IgE-mediated Responses Research Articles

Climate Change and Air Pollution: Effects on Respiratory Allergy.

A body of evidence suggests that major changes involving the atmosphere and the climate, including global warming induced by anthropogenic factors, have impact on the biosphere and human environment. Studies on the effects of climate change on respiratory allergy are still lacking and current knowledge is provided by epidemiological and experimental studies on the relationship between allergic respiratory diseases, asthma and environmental factors, such as meteorological variables, airborne allergens, and air pollution. Urbanization with its high levels of vehicle emissions, and a westernized lifestyle are linked to the rising frequency of respiratory allergic diseases and bronchial asthma observed over recent decades in most industrialized countries. However, it is not easy to evaluate the impact of climate changes and air pollution on the prevalence of asthma in the general population and on the timing of asthma exacerbations, although the global rise in asthma prevalence and severity could also be an effect of air pollution and climate change. Since airborne allergens and air pollutants are frequently increased contemporaneously in the atmosphere, an enhanced IgE-mediated response to aeroallergens and enhanced airway inflammation could account for the increasing frequency of respiratory allergy and asthma in atopic subjects in the last 5 decades. Pollen allergy is frequently used to study the relationship between air pollution and respiratory allergic diseases, such as rhinitis and bronchial asthma. Epidemiologic studies have demonstrated that urbanization, high levels of vehicle emissions, and westernized lifestyle are correlated with an increased frequency of respiratory allergy prevalently in people who live in urban areas in comparison with people living in rural areas. Climatic factors (temperature, wind speed, humidity, thunderstorms, etc.) can affect both components (biological and chemical) of this interaction.

Effects on asthma and respiratory allergy of Climate change and air pollution

The major changes to our world are those involving the atmosphere and the climate, including global warming induced by anthropogenic factors, with impact on the biosphere and human environment. Studies on the effects of climate changes on respiratory allergy are still lacking and current knowledge is provided by epidemiological and experimental studies on the relationship between allergic respiratory diseases, asthma and environmental factors, like meteorological variables, airborne allergens and air pollution. Epidemiologic studies have demonstrated that urbanization, high levels of vehicle emissions and westernized lifestyle are correlated with an increased frequency of respiratory allergy, mainly in people who live in urban areas in comparison with people living in rural areas. However, it is not easy to evaluate the impact of climate changes and air pollution on the prevalence of asthma in general and on the timing of asthma exacerbations, although the global rise in asthma prevalence and severity could be also considered an effect of air pollution and climate changes. Since airborne allergens and air pollutants are frequently increased contemporaneously in the atmosphere, enhanced IgE-mediated response to aeroallergens and enhanced airway inflammation could account for the increasing frequency of respiratory allergy and asthma in atopic subjects in the last five decades. Pollen allergy is frequently used to study the interrelationship between air pollution and respiratory allergic diseases such as rhinitis and bronchial asthma. Climatic factors (temperature, wind speed, humidity, thunderstorms, etc) can affect both components (biological and chemical) of this interaction. Scientific societies should be involved in advocacy activities, such as those realized by the Global Alliance against chronic Respiratory Diseases (GARD).

Effects on asthma and respiratory allergy of Climate change and air pollution.

The major changes to our world are those involving the atmosphere and the climate, including global warming induced by anthropogenic factors, with impact on the biosphere and human environment. Studies on the effects of climate changes on respiratory allergy are still lacking and current knowledge is provided by epidemiological and experimental studies on the relationship between allergic respiratory diseases, asthma and environmental factors, like meteorological variables, airborne allergens and air pollution.Epidemiologic studies have demonstrated that urbanization, high levels of vehicle emissions and westernized lifestyle are correlated with an increased frequency of respiratory allergy, mainly in people who live in urban areas in comparison with people living in rural areas.However, it is not easy to evaluate the impact of climate changes and air pollution on the prevalence of asthma in general and on the timing of asthma exacerbations, although the global rise in asthma prevalence and severity could be also considered an effect of air pollution and climate changes. Since airborne allergens and air pollutants are frequently increased contemporaneously in the atmosphere, enhanced IgE-mediated response to aeroallergens and enhanced airway inflammation could account for the increasing frequency of respiratory allergy and asthma in atopic subjects in the last five decades. Pollen allergy is frequently used to study the interrelationship between air pollution and respiratory allergic diseases such as rhinitis and bronchial asthma. Climatic factors (temperature, wind speed, humidity, thunderstorms, etc) can affect both components (biological and chemical) of this interaction. Scientific societies should be involved in advocacy activities, such as those realized by the Global Alliance against chronic Respiratory Diseases (GARD).

Comparisons of Allergenic and Metazoan Parasite Proteins: Allergy the Price of Immunity.

Allergic reactions can be considered as maladaptive IgE immune responses towards environmental antigens. Intriguingly, these mechanisms are observed to be very similar to those implicated in the acquisition of an important degree of immunity against metazoan parasites (helminths and arthropods) in mammalian hosts. Based on the hypothesis that IgE-mediated immune responses evolved in mammals to provide extra protection against metazoan parasites rather than to cause allergy, we predict that the environmental allergens will share key properties with the metazoan parasite antigens that are specifically targeted by IgE in infected human populations. We seek to test this prediction by examining if significant similarity exists between molecular features of allergens and helminth proteins that induce an IgE response in the human host. By employing various computational approaches, 2712 unique protein molecules that are known IgE antigens were searched against a dataset of proteins from helminths and parasitic arthropods, resulting in a comprehensive list of 2445 parasite proteins that show significant similarity through sequence and structure with allergenic proteins. Nearly half of these parasite proteins from 31 species fall within the 10 most abundant allergenic protein domain families (EF-hand, Tropomyosin, CAP, Profilin, Lipocalin, Trypsin-like serine protease, Cupin, BetV1, Expansin and Prolamin). We identified epitopic-like regions in 206 parasite proteins and present the first example of a plant protein (BetV1) that is the commonest allergen in pollen in a worm, and confirming it as the target of IgE in schistosomiasis infected humans. The identification of significant similarity, inclusive of the epitopic regions, between allergens and helminth proteins against which IgE is an observed marker of protective immunity explains the ‘off-target’ effects of the IgE-mediated immune system in allergy. All these findings can impact the discovery and design of molecules used in immunotherapy of allergic conditions.

Iron Requirements for Infants with Cow Milk Protein Allergy

H istorically, cow milk has been used as a major source of protein and balanced nutrition for infants and children in resource-rich and resource-constrained countries. It is a rich source of energy, protein, and calcium. It is also an important source of fat; many of its fatty acids are readily metabolized to essential omega-3 fatty acids. Regular consumption of milk during childhood has been shown to enhance bone density later in life. However, reliance upon whole pasteurized cow milk as the sole or major source of nutrition for infants during the first year of life can increase the risk for iron deficiency and, in extreme cases, iron-deficient anemia (IDA) for a number of reasons. In 1972, Woodruff et al showed that 7 of 12 infants (ages 7-17 months) with IDA who ingested between 720 and 1920 mL whole milk daily had higher albumin turnover rates than a group of 5 normal infants. Parenteral iron had no effect on albumin turnover, but replacing whole milk with reconstituted evaporated milk or soy formula decreased the high albumin turnover rates to normal levels, suggesting that large amounts of cow milk protein could result in iron and protein loss in the gastrointestinal tract. Cow milk contains low levels of ascorbic acid, a factor that increases iron absorption, and certain proteins that negatively impact iron absorption. Cow milk contains about 4 times more calcium than human milk, and calcium negatively impacts iron absorption. Furthermore, cow milk has a higher protein concentration than human milk, and ingestion of large amounts can lead to metabolic and fluid imbalances, particularly in children with febrile illnesses. Thus, several entities have recommended against whole cow milk ingestion until 9-12 months and then, only when given in moderate amounts in conjunction with appropriate complementary foods.

Curcumin Ingestion Inhibits Mastocytosis and Suppresses Intestinal Anaphylaxis in a Murine Model of Food Allergy.

IgE antibodies and mast cells play critical roles in the establishment of allergic responses to food antigens. Curcumin, the active ingredient of the curry spice turmeric, has anti-inflammatory properties, and thus may have the capacity to regulate Th2 cells and mucosal mast cell function during allergic responses. We assessed whether curcumin ingestion during oral allergen exposure can modulate the development of food allergy using a murine model of ovalbumin (OVA)-induced intestinal anaphylaxis. Herein, we demonstrate that frequent ingestion of curcumin during oral OVA exposure inhibits the development of mastocytosis and intestinal anaphylaxis in OVA-challenged allergic mice. Intragastric (i.g.) exposure to OVA in sensitized BALB/c mice induced a robust IgE-mediated response accompanied by enhanced OVA-IgE levels, intestinal mastocytosis, elevated serum mMCP-1, and acute diarrhea. In contrast, mice exposed to oral curcumin throughout the experimental regimen appeared to be normal and did not exhibit intense allergic diarrhea or a significant enhancement of OVA-IgE and intestinal mast cell expansion and activation. Furthermore, allergic diarrhea, mast cell activation and expansion, and Th2 responses were also suppressed in mice exposed to curcumin during the OVA-challenge phase alone, despite the presence of elevated levels of OVA-IgE, suggesting that curcumin may have a direct suppressive effect on intestinal mast cell activation and reverse food allergy symptoms in allergen-sensitized individuals. This was confirmed by observations that curcumin attenuated the expansion of both adoptively transferred bone marrow-derived mast cells (BMMCs), and inhibited their survival and activation during cell culture. Finally, the suppression of intestinal anaphylaxis by curcumin was directly linked with the inhibition of NF-κB activation in curcumin-treated allergic mice, and curcumin inhibited the phosphorylation of the p65 subunit of NF-κB in BMMCs. In summary, our data demonstrates a protective role for curcumin during allergic responses to food antigens, suggesting that frequent ingestion of this spice may modulate the outcome of disease in susceptible individuals.

Вкупен, групно специфичен и специфичен ИгЕ кон храна во серум од пациенти упатени за испитување на алергија во Република Македонија

INTRODUCTION: The term "food allergy" refers to a patient's immune response directed towards food. Food allergy is a ''negative health effect arising from a specific immune response that occurs during repeated exposure to certain foods". This definition includes immune responses that are IgE-mediated, non-IgE-mediated or combinations of both. IgE-mediated reactions are characterized by the acute onset of symptoms, usually within two hours after intake or exposure to food and symptoms frequently involve abnormalities of the skin, gastrointestinal tract and/or the respiratory tract. Even though any food may bear the potential for mediating an allergic reaction and more than 170 foods have been reported to cause IgE-mediated immune responses, it is a rather small number of foods that have been found to cause the majority of allergic reactions. They are described in the literature as "major food allergens'', and include: peanuts, nuts, eggs, milk, fish, crabs, shellfish, wheat and soy. Globally, the prevalence of food allergies seems to be on the rise and increases in incidence are observed in almost all countries. Food allergy prevalence varies in a manner that is dependent on the respective culture and population.OBJECTIVES: The objectives of this study include: the quantitative examination of total and specific IgE levels from blood serum in response to allergens from animal and plant-derived foods in patients suspected of food allergy; the determination of the degree of an allergic reaction; the qualitative examination of group-specific IgE; the correlation between the total and specific IgE antibodies to food allergens of plant and animal origin, and the calculation of the percentage of food allergies in the Macedonian population.MATERIALS AND METHODS: Eight thousand eight hundred ninety eight (8898) consecutive patients tested for allergies over a ten year period (from 01.01.2001 to 01.01.2011) at the Institute of Immunobiology and Human Genetics were analyzed retrospectively. All patients were grouped according to gender, age, and place of residence and according to the analysis of total and specific IgE to allergens originating from plant and animal food. The quantitative and qualitative determination of total IgE, specific IgE and specific IgE to groups of food allergens was performed with the UniCAP100 System (Pharmacia, Uppsala, Sweden).RESULTS: The results were statistically processed and organized in tables and graphs. The number of patients being tested for allergies grew continually over the ten year period. Most patients originated from Skopje (1.2% of the city population), whereas the rest were from other Macedonian cities, whose number remained below 1% with respect to the total population of their respective city of originThe results for the distribution of the patient number in relation to the total IgE concentration group revealed that most of the patients had normal total IgE levels.Furthermore, total IgE levels varied in a statistically significant manner between the respective age groups (p <0.01, <0.05). Gender-specific analyses revealed that the geometric mean for the total serum IgE levels was higher in men compared to those in women, or p <0.01, t (3271) = 3732; p = 0.00, <0.01, <0.05, which means that there is a statistically significant difference between total IgE in men and women.Moreover, the various food-specific IgE antibody concentration levels were found to be dependent on the respective patient age group.There was a significant correlation between total IgE and egg white, milk, alpha-lactalbumin and casein. A further significant correlation was found between total IgE and group-specific IgE: mixture of food, meat mixture, a mixture of fruit and a cereal mixture. 28.5% of all analyzed patients had a positive finding for IgE antibodies in their blood, while 71.5% were negative.CONCLUSION: The increase in the number of patients with food allergy may be due to an ever increasing trend in the use of ethnic or exotic food ingredients. Another cause may be the greater exposure to artificial, factory-processed food products. Differences in admitted patient number originating from various cities in the Republic of Macedonia can be explained by the different awareness levels of family doctors for the available analyses performed at Institute of Immunobiology and Human Genetics, the geographical distance of the cities to Skopje. Our findings highlight the need for opening additional allergologic laboratories in several cities in the country. The large number of patients that tested negative for food allergies illustrate the need for further education of the primary care physicians by means of seminars, conferences and lectures.

Didox suppresses IgE-mediated mast cell response (HYP4P.317)

Abstract Mast cells play a central role in allergic reactions through high-affinity IgE receptor (FcεRI)-mediated responses. FcεRI cross-linking on mast cells activates multiple signaling pathways that lead to sustained inflammation through degranulation, prolonged generation of reactive oxygen species, and production of various cytokines and chemokines. These cellular responses are involved in inflammatory diseases including asthma, rheumatoid arthritis, multiple sclerosis and heart disease. As a synthetic anti-oxidant and a potent ribonucleotide reductase inhibitor capable of suppressing gene expression, Didox (3,4-Dihyroxybenzohydroxamic acid) has become an attractive therapeutic for treating inflammatory diseases. Here we investigated the anti-inflammatory abilities of Didox as a therapeutic approach to attenuate the allergic response. Our results show that Didox treatment yields a dose-dependent reduction in IgE-stimulated cytokine secretion among bone marrow-derived mast cell (BMMC). These effects are not directly linked to reduced receptor expression, or an increase in cell death and suggest a decrease in signaling associated with cytokine secretion. Together these data could indicate a role for Didox in the treatment of MC-associated inflammatory and autoimmune diseases.

Mo1595 Outcome of Capsule Endoscopy in Small Bowel Diseases: a Single Center Experience of 942 Capsule Endoscopy Procedures Over 11 Years

was!1-31,7 mcg/l, mean3.39 6.45) in CLE+;!1-11.4 mcg/l, mean 3.47 3.83in URT+;!1-1.57mcg/l, mean 1.03 0.3in HC, which was not significant. Conclusions: Our results indicate that patients with urticaria+IBS may suffer from food intolerance and respond to exclusion diet. They display the same deficits as IBS patients without urticaria in mucosal barrier integrity, accompanied by a trend to increased eosinophils in duodenal biopsies in URT+ with significantly higher concentrations of ECP than HC, which suggest both IgE and non-IgE mediated response in the urticarial patients. Larger studies are needed to confirm these small data.

Flow cytometric analysis of drug-Induced basophil histamine release.

Histamine and its release can be studied by multicolor flow cytometry on a single cell level by an enzyme affinity method (HistaFlow®). However, for the time-being, the clinical and scientific application of the HistaFlow® technique remains limited. This study aims at verifying the reliability of the HistaFlow® as an instrument to quantify IgE-mediated basophil responses to drugs, i.e., rocuronium, which are believed to be less potent basophil activators than large proteinaceous allergens. Ten patients and three exposed control individuals were included in this study. Each subject underwent in vitro basophil activation tests (HistaFlow®) with 0.16 and 1.6 mmol/L rocuronium. Patients showed an activation of basophils ranging from 11 to 86% of CD63 positive basophils and a median histamine release per cell from 68 to 100% after stimulation with an optimal concentration of 1.6 mmol/L rocuronium. For the control individuals no activation was demonstrable. This study confirms that the HistaFlow® technique is a reliable tool to study histamine release by individual cells in response to drugs. Although the HistaFlow® technique will probably not add to the diagnostic management of rocuronium allergy, our findings suggest that the technique could constitute an important asset for future studies on the pathomechanism(s) of immediate drug hypersensitivity reactions. © 2015 International Clinical Cytometry Society.

Is the analysis of histamine and/or interleukin-4 release after isocyanate challenge useful in the identification of patients with IgE-mediated isocyanate asthma?

Isocyanates are a well-known and frequent cause of occupational asthma. The implementation of specific inhalation challenges (SICs) is the gold standard in asthma diagnosis supporting occupational case history, lung function testing, specific skin prick tests and the detection of specific IgE. However, the diagnosis is not always definitive. An interesting new approach, analyses of individual genetic susceptibilities, requires discrimination between a positive SIC reaction arising from IgE-mediated immune responses and one from other pathophysiological mechanisms. Hence, additional refinement tools would be helpful in defining sub-classes of occupational asthma and diagnosis. We used total IgE levels, specific IgE and SIC results for sub-classification of 27 symptomatic isocyanate workers studied. Some mutations in glutathione S-transferases (GSTs) are suspected either to enhance or to decrease the individual risk in the development of isocyanate asthma. Our patient groups were assessed for the point mutations GSTP1*I105V and GSTP1*A114V as well as deletions (null mutations) of GSTM1 and GSTT1. There seems to be a higher risk in developing IgE-mediated reactions when GSTM1 is deleted, while GSTT1 deletions were found more frequently in the SIC positive group. Blood samples taken before SIC, 30–60min and 24h after SIC, were analyzed for histamine and IL-4, classical markers for the IgE-mediated antigen-specific activation of basophils or mast cells. We suggest that the utility of histamine measurements might provide an additional useful marker reflecting isocyanate-induced cellular reactions (although the sampling times require optimization). The promising measurement of IL-4 is not feasible at present due to the lack of a reliable, validated assay.

Contribution of autoallergy to the pathogenesis in the NOD mice

The immunoglobulin isotype IgE is commonly associated with allergy. However, its involvement in autoimmune disease in general, and Type 1 diabetes (T1D) in particular, is still not completely clarified, nonetheless IgE has been observed in patients with T1D. In this article, we aimed to elucidate the contribution of IgE in the pathogenesis of the disease in a spontaneous model for T1D, i.e. the NOD mouse. We observed increased levels of IgE in splenic, lymph node and peripheral blood B cells in the NOD mice compared to the control C57BL/6 (B6) mice. No correlation was found between the IgE levels on B cells and those in the sera of these mice, indicating a B cell intrinsic property mediating IgE capture in NOD. Functionally, the B cells from NOD were similar to B6 in rescuing the IgE-mediated immune response via the low affinity receptor CD23 in a transgenic adoptive transfer system. However, the involvement of IgE in diabetes development was clearly demonstrated, as treatment with anti-IgE antibodies delayed the incidence of the diabetes in the NOD mice compared to the PBS treated group. Pancreas sections from a 13-week-old NOD revealed the presence of tertiary lymphoid structures with T cells, B cells, germinal centers and IgE suggesting the presence of autoantigen specific IgE. Our study provides an insight to the commonly overlooked immunoglobulin IgE and its potential role in autoimmunity.

IgE Sensitization to Thaumetopoea pityocampa: Diagnostic Utility of a Setae Extract, Clinical Picture and Associated Risk Factors

Background: Setae from Thaumetopoea pityocampa larvae (the pine processionary moth or PPM) can induce hypersensitivity reactions, but their clinical role in IgE-mediated responses is still subject to discussion. The aim of this study was to evaluate a setae extract for in vivo and in vitro diagnosis in nonhospitalized patients with reactions to PPM. Methods: Forty-eight adult patients presenting with PPM cutaneous reactions were studied by skin prick test (SPT) and specific IgE using setae and whole larval (WL) extracts. Biological standardized extracts were used for skin tests. Results: A total of 47.9% patients had a positive SPT for PPM (70% to both extracts, 17% only to the WL extract and 13% only to the setae extract). IgE immunoblotting detected several reactive bands in 91% of the SPT-positive cases. In multivariate analysis, male sex, immediate latency (<1 h) and duration of skin symptoms (<24 h) were independent predictors of a positive SPT. Conclusions: IgE sensitization to PPM was found in 48% of the study patients, which was associated with immediate reactions and evanescent cutaneous lesions. Most of these patients reacted to both WL and setae extracts, but some reacted to only one of them. According to our data, skin and in vitro tests to PPM should be performed using both extracts.

The major birch pollen allergen Bet v 1 induces different responses in dendritic cells of birch pollen allergic and healthy individuals.

Dendritic cells play a fundamental role in shaping the immune response to allergens. The events that lead to allergic sensitization or tolerance induction during the interaction of the major birch pollen allergen Bet v 1 and dendritic cells are not very well studied. Here, we analyzed the uptake of Bet v 1 and the cross-reactive celery allergen Api g 1 by immature monocyte-derived dendritic cells (iMoDCs) of allergic and normal donors. In addition, we characterized the allergen-triggered intracellular signaling and transcriptional events. Uptake kinetics, competitive binding, and internalization pathways of labeled allergens by iMoDCs were visualized by live-cell imaging. Surface-bound IgE was detected by immunofluorescence microscopy and flow cytometry. Allergen- and IgE-induced gene expression of early growth response genes and Th1 and Th2 related cytokines and chemokines were analyzed by real-time PCR. Phosporylation of signaling kinases was analyzed by Western blot. Internalization of Bet v 1 by iMoDCs of both donor groups, likely by receptor-mediated caveolar endocytosis, followed similar kinetics. Bet v 1 outcompeted Api g 1 in cell surface binding and uptake. MoDCs of allergic and healthy donors displayed surface-bound IgE and showed a pronounced upregulation of Th2 cytokine- and NFκB-dependent genes upon non-specific Fcε receptor cross-linking. In contrast to these IgE-mediated responses, Bet v 1-stimulation increased transcript levels of the Th2 cytokines IL-4 and IL-13 but not of NFκB-related genes in MoDCs of BP allergic donors. Cells of healthy donors were either unresponsive or showed elevated mRNA levels of Th1-promoting chemokines. Moreover, Bet v 1 was able to induce Erk1/2 and p38 MAPK activation in BP allergics but only a slight p38 activation in normal donors. In conclusion, our data indicate that Bet v 1 favors the activation of a Th2 program only in DCs of BP allergic individuals.

Inhibitory Effect of Methyleugenol on IgE‐Mediated Allergic Inflammation in RBL‐2H3 Cells

Allergic diseases, such as asthma and allergic rhinitis, are common. Therefore, the discovery of therapeutic drugs for these conditions is essential. Methyleugenol (ME) is a natural compound with antiallergic, antianaphylactic, antinociceptive, and anti-inflammatory effects. This study examined the antiallergic effect of ME on IgE-mediated inflammatory responses and its antiallergy mechanism in the mast cell line, RBL-2H3. We found that ME significantly inhibited the release of β-hexosaminidase, tumor necrosis factor- (TNF-) α, and interleukin- (IL-) 4, and was not cytotoxic at the tested concentrations (0–100 μM). Additionally, ME markedly reduced the production of the proinflammatory lipid mediators prostaglandin E2 (PGE2), prostaglandin D2 (PGD2), leukotriene B4 (LTB4), and leukotriene C4 (LTC4). We further evaluated the effect of ME on the early stages of the FcεRI cascade. ME significantly inhibited Syk phosphorylation and expression but had no effect on Lyn. Furthermore, it suppressed ERK1/2, p38, and JNK phosphorylation, which is implicated in proinflammatory cytokine expression. ME also decreased cytosolic phospholipase A2 (cPLA2) and 5-lipoxygenase (5-LO) phosphorylation and cyclooxygenase-2 (COX-2) expression. These results suggest that ME inhibits allergic response by suppressing the activation of Syk, ERK1/2, p38, JNK, cPLA2, and 5-LO. Furthermore, the strong inhibition of COX-2 expression may also contribute to the antiallergic action of ME. Our study provides further information about the biological functions of ME.

IgE/antigen-mediated enhancement of IgE production is a mechanism underlying the exacerbation of airway inflammation and remodelling in mice.

IgE is known to enhance some antibody responses to specific antigens, but whether this contributes to allergic asthma remains unclear. We have previously found that repeated antigen challenges in mice sensitized with antigen-specific IgE monoclonal antibody (mAb) exacerbated airway inflammation and remodelling accompanied by increased levels of endogenous antigen-specific IgE and IgG1. Here, we investigated whether IgE/antigen-mediated enhancement of endogenous IgE production contributes to the exacerbation of airway inflammation and remodelling. BALB/c mice passively sensitized with ovalbumin (OVA) -specific IgE mAb were challenged with OVA intratracheally seven times; anti-IgE mAb was intraperitoneally administered 1 day before the fourth challenge. Treatment with anti-IgE mAb inhibited the increased level of endogenous OVA-specific IgE in serum, but not OVA-specific IgG1, and a biphasic increase in airway resistance at the fourth challenge. Furthermore, a biphasic increase in airway resistance, airway hyper-responsiveness to methacholine, OVA-specific IgE and IgG1 production, and infiltrations by neutrophils and eosinophils in the lungs at the seventh challenge were suppressed by treatment; airway remodelling, such as goblet cell hyperplasia and sub-epithelial fibrosis, was also reduced. In addition, the production of interleukin-17A, interleukin-33 and CXCL1 in the lungs related to these IgE-mediated responses was decreased by treatment. Collectively, we found that the mechanism leading to the exacerbation of allergic asthma is closely related to IgE/antigen-mediated enhancement of IgE production, suggesting that this may create a vicious circle leading to the chronic status in asthmatic patients having levels of antigen-specific IgE ready to form complexes with antigen.

Hypersensitivity reactions to intravenous iron: guidance for risk minimization and management.

Intravenous iron is widely used for the treatment of iron deficiency anemia when oral iron is inappropriate, ineffective or poorly tolerated. Acute hypersensitivity reactions during iron infusions are very rare but can be life-threatening. This paper reviews their frequency, pathogenesis and risk factors, and provides recommendations about their management and prevention. Complement activation-related pseudo-allergy triggered by iron nanoparticles is probably a more frequent pathogenetic mechanism in acute reactions to current formulations of intravenous iron than is an immunological IgE-mediated response. Major risk factors for hypersensitivity reactions include a previous reaction to an iron infusion, a fast iron infusion rate, multiple drug allergies, severe atopy, and possibly systemic inflammatory diseases. Early pregnancy is a contraindication to iron infusions, while old age and serious co-morbidity may worsen the impact of acute reactions if they occur. Management of iron infusions requires meticulous observation, and, in the event of an adverse reaction, prompt recognition and severity-related interventions by well-trained medical and nursing staff.

Autocrine hemokinin-1 functions as an endogenous adjuvant for IgE-mediated mast cell inflammatory responses

Efficient development of atopic diseases requires interactions between allergen and adjuvant to initiate and amplify the underlying inflammatory responses. Substance P (SP) and hemokinin-1 (HK-1) are neuropeptides that signal through the neurokinin-1 receptor (NK1R) to promote inflammation. Mast cells initiate the symptoms and tissue effects of atopic disorders, secreting TNF and IL-6 after FcεRI cross-linking by antigen-IgE complexes (FcεRI-activated mast cells [FcεRI-MCs]). Additionally, MCs express the NK1R, suggesting an adjuvant role for NK1R agonists in FcεRI-MC-mediated pathologies; however, in-depth research addressing this relevant aspect of MC biology is lacking. We sought to investigate the effect of NK1R signaling and the individual roles of SP and HK-1 as potential adjuvants for FcεRI-MC-mediated allergic disorders. Bone marrow-derived mast cells (BMMCs) from C57BL/6 wild-type (WT) or NK1R(-/-) mice were used to investigate the effects of NK1R signaling on FcεRI-MCs. BMMCs generated from Tac1(-/-) mice or after culture with Tac4 small interfering RNA were used to address the adjuvancy of SP and HK-1. WT, NK1R(-/-), and c-Kit(W-sh/W-sh) mice reconstituted with WT or NK1R(-/-) BMMCs were used to evaluate NK1R signaling on FcεRI-MC-mediated passive local and systemic anaphylaxis and on airway inflammation. FcεRI-activated MCs upregulated NK1R and HK-1 transcripts and protein synthesis, without modifying SP expression. In a positive signaling loop HK-1 promoted TNF and IL-6 secretion by MC degranulation and protein synthesis, the latter through the phosphoinositide 3-kinase/Akt/nuclear factor κB pathways. Invivo NK1R signaling was necessary for the development of passive local and systemic anaphylaxis and airway inflammation. FcεRI stimulation of MCs promotes autocrine secretion of HK-1, which signals through NK1R to provide adjuvancy for efficient development of FcεRI-MC-mediated disorders.

Tetraspanin CD151 specifically regulates ERK1/2 signaling to limit FcεRI-mediated production of cytokines by mast cells (HYP3P.349)

Abstract Mast cells and basophils are granulocytes critical in the pathogenesis of allergic disease due to the release of preformed and newly synthesized mediators. Tetraspanins are emerging as novel modulators of signals for cellular activation, however, mechanistic understanding of their function is currently lacking. We found tetraspanin CD151 to be specifically induced in human and mouse mast cells upon IgE stimulation, suggesting a functional role in activation of these cells. Here, we show that CD151 modulates IgE-induced mast cell activation by exerting selective control over downstream pathways regulating de novo synthesis of cytokines IL-4, IL-13 and TNF-α. Mechanistically, CD151 selectively targets IgE-induced activation of ERK1/2, associated with cytokine production, but has no regulatory effect on PLCγ1 or calcium release necessary for degranulation. Inhibition of ERK1/2 blocks the exaggerated induction of cytokines by CD151 deficient mast cells. In vivo, CD151 deficiency significantly exacerbates IgE-mediated late phase response in a murine model of passive cutaneous anaphylaxis. Collectively, our data indicate that CD151 functions in the late phase of IgE-induced mast cell activation by limiting cytokine synthesis.

The use of single versus multiple antigens in specific allergen immunotherapy for allergic rhinitis

Allergen-specific immunotherapy (AIT) targets the IgE-mediated response to specific allergen(s). Accordingly, a monosensitized patient would be the ideal candidate for AIT. However, most patients are polysensitized; thus, two main problems emerge: first, whether AIT with a clinically relevant allergen is effective in polysensitized patients, and second, whether the use of a few allergens (European approach) or of mixtures containing all the possibly sensitizing allergens (USA approach) should be used. Of note, only in recent years has the so-called 'component resolved diagnosis' introduced new diagnostic opportunities. In the present article, the available experimental data concerning the controversial aspects of single versus multiallergen AIT are reviewed. Some data are only available from isolated studies, which are often not controlled, and few trials on the argument have been recently conducted. Main findings are that AIT can be effective in both monosensitized and polysensitized patients, as shown by large trials with grass extracts. The evidence for the efficacy of allergen mixes is still weak, but component-resolved diagnosis could represent a valuable help in selecting the allergen. As a matter of fact, comparative trials on multiple versus single allergen immunotherapy would be expensive and time-consuming: this justifies the paucity of data.