Late-phase Allergic Responses Research Articles

Nasal IL-13 production identifies patients with late-phase allergic responses

There is limited knowledge on how local cytokine secretion patterns after nasal allergen challenge correlate with clinical symptoms especially with regard to the "late allergic response," which occurs in approximately 40% to 50% of patients with allergy. We sought to characterize the immunologic and clinical nasal responses to birch pollen allergen challenge with a special focus on the late allergic response. In this randomized, double-blind, placebo-controlled trial, birch pollen-allergic participants were challenged with birch pollen extract (n= 20) or placebo (n= 10) on 3 consecutive days. On days 1 and 3, nasal secretions were collected at selected time points over a 24-hour time course for the measurement of 33 inflammatory mediators. Clinical responses were determined through subjective symptom scores and objective nasal airflow measurements. Provoked participants had significantly greater clinical responses and showed significant increases in tryptase and the soluble IL-33 receptor serum stimulation 2 (sST2) in nasal secretions within minutes compared with the placebo group. Eight of 20 provoked participants displayed high IL-13 levels 2 to 8 hours after allergen provocation. This group also showed significant changes in clinical parameters, with a secondary drop in nasal airflow measured by peak nasal inspiratory flow and increased symptoms of nasal obstruction, which significantly differed from IL-13 nonresponders after 6 hours. IL-13 response status correlates with clinical responses and type 2 cytokine responses in the late phase after allergen provocation.

Comparison of Allergic Rhinitis and Bronchial Asthma Impacts on Tympanometric Parameters in Children at Kano, Nigeria

Background: Allergic rhinitis (AR) is a multifocal IgE-mediated type I hypersensitivity reaction that affects sino-nasal mucosa and is characterized by excessive sneezing, watery rhinorrhea, nasal itching, nasal stuffiness and eyes itching. Bronchial asthma (BA) is one of the common childhood diseases that affects the respiratory system characterized by recurrent cough, wheezing, chest tightness and difficulty with breathing. The two conditions are different manifestations of allergic disease of the airway; the composition of the inflammatory substrate in the mucosa of allergic patients is similar to the late-phase allergic response seen elsewhere in the respiratory tract, such as in bronchial asthma. Aim: The aim was to compare the impacts of allergic rhinitis and bronchial asthma on tympanometric parameters in children. Patients & Methods: This is a hospital based comparative cross-sectional study. Two groups of participants aged 4 - 12 years, one group with documented clinical diagnosis of allergic rhinitis and the other group with documented clinical diagnosis of bronchial asthma were consecutively selected from ear, nose and throat (ENT) and pediatrics cardiopulmonary outpatient clinics of Aminu Kano Teaching Hospital Kano respectively. Equal number of children aged 4 - 12 years with no history of ENT diseases or bronchial asthma that were selected from elementary schools within the same community served as a control group. An interviewer-administered questionnaire was filled out for all the participants, complete ENT and chest examinations were carried out and subsequently all the selected participants had tympanometry done, findings were recorded and analyzed. Results: The mean age of participants with bronchial asthma was found to be 7.5 ± 2.6 years while participants with allergic rhinitis had the mean age of 6.8 ± 2.1 years. The mean middle ear pressure (MEP) of participants with bronchial asthma was found to be -15.22 dapa and -40.32 dapa in those with allergic rhinitis. Acoustic reflex was found to be absent in 15.4% of the participants with bronchial asthma and 29.6% of allergic rhinitis participants. Type B tympanogram was found in 2.8% of bronchial asthma participants and 7.3% in participants with allergic rhinitis. Type C tympanogram was found in 4.6% of participants with bronchial asthma and 15.5% of participants with allergic rhinitis. Type A tympanogram was found in 90% of participants with bronchial asthma and 75% of participants with allergic rhinitis. The difference between type A, B and C tympanograms of participants with bronchial asthma and those with allergic rhinitis was found to be statistically significant (Type A χ2 = 14.62, df = 4, p value = 0.01, Type B χ2 = 14.06, df = 4, p value = 0.01, Type C χ2 = 17.01, df = 6, p value = 0.01). Conclusion: Participants with allergic rhinitis were found to have more abnormalities of tympanometric parameters compared to participants with bronchial asthma which signifies allergic rhinitis conferred an increased risk of having middle ear diseases and otitis media with effusion compared to bronchial asthma.

Chemokines in allergic conjunctivitis.

Chemokines are a large group of low molecular weight cytokines that attract and activate leukocytes throughout the body and therefore have a key role in the framework of late-phase allergic responses. The purpose of this article is to provide an overview of the main chemokines involved in allergic conjunctivitis, their primary functions and their physiological roles, and therapies targeted at chemokines and their receptors for ocular allergic diseases. In recent years, there have been considerable advances in the understanding of ocular pathophysiology of ocular surface inflammatory diseases including both allergic eye diseases and dry eye syndrome. Several therapies being developed for dry eye inflammation are recognized as possible therapies for ocular allergic diseases as there are often common chemokines involved in both disease spectra. Chemokines represent an integral part of the late-phase cascade of ocular allergic inflammation. A deep understanding of specific chemokines and their interactions will help in targeting therapies to effectively manage ocular clinical findings and symptoms of allergic eye disease.

Effect of inhaled corticosteroids on small airways in asthmatics using impulse oscillometry

Background The abnormalities in the small airways contribute to the symptoms of asthma. The small airways dysfunction may be attributed to many factors; mainly inflammation, remodeling, and changes in the surrounding tissue. Small airways affection associates with worse control of asthma, more frequent exacerbations, presence of nocturnal symptoms, more severe bronchial hyper-responsiveness, exercise-induced asthmatic symptoms, and the late-phase allergic response. Forced oscillation technique (FOT) was found to have higher sensitivity to inhaled corticosteroid (ICS) or to β-agonist inhalation than spirometry. Both ICS and β-agonists improve small-airway function, and FOT responses manifest eminent changes in indices of peripheral airway obstruction. In contrast, spirometric sensitivity to small-airway function is less eminent. Accordingly, it is expected that FOT might provide useful indices of peripheral airway change in response to therapeutic interventions. Aim The aim of this study was to evaluate the effect of regular use of ICS on small-airway function of asthmatic patients using impulse oscillometry (IOS). Patients and methods The study was carried out at Kobry El-Qobba Military Chest Hospital on 30 patients newly diagnosed as having mild and moderate bronchial asthma. Spirometric lung functions and IOS were done at baseline and then after 1 and 3 months of regular use of proper dosage of ICS to assess the effect on small-airway function. Results Results revealed that there was highly statistically significant improvement regarding changes in forced expiratory volume in 1 s, forced vital capacity, forced expiratory volume in 1 s/forced vital capacity, and maximum mid-expiratory flow (MMEF) 25–75 when comparing 1 day, 1 month, and 3 months. Moreover, there was statistically significant improvement regarding the R5, R20, and X5 when comparing 1 day, 1 month, and 3 months. Regular ICS use provides progressive improvement over time in both spirometry and IOS parameters. Both spirometric and IOS parameters were equally sensitive in detecting change of small-airway function. Conclusion Small-airway involvement in the pathogenesis of asthma will no longer be missed as it can be measured either qualitatively, as the presence or absence of high peripheral resistance values, or quantitatively through measuring the reactance. The more the patient is adherent to his or her daily recommended dose of ICS, the more evident is the improvement in his or her IOS and spirometric parameters including parameters that measure the small airways affection, starting from the very first few weeks of proper treatment. Using IOS is equally sensitive as spirometry in diagnosis and follow-up of adult asthmatic patients.

Myeloid Cells in Asthma.

Asthma is a heterogeneous chronic inflammatory disorder of the airways, and not surprisingly, many myeloid cells play a crucial role in pathogenesis. Antigen-presenting dendritic cells are the first to recognize the allergens, pollutants, and viruses that are implicated in asthma pathogenesis, and subsequently initiate the adaptive immune response by migrating to lymph nodes. Eosinophils are the hallmark of type 2 inflammation, releasing toxic compounds in the airways and contributing to airway remodeling. Mast cells and basophils control both the early- and late-phase allergic response and contribute to alterations in smooth muscle reactivity. Finally, relatively little is known about neutrophils and macrophages in this disease. Although many of these myeloid cells respond well to treatment with inhaled steroids, there is now an increasing armamentarium of targeted biologicals that can specifically eliminate only one myeloid cell population, like eosinophils. It is only with those new tools that we will be able to fully understand the role of myeloid cells in chronic asthma in humans.

Pathogenesis of rhinitis.

Rhinitis is a heterogeneous condition that has been associated with inflammatory responses as in allergic rhinitis but can also occur in the absence of inflammation such as in so-called idiopathic (previously 'vasomotor') rhinitis. Allergic rhinitis affects approximately one in four of the population of westernized countries and is characterized by typical symptoms of nasal itching, sneezing, watery discharge and congestion. The intention of this review is to illustrate key concepts of the pathogenesis of rhinitis. Imbalance in innate and adaptive immunity together with environmental factors is likely to play major roles. In allergic rhinitis, initial allergen exposure and sensitization involves antigen-presenting cells, T and B lymphocytes and results in the generation of allergen-specific T cells and allergen-specific IgE antibodies. On re-exposure to relevant allergens, cross-linking of IgE on mast cells results in the release of mediators of hypersensitivity such as histamine and immediate nasal symptoms. Within hours, there is an infiltration by inflammatory cells, particularly Th2 T lymphocytes, eosinophils and basophils into nasal mucosal tissue that results in the late-phase allergic response. Evidence for nasal priming and whether or not remodelling may be a feature of allergic rhinitis will be reviewed. The occurrence of so-called local allergic rhinitis in the absence of systemic IgE will be discussed. Non-allergic (non-IgE-mediated) rhinitis will be considered in the context of inflammatory and non-inflammatory disorders.

Advances in asthma 2015: Across the lifespan

In 2015, progress in understanding asthma ranged from insights to asthma inception, exacerbations, and severity to advancements that will improve disease management throughout the lifespan. 2015's insights to asthma inception included how the intestinal microbiome affects asthma expression with the identification of specific gastrointestinal bacterial taxa in early infancy associated with less asthma risk, possibly by promoting regulatory immune development at a critical early age. The relevance of epigenetic mechanisms in regulating asthma-related gene expression was strengthened. Predicting and preventing exacerbations throughout life might help to reduce progressive lung function decrease and disease severity in adulthood. Although allergy has long been linked to asthma exacerbations, a mechanism through which IgE impairs rhinovirus immunity and underlies asthma exacerbations was demonstrated and improved by anti-IgE therapy (omalizumab). Other key molecular pathways underlying asthma exacerbations, such as cadherin-related family member 3 (CDHR3) and orosomucoid like 3 (ORMDL3), were elucidated. New anti-IL-5 therapeutics, mepolizumab and reslizumab, were US Food and Drug Administration approved for the treatment of patients with severe eosinophilic asthma. In a clinical trial the novel therapeutic inhaled GATA3 mRNA-specific DNAzyme attenuated early- and late-phase allergic responses to inhaled allergen. These current findings are significant steps toward addressing unmet needs in asthma prevention, severity modification, disparities, and lifespan outcomes.

Anti-IgE treatment, airway inflammation and remodelling in severe allergic asthma: current knowledge and future perspectives.

Asthma is a disorder of the airways involving various inflammatory cells and mediators and characterised by bronchial hyperresponsiveness, chronic inflammation and structural alterations in the airways, also known as remodelling. IgE is an important mediator of allergic reactions and has a central role in allergic asthma pathophysiology, as it is implicated in both the early and late phase allergic response. Moreover, clinical and mechanistic evidence has lately emerged, implicating IgE in the development of airway remodelling. The use of monoclonal antibodies targeting IgE, such as omalizumab, has proven very effective in improving respiratory symptoms and quality of life, while reducing asthma exacerbations, emergency room visits and the use of systemic corticosteroids in allergic severe asthma. These effects are believed to be mainly mediated by omalizumab's inhibitory effect on the initiation and further propagation of the allergic inflammation cascade. However, there is evidence to suggest that anti-IgE treatment remains effective long after it has been discontinued. In part, these findings could be attributed to the possible ameliorating effects of anti-IgE treatment on airway remodelling. In this review, we discuss recent findings supporting the notion that anti-IgE treatment modulates the complex immune responses that manifest clinically as asthma and ameliorates airway remodelling changes often observed in allergic severe asthma phenotypes.

Distinguishing benign from pathologic TH2 immunity in atopic children

Although most children with asthma and rhinitis are sensitized to aeroallergens, only a minority of sensitized children are symptomatic, implying the underlying operation of efficient anti-inflammatory control mechanisms. We sought to identify endogenous control mechanisms that attenuate expression of IgE-associated responsiveness to aeroallergens in sensitized children. In 3 independent population samples we analyzed relationships between aeroallergen-specific IgE and corresponding allergen-specific IgG (sIgG) and associated immunophenotypes in atopic children and susceptibility to asthma and rhinitis, focusing on responses to house dust mite and grass. Among mite-sensitized children across all populations and at different ages, house dust mite-specific IgG/IgE ratios (but not IgG4/IgE ratios) were significantly lower in children with asthma compared with ratios in those without asthma and lowest among the most severely symptomatic. This finding was mirrored by relationships between rhinitis and antibody responses to grass. Depending on age/allergen specificity, 20% to 40% of children with allergen-specific IgE (sIgE) of 0.35 kU/L or greater had negative skin test responses, and these children also expressed the high sIgG/sIgE immunophenotype. sIgG1 from these children inhibited allergen-induced IgE-dependent basophil activation in a dose-dependent fashion. Profiling of aeroallergen-specific CD4(+) TH memory responses revealed positive associations between sIgG/sIgE ratios and IL-10-dependent gene signatures and significantly higher IL-10/TH2 cytokine (protein) ratios among nonsymptomatic children. In addition to its role in blocking TH2 effector activation in the late-phase allergic response, IL-10 is a known IgG1 switch factor. We posit that its production during allergen-induced memory responses contributes significantly to attenuation of inflammation through promoting IgG1-mediated damping of the FcεRI-dependent acute-phase reaction. sIgG1/sIgE balance might represent a readily accessible therapeutic target for asthma/rhinitis control.

Resveratrol suppresses type 2 cytokine induction in basophilic mast cell and Th2 cell infiltration in PCA mice

Cytokines released from mast cells, may play roles to initiate and maintain allergic responses. The high amount of cytokines accumulation can excite the late‐phase allergic responses, and it happens in consistence with migration of other leukocytes including neutrophils, lymphocytes, eosinophils and macrophages. Therefore, this study was conducted to test the resveratrol effects on IgE‐mediated basophilic mast cell and passive cutaneous anaphylaxis (PCA) in mice <em style=”mso‐bidi‐font‐style: normal;”>via cytokine suppression. Basophilic mast cells were sensitized with anti‐dinitrophenyl‐immunoglobulin E (anti‐DNP‐Ig E) and then pre‐treated with 1‐25 uM resveratrol depending on treatments. The DNP‐human serum albumin antigen was subsequently stimulated and all cells were then sampled for analysis. Similar <em style=”mso‐bidi‐font‐style: normal;”>in vivo experiment was conducted due to oral administration of 10 mg/kg resveratrol to BALB/c mouse (n = 5). Resveratrol diminished the secretion of interleukin (IL)‐3, IL‐4, IL‐13 and tumor necrosis factor(TNF)‐α in anti‐DNP‐IgE‐sensitized cells. Oral administration of 10 mg/kg resveratrol also reduced serum IL‐3, IL‐4, IL‐13 and TNF‐α level, on the contrary high level of IL‐3, ‐4 and ‐13 and TNF‐a were determined when BALB/c were sensitized and then challenged to DNP‐HSA. All DNP‐HSA mouse had high Tyrosine kinase (Tyk) 2 and Signal Transducer and Activator of Transcription (STAT). Resveratrol alleviated T cell infiltration of ear and dorsal skin in mice. In summary, the results indicated that the resveratrol administration lightened Type 2 cytokine releases and then alleviated the cytokine‐mediated allergic responses.

Calpain-1 contributes to IgE-mediated mast cell activation.

Mast cells play a central role in allergy through secretion of both preformed and newly synthesized mediators. Mast cell mediator secretion is controlled by a complex network of signaling events. Despite intensive studies, signaling pathways in the regulation of mast cell mediator secretion remain incompletely defined. In this study, we examined the role of calpain in IgE-dependent mast cell activation. IgE-mediated activation of mouse bone marrow-derived mast cells enhanced calpain activity. Inhibition of calpain activity by a number of calpain inhibitors reduced IgE-mediated mast cell degranulation both in vitro and in vivo. Calpain inhibitors blocked IgE-mediated TNF and IL-6 production in vitro and reduced late-phase allergic response in vivo. Importantly, mouse calpain-1 null bone marrow-derived mast cells showed reduced IgE-mediated mast cell degranulation in vitro and in vivo, diminished cytokine and chemokine production in vitro, and impaired late-phase allergic response in vivo. Further studies revealed that calpain-1 deficiency led to specific attenuation of IκB-NF-κB pathway and IKK-SNAP23 pathway, whereas calcium flux, MAPK, Akt, and NFAT pathway proceed normally in IgE-activated calpain-1 null mast cells. Thus, calpain-1 is identified as a novel regulator in IgE-mediated mast cell activation and could serve as a potential therapeutic target for the management of allergic inflammation.

Small-airways dysfunction associates with respiratory symptoms and clinical features of asthma: A systematic review

Traditionally, asthma has been considered a disease that predominantly involves the large airways. Today, this concept is being challenged, and increasing evidence has become available showing that abnormalities in the small airways also contribute to the clinical expression of asthma. The small airways can be affected by inflammation, remodeling, and changes in the surrounding tissue, all contributing to small-airways dysfunction. In this article we have performed a systematic review of the literature on the association between small-airways dysfunction and clinical signs and symptoms of asthma. This review shows that small-airways dysfunction associates with worse control of asthma, higher numbers of exacerbations, the presence of nocturnal asthma, more severe bronchial hyperresponsiveness, exercise-induced asthma, and the late-phase allergic response. Importantly, small-airways dysfunction can already be present in patients with mild asthma. Our review provides suggestive evidence that a better response of the small airways to inhaled steroids or montelukast associates with better asthma control. For this reason, an early recognition of small-airways dysfunction is important because it enables the physician to start timely treatment to target the small airways. It is important to develop simpler and more reliable tools (eg, questionnaires or bronchial provocation tests with small-particle stimuli) to assess the presence and extent of small-airways dysfunction in daily clinical practice.

Comparison of Timothy grass pollen extract‐ and single major allergen‐induced gene expression and mediator release in airway epithelial cells: a meta‐analysis

Seasonal allergic rhinitis (AR) is a global health problem and its prevalence has increased considerably in the last decades. As the allergic response with its clinical manifestations is triggered by only a few proteins within natural extracts, there is an increasing tendency for single-component-resolved diagnosis and immunotherapy. As natural exposure is not to single proteins, but to complex mixtures of molecules, we were interested in comparing the activation of respiratory epithelial cells induced by the purified major allergen Phl p 1 with the induction caused by a complete extract of Timothy grass pollen (GPE). NCI-H292 cells were exposed to GPE or Ph1 p 1 for 24h, isolated RNA and cell culture supernatants were used for microarray analysis, multiplex enzyme-linked immunosorbant assay (ELISA) and subsequent analysis. We found 262 genes that showed a GPE-induced change of at least 3-fold, whereas Ph1 p 1-stimulation resulted in 71 genes with a fold induction of more than 3-fold. Besides genes that were regulated by both stimuli, we also detected genes displaying an opposite response after stimulation, suggesting that GPE might be more than purified major allergens with regard to induced immune responses. Additional components within GPE and the resulting modulation of general processes affecting gene transcription and signalling pathways might be crucial to maintain/overcome the diseased phenotype and to induce the influx of cells contributing to late-phase allergic responses. When the initial process of sensitization is the matter of interest or late-phase allergic responses, one might miss important immune modulatory molecules and their interaction with allergens by applying single components only.

Optimisation of grass pollen nasal allergen challenge for assessment of clinical and immunological outcomes

Nasal allergen challenge can be used to assess the clinical and immunological aspects of rhinitis due to inhalant allergens. We aimed to develop a reproducible technique for grass pollen nasal allergen challenge and to study biomarkers within nasal secretions.20 Grass pollen allergic individuals underwent nasal challenges with purified Timothy grass allergen. An initial dose-titration challenge was used to determine dose–response characteristics. Subsequently, volunteers underwent 3 further challenges using individualised threshold doses. Symptom scores, visual analogue scores, and peak nasal inspiratory flow (PNIF) were recorded at baseline and up to 6h after challenge. Nasal secretions were collected at each time point using synthetic filter papers or absorptive polyurethane sponges and analysed for IL-4, -5, -10, -13, IFN-γ, Tryptase and Eosinophil Cationic Protein (ECP).Challenges gave reproducible symptom scores and decreased PNIF. Tryptase levels in nasal fluid peaked at 5min after challenge and returned to baseline levels at 1h. ECP, IL-5, IL-13 and IL-4 levels were increased from 2–3h and showed progressive increases to 5–6h. Sponges proved the superior nasal fluid sampling technique.We have developed a reproducible nasal allergen challenge technique. This may be used as a surrogate clinical endpoint in trials assessing the efficacy of treatments for allergic rhinitis. Tryptase in local nasal secretions is a potential biomarker of the early phase response; ECP and the Th2 cytokines IL-5, -13 and −4 markers of late phase allergic responses. Our model allows correlation between clinical responses and local biomarkers following nasal allergen challenge.

Identification of genes and proteins specifically regulated by costimulation of mast cell Fcε Receptor I and chemokine receptor 1

Mast cell function is a critical component of allergic reactions. Mast cell responses mediated by the high-affinity immunoglobulin E receptor FcεRI can be enhanced by co-activation of additional receptors such as CC chemokine receptor 1 (CCR1). To examine the downstream effects of FcεRI-CCR1 costimulation, rat basophilic leukemia cells stably transfected with CCR1 (RBL-CCR1 cells) were sensitized and activated with antigen and/or the CCR1 ligand CC chemokine ligand (CCL) 3. Gene and protein expression were determined at 3h and 24h post-activation, respectively, using GeneChip and Luminex bead assays. Gene microarray analysis demonstrated that 32 genes were differentially regulated in response to costimulation, as opposed to stimulation with antigen or CCL3 alone. The genes most significantly up-regulated by FcεRI-CCR1 costimulation were Ccl7, Rgs1, Emp1 and RT1-S3. CCL7 protein was also expressed at higher levels 24h after dual receptor activation, although RGS1, EMP1 and RT1-S3 were not. Of the panel of chemokines and cytokines tested, only CCL2, CCL7 and interleukin (IL)-6 were expressed at higher levels following costimulation. IL-6 expression was seen only after FcεRI-CCR1 costimulation, although the amount expressed was very low. CCL7, CCL2 and IL-6 might play roles in mast cell regulation of late-phase allergic responses.

MAPK Kinase 3 Specifically Regulates FcεRI-Mediated IL-4 Production by Mast Cells

Mast cells play a central role in allergic inflammation and are activated through cross-linking of FcεRI receptor-bound IgE, initiating a signaling cascade resulting in production of biologically potent mediators. Signaling pathways in the regulation of specific mediators remain incompletely defined. In this study, we examined the role of MAPK kinase 3 (MKK3) in IgE-dependent mast cell activation. In an in vivo model of passive cutaneous anaphylaxis, MKK3-deficient mice showed a deficit in late-phase IgE-dependent inflammation. To characterize the mechanism of this deficiency, we cultured bone marrow-derived mast cells (BMMCs) from wild-type and MKK3-deficient mice. We found that FcεRI-mediated mast cell activation induced rapid MKK3 phosphorylation by 5 min, diminishing slowly after 6 h. In MKK3-deficient BMMCs, phosphorylation of p38 was reduced at early and later time points. Among 40 cytokines tested using a protein array, IL-4 was the only cytokine specifically downregulated in MKK3-deficient BMMCs. Reduced IL-4 expression was seen in the local skin of MKK3-deficient mice following passive cutaneous allergic reaction. Furthermore, early growth response-1 (Egr1) bound to the promoter of IL-4 in FcεRI-activated mast cells, and Egr1 transcription factor activity was diminished in MKK3-deficient BMMCs. Finally, mast cell-deficient mice reconstituted with MKK3-deficient BMMCs displayed a significantly impaired late-phase allergic inflammatory response. Thus, mast cell MKK3 signaling contributes to IgE-dependent allergic inflammation and is a specific regulator of FcεRI-induced IL-4 production.

Mechanisms of IgE Inflammation

The prevalence of diseases such as allergic asthma and rhinitis continues to increase in the United States, affecting millions of people. It is well-established that allergy contributes to the pathogenesis of most asthma, especially in children and young adults. Despite current therapy (eg, inhaled corticosteroids, anti-leukotrienes, and bronchodilators), patients with moderate to severe asthma remain symptomatic and experience frequent exacerbations of disease requiring oral corticosteroids, emergency department treatments, and hospitalizations. Allergic diseases are traditionally referred to as immediate or type 1 hypersensitivity reactions, with IgE as a critical factor. IgE is involved in allergic inflammation, especially in early-phase response, but it may also be involved in the late-phase allergic response. A direct correlation between serum IgE levels and asthma exists. As logarithm IgE values increase, asthma prevalence increases linearly, even in patients who are categorized as having nonallergic asthma. In addition, there is a significant, although low association in allergic rhinitis with IgE levels and positive skin test reactivity to pollens. Recent advances in our understanding of the role of IgE in allergic inflammation have led to the development of a monoclonal antibody to IgE that reduces IgE levels, thereby reducing allergic inflammation. This review aims to provide an overview of the basic science of the IgE molecule and the clinical efficacy of anti-IgE therapy in allergic and asthmatic diseases.

Suppression of Th2-Driven Airway Inflammation by Allergen Immunotherapy Is Independent of B Cell and Ig Responses in Mice

Allergen-specific immunotherapy (IT) uniquely renders long-term relief from allergic symptoms and is associated with elevated serum levels of allergen-specific IgG and IgA. The allergen-specific IgG response induced by IT treatment was shown to be critical for suppression of the immediate phase of the allergic response in mice, and this suppression was partially dependent on signaling through FcγRIIB. To investigate the relevance of the allergen-specific IgG responses for suppression of the Th2-driven late-phase allergic response, we performed IT in a mouse model of allergic asthma in the absence of FcγRIIB or FcγRI/FcγRIII signaling. We found that suppression of Th2 cell activity, allergic inflammation, and allergen-specific IgE responses is independent of FcγRIIB and FcγRI/FcγRIII signaling. Moreover, we show that the IT-induced allergen-specific systemic IgG or IgA responses and B cell function are dispensable for suppression of the late-phase allergic response by IT treatment. Finally, we found that the secretory mucosal IgA response also is not required for suppression of the Th2-driven allergic inflammation by IT. These data are in contrast to the suppression of the immediate phase of the allergic response, which is critically dependent on the induced allergen-specific serum IgG response. Hence, IT-induced suppression of the immediate and late phases of the allergic response is governed by divergent and independent mechanisms. Our data show that the IT-induced suppression of the Th2 cell-dependent late-phase allergic response is independent of the allergen-specific IgG and IgA responses that are associated with IT treatment.

Desloratadine: a review of pharmacology and clinical efficacy in allergic rhinitis and urticaria

Desloratadine is a second-generation nonsedating antihistamine currently used in the treatment of allergic rhinitis and chronic idiopathic urticaria. It is the major active metabolite of loratadine. The binding affinity of desloratadine for H1 receptors is the highest among all antihistamines. Besides the effects of desloratadine on H1 receptors, it may also reduce the release of anti-inflammatory cytokines and other mediators involved in the early- and late-phase allergic response. Desloratadine is well-tolerated, and most adverse events reported are mild/moderate and experienced by a small proportion of the patients. Many large, randomized, double-blind, placebo-controlled trials have confirmed that desloratadine is effective against symptoms of intermittent and persistent allergic rhinitis. Patients with chronic idiopathic urticaria also experience marked relief of symptoms upon treatment with desloratadine, since urticarial symptoms in chronic idiopathic urticaria are largely mediated by histamine.

The roles of the prostaglandin D2 receptors DP1 and CRTH2 in promoting allergic responses

Prostaglandin D(2) (PGD(2)) is produced by mast cells, Th2 lymphocytes and dendritic cells and has been detected in high concentrations at sites of allergic inflammation. PGD(2) exerts its inflammatory effects through high affinity interactions with the G protein coupled receptors DP(1) and chemoattractant-homologous receptor expressed on Th2 cells (CRTH2, also known as DP(2)). DP(1) and CRTH2 act in concert to promote a number of biological effects associated with the development and maintenance of the allergic response. During the process of allergen sensitization, DP(1) activation may enhance polarization of Th0 cells to Th2 cells by inhibiting production of interleukin 12 by dendritic cells. Upon exposure to allergen in sensitized individuals, activation of DP(1) may contribute to the long lasting blood flow changes in the target organ. CRTH2 is expressed by Th2 lymphocytes, eosinophils and basophils and may mediate the recruitment of these cell types during the late phase allergic response. The role played by CRTH2 in promoting the production of Th2 cytokines and IgE make antagonism of this receptor a particularly attractive approach to the treatment of chronic allergic disease.