Allergy in an Evolutionary Framework.

Respiratory allergy including bronchial asthma and food allergy have gained epidemic character in the last decades in industrialized countries. Much has been learned with respect to the pathophysiology of allergic disease and this has facilitated specific therapies. Allergy is a chronic disease, and being so prevalent claims to search for evolutionary causes of the general susceptibility of humans as a species to react to environmental antigens in a Th2 type immune reaction with IgE production. In an evolutionary analysis of Allergy, necessary questions addressed in this review are "Why does IgE exist or why did IgE evolve?" as well as from the point of view of the mismatch hypothesis, "Why is there an Allergy epidemic?" Recent studies on the possible biological and protective role of IgE against parasites, arthropods, venoms or toxins are challenging the widely accepted definition of allergens as generally innocuous antigens. Combining the immunologic danger model and the toxin hypothesis for allergies, the allergic response could have evolved with an adaptive value and allergens could be proxies for other putative noxious agents. The last decades yielded with vast molecular data of allergens. With available bioinformatics tools, we therefore also describe that evolutionary theory could be applied to prevent allergy, estimate cross-reactivity, to design allergen-specific immunotherapy and to assess the risks of novel foods.

International Consensus Statement on Allergy and Rhinology: Allergic Rhinitis.

BACKGROUND: Critical examination of the quality and validity of available allergic rhinitis (AR) literature is necessary to improve understanding and to appropriately translate this knowledge to clinical care of the AR patient. To evaluate the existing AR literature, international multidisciplinary experts with an interest in AR have produced the International Consensus statement on Allergy and Rhinology: Allergic Rhinitis (ICAR:AR). METHODS: Using previously described methodology, specific topics were developed relating to AR. Each topic was assigned a literature review, evidence-based review (EBR), or evidence-based review with recommendations (EBRR) format as dictated by available evidence and purpose within the ICAR:AR document. Following iterative reviews of each topic, the ICAR:AR document was synthesized and reviewed by all authors for consensus. RESULTS: The ICAR:AR document addresses over 100 individual topics related to AR, including diagnosis, pathophysiology, epidemiology, disease burden, risk factors for the development of AR, allergy testing modalities, treatment, and other conditions/comorbidities associated with AR. CONCLUSION: This critical review of the AR literature has identified several strengths; providers can be confident that treatment decisions are supported by rigorous studies. However, there are also substantial gaps in the AR literature. These knowledge gaps should be viewed as opportunities for improvement, as often the things that we teach and the medicine that we practice are not based on the best quality evidence. This document aims to highlight the strengths and weaknesses of the AR literature to identify areas for future AR research and improved understanding.

Food allergy.

Food allergies manifest in a variety of clinical conditions within the gastrointestinal tract, skin and lungs, with the most dramatic and sometimes fatal manifestation being anaphylactic shock. Major progress has been made in basic, translational and clinical research, leading to a better understanding of the underlying immunological mechanisms that lead to the breakdown of clinical and immunological tolerance against food antigens, which can result in either immunoglobulin E (IgE)-mediated reactions or non-IgE-mediated reactions. Lifestyle factors, dietary habits and maternal-neonatal interactions play a pivotal part in triggering the onset of food allergies, including qualitative and quantitative composition of the microbiota. These factors seem to have the greatest influence early in life, an observation that has led to the generation of hypotheses to explain the food allergy epidemic, including the dual-allergen exposure hypothesis. These hypotheses have fuelled research in preventive strategies that seek to establish desensitization to allergens and/or tolerance to allergens in affected individuals. Allergen-nonspecific therapeutic strategies have also been investigated in a number of clinical trials, which will eventually improve the treatment options for patients with food allergy.

Food-Induced Acute Pancreatitis.

Food allergy, a commonly increasing problem worldwide, defined as an adverse immune response to food. A variety of immune-related effector cells such as mast cells, eosinophils, neutrophils, and T cells are involved in food-related allergic responses categorized as IgE mediated, non-IgE mediated, and mixed (IgE and non-IgE) depending upon underlying immunological mechanisms. The dietary antigens mainly target the gastrointestinal tract including pancreas that gets inflamed due to food allergy and leads acute pancreatitis. Reports indicate several food proteins induce pancreatitis; however, detailed underlying mechanism of food-induced pancreatitis is unexplored. The aim of the review is to understand and update the current scenario of food-induced pancreatitis. A comprehensive literature search of relevant research articles has been performed through PubMed, and articles were chosen based on their relevance to food allergen-mediated pancreatitis. Several cases in the literature indicate that acute pancreatitis has been provoked after the consumption of mustard, milk, egg, banana, fish, and kiwi fruits. Food-induced pancreatitis is an ignored and unexplored area of research. The review highlights the significance of food in the development of pancreatitis and draws the attention of physicians and scientists to consider food allergies as a possible cause for initiation of pancreatitis pathogenesis.

LAT is essential for the mast cell stabilising effect of tHGA in IgE-mediated mast cell activation.

Mast cells play a central role in the pathogenesis of allergic reaction. Activation of mast cells by antigens is strictly dependent on the influx of extracellular calcium that involves a complex interaction between signalling molecules located within the cells. We have previously reported that tHGA, an active compound originally isolated from a local shrub known as Melicope ptelefolia, prevented IgE-mediated mast cell activation and passive systemic anaphylaxis by suppressing the release of interleukin-4 (IL-4) and tumour necrosis factor (TNF)-α from activated rat basophilic leukaemia (RBL)-2H3 cells. However, the mechanism of action (MOA) as well as the molecular target underlying the mast cell stabilising effect of tHGA has not been previously investigated. In this study, DNP-IgE-sensitised RBL-2H3 cells were pre-treated with tHGA before challenged with DNP-BSA. To dissect the MOA of tHGA in IgE-mediated mast cell activation, the effect of tHGA on the transcription of IL-4 and TNF-α mRNA was determined using Real Time-Polymerase Chain Reaction (qPCR) followed by Calcium Influx Assay to confirm the involvement of calcium in the activation of mast cells. The protein lysates were analysed by using Western Blot to determine the effect of tHGA on various important signalling molecules in the LAT-PLCγ-MAPK and PI3K-NFκB pathways. In order to identify the molecular target of tHGA in IgE-mediated mast cell activation, the LAT and LAT2 genes in RBL-2H3 cells were knocked-down by using RNA interference to establish a LAT/LAT2 competition model. The results showed that tHGA inhibited the transcription of IL-4 and TNF-α as a result of the suppression of calcium influx in activated RBL-2H3 cells. The results from Western Blot revealed that tHGA primarily inhibited the LAT-PLCγ-MAPK pathway with partial inhibition on the PI3K-p65 pathway without affecting Syk. The results from RNAi further demonstrated that tHGA failed to inhibit the release of mediators associated with mast cell degranulation under the LAT/LAT2 competition model in the absence of LAT. Collectively, this study concluded that the molecular target of tHGA could be LAT and may provide a basis for the development of a mast cell stabiliser which targets LAT.

Phosphatidlyinositol-3-kinase C2 beta (PI3KC2ß) is a potential new target to treat IgE mediated disease.

Cross linking of the IgE receptor (FcεRI) on mast cells plays a critical role in IgE-dependent allergy including allergic rhinitis, asthma, anaphylaxis, and delayed type hypersensitivity reactions. The Ca2+ activated K+ channel, KCa3.1, plays a critical role in IgE-stimulated Ca2+ entry and degranulation in mast cells by helping to maintain a negative membrane potential, which provides an electrochemical gradient to drive Ca2+ influx. Of the 3 classes of PI3K, the class II PI3Ks are the least studied and little is known about the roles for class II PI3Ks in vivo in the context of the whole organism under normal and pathological conditions. Studying bone marrow derived mast cells (BMMC) isolated from PI3KC2ß-/- mice, we now show that the class II PI3KC2ß is critical for FcεRI stimulated KCa3.1 channel activation and the subsequent activation of mast cells. We found FcεRI-stimulated Ca2+ entry, cytokine production, and degranulation are decreased in BMMC isolated from PI3KC2ß-/- mice. In addition, PI3KC2ß-/- mice are markedly resistant to both passive cutaneous and passive systemic anaphylaxis. These findings identify PI3KC2ß as a new pharmacologic target to treat IgE-mediated disease.

Mast Cells and IgE can Enhance Survival During Innate and Acquired Host Responses to Venoms.

Mast cells and immunoglobulin E (IgE) antibodies are thought to promote health by contributing to host responses to certain parasites, but other beneficial functions have remained obscure. Venoms provoke innate inflammatory responses and pathology reflecting the activities of the contained toxins. Venoms also can induce allergic sensitization and development of venom-specific IgE antibodies, which can predispose some subjects to exhibit anaphylaxis upon subsequent exposure to the relevant venom. We found that innate functions of mast cells, including degradation of venom toxins by mast cell-derived proteases, enhanced survival in mice injected with venoms from the honeybee, two species of scorpion, three species of poisonous snakes, or the Gila monster. We also found that mice injected with sub-lethal amounts of honeybee or Russell's viper venom exhibited enhanced survival after subsequent challenge with potentially lethal amounts of that venom, and that IgE antibodies, FcεRI, and probably mast cells contributed to such acquired resistance.

Eosinophilic esophagitis: unclear roles of IgE and eosinophils.

Eosinophilic esophagitis (EoE) is a chronic inflammatory disease of the oesophagus. Recognized as a distinct entity only two decades ago, the emergence of the disease along with the availability of new technologies has rapidly opened new research avenues and outlined the main features of the pathogenesis of EoE. Yet, each advance in our understanding of the disease has raised new questions about the previous consensus. Currently, new subsets of the disease challenge our diagnostic criteria. For instance, it was believed that EoE did not respond to proton pump inhibitor (PPI) therapy; however, it has now been shown that a substantial proportion of EoE patients indeed respond to PPIs. In addition, a new subset of patients not even presenting eosinophil infiltrates in the oesophagus has also been described. Moreover, approaches for better understanding the heritability of the disease bring into question the dogma of predominant genetic involvement. Furthermore, the specificity and sensitivity of allergy testing for targeted food avoidance is highly controversial, and the production of specific antibodies in EoE now includes IgG4 in addition to IgE. In conclusion, EoE is perceived as 'a moving target' and the aim of this review was to summarize the current understanding of EoE pathogenesis.

Antibody to FcεRIα Suppresses Immunoglobulin E Binding to High-Affinity Receptor I in Allergic Inflammation.

PURPOSE: High-affinity receptor I (FcεRI) on mast cells and basophils plays a key role in the immunoglobulin E (IgE)-mediated type I hypersensitivity mediated by allergen cross-linking of the specific IgE-FcεRI complex. Thus, prevention of IgE binding to FcεRI on these cells is an effective therapy for allergic disease. We have developed a strategy to disrupt IgE binding to FcεRI using an antibody targeting FcεRIα. MATERIALS AND METHODS: Fab fragment antibodies, which lack the Fc domain, with high affinity and specificity for FcεRIα and effective inhibitory activity against IgE-FcεRI binding were screened. IgE-induced histamine, ß-hexosaminidase and Ca²âº release in basophils were determined by ELISA. A B6.Cg-Fcer1a(tm1Knt) Tg(FCER1A)1Bhk/J mouse model of passive cutaneous anaphylaxis (PCA) was used to examine the inhibitory effect of NPB311 on allergic skin inflammation. RESULTS: NPB311 exhibited high affinity to human FcεRIα (KD=4 nM) and inhibited histamine, ß-hexosaminidase and Ca²âº release in a concentration-dependent manner in hFcεRI-expressing cells. In hFcεRIα-expressing mice, dye leakage was higher in the PCA group than in controls, but decreased after NPB311 treatment. NPB311 could form a complex with FcεRIα and inhibit the release of inflammation mediators. CONCLUSION: Our approach for producing anti-FcεRIα Fab fragment antibody NPB311 may enable clinical application to a therapeutic pathway in IgE/FcεRI-mediated diseases.

FOXP3+ Tregs require WASP to restrain Th2-mediated food allergy.

In addition to the infectious consequences of immunodeficiency, patients with Wiskott-Aldrich syndrome (WAS) often suffer from poorly understood exaggerated immune responses that result in autoimmunity and elevated levels of serum IgE. Here, we have shown that WAS patients and mice deficient in WAS protein (WASP) frequently develop IgE-mediated reactions to common food allergens. WASP-deficient animals displayed an adjuvant-free IgE-sensitization to chow antigens that was most pronounced for wheat and soy and occurred under specific pathogen-free as well as germ-free housing conditions. Conditional deletion of Was in FOXP3+ Tregs resulted in more severe Th2-type intestinal inflammation than that observed in mice with global WASP deficiency, indicating that allergic responses to food allergens are dependent upon loss of WASP expression in this immune compartment. While WASP-deficient Tregs efficiently contained Th1- and Th17-type effector differentiation in vivo, they failed to restrain Th2 effector responses that drive allergic intestinal inflammation. Loss of WASP was phenotypically associated with increased GATA3 expression in effector memory FOXP3+ Tregs, but not in naive-like FOXP3+ Tregs, an effect that occurred independently of increased IL-4 signaling. Our results reveal a Treg-specific role for WASP that is required for prevention of Th2 effector cell differentiation and allergic sensitization to dietary antigens.

Different activation signals induce distinct mast cell degranulation strategies.

Mast cells (MCs) influence intercellular communication during inflammation by secreting cytoplasmic granules that contain diverse mediators. Here, we have demonstrated that MCs decode different activation stimuli into spatially and temporally distinct patterns of granule secretion. Certain signals, including substance P, the complement anaphylatoxins C3a and C5a, and endothelin 1, induced human MCs rapidly to secrete small and relatively spherical granule structures, a pattern consistent with the secretion of individual granules. Conversely, activating MCs with anti-IgE increased the time partition between signaling and secretion, which was associated with a period of sustained elevation of intracellular calcium and formation of larger and more heterogeneously shaped granule structures that underwent prolonged exteriorization. Pharmacological inhibition of IKK-ß during IgE-dependent stimulation strongly reduced the time partition between signaling and secretion, inhibited SNAP23/STX4 complex formation, and switched the degranulation pattern into one that resembled degranulation induced by substance P. IgE-dependent and substance P-dependent activation in vivo also induced different patterns of mouse MC degranulation that were associated with distinct local and systemic pathophysiological responses. These findings show that cytoplasmic granule secretion from MCs that occurs in response to different activating stimuli can exhibit distinct dynamics and features that are associated with distinct patterns of MC-dependent inflammation.

The Prevalence and Natural History of Food Allergy.

Numerous studies have demonstrated that the prevalence of food allergy is increasing. Not only are more children being diagnosed with food allergies, but studies suggest that when people outgrow their food allergies, it is taking longer than was previously thought. Studies in recent years have noted factors that may lead to a lower likelihood of developing a food allergy, including the early introduction of common food allergens, having a sufficient vitamin D level, or having a higher maternal intake of peanut early in pregnancy. Given a recent report that sensitization to common food allergens did not increase from the late 1980s/early 1990s to the mid-2000s, further studies will need to examine if the rise in food allergy prevalence is due to a change in the relationship between sensitization and clinical allergy or changes in the recognition and diagnosis of food allergy.

Epigallocatechin gallate suppresses Chlamydia pneumoniae mediated IgE responses in peripheral blood mononuclear cells: a pilot study.

BACKGROUND: Chlamydia pneumoniae (C. pneumoniae) causes respiratory infection in children and adults and is associated with asthma and induction of immunoglobulin E (IgE) responses. Previous studies in our laboratory reported that green tea extract (GTE) and its catechin, epigallocatechin gallate (EGCG) have immunoregulatory effects on IgE responses. Whereas tea polyphenols have in vitro inhibitory effects on the proliferation of C. pneumoniae, the in vitro effects of EGCG on C. pneumoniae- mediated IgE responses haven't been studied. We sought to clarify the in vitro effect of EGCG on C. pneumoniae mediated IgE responses by peripheral blood mononuclear cells (PBMC) in asthma. METHODS: PBMC from subjects with asthma and non-asthmatic controls were incubated with C. pneumoniae and cultured for 10 days ±EGCG (0.5, 5.0, 50 ng/mL). IgE levels in supernatants were determined (ELISA). RESULTS: Elevated IgE levels were detected in supernatants of PBMC from an asthma patient (2.6 ng/mL), whereas IgE levels of PBMC from non-asthmatics were low (<2.0 ng/mL) at baseline. When EGCG (0.5-50 ng/mL) was added to PBMC from the asthma patient, IgE production was suppressed in a dose-dependent manner (10-30%), compared with no EGCG. When PBMC from the asthma patient were incubated with C. pneumoniae, IgE production was suppressed (70%); when PBMC from non-asthmatics were incubated with C. pneumoniae, IgE levels remained undetectable (<2.0 ng/mL). When EGCG (0.5-50 ng/mL) was added to PBMC from the asthma patient, C. pneumoniae-induced IgE production was suppressed moderately (35-48%). CONCLUSIONS: EGCG suppressed C. pneumoniae- mediated IgE responses in PBMC from a patient with asthma.

IgE mediates broncho-vascular remodeling after neonatal sensitization in mice.

The temporal origins of childhood asthma are incompletely understood. We hypothesize that allergen sensitization which begins in early infancy causes IgE-mediated airway and vascular remodeling, and airway hyper-responsiveness. Mice were sensitized with ovalbumin (OVA) without or with anti-IgE antibody from postnatal day (P) 10 through P42. We studied airway resistance in response to Methacholine (MCh) challenge, bronchoalveolar lavage fluid (BAL) inflammatory cell content, immunohistochemistry for inflammation, alpha-smooth muscle actin (alpha-SMA) and platelet/endothelial cell adhesion molecule (PECAM) proteins, and Western blotting for vascular endothelial growth factor (VEGF) protein. Compared to controls, mice treated with OVA had increased airway resistance (baseline: 192% of control; MCH 12 mg/mL 170% of control; P less than 0.0.5). OVA treatment also increased lung alpha-SMA, VEGF and PECAM compared to controls. Inflammatory cells in the BAL and perivascular and peribronchiolar inflammatory cell infiltrates increased over controls with OVA exposure. These changes were counteracted by anti-IgE treatment. We conclude that mice sensitized in early infancy develop an IgE-mediated hyper-reactive airway disease with airway and vascular remodeling. Preventive approaches in early infancy of at-risk individuals may reduce childhood asthma.

IgE Inhibits Toll-like Receptor 7- and Toll-like Receptor 9-Mediated Expression of Interferon-α by Plasmacytoid Dendritic Cells in Patients With Systemic Lupus Erythematosus.

OBJECTIVE: Plasmacytoid dendritic cells (PDCs) play a central role in pathogenesis of systemic lupus erythematosus (SLE) through their unique ability to produce large amounts of type I interferon (IFN) upon Toll-like receptor 7 (TLR-7) and TLR-9 triggering. PDCs express specific surface regulatory receptors involved in negative regulation of IFNα secretion. These receptors use the γ-chain of high-affinity Fc receptor (FcR) for IgE, FcɛRI. We undertook this study to test our hypothesis that IgE engagement of FcɛRI on PDCs may impact IFNα production in SLE patients. METHODS: Serum levels of total IgE were measured in healthy volunteers, SLE patients, and patients with IgE-dependent allergic disorders. FcɛRI expression on PDCs from SLE patients was evaluated by flow cytometry. Purified PDCs were incubated with monoclonal IgE for 24 hours, then stimulated for 18 hours with TLR agonists or immune complexes (ICs). IFNα production by PDCs was detected by quantitative real-time polymerase chain reaction (PCR) and enzyme-linked immunosorbent assay. Expression of TLR-7, TLR-9, and IFN regulatory factor 7 (IRF-7) in PDCs was quantified by quantitative real-time PCR. RESULTS: We observed significantly higher IgE levels in SLE patients with quiescent disease than in those with active disease. In SLE patients, IgE levels correlated inversely with disease activity. IgE levels were not associated with the presence of antinuclear IgE. Purified PDCs treated for 24 hours with monoclonal IgE up-regulated FcɛRI expression in an IgE dose-dependent manner. IgE-treated PDCs significantly decreased IFNα secretion and down-regulated CCR7 expression upon stimulation with TLR-7 and TLR-9 ligands and ICs from lupus patients. IgE treatment down-regulated expression of TLR-9 and IRF-7. CONCLUSION: Our results support the notion that IgE plays a protective role in SLE pathogenesis through the modulation of inflammatory response by PDCs.

A Longitudinal Study of Association between Heavy Metals and Itchy Eyes, Coughing in Chronic Cough Patients: Related with Non-Immunoglobulin E Mediated Mechanism.

The association between heavy metals exposure and respiratory diseases or allergic sensitization showing high serum immunoglobulin E (IgE) has been suggested. However, previous findings have been inconsistent and the mechanisms responsible remain unclear. We evaluated heavy metal exposure and its association with coughing, itchy eyes in chronic cough patients with different IgE levels. Ninety outpatients in Kanazawa University Hospital were recruited between January-June 2011. Subjects whose total IgE measured by radioimmunosorbent test were asked to record their daily symptoms. We collected daily total suspended particles (TSP) from which concentrations of calcium (Ca), cadmium (Cd), chromium (Cr), iron (Fe), manganese (Mn), nickel (Ni), and lead (Pb) were determined then divided into high and low level groups. Generalized estimating equations were applied to compute the relationship between concentrations of these metals and symptoms. All metals at high levels were significantly associated with itchy eyes compared with low levels, with exception of Ca, the six others were significant in patients with IgE < 250 IU/mL. Cd, Fe, Mn had association with coughing (odds ratio-OR (95% confidence interval-CI): 1.13 (1.03, 1.24), 1.22 (1.05, 1.42), and 1.13 (1.01, 1.27), respectively), this relationship remained significant for Cd (OR (95% CI): 1.14 (1.03, 1.27)) and Mn (OR (95% CI): 1.15 (1.00, 1.31)) in patients with lower IgE. Our findings demonstrate the relationship between aerial heavy metals and itchy eyes, coughing in chronic cough patients, suggesting these symptoms may be due to a non-IgE mediated mechanism.

Pathophysiology of Food Allergy.

Food allergy is a growing public health problem that is estimated to affect 4% to 8% of children and 5% of adults. In this review, we discuss our current understanding of the pathophysiology of food allergy, from oral tolerance, to sensitization, and lastly the elicitation of an allergic response. As much of the existing evidence for the mechanisms of food allergy is derived from animal models, we include these studies where relevant. In addition, whenever possible, we review similar evidence involved in human disease and provide applications for consideration in clinical practice.

Comparison of two scales for evaluation of smile and dental attractiveness

OBJECTIVE: To compare the visual analogue scale (VAS) and the simplified Q-sort method used to investigate the highest level of agreement among dentists, orthodontists and laypeople when assessing smile and dental attractiveness. MATERIAL AND METHODS: An album containing 258 photos of 86 individuals with their lips at rest, a slight and broad smile, was assessed by 25 dentists (general clinicians and various specialties), 23 orthodontists and 27 laypeople with regard to smile and dental attractiveness. To this end, both VAS and simplified Q-sort method were used. Agreements were calculated by intraclass correlation coefficient (ICC). RESULTS: For the single measurement between the VAS method and the simplified Q-sort method, all simplified Q-sort rates were higher in all groups. The simplified Q-sort method results ranged between 0.42 and 0.49 while those of the VAS method varied between 0.37 and 0.42. The simplified Q-sort method also presented higher mean measurement values (0.95 and 0.96) in comparison to VAS (0.94 and 0.95). CONCLUSIONS: Both scales may be considered reliable for evaluating smile and dental attractiveness; however, the simplified Q-Sort method presented slightly higher values than the VAS method. .

OBJETIVO: comparar a escala visual analógica (EVA) e o método Q-sort simplificado quanto à maior concordância nas avaliações entre cirurgiões-dentistas, ortodontistas e leigos em atratividade dentária e do sorriso. MÉTODOS: 258 fotografias, provenientes de 86 indivíduos, fotografados com os lábios em repouso, sorriso leve e sorriso amplo, foram avaliadas quanto à atratividade dentária e do sorriso por meio da EVA e do Q-sort simplificado por 25 cirurgiões-dentistas (clínicos gerais e especialidades diversas), 23 Ortodontistas e 27 leigos. As concordâncias foram calculadas pelo Coeficiente de Correlação Intraclasse (ICC). RESULTADOS: para medida única entre a EVA e o método Q-sort simplificado, todas as taxas do Q-sort simplificado foram maiores em todos os grupos. O resultado do Q-sort simplificado variou entre 0,42 e 0,49, e da EVA entre 0,37 e 0,42. O Q-sort simplificado também apresentou valores de medida média superiores (0,95 e 0,96) em relação à EVA (0,94 e 0,95). CONCLUSÃO: pode-se considerar que ambas as escalas são confiáveis para avaliação da atratividade dentária e do sorriso; porém, o método Q-sort simplificado apresentou valores ligeiramente maiores que os da EVA. .