Allergen-induced Responses Research Articles

Raw Cow's Milk Reduces Allergic Symptoms in a Murine Model for Food Allergy-A Potential Role For Epigenetic Modifications.

Epidemiological studies identified raw cow’s milk consumption as an important environmental exposure that prevents allergic diseases. In the present study, we investigated whether raw cow’s milk has the capacity to induce tolerance to an unrelated, non-milk, food allergen. Histone acetylation of T cell genes was investigated to assess potential epigenetic regulation. Female C3H/HeOuJ mice were sensitized and challenged to ovalbumin. Prior to sensitization, the mice were treated with raw milk, processed milk, or phosphate-buffered saline for eight days. Allergic symptoms were assessed after challenge and histone modifications in T cell-related genes of splenocyte-derived CD4+ T cells and the mesenteric lymph nodes were analyzed after milk exposure and after challenge. Unlike processed milk, raw milk decreased allergic symptoms. After raw milk exposure, histone acetylation of Th1-, Th2-, and regulatory T cell-related genes of splenocyte-derived CD4+ T cells was higher than after processed milk exposure. After allergy induction, this general immune stimulation was resolved and histone acetylation of Th2 genes was lower when compared to processed milk. Raw milk reduces allergic symptoms to an unrelated, non-milk, food allergen in a murine model for food allergy. The activation of T cell-related genes could be responsible for the observed tolerance induction, which suggested that epigenetic modifications contribute to the allergy-protective effect of raw milk.

Bitter Taste Receptors for Asthma Therapeutics

Clinical management of asthma and chronic obstructive pulmonary disease (COPD) has primarily relied on the use of beta 2 adrenergic receptor agonists (bronchodilators) and corticosteroids, and more recently, monoclonal antibody therapies (biologics) targeting specific cytokines and their functions. Although these approaches provide relief from exacerbations, questions remain on their long-term efficacy and safety. Furthermore, current therapeutics do not address progressive airway remodeling (AR), a key pathological feature of severe obstructive lung disease. Strikingly, agonists of the bitter taste receptors (TAS2Rs) deliver robust bronchodilation, curtail allergen-induced inflammatory responses in the airways and regulate airway smooth muscle (ASM) cell proliferation and mitigate features of AR in vitro and in animal models. The scope of this review is to provide a comprehensive and systematic insight into our current understanding of TAS2Rs with an emphasis on the molecular events that ensue TAS2R activation in distinct airway cell types and expand on the pleiotropic effects of TAS2R targeting in mitigating various pathological features of obstructive lung diseases. Finally, we will discuss specific opportunities that could help the development of selective agonists for specific TAS2R subtypes in the treatment of asthma.

Discovery of Novel UV-Filters with Favorable Safety Profiles in the 5-Arylideneimidazolidine-2,4-dione Derivatives Group.

Effective protection from the harmful effects of UV radiation may be achieved by using sunscreens containing organic or inorganic UV filters. The number of currently available UV filters is limited and some of the allowed molecules possess limitations such as systemic absorption, endocrine disruption properties, contact and photocontact allergy induction, and low photostability. In the search for new organic UV filters we designed and synthesized a series consisting of 5-benzylidene and 5-(3-phenylprop-2-en-1-ylidene)imidazolidine-2,4-dione (hydantoin) derivatives. The photoprotective activity of the tested compounds was confirmed in methanol solutions and macrogol formulations. The most promising compounds possessed similar UV protection parameter values as selected commercially available UV filters. The compound diethyl 2,2′-((Z)-4-((E)-3-(4-methoxyphenyl)allylidene)-2,5-dioxoimidazolidine-1,3-diyl)diacetate (4g) was characterized as an especially efficient UVA photoprotective agent with a UVA PF of 6.83 ± 0.05 and favorable photostability. Diethyl 2,2′-((Z)-4-(4-methoxybenzylidene)-2,5-dioxo- imidazolidine-1,3-diyl)diacetate (3b) was the most promising UVB-filter, with a SPFin vitro of 3.07 ± 0.04 and very good solubility and photostability. The main photodegradation products were geometric isomers of the parent compounds. These compounds were also shown to be non-cytotoxic at concentrations up to 50 µM when tested on three types of human skin cells and possess no estrogenic activity, according to the results of a MCF-7 breast cancer model.

High dietary fat intake induces a microbiota signature that promotes food allergy

Diet-induced obesity and food allergies increase in tandem, but a potential cause-and-effect relationship between these diseases of affluence remains to be tested. We sought to test the role of high dietary fat intake, diet-induced obesity, and associated changes in gut microbial community structure on food allergy pathogenesis. Mice were fed a high-fat diet (HFD) for 12weeks before food allergen sensitization on an atopic dermatitis-like skin lesion, followed by intragastric allergen challenge to induce experimental food allergy. Germ-free animals were colonized with a signature HFD or lean microbiota for 8weeks before induction of food allergy. Food-induced allergic responses were quantified by using a clinical allergy score, serum IgE levels, serum mouse mast cell protease 1 concentrations, and type 2 cytokine responses. Accumulation of intestinal mast cells was examined by using flow cytometry and chloroacetate esterase tissue staining. Changes in the gut microbial community structure were assessed by using high-throughput 16S ribosomal DNA gene sequencing. HFD-induced obesity potentiates food-induced allergic responses associated with dysregulated intestinal effector mast cell responses, increased intestinal permeability, and gut dysbiosis. An HFD-associated microbiome was transmissible to germ-free mice, with the gut microbial community structure of recipients segregating according to the microbiota input source. Independent of an obese state, an HFD-associated gut microbiome was sufficient to confer enhanced susceptibility to food allergy. These findings identify HFD-induced microbial alterations as risk factors for experimental food allergy and uncouple a pathogenic role of an HFD-associated microbiome from obesity. Postdieting microbiome alterations caused by overindulgence of dietary fat might increase susceptibility to food allergy.

Abstract # 3086 Oral sensitization to a milk allergen triggers behavioral changes and neuroinflammatory responses in male C57BL/6 mice

Consumption of a certain food item, such as cow’s milk or wheat gluten, is reportedly associated with behavioral changes in susceptible individuals and thought to exacerbate the symptoms of neuropsychiatric disorders such as anxiety, depression, ADHD and autism. However, causative evidence is limited and the mechanism is unknown. Because food hypersensitivities do not always manifest as anaphylaxis or other obvious reactions, suspected food-induced behavioral changes may be non-anaphylactic symptoms involving the central nervous system. To determine whether a common food allergen would indeed cause behavioral changes without severe reactions, a mouse model of milk allergy was developed and peripheral and central immune responses were investigated. Four-week-old male and female C57BL/6 mice were given β -lactoglobulin (BLG), a major cow’s milk allergen, in the presence of an adjuvant or the adjuvant alone via weekly oral gavage for 5 weeks. All animals were challenged with BLG during the 6th and 7th weeks and their behavior was assessed. BLG-sensitized males, but not females, exhibited increased grooming and anxiety-like behavior compared to sex-matched adjuvant-only mice. Associated with the behavioral phenotype, BLG-specific IgE in serum and proinflammatory cytokines in the ileum and brain were elevated in male BLG-sensitized mice. These results provide evidence that a food allergen-induced inflammatory response in the gut may communicate with the brain and affect behavior without a severe allergic reaction.

Addressing the conundrums of p-phenylenediamine hair dye allergy by applying Friedmann's principles of contact sensitization.

In the first conundrum, permanent hair dyeing involves the use of aromatic amines such as p-phenylenediamine (PPD), whose oxidation is pivotal to the dyeing process, but also generates potent allergens. Despite prolonged efforts by industry to search for safer alternatives, hair dyeing is still reliant on this type of aromatic amine. In the second conundrum, patch testing with 1% PPD remains the most useful screen for hair dye contact allergy. However, there is a very small but real risk of actively sensitizing the patient. Lowering the PPD concentration below 1% significantly reduces test sensitivity and diagnostic utility. Here, we argue that by applying Friedmann's principles of contact sensitization each conundrum can be addressed from a new perspective. These principles indicate that, when the exposed area of skin is small (<1 cm2 ), induction of contact allergy is sharply reduced, whereas elicitation of allergy is unaffected. Careful reflection on this principle suggests that we can predict where hair dye sensitization is most likely to occur, indicates a strategy to reduce the chance of contact sensitization occurring in consumers as a result of hair dyeing, and how we might mitigate the risk of active sensitization resulting from diagnostic patch testing.

CD4+ T cells induce productions of IL-5 and IL-13 through MHCII on ILC2s in a murine model of allergic rhinitis

ObjectiveCD4+ T cells play an important role not only in the induction of allergy but also in allergic inflammation. Group 2 innate lymphoid cells (ILC2s) also mediate type 2 immune responses in allergic rhinitis (AR). However, the relationships between CD4+ T cells and ILC2s in allergic condition are currently not well defined. The study aimed to evaluate the potential influences of CD4+ T cells on ILC2s in the murine model of AR. MethodsA murine model of AR was established using ovalbumin (OVA), and OVA-induced ILC2s were sorted and purified from the mouse nasal-associated lymphoid tissue (NALT), and cultured in vitro. Then, the expression of major histocompatibility complex class II (MHCII) on ILC2s was examined. CD4+ T cells were separated from AR mice peripheral blood mononuclear cells (PBMCs). After that, productions of IL-5 and IL-13 on ILC2s cultures were assessed when CD4+ T cells or plus anti-MHCII antibody or anti-CD4 antibody were administered into the cultures. Finally, we adoptively transferred ILC2s alone or ILC2s plus anti-MHCII antibody to the murine model of AR to investigate their roles in the nasal allergic inflammation. ResultsWe showed that ILC2s could be induced by OVA in the mouse NALT. The number and percentage of ILC2s in AR mice were increased. MHCII was expressed on ILC2s, and its protein and mRNA were all enhanced in allergic condition. IL-5 and IL-13 proteins and mRNAs were elevated after CD4+ T cells administration, and were reduced after these cells plus anti-MHCII antibody or anti-CD4 antibody application. Numbers of sneezing and nasal rubbing as well as counts of eosinophils in nasal lavage fluid (NLF) were all enhanced after the adoptive transfer of ILC2s when compared to AR mice. IL-5 and IL-13 in the NLF of allergic mice were also increased in comparison with AR group. However, above parameters were all decreased after the transfer of ILC2s plus anti-MHCII antibody versus AR mice or ILC2s-treated ones. ConclusionThese findings show that CD4+ T cells induce productions of IL-5 and IL-13 through MHCII on ILC2s in AR mice models.

Regulatory Immune Mechanisms in Tolerance to Food Allergy.

Oral tolerance can develop after frequent exposure to food allergens. Upon ingestion, food is digested into small protein fragments in the gastrointestinal tract. Small food particles are later absorbed into the human body. Interestingly, some of these ingested food proteins can cause allergic immune responses, which can lead to food allergy. So far it has not been completely elucidated how these proteins become immunogenic and cause food allergies. In contrast, oral tolerance helps to prevent the pathologic reactions against different types of food antigens from animal or plant origin. Tolerance to food is mainly acquired by dendritic cells, epithelial cells in the gut, and the gut microbiome. A subset of CD103+ DCs is capable of inducing T regulatory cells (Treg cells) that express anti-inflammatory cytokines. Anergic T cells also contribute to oral tolerance, by reducing the number of effector cells. Similar to Treg cells, B regulatory cells (Breg cells) suppress effector T cells and contribute to the immune tolerance to food allergens. Furthermore, the human microbiome is an essential mediator in the induction of oral tolerance or food allergy. In this review, we outline the current understanding of regulatory immune mechanisms in oral tolerance. The biological changes reflecting early consequences of immune stimulation with food allergens should provide useful information for the development of novel therapeutic treatments.

Short contact with nickel causes allergic contact dermatitis

Allergic contact dermatitis is a common type of eczema that causes inflammation when skin comes into contact with certain substances. Although it is well accepted that long term skin contact can cause nickel allergy and dermatitis, the significance of relatively short and repeated nickel exposure in relation to induction and elicitation (i.e. first triggering) of nickel allergy has been less explored, and it has been proposed that short skin contact with nickel is safe. A study conducted in Denmark and Sweden attempted to test this proposition by examining whether repeated skin contact with nickel over short time periods would elicit allergic contact dermatitis. 16 adults who were known to have nickel allergy were tested along with a further 10 non‐allergic control subjects (a control subject is a healthy individual used for comparison). The subjects were exposed to nickel and aluminium discs on each forearm and each earlobe for 3 x 10 minutes. Also, one arm would be treated for 24 hours beforehand with 0.5% sodium lauryl sulfate (SLS) under occlusion (meaning the solution was applied then wrapped up with plastic wrap or cloth). SLS is added to bath products and detergents to make them foam and is a common cause of skin reactions. The purpose of this was to monitor differences in reactions to nickel in skin that was either normal or already irritated (by the SLS). Each nickel and aluminium site was evaluated and blood flow measured, as increased blood flow can show that skin is reacting to nickel. 62.5% of nickel allergic subjects reacted to nickel on the SLS treated arm. The nickel exposed skin also caused significantly more blood flow than aluminium exposed skin. No change in reactivity or blood flow was seen in any non‐SLS nickel exposed arms in nickel allergic patients, or in any control subjects. This study shows that relatively short repeated contact with nickel can elicit allergic contact dermatitis in irritated skin in people who already have a nickel allergy. The results support the restrictions in current nickel regulation.

Probabilistic prediction of human skin sensitiser potency for use in next generation risk assessment

Our aim is to develop and apply next generation approaches to skin allergy risk assessment that do not require new animal test data and better quantify uncertainties. We introduce the concept of the population threshold – a chemical-specific exposure level at which no individual in a population will experience induction of contact allergy to a chemical. A Bayesian multilevel (hierarchical) regression model is developed to estimate this population threshold under the conditions of a human-repeat-insult-patch-test. The approach is built on historical human (HRIPT) and murine (LLNA) data but, importantly, enables prediction based on in vitro (DPRA, Keratinosens™, hCLAT and U-SENS™) data. The Bayesian probabilistic framework allows us to explicitly quantify the uncertainty in the population threshold. Our skin allergy risk assessment defined approach (SARA DA) is used to estimate population thresholds for 30 chemicals using a weight-of-evidence across publicly available human, murine and in vitro data. Additionally, estimates for a further 43 chemicals are presented using chemical-specific data from in vitro assays only. Comparisons are made with current risk assessment metrics and across data types. We demonstrate that the approach can be used to derive a point-of-departure for next generation risk assessment based on in vitro data only.

258 - The transient receptor potential vanilloid 1 (TRPV1) channel is a critical factor in allergen-induced innate immune responses in the airway epithelium

The airway epithelium plays a critical role in innate responses to asthma-relevant protease allergens, such as house dust mite (HDM) or Alternaria alternata (ALT), by rapid secretion of IL-1 family alarmins, such as interleukin (IL)-1α and IL-33, that orchestrate appropriate type 2 immune responses. Previous studies indicate that allergen-induced IL-33 secretion is mediated by protease-activated receptors (PAR2) and type 2 purinergic receptors (P2RY2), which induce Ca2+-dependent signaling and activation of the NADPH oxidase dual oxidase 1 (DUOX1). Transient receptor potential (TRP) Ca2+ channels such as TRP Vanilloid 1 (TRPV1) are important in e.g. pain responses, often in coordination with PAR2 and P2YR2 activation, and TRPV1 has recently been implicated in asthma pathology. Using a panel of pharmacological inhibitors and activators of P2YR2, PAR2, and TRPV1, we observed that each of these receptors can provoke activation of DUOX1 and secretion of IL-33 in primary human nasal epithelial (HNE) cells. Further mechanistic studies using primary mouse tracheal epithelial cells (MTECs) or human bronchial epithelial cells (HBE1) confirmed these findings, and showed that TRPV1 contributes importantly to innate responses to HDM and ALT, and the danger signal ATP which activates P2YR2, as shown by activation of DUOX1-dependent H2O2 production, activation of epidermal growth factor receptor signaling, and rapid secretion of IL-33, which were prevented using TRPV1 antagonists or TRPV1-siRNA. Strikingly, inhibition or siRNA silencing of P2YR2 also prevented innate responses to the TRPV1 activator capsaicin, highlighting a close functional relationship of these airway epithelial surface receptors in the innate allergen responses. Finally, airway IL-33 secretion and subsequent type 2 cytokine production in mice in response to acute airway HDM challenge were markedly impaired in TRPV1-deficient mice. Overall, our studies indicate a complex relationship between various receptor types in epithelial responses to environmental triggers, and highlight the importance of TRPV1 in such epithelial responses.

Reduced risk of allergy induction for hairdressers? An occupational risk assessment for the new oxidative hair dye 2-methoxymethyl-p-phenylenediamine

Reduced risk of allergy induction for hairdressers? An occupational risk assessment for the new oxidative hair dye 2-methoxymethyl-p-phenylenediamine

Bcl2L12 plays a critical role in the development of intestinal allergy

The skewed T helper (Th) 2 response plays a central role in the pathogenesis of allergic diseases, while its initiating factors remain elusive. Recent studies indicate that Bcl2 like protein-12 (Bcl2L12) is associated with the Th2-biased inflammation. This study is designed to test a hypothesis that Bcl2L12 plays a critical role in the initiation of allergic response. In this study, peripheral CD4+ T cells were isolated from food allergy (FA) patients and healthy subjects; A mouse FA model was developed to test the role of Bcl2L12 in induction of allergic response in the intestine. The results showed that expression of Bcl2L12 by CD4+ T cells was higher in FA patients and FA mice and positively correlated with expression of Th2 cytokines. CD4+ T cells from FA patients showed a Bcl2L12-dependent tendency to differentiate into Th2 cells. Bcl2L12 played a crucial role in induction of allergic response in the intestine. Physical contact between Bcl2L12 and GATA3 facilitated GATA3 to bind Il4 promoter to promote expression of IL-4. Adoptive transfer with Bcl2L12-deficient CD4+ T cells to Rag2¯/¯ mice did not reconstitute the efficient CD4+ T cell response as the mice could not be induced FA, while Rag2¯/¯ mice received WT CD4+ T cell transfer were induced FA. In conclusion, Bcl2L12 plays a crucial role in the induction of Th2 polarization and allergic response in the intestine. The Bcl2L12 in CD4+ T cells may be a potential target for the treatment of FA.

The ameliorative effect of berberine and coenzyme Q10 in an ovalbumin-induced allergic rhinitis model.

Berberine and coenzyme Q10 (CoQ10) are agents with anti-inflammatory and antioxidant characteristics. The purpose of this study was to investigate the effectiveness of berberine and CoQ10 on allergic rhinitis. This study involved 30 Sprague-Dawley rats, and allergic rhinitis model was established with induction of ovalbumin. Rats were randomized into five groups. The first represented the control group, in which no allergy was established. The second represented the allergy group, in which allergy was induced but no treatment was given. In the remaining three groups, following induction of allergy, desloratadine at a dose of 10mg/kg was given to Group 3, 100mg/kg dose of berberine to Group 4, and 20mg/kg dose of CoQ10 to Group 5. Nasal symptom scores, and plasma immunoglobulin-E, interleukin (IL)-4, IL-13, malondialdehyde (MDA) and nitric oxide (NO) levels were examined at the end of the study. Rats' nasal tissues were also subjected to histopathological immunohistochemical examination. Nasal symptom scores, and plasma immunoglobulin-E, IL-4, IL-13, MDA and NO levels increased significantly in rats with induced allergic rhinitis. Berberine and CoQ10 significantly reduced these elevated levels. CoQ10 was also found as effective as desloratadin in terms of nasal symptom scores and biochemical parameters. At histopathological examination, severe allergic inflammation was observed in rats from allergic rhinitis group. At all treatment groups, the histopathological changes were significantly improved and only a mild inflammation was determined. Also, immunochemistry showed a significant improvement in all three treatment groups. Coenzyme Q10 and berberine were both effective in suppressing allergy symptoms. We think that berberine and coenzyme Q10 can usefully be employed as therapy due to their antioxidant and anti-inflammatory effects in an experimentally induced allergic rhinitis model.

A phase IIa proof-of-concept, placebo-controlled, randomized, double-blind, crossover, single-dose clinical trial of a new class of bronchodilator for acute asthma

BackgroundThis study evaluates a novel bronchodilator, S1226, for its efficacy in reversing allergen-induced bronchoconstriction in subjects with mild, allergic asthma. S1226 is a new class of bronchodilator that is an aerosol/vapor/gas mixture combining pharmacological and biophysical principles for a novel mode of action. It contains a potent bronchodilator gas (carbon dioxide or CO2) and nebulized perflubron (a synthetic surfactant possessing mucolytic properties). It has demonstrated rapid reversal of allergen-induced bronchoconstriction in an ovine study model.MethodsThis was a phase IIa proof-of-concept, placebo-controlled, randomized, double-blind, crossover single-dose clinical trial to evaluate the safety, tolerability, and efficacy of S1226 (8% CO2) administered by nebulization following an allergen-induced early asthmatic response in 12 subjects with mild, allergic asthma. Primary safety endpoints were adverse events, vital signs, pulse oximetry, and spirometry. Efficacy endpoints included bronchodilator response (measured as the forced expiratory volume in 1 s or FEV1) over time, the area under the curve of FEV1 for the early asthmatic response over time, and achievement of responder status, defined as a 12% improvement after the allergen challenge.ResultsNo significant safety issues were observed. All adverse events were non-serious, mild, and transient. There was a statistically significant decrease in peripheral blood oxygenation levels over time in the placebo group following allergen inhalation, whereas blood oxygenation was maintained at normal levels in the S1226-treated subjects (P = 0.028). This effect was greatest 5 min after start of treatment (P < 0.001). The recovery rate was faster but not significantly so (P = 0.272) for S1226 compared to the placebo at earlier time points (5, 10, and 15 min), as assessed by ≥12% reversal of FEV1. The recovery of FEV1 over time was significantly greater (P = 0.04) with S1226 compared to the placebo.ConclusionsS1226 was safe, tolerated well, and provided bronchodilation and improved blood oxygenation in subjects with mild atopic asthma following allergen-induced bronchoconstriction. Additional studies to optimize the therapeutic response are indicated.Trial registrationClinicalTrials.gov, NCT02334553. Registered on 12 November 2014.

Saturated fat-induced food allergy: A paradigm for unfolded protein response (UPR)-mediated allergic inflammation

Abstract Murine food allergy induction and maintenance is promoted by increased epithelial permeability and requires the pro-Th2 cytokines: IL-25, IL-33, and TSLP, but how allergens increase permeability and induce pro-Th2 cytokines is unknown. Saturated fats increase intestinal permeability, promote intestinal epithelial pro-Th2 cytokine expression and induce the UPR in several cell types. Two common food allergens, milk and eggs, contain considerable saturated fat. These observations suggested that saturated fats in food might promote allergy by inducing the UPR, which in turn, induces the pro-Th2 cytokines. To test this, quantitative PCR was used to evaluate the ability of heavy cream and egg yolk plasma (EYP, the fat-containing fraction of egg) to induce UPR-associated and pro-Th2 cytokine gene expression in transformed human intestinal epithelial CACO2 cells. Metformin, 4-PBA and TUDCA were used to block the UPR. EYP and cream, but not protein-rich, lipid-poor egg white, increased CACO2 cell UPR-associated gene expression, followed by increased pro-Th2 cytokine expression. This was blocked by the UPR antagonists and by a lipase antagonist that prevents fat absorption. EYP and cream, but not egg white, also increased epithelial permeability; this was blocked by metformin. In BALB/c mice, food allergy (detected as hypothermia and diarrhea) was induced by skin sensitization with egg white + EYP, followed by oral gavage with egg white + EYP. Metformin and TUDCA each prevented food allergy development and strongly suppressed established food allergy. These observations support our hypothesis and suggest that the saturated fat content of egg and milk contributes to their allergenicity.

Determining Food Allergens by Skin Sensitization in Mice.

A food allergy is a chronic inflammatory disease against dietary antigens with high prevalence in industrialized countries. Because there is currently no cure for food allergies, avoiding the allergen is crucial for the prevention of an allergic reaction. Therefore, a further understanding of the pathogenesis and risk factors that augment the sensitization to food allergens is required. We have previously developed a food allergy mouse model using transdermal sensitization, which influences the susceptibility to food allergies. In this model, mice sensitized with partially hydrolyzed wheat protein (HWP) successfully resembled the major features of HWP-sensitized and wheat allergy-induced patients. In this article, we describe transdermal sensitization of food allergens and induction of immediate-type food allergies in mice. The methodology detailed here was mainly adapted from an original work by Adachi and colleagues with some modifications to the dressing methods to reduce stress. © 2018 by John Wiley & Sons, Inc.

Knob protein enhances epithelial barrier integrity and attenuates airway inflammation

Altered epithelial physical and functional barrier properties along with TH1/TH2 immune dysregulation are features of allergic asthma. Regulation of junction proteins to improve barrier function of airway epithelial cells has the potential for alleviation of allergic airway inflammation. We sought to determine the immunomodulatory effect of knob protein of the adenoviral capsid on allergic asthma and to investigate its mechanism of action on airway epithelial junction proteins and barrier function. Airway inflammation, including junction protein expression, was evaluated in allergen-challenged mice with and without treatment with knob. Human bronchial epithelial cells were exposed to knob, and its effects on expression of junction proteins and barrier integrity were determined. Administration of knob to allergen-challenged mice suppressed airway inflammation (eosinophilia, airway hyperresponsiveness, and IL-5 levels) and prevented allergen-induced loss of airway epithelial occludin and E-cadherin expression. Additionally, knob decreased expression of TH2-promoting inflammatory mediators, specifically IL-33, by murine lung epithelial cells. At a cellular level, treatment of human bronchial epithelial cells with knob activated c-Jun N-terminal kinase, increased expression of occludin and E-cadherin, and enhanced epithelial barrier integrity. Increased expression of junction proteins mediated by knob leading to enhanced epithelial barrier function might mitigate the allergen-induced airway inflammatory response, including asthma.

Mast cells signal their importance in health and disease

FcεRI is the primary receptor in mast cells that mediates allergic reactions by inducing rapid release of mediators, an adaptive immune response that might have evolved as a host defense against parasites and venoms. Yet it is apparent that mast cells are also activated through non-IgE receptors, the significance of which is just beginning to be understood. This includes the Mas-related G protein-coupled receptor X2, which might contribute to reactions to diverse antimicrobials and polybasic compounds, and the adhesion G protein-coupled receptor E2, variants of which are associated with familial vibratory urticaria and are activated by mechanical vibration. Similarly, mast cells have long been recognized as the main repository for histamine, heparin, and proteases. Recent evidence also points to new functions, modes of delivery, and mechanisms of action of mast cell proteases that add new dimensions to the roles of mast cells in human biology. In addition, exposure of mast cells to environmental cues can quantitatively and qualitatively modulate their responses and thus their effect on allergic inflammation. Illustrating this paradigm, we summarize a number of recent studies implicating the injury/tissue damage cytokine IL-33 as a modulator of allergen-induced mast cell responses. We also discuss the discovery of markers associated with transformed mast cellsand new potential directions in suppressing mast cell activity.

Induction of allergic responses in experimental murine model by long-term intranasal exposure of House Dust Mite(HDM) allergen

Induction of allergic responses in experimental murine model by long-term intranasal exposure of House Dust Mite(HDM) allergen