critical for the activation of naive CD4(+) T cells and are considered professional antigen-presenting cells (APCs), as are macrophages and B cells. Recently, several innate type 2 immune cells, such as basophils, mast cells (MCs), eosinophils, and innate type 2 lymphocytes (ILC2), have also emerged as harboring APC behavior. Through surface expression or transfer of peptide-loaded MHCII, expression of costimulatory and co-inhibitory molecules, as well as the secretion of polarizing cytokines, these innate cells can extensively communicate with effector and regulatory CD4(+) T cells. An exciting new concept is that the complementary tasks of these 'amateur' APCs contribute to shaping and regulating adaptive immunity to allergens and helminths, often in collaboration with professional APCs.

Yazıcı, Haşmet (Balikesir Author), Object: To prepare a national guideline for Oto-rhinolaryngologist who treat allergic rhinitis patients Methods: The study was conducted by three authors, namely the writing support team. The support team made the study plan, determined the writing instructions, chose the subgroups including the advisory committee, the advisors for authors and the authors. A workshop was organized at the very beginning to explain the details of the study to the team. Advisors took the chance to meet their coworkers in their subgroups and determined the main headings and subheadings of the guideline, together with the authors. After key words were determined by the authors, literature search was done in various databases. The authors keep in touch with the advisors and the advisors with the advisory committee and the support group at every stage of the study. National and International published articles as well as the abstracts of unpublished studies, imperatively presented in National Congresses, were included in this guideline. Only Guideline and meta-analyses published in last seven years (2013- 2017) and randomized controlled studies published in last two years (2015- 2017) were included. After all work was completed by the subgroups, support team brought all work together and edited the article. Results: A detailed guideline about all aspects of allergic rhinitis was created. Conclusion: The authors believe that this guideline will enable a compact and up-to-date information on allergic rhinitis to healthcare professionals. This guideline is the first in the field of Otolaryngology in Turkey. It should be updated at regular intervals.

Allergen-specific immunotherapy (AIT) is the mainstay treatment for the cure of allergic disorders, with depicted efficacy and safety by several trials and meta-analysis. AIT impressively contributes to the management of allergic rhinitis, asthma and venom allergies. Food allergy is a new arena for AIT with promising results, especially via novel administration routes. Cell subsets with regulatory capacities are induced during AIT. IL-10 and transforming growth factor (TGF)-beta are the main suppressor cytokines, in addition to surface molecules such as cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) and programmed cell death protein-1 (PD-1) within the micro milieu. Modified T- and B-cell responses and antibody isotypes, increased activity thresholds for eosinophils, basophils and mast cells and consequent limitation of inflammatory cascades altogether induce and maintain a state of sustained allergen-specific unresponsiveness. Established tolerance is reflected into the clinical perspectives as improvement of allergy symptoms together with reduced medication requirements and evolved disease severity. Long treatment durations, costs, reduced patient compliance and risk of severe, even life-threatening adverse reactions during treatment stand as major limiting factors for AIT. By development of purified non-allergenic, highly-immunogenic modified allergen extracts, and combinational usage of them with novel adjuvant molecules via new routes may shorten treatment durations and possibly reduce these drawbacks. AIT is the best model for custom-tailored therapy of allergic disorders. Better characterization of disease endotypes, definition of specific biomarkers for diagnosis and therapy follow-up, as well as precision medicine approaches may further contribute to success of AIT in management of allergic disorders.

Application of allergens onto the sublingual epithelium is used to desensitize allergic individuals, a treatment known as sublingual immunotherapy. However, the response of sublingual epithelial cells to house dust mite allergen and potential tolerance-promoting adjuvants such as Toll-like receptor (TLR) ligands and calcitriol has not been investigated. In order to study this, primary sublingual epithelial cells were isolated from dogs and cultured in vitro. After 24-h incubation with a Dermatophagoides farinae extract, a Dermatophagoides pteronyssinus extract, TLR2 ligands (FSL-1, heat-killed Listeria monocytogenes, Pam3CSK4), a TLR3 ligand (poly I:C), a TLR4 ligand [lipopolysaccharide (LPS)], and calcitriol (1,25-dihydroxyvitamin D3), viability of the cells was analyzed using an MTT test, and their secretion of interleukin 6 (IL-6), IL-10, CXCL8, and transforming growth factor β1 (TGF-β1) was measured by enzyme-linked immunosorbent assay. Additionally, to evaluate its potential effect as an adjuvant, sublingual epithelial cells were incubated with calcitriol in combination with a D. farinae extract followed by measurement of CXCL8 secretion. Furthermore, the effect of D. farinae and calcitriol on the transcriptome was assessed by RNA sequencing. The viability of the sublingual epithelial cells was significantly decreased by poly I:C, but not by the other stimuli. CXCL8 secretion was significantly increased by D. farinae extract and all TLR ligands apart from LPS. Calcitriol significantly decreased CXCL8 secretion, and coadministration with D. farinae extract reduced CXCL8 concentrations to levels seen in unstimulated sublingual epithelial cells. Although detectable, TGF-β1 secretion could not be modulated by any of the stimuli. Interleukin 6 and IL-10 could not be detected at the protein or at the mRNA level. It can be concluded that a D. farinae extract and TLR ligands augment the secretion of the proinflammatory chemokine CXCL8, which might interfere with sublingual desensitization. On the other hand, CXCL8 secretion was reduced by coapplication of calcitriol and a D. farinae extract. Calcitriol therefore seems to be a suitable candidate to be used as adjuvant during sublingual immunotherapy.

Summary The airway epithelium represents a physical barrier to the external environment acting as the first line of defence against potentially harmful environmental stimuli including microbes and allergens. However, lung epithelial cells are increasingly recognized as active effectors of microbial defence, contributing to both innate and adaptive immune function in the lower respiratory tract. These cells express an ample repertoire of pattern recognition receptors with specificity for conserved microbial and host motifs. Modern molecular techniques have uncovered the complexity of the lower respiratory tract microbiome. The interaction between the microbiota and the airway epithelium is key to understanding how stable immune homeostasis is maintained. Loss of epithelial integrity following exposure to infection can result in the onset of inflammation in susceptible individuals and may culminate in lung disease. Here we discuss the current knowledge regarding the molecular and cellular mechanisms by which the pulmonary epithelium interacts with the lung microbiome in shaping immunity in the lung. Specifically, we focus on the interactions between the lung microbiome and the cells of the conducting airways in modulating immune cell regulation, and how defects in barrier structure and function may culminate in lung disease. Understanding these interactions is fundamental in the search for more effective therapies for respiratory diseases., The respiratory epithelium provides a highly effective barrier acting as the first line of defence against potentially harmful environmental stimuli including microbes and allergens.

Airway epithelial barrier dysfunction is frequently observed in asthma and may have important implications. The physical barrier function of the airway epithelium is tightly interwoven with its immunomodulatory actions, while abnormal epithelial repair responses may contribute to remodelling of the airway wall. We propose that abnormalities in the airway epithelial barrier play a crucial role in the sensitization to allergens and pathogenesis of asthma. Many of the identified susceptibility genes for asthma are expressed in the airway epithelium, supporting the notion that events at the airway epithelial surface are critical for the development of the disease. However, the exact mechanisms by which the expression of epithelial susceptibility genes translates into a functionally altered response to environmental risk factors of asthma are still unknown. Interactions between genetic factors and epigenetic regulatory mechanisms may be crucial for asthma susceptibility. Understanding these mechanisms may lead to identification of novel targets for asthma intervention by targeting the airway epithelium. Moreover, exciting new insights have come from recent studies using single‐cell RNA sequencing (scRNA‐Seq) to study the airway epithelium in asthma. This review focuses on the role of airway epithelial barrier function in the susceptibility to develop asthma and novel insights in the modulation of epithelial cell dysfunction in asthma.

Asthma and chronic obstructive pulmonary disease (COPD) cause significant morbidity and mortality worldwide. In the context of disease pathogenesis, both asthma and COPD involve chronic inflammation of the lung and are characterised by the abnormal release of inflammatory cytokines, dysregulated immune cell activity and remodelling of the airways. To date, current treatments still only manage symptoms and do not reverse the primary disease processes. In recent work, interleukin (IL)-1α and IL-1β have been suggested to play important roles in both asthma and COPD. In this review, we summarise overwhelming pre-clinical evidence for dysregulated signalling of IL-1α and IL-1β contributing to disease pathogenesis and discuss the paradox of IL-1 therapeutic studies in asthma and COPD. This is particularly important given recent completed and ongoing clinical trials with IL-1 biologics that have had varying degrees of failure and success as therapeutics for disease modification in asthma and COPD.

Human milk contains proteins and/or protein fragments that originate from nonhuman organisms. These proteinaceous molecules, of which the secretion might be related to the mother&rsquo, s allergy status, could be involved in the development of the immune system of the infant. This may lead, for example, to sensitization or the induction of allergen-specific tolerance. The aim of this study was to investigate the relation between maternal allergy and the levels of nonhuman proteinaceous molecules in their milk. In this study, we analysed trypsin-digested human milk serum proteins of 10 allergic mothers and 10 nonallergic mothers. A search was carried out to identify peptide sequences originating from bovine or other allergenic proteins. Several methods were applied to confirm the identification of these sequences, and the differences between both groups were investigated. Out of the 78 identified nonhuman peptide sequences, 62 sequences matched Bos taurus proteins. Eight peptide sequences of bovine &beta, lactoglobulin had significantly higher levels in milk from allergic mothers than in milk from nonallergic mothers. Dietary bovine &beta, lactoglobulin may be absorbed through the intestinal barrier and secreted into human milk. This seems to be significantly higher in allergic mothers and might have consequences for the development of the immune system of their breastfed infant.

Background: Allergic rhinitis induced by house dust mites (HDMs) is a highly prevalent but often underdiagnosed and undertreated/untreated chronic disease. It often has a negative impact on sleep, work, leisure activities, and health-related quality of life. Allergen immunotherapy is a proven, safe treatment for respiratory allergies. Objective: We sought to assess the efficacy and safety of a 300 index of reactivity (IR) sublingual tablet formulation of Dermatophagoides pteronyssinus:Dermatophagoides farinae 1:1 extract in adolescents (aged >_12) and adults with moderate to severe HDM-induced allergic rhinitis. Methods: In a phase III, international, double-blind, placebo controlled, randomized clinical trial, participants received approximately 12 months of treatment with placebo or the 300 IR tablet. The primary end point was the average total combined score during 4 weeks at the end of the treatment period. Results: A total of 1607 participants were randomized, and 1476 (including 555 [37.6%] with concomitant mild controlled asthma at inclusion) comprised the full analysis set. Over the primary evaluation period, the least squares mean average total combined score in the 300 IR group (3.62) was significantly lower (P Superscript/Subscript Available

BackgroundBoth subcutaneous and sublingual allergen immunotherapy (SCIT and SLIT) have been shown to effectively suppress allergic manifestations upon allergen exposure, providing long-term relief from symptoms in allergic disorders including allergic asthma. Clinical studies directly comparing SCIT and SLIT report a different kinetics and magnitude of immunological changes induced during treatment. Comparative studies into the mechanisms underlying immune suppression in SCIT and SLIT are lacking.ObjectiveWe aimed to establish an experimental model for grass pollen (GP) SCIT and SLIT that would allow a head-to-head comparison of the two treatments.MethodsBALB/c mice were sensitized with GP extract, followed by SCIT and SLIT treatments with various GP dosages. Subsequently, we challenged mice with GP and measured airway responsiveness (AHR), GP-specific immunoglobulins, ear swelling tests (EST), eosinophilic inflammation in bronchoalveolar lavage fluid (BALF), and T cell cytokine release after restimulation of lung cells (IL-5, IL-10, and IL-13).ResultsWe find that SLIT treatment was able to suppress allergen-induced AHR, while allergic inflammation was not effectively suppressed even at the highest GP dose in this model. In contrast, SCIT treatment induced higher levels of GP-specific IgG1, while SLIT was superior in inducing a GP-specific IgG2a response, which was associated with increased Th1 activity in lung tissue after SLIT, but not SCIT treatment. Interestingly, SCIT was able to suppress Th2-type cytokine production in lung cell suspensions, while SLIT failed to do so.Conclusions and clinical relevanceIn conclusion, GP-SCIT suppresses Th2 inflammation and induced neutralizing antibodies, while GP-SLIT suppresses the clinically relevant lung function parameters in an asthma mouse model, indicating that the two application routes depend on partially divergent mechanisms of tolerance induction. Interestingly, these data mirror observations in clinical studies, underscoring the translational value of these mouse models.

Children with atopic dermatitis show an increased risk to develop asthma later in life, a phenomenon referred to as "atopic march," which emphasizes the need for secondary prevention therapies. This study aimed to investigate whether relief of skin inflammation by glucocorticoids and peroxisome proliferator-activated receptor agonists might influence the subsequent development of asthma in a murine model for the atopic march in which mice were repeatedly exposed to house dust mite via the skin, followed by exposure to house dust mite in lungs. To abrogate atopic dermatitis, mice received topical treatment with glucocorticoid receptor/peroxisome proliferator-activated receptor-gamma agonists. Nuclear receptor ligand effects were assessed on primary keratinocytes and dendritic cells, as central players in skin inflammation. Prior house dust mite-induced skin inflammation aggravates allergic airway inflammation and induces a mixed T helper type 2/T helper type 17 response in the lungs. Cutaneous combined activation of glucocorticoid receptor/peroxisome proliferator-activated receptor-gamma reduced skin inflammation to a higher extent compared to single activation. Additive anti-inflammatory effects were more prominent in dendritic cells, as compared to keratinocytes. Alleviation of allergic skin inflammation by activation of glucocorticoid receptor/peroxisome proliferator-activated receptor-gamma appeared insufficient to avoid the allergic immune response in the lungs, but efficiently reduced asthma severity by counteracting the Th17 response. Glucocorticoid receptor/peroxisome proliferator-activated receptor-gamma co-activation represents a potent remedy against allergic skin inflammation and worsening of atopic march.

Background A novel subcutaneous allergen immunotherapy formulation (gpASIT+™) containing Lolium perenne peptides (LPP) and having a short up-dosing phase has been developed to treat grass pollen–induced seasonal allergic rhinoconjunctivitis. We investigated peptide immunotherapy containing the hydrolysate from perennial ryegrass allergens for the optimum dose in terms of clinical efficacy, immunogenicity and safety. Methods This prospective, double-blind, placebo-controlled, phase IIb, parallel, four-arm, dose-finding study randomized 198 grass pollen–allergic adults to receive placebo or cumulative doses of 70, 170 or 370 μg LPP. All patients received weekly subcutaneous injections, with the active treatment groups reaching assigned doses within 2, 3 and 4 weeks, respectively. Efficacy was assessed by comparing conjunctival provocation test (CPT) reactions at baseline, after 4 weeks and after completion. Grass pollen–specific immunoglobulins were analysed before and after treatment. Results Conjunctival provocation test (CPT) response thresholds improved from baseline to V7 by at least one concentration step in 51.2% (170 μg; P = .023), 46.3% (370 μg), and 38.6% (70 μg) of patients receiving LPP vs 25.6% of patients receiving placebo (modified per-protocol set). Also, 39% of patients in the 170-μg group became nonreactive to CPT vs 18% in the placebo group. Facilitated allergen-binding assays revealed a highly significant (P < .001) dose-dependent reduction in IgE allergen binding across all treatment groups (70 μg: 17.1%; 170 μg: 18.8%; 370 μg: 26.4%). Specific IgG4 levels increased to 1.6-fold (70 μg), 3.1-fold (170 μg) and 3.9-fold (370 μg) (mPP). Conclusion Three-week immunotherapy with 170 μg LPP reduced CPT reactivity significantly and increased protective specific antibodies.

House-dust mites (HDM) allergy is the prevailing condition in subjects allergic to inhalants. Clinical studies with HDM extracts—either subcutaneous (SCIT) or sublingual (SLIT) have long been characterized by small sample size, varying allergen doses, and poorly defined endpoints assessing disease severity. In the last decade, well-designed, randomized, controlled studies recruiting thousands of patients have been conducted with newly developed HDM sublingual tablets (SQ®-HDM tablets). This drug is easily dispersible in the oral cavity due to the patented Zydis® technology and its allergen composition is balanced in terms of group I and group II major mite allergen content, reflecting the equal contribution of the two components to HDM sensitization. HDM is the most common allergen associated with asthma. Clinical efficacy of the SQ® HDM SLIT-tablet in HDM allergic asthma has been evaluated in randomized, double-blind, placebo-controlled trials. Both endpoints related to “present” asthma control (inhaled corticosteroid—ICS) as well as endpoints related to “future” asthma control (occurrence of asthma exacerbations) were included in these studies, in agreement with GINA (Global Initiative for Asthma) guidelines. Based on the positive results of these studies, SQ®-HDM SLIT-tablets were approved Europe-wide as registered drug for treating moderate-to-severe allergic rhinitis with or without allergic asthma and not well controlled HDM allergic asthma, associated with allergic rhinitis of any severity. GINA guidelines in 2017 included SLIT-tablet-based immunotherapy as an “add-on” treatment for asthmatic patients sensitized to HDM; indeed, allergen immunotherapy (AIT) is considered to be a complementary treatment option that targets the immunological of allergic diseases, representing the only treatment potentially disease-modifier or, at least, with a long-term efficacy. The availability of a safe, standardized, registered treatment for HDM respiratory allergies is pivotal in the immunotherapy field, pushing it out of a century-long limbo of amatorial interest towards the full dignity deserved by the only casual treatment of respiratory allergies.

Asthma is a chronic respiratory condition, which is highly prevalent worldwide. Although no cure is currently available, it is well recognized that some asthma patients can spontaneously enter remission of the disease later in life. Asthma remission is characterized by absence of symptoms and lack of asthma-medication use. Subjects in asthma remission can be divided into two groups: those in clinical remission and those in complete remission. In clinical asthma remission, subjects still have a degree of lung functional impairment or bronchial hyperresponsiveness, while in complete asthma remission, these features are no longer present. Over longer periods, the latter group is less likely to relapse. This remission group is of great scientific interest due to the higher potential to find biomarkers or biological pathways that elicit or are associated with asthma remission. Despite the fact that the definition of asthma remission varies between studies, some factors are reproducibly observed to be associated with remitted asthma. Among these are lower levels of inflammatory markers, which are lowest in complete remission. Additionally, in both groups some degree of airway remodeling is present. Still, the pathological disease state of asthma remission has been poorly investigated. Future research should focus on at least two aspects: further characterisation of the small airways and airway walls in order to determine histologically true remission, and more thorough biological pathway analyses to explore triggers that elicit this phenomenon. Ultimately, this will result in pharmacological targets that provide the potential to steer the course of asthma towards remission. (C) 2019 Elsevier Inc. All rights reserved.

Asthma is a common lung disease affecting 300 million people worldwide. Allergic asthma is recognized as a prototypical Th2 disorder, orchestrated by an aberrant adaptive CD4+ T helper (Th2/Th17) cell immune response against airborne allergens, that leads to eosinophilic inflammation, reversible bronchoconstriction, and mucus overproduction. Other forms of asthma are controlled by an eosinophil-rich innate ILC2 response driven by epithelial damage, whereas in some patients with more neutrophilia, the disease is driven by Th17 cells. Dendritic cells (DCs) and macrophages are crucial regulators of type 2 immunity in asthma. Numerous lipid mediators including the eicosanoids prostaglandins and leukotrienes influence key functions of these cells, leading to either pro- or anti-inflammatory effects on disease outcome. In this review, we will discuss how eicosanoids affect the functions of DCs and macrophages in the asthmatic lung and how this leads to aberrant T cell differentiation that causes disease.

BackgroundAllergen-specific immunotherapy can induce long-term suppression of allergic symptoms, reduce medication use, and prevent exacerbations of allergic rhinitis and asthma. Current treatment is based on crude allergen extracts, which contain immunostimulatory components such as -glucans, chitins, and endotoxin. Use of purified or recombinant allergens might therefore increase efficacy of treatment.AimsHere, we test application of purified natural group 1 and 2 allergens from Dermatophagoides pteronyssinus (Der p) for subcutaneous immunotherapy (SCIT) treatment in a house dust mite (HDM)-driven mouse model of allergic asthma.Materials and methodsHDM-sensitized mice received SCIT with crude HDM extract, a mixture of purified Der p1 and 2 (DerP1/2), or placebo. Upon challenges, we measured specific immunoglobulin responses, allergen-induced ear swelling response (ESR), airway hyperresponsiveness (AHR), and inflammation in bronchoalveolar lavage fluid (BAL) and lung tissue.ResultsESR measurement shows suppression of early allergic response in HDM-SCIT- and DerP1/2-SCIT-treated mice. Both HDM-SCIT and DerP1/2-SCIT are able to suppress AHR and eosinophilic inflammation. In contrast, only DerP1/2-SCIT is able to significantly suppress type 2 cytokines in lung tissue and BAL fluid. Moreover, DerP1/2-SCIT treatment is uniquely able suppress CCL20 and showed a trend toward suppression of IL-33, CCL17 and eotaxin levels in lung tissue.DiscussionTaken together, these data show that purified DerP1/2-SCIT is able to not only suppress AHR and inflammation, but also has superior activity toward suppression of Th2 cells and HDM-induced activation of lung structural cells including airway epithelium.ConclusionsWe postulate that treatment with purified natural major allergens derived from HDM will likely increase clinical efficacy of SCIT.

In the last few decades, our understanding of Langerhans cells (LCs) has drastically changed based on novel findings regarding the developmental origin and biological functions of these epidermis-specific resident immune cells. It has become clear that LCs not only exert pivotal roles in immune surveillance and homeostasis but also impact on pathology by either inducing tolerance or mediating inflammation. Their unique capabilities to self-renew within the epidermis, while also being able to migrate to lymph nodes in order to present antigen, place LCs in a key position to sample the local environment and decide on the appropriate cutaneous immune response. Exciting new data distinguishing LCs from Langerin(+) dermal dendritic cells (DCs) on a functional and ontogenic level reveal crucial roles for LCs in trauma and various skin pathologies, which will be thoroughly discussed here. However, despite rapid progress in the field, the exact role of LCs during immune responses has not been completely elucidated. This review focuses on what mouse models that have been developed in order to enable the study of murine LCs and other Langerin-expressing DCs have taught us about LC development and function.

Background. Atopic dermatitis (AD) is an early and important step in the propagation of the allergic march, enhancing food and respiratory allergies via epicutaneous sensitisation to allergens. Objectives. To determine the prevalence and patterns of aeroallergen sensitisation, asthma and allergic rhinitis in South African (SA) children with AD. Methods. This was a prospective, observational study in a paediatric university hospital in Cape Town, SA. Children with moderate to severe AD, aged 6 months - 10 years, were recruited randomly and investigated for food sensitisation and allergy. They were assessed for sensitisation to aeroallergens by the immuno solid-phase allergen chip test. House-dust mite DerP and DerF, dust mite Eur m, Timothy grass, Bermuda grass, tree pollen, mould (Alternaria), cat and dog sensitisation patterns were analysed. Symptoms of asthma and allergic rhinitis were elicited using a questionnaire modified from the International Study of Asthma and Allergies in Childhood study questions. Results. One hundred participants (59 black Africans and 41 of mixed ethnicity) were enrolled (median age 42 months). Of the participants, 39% had symptoms of asthma and 53% symptoms of allergic rhinitis; 89% tested positive to at least one aeroallergen, most commonly house-dust mite DerP or DerF (81%), dust mite Eur m (51%), Timothy grass (36%) and cat (35%). Asthma, allergic rhinitis and aeroallergen sensitisation all increased with increasing age, while food allergy decreased with age. Food allergy was not an independent risk factor for respiratory allergies. Children were sensitised to indoor allergens (house-dust mite, pets) from an early age, while pollen allergies increased with age. Conclusions. In this cohort of SA children with moderate to severe AD, comorbidity with respiratory allergies was high. The prevalence of respiratory allergies increased with age while food allergy decreased with age, in keeping with the pattern of the allergic march. Seasonal allergies increased with age, while house-dust mite and pet allergy peaked in younger children, in keeping with early exposure via a defective skin barrier. Early and effective restoration of the skin barrier in AD may be a target for reducing aeroallergen-related diseases.S Afr Med J 2017;107(10):904-909.

The airway epithelium regulates responses to aeroallergens, acting as a physical and immunological barrier. In asthma, epithelial barrier function and the expression of adherens junction protein E-cadherin is compromised, but it is unknown whether this is cause or consequence of the disease. We hypothesized that airway epithelial loss of E-cadherin is a critical step in the development of manifestations of asthma. We generated a transgenic mouse model with conditional loss of E-cadherin in lung epithelial cells at birth and onwards. We observed normal lung development at the time of birth in mice lacking E-cadherin in the lung epithelium. However, E-cadherin deficiency led to progressive epithelial damage in mice growing into adulthood, as evidenced by airway epithelial denudation, decreased zonula occludens (ZO)-1 expression, loss of ciliated cells, and enlarged alveolar spaces. In addition, spontaneous goblet cell metaplasia with mucus production was observed. These epithelial changes were accompanied by elevated levels of the epithelial-derived chemokine CCL17, infiltration of eosinophils and dendritic cells, and mucus production. In conclusion, loss of E-cadherin induces features in the lung reminiscent of those observed in asthma, indicating that the disruption of E-cadherin-mediated cell-cell contacts may play a key role in the development of asthma manifestations.

Epithelial cell lines are often used to evaluate the effect of exogenous/endogenous stimuli on epithelial barrier function and innate immune responses in allergic airway diseases, without clear view on differences between epithelial cell lines and primary nasal epithelial cell responses. In this observational study, we compared the response of Calu-3 and primary nasal epithelial cells to two relevant exogenous stimuli: i.e. Staphylococcus aureus enterotoxin B (SEB) and house dust mite (HDM). Stimulation of Calu-3 cells with SEB decreased epithelial integrity in a dose dependent manner, which was associated with a significant increase in IL-6 and IL-8 production. In contrast, no alteration in barrier integrity or IL-6 and IL-8 production was seen when primary nasal epithelial cells were stimulated with SEB. HDM extract altered the integrity of primary nasal epithelial cells, but not of Calu-3 epithelial cells. Increased IL-8 production was seen after stimulation with HDM in primary nasal epithelial cells and not in Calu-3 epithelial cells. In conclusion, immune and barrier function differ between different epithelial cell types studied. As a consequence, care must be taken when interpreting data using different epithelial cell types. Electronic supplementary material The online version of this article (10.1186/s13601-018-0225-8) contains supplementary material, which is available to authorized users.

Objective Because most children with asthma now use inhaled corticosteroids (ICS), the added benefit of immunotherapy in asthmatic children needs to be examined. We re-assessed the effectiveness of subcutaneous (SCIT) and sublingual immunotherapy (SLIT) in childhood asthma treatment focusing on studies with patient-relevant outcome measures and children using ICS.Methods We used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to systematically search and appraise the evidence using predefined critical patient-relevant outcomes (asthma symptoms, asthma control and exacerbations). We searched to retrieve systematic reviews and randomised controlled trials on immunotherapy for asthma in children (1960-2017). We assessed the quality of the body of evidence with GRADE criteria.Results The quality of the evidence for SCIT was very low due to a large risk of bias and indirectness (dated studies in children not using ICS). No effect of SCIT was found for asthma symptoms; no studies reported on asthma control. For asthma exacerbations, studies favoured SCIT. We have little confidence in this effect estimate, due to the very low quality of evidence. For SLIT, quality of the evidence was very low due to a large risk of bias, indirectness and imprecision. The outcome 'asthma symptoms' could not be calculated due to lack of standardisation and large clinical heterogeneity. Other predefined outcomes were not reported.Conclusion The beneficial effects of immunotherapy in childhood asthma found in earlier reviews are no longer considered applicable, because of indirectness (studies performed in children not being treated according to current asthma guidelines with ICS). There was absence of evidence to properly determine the effectiveness or lack thereof of immunotherapy in asthma treatment in children with ICS.

Introduction: Specific immunotherapy has shown to be very useful for allergy control in dogs, with a common success rate ranging from 65% to 70%. However, this efficacy could probably be improved and the identification of individual allergomes, with the choice of more adequate molecular allergen pools for specific immunotherapy, being the strategy. Aim: To map Dermatophagoides pteronyssinus (Der p) allergens for mite-sensitized atopic dogs, for better under- standing how individual allergograms may influence the response to house-dust mite immunotherapy. Material and methods: To identify the Der p mite allergome for dogs, 20 individuals allergic to dust-mites and sen- sitized to Der p, were selected. The extract from Der p was submitted to isoelectric focusing (IEF), one-dimensional (1-D) and two-dimensional (2-D) sodium dodecyl sulphate polyacrylamide gel electrophoresis (SDS-PAGE). Separated proteins were blotted onto polyvinylidene difluoride (PVDF) membranes and immunoblottings were performed with patient sera. Allergen-bound specific IgE was detected. Results: Eleven allergens were identified from isoelectric focusing (IEF), as well as from 1-D SDS PAGE. From 2-D SDS-PAGE, 24 spots were identified. Conclusions: Several similarities were found between dog and human allergograms and no absolute correlation between sensitization and allergy was observed either. As in humans, different individual allergograms do not seem to implicate different clinical patterns, but may influence the response to specific immunotherapy. The molecular epidemiology approach in veterinary allergy management, by the characterization of individual patients' allergoms and by choosing the best molecular allergen pool for each patient could also improve the efficacy of allergy immu- notherapy.

ObjectiveBecause most children with asthma now use inhaled corticosteroids (ICS), the added benefit of immunotherapy in asthmatic children needs to be examined. We re-assessed the effectiveness of subcutaneous (SCIT) and sublingual immunotherapy (SLIT) in childhood asthma treatment focusing on studies with patient-relevant outcome measures and children using ICS.MethodsWe used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to systematically search and appraise the evidence using predefined critical patient-relevant outcomes (asthma symptoms, asthma control and exacerbations). We searched to retrieve systematic reviews and randomised controlled trials on immunotherapy for asthma in children (1960–2017). We assessed the quality of the body of evidence with GRADE criteria.ResultsThe quality of the evidence for SCIT was very low due to a large risk of bias and indirectness (dated studies in children not using ICS). No effect of SCIT was found for asthma symptoms; no studies reported on asthma control. For asthma exacerbations, studies favoured SCIT. We have little confidence in this effect estimate, due to the very low quality of evidence. For SLIT, quality of the evidence was very low due to a large risk of bias, indirectness and imprecision. The outcome ‘asthma symptoms’ could not be calculated due to lack of standardisation and large clinical heterogeneity. Other predefined outcomes were not reported.ConclusionThe beneficial effects of immunotherapy in childhood asthma found in earlier reviews are no longer considered applicable, because of indirectness (studies performed in children not being treated according to current asthma guidelines with ICS). There was absence of evidence to properly determine the effectiveness or lack thereof of immunotherapy in asthma treatment in children with ICS.

In allergen-sensitised asthmatic individuals, allergen-specific type-2 T-helper cells proliferate and secrete type-2 cytokines (e.g. interleukin (IL)-4, -5 and -13), driving the airway inflammatory response that gives rise to the clinical symptoms of asthma. Both early-life sensitisation to aeroallergens and lower respiratory viral infections are important environmental risk factors for developing asthma. Additionally, respiratory viral infections are the most common trigger for asthma exacerbations. Of interest, many asthma susceptibility genes are expressed in the airway epithelium [1], which forms the first continuous line of defence against inhaled environmental insults, including viruses and aeroallergens. Impaired immune regulation and failure to maintain tolerance to allergens is thought to contribute to allergic sensitisation. Asthma epithelium may be deficient in its innate immune defence against viral infections, resulting in increased viral replication upon rhinovirus infection compared to nonasthma-derived epithelial cultures [2]. Furthermore, there is evidence for loss of the mucosal immune barrier in asthma, with disruption of epithelial integrity [1, 3]. This may lead not only to increased permeability, but also to the release of pro-inflammatory mediators, specifically of cytokines that drive type-2 responses [3, 4]. We recently observed that the ability of allergens to disrupt epithelial barrier function is related to the development of type-2-mediated inflammation in asthma [5, 6]. Furthermore, we demonstrated that healthy murine lung epithelium is a potent inhibitor of T-cell proliferation and that this inhibition is lost upon viral infection [7]. It is unknown if this immune regulatory effect is displayed by human epithelium and is dysregulated in asthma. We hypothesise that changes in this regulatory effect translate into aberrant regulation of T-cell responses in asthma. We studied the epithelial regulation of T-cell proliferation and cytokine responses upon epithelial stimulation with a viral mimic, using co-culture of human T-cells and primary bronchial epithelial cells (PBECs) from healthy controls and asthma patients.

Inducible bronchus-associated lymphoid tissue (iBALT) is a long lasting tertiary lymphoid tissue that can be induced following influenza A virus (IAV) infection. Previous studies have shown that iBALT structures containing germinal center (GC) B cells protect against repeated infection by contributing locally to the cellular and humoral immune response. If we are to exploit this in vaccination strategies, we need a better understanding on how iBALT structures are induced. One hypothesis is that the strength of the initial innate response dictates induction of iBALT. In the present study, we investigated the role of interleukin (IL)-1 and IL-1R signaling on iBALT formation. Mice lacking the IL-1R had a delayed viral clearance and, thus, a prolonged exposure to viral replication, leading to increased disease severity, compared to wild-type mice. Contradictorily, iBALT formation following clearance of the virus was heavily compromised in Il1r1(-/-) mice. Quantification of gene induction after IAV infection demonstrated induction of IL-1 alpha and to a much lesser extent of IL-1 beta. Administration of recombinant IL-1 alpha to the lungs of wild-type mice, early but not late, after IAV infection led to more pronounced iBALT formation and an increased amount of GC B cells in the lungs. Bone marrow chimeric mice identified the stromal compartment as the crucial IL -1 responsive cell for iBALT induction. Mechanistically, Q-PCR analysis of lung homogenates revealed a strongly diminished production of CXCL13, a B cell-attracting chemokine, in Il1r(-/-) mice during the early innate phase of IAV infection. These experiments demonstrate that appropriate innate IL-1 alpha-IL-1R signaling is necessary for IAV clearance and at the same time instructs the formation of organized tertiary lymphoid tissues through induction of CXCL13 early after infection. These findings are discussed in the light of recent insights on the pathogenesis of tertiary lymphoid organ formation in the lung in various diseases where the IL-1 axis is hyperactive, such as rheumatoid arthritis and COPD.

Background: Emerging studies suggest that enhanced glycolysis accompanies inflammatory responses. Virtually nothing is known about the relevance of glycolysis in patients with allergic asthma. Objectives: We sought to determine whether glycolysis is altered in patients with allergic asthma and to address its importance in the pathogenesis of allergic asthma. Methods: We examined alterations in glycolysis in sputum samples from asthmatic patients and primary human nasal cells and used murine models of allergic asthma, as well as primary mouse tracheal epithelial cells, to evaluate the relevance of glycolysis. Results: In a murine model of allergic asthma, glycolysis was induced in the lungs in an IL-1-dependent manner. Furthermore, administration of IL-1 beta into the airways stimulated lactate production and expression of glycolytic enzymes, with notable expression of lactate dehydrogenase A occurring in the airway epithelium. Indeed, exposure of mouse tracheal epithelial cells to IL-1 beta or IL-1 alpha resulted in increased glycolytic flux, glucose use, expression of glycolysis genes, and lactate production. Enhanced glycolysis was required for IL-1 beta- or IL-1 alpha-mediated proinflammatory responses and the stimulatory effects of IL-1 beta on house dust mite (HDM)-induced release of thymic stromal lymphopoietin and GM-CSF from tracheal epithelial cells. Inhibitor of kappa B kinase epsilon was downstream of HDM or IL-1 beta and required for HDM-induced glycolysis and pathogenesis of allergic airways disease. Small interfering RNA ablation of lactate dehydrogenase A attenuated HDM-induced increases in lactate levels and attenuated HDM-induced disease. Primary nasal epithelial cells from asthmatic patients intrinsically produced more lactate compared with cells from healthy subjects. Lactate content was significantly higher in sputum supernatants from asthmatic patients, notably those with greater than 61% neutrophils. A positive correlation was observed between sputum lactate and IL-1 beta levels, and lactate content correlated negatively with lung function. Conclusions: Collectively, these findings demonstrate that IL-1 beta/inhibitory kappa B kinase epsilon signaling plays an important role in HDM-induced glycolysis and pathogenesis of allergic airways disease.

Allergic asthma is a disease characterized by persistent allergen-driven airway inflammation, remodeling, and airway hyperresponsiveness. CD4 + T-cells, especially T-helper type 2 cells, play a critical role in orchestrating the disease process through the release of the cytokines IL-4, IL-5, and IL-13. Allergen-specific immunotherapy (SIT) is currently the only treatment with a long-term effect via modifying the natural course of allergy by interfering with the underlying immunological mechanisms. However, although SIT is effective in allergic rhinitis and insect venom allergy, in allergic asthma it seldom results in complete alleviation of the symptoms. Improvement of SIT is needed to enhance its efficacy in asthmatic patients. Herein, the immunoregulatory mechanisms underlying the beneficial effects of SIT are discussed with the ultimate aim to improve its treatment efficacy. Keywords: allergic asthma; immunotherapy; dendritic cell; regulatory T cells; Th2 lymphocytes; hyperresponsiveness; eosinophilia; IgE; IL-10 (Published: 21 June 2010) Citation: Libyan J Med 2010, 5: 5303 - DOI: 10.3402/ljm.v5i0.5303

Background: The IL-1 family member IL-33 plays a critical role in type 2 innate immune responses to allergens and is an important mediator of allergic asthma. The mechanisms by which allergens provoke epithelial IL-33 secretion are still poorly understood.Objective: Based on previous findings indicating involvement of the NADPH oxidase dual oxidase 1 (DUOX1) in epithelial wound responses, we explored the potential involvement of DUOX1 in allergen-induced IL-33 secretion and potential alterations in airways of asthmatic patients.Methods: Cultured human or murine airway epithelial cells or mice were subjected to acute challenge with Alternaria alternata or house dust mite, and secretion of IL-33 and activation of subsequent type 2 responses were determined. The role of DUOX1 was explored by using small interfering RNA approaches and DUOX1-deficient mice. Cultured nasal epithelial cells from healthy subjects or asthmatic patients were evaluated for DUOX1 expression and allergen-induced responses.Results: In vitro or in vivo allergen challenge resulted in rapid airway epithelial IL-33 secretion, which depended critically on DUOX1-mediated activation of epithelial epidermal growth factor receptor and the protease calpain-2 through a redox-dependent mechanism involving cysteine oxidation within epidermal growth factor receptor and the tyrosine kinase Src. Primary nasal epithelial cells from patients with allergic asthma were found to express increased DUOX1 and IL-33 levels and demonstrated enhanced IL-33 secretion in response to allergen challenge compared with values seen in nasal epithelial cells from nonasthmatic subjects.Conclusion: Our findings implicate epithelial DUOX1 as a pivotal mediator of IL-33-dependent activation of innate airway type 2 immune responses to common airborne allergens and indicate that enhanced DUOX1 expression and IL-33 secretion might present important contributing features of allergic asthma.

Background: The alarmin interleukin 33 (IL-33) and its receptor ST2 play an important role in mucosal barrier tissues, and seem to be crucial for Th2-cell mediated host defense. Galacto-oligosaccharides (GOS), used in infant formulas, exhibit gut and immune modulatory effects. To enhance our understanding of the immunomodulatory capacity of GOS, this study investigated the impact of dietary GOS intervention on IL-33 and ST2 expression related to intestinal barrier dysfunction and asthma. Methods: B6C3F1 and BALB/c mice were fed a control diet with or without 1% GOS. To simulate intestinal barrier dysfunction, B6C3F1 mice received a gavage with the mycotoxin deoxynivalenol (DON). To mimic asthma-like inflammatory airway responses, BALB/c mice were sensitized on day 0 and challenged on days 7-11 with house-dust mite (HDM) allergen. Samples from the intestines and lungs were collected for IL-33 and ST2 analysis by qRT-PCR, immunoblotting and immunohistochemistry. Results: Dietary GOS counteracted the DON-induced IL-33 mRNA expression and changed the IL-33 distribution pattern in the mouse small intestine. The IL-33 mRNA expression was positively correlated to the intestinal permeability. A strong positive correlation was also observed between IL-33 mRNA expression in the lung and the number of bronchoalveolar fluid cells. Reduced levels of IL-33 protein, altered IL-33 distribution and reduced ST2 mRNA expression were observed in the lungs of HDM-allergic mice after GOS intervention. Conclusions: Dietary GOS mitigated IL-33 at the mucosal surfaces in a murine model for intestinal barrier dysfunction and HDM-induced asthma. This promising effect may open up new avenues to use GOS not only as a prebiotic in infant nutrition, but also as a functional ingredient that targets inflammatory processes and allergies associated with IL-33 expression.

Asthma is a heterogeneous disease whose etiology is poorly understood but is likely to involve innate responses to inhaled microbial components that are found in allergens. The influence of these components on pulmonary inflammation has been largely studied in the context of individual agonists, despite knowledge that they can have synergistic effects when used in combination. Here we have explored the effects of LPS and beta-glucan, two commonly-encountered microbial agonists, on the pathogenesis of allergic and non-allergic respiratory responses to house dust mite allergen. Notably, sensitization with these microbial components in combination acted synergistically to promote robust neutrophilic inflammation, which involved both Dectin-1 and TLR-4. This pulmonary neutrophilic inflammation was corticosteroid-refractory, resembling that found in patients with severe asthma. Thus our results provide key new insights into how microbial components influence the development of respiratory pathology.

Background: The relationship between mite and pet allergen exposure in infancy and the subsequent development of sensitization and asthma is complex.Objective: We prospectively investigated the effect of allergen exposure at 3 months of age on the development of sensitization, wheeze, and physician-diagnosed asthma in the first 4 years of life in a birth cohort of children with and without an atopic mother.Methods: Children participated in the Prevention and Incidence of Asthma and Mite Allergy study. Allergen exposure at 3 months of age was determined from mattress dust samples. Specific IgE to inhalant allergens was measured at 4 years of age, and information about wheeze and physician-diagnosed asthma was collected with yearly questionnaires.Results: Mite and cat allergen exposure in infancy were associated with an increased risk of specific sensitization to house dust mite and cat, respectively, at 4 years of age. There were borderline significant associations between cat allergen exposure and persistent wheeze in the total study population and between dog allergen exposure and persistent wheeze in children with a nonatopic mother. In children with an atopic mother, there was some indication of a positive association between mite allergen exposure and physician-diagnosed asthma.Conclusion: Early house dust mite and cat allergen exposure might lead to sensitization and, in case of cat allergen exposure, to persistent wheeze. Early mite and dog allergen exposure might lead to asthma and persistent wheeze, respectively, but only in subgroups defined by maternal atopy.