IgE-mediated Allergic Responses Research Articles

Isoflavones Suppress the Expression of the FcεRI High-Affinity Immunoglobulin E Receptor Independent of the Estrogen Receptor

Isoflavones found in soybeans and soy products possess clinically relevant properties. However, the anti-allergic effect of isoflavones has been poorly studied. We examined the effects of isoflavones, genistein, daidzein, and equol, on the expression of the high-affinity immunoglobulin E (IgE) receptor, FcεRI, which plays a central role in IgE-mediated allergic response. Flow cytometric analysis showed that all of these isoflavones reduced the cell surface expression of FcεRI on mouse bone-marrow-derived mast cells and human basophilic KU812 cells. All isoflavones decreased the levels of the FcεRIα mRNA in the cells. Genistein reduced the mRNA expression of the β chain, and daidzein and equol downregulated that of the γ chain. The suppressive effects of isoflavones on FcεRI expression were unaffected by ICI 182,780, an estrogen receptor antagonist, suggesting that these effects were independent of estrogen receptors.

A study of IgE sensitization and skin response to histamine in Asian-Pacific American adults.

Allergic disorders and skin response to histamine have been noted to vary in different ethnicities. We investigated IgE-mediated allergic sensitization and skin response to histamine in Asian Pacific Americans (APAs), black and Hispanic Americans, and white adults. A retrospective questionnaire-based study was performed of 2222 adults presenting at a New York City allergy referral center from 1994 to 2003. Questionnaire data included sex, age, and ethnicity and personal and family history of atopic disorders. Skin-prick test (SPT) data included saline and histamine controls and response to a standardized panel of 10 aeroallergens. APA patients had a lower odds of asthma (adjusted odds ratio [aOR], 0.68; 95% confidence interval [CI], 0.52-0.89; p = 0.005) and/or animal allergies (aOR, 0.64; 95% CI, 0.50-0.82; p = 0.0003). Histamine response was not significantly different in APA (aOR, 0.90; 95% CI, 0.73-1.12; p = 0.36) or Hispanic Americans (aOR, 1.03; 95% CI, 0.85-1.24; p = 0.76), but was higher in black Americans (aOR, 2.32; 95% CI, 1.67-3.21; p < 0.0001). APA had higher odds of a positive SPT to trees (aOR, 1.49; 95% CI, 1.16-1.91; p = 0.002), grasses (aOR, 1.32; 95% CI, 1.05-1.43; p = 0.02), feathers (aOR, 1.65; 95% CI, 1.31-2.09; p < 0.0001), and cockroaches (aOR, 1.37; 95% CI, 1.10-1.62; p = 0.005). Moreover, APA had a higher total number of positive SPTs when compared with white patients (5.5 ± 3.2 versus 4.9 ± 3.3; aOR, 1.34; 95% CI, 1.10-1.62 p = 0.004). APA adults in our patient population had more IgE sensitizations but not an increased skin response to histamine. In contrast, black Americans had increased skin response to histamine.

KTJ406 Inhibits IgE-Mediated Allergic Response in Mast Cells

KTJ406 Inhibits IgE-Mediated Allergic Response in Mast Cells

Inhibitory effects of dietary resveratrol on allergic responses in mast cells and passive cutaneous anaphylaxis in mice

Resveratrol is a polyphenol rich in the skin of red grapes and is effective in anti‐tumor and anti‐inflammation. We investigated the suppressive effects of resveratrol on IgE‐mediated allergic response in RBL‐2H3 mast cells and on passive cutaneous anaphylaxis (PCA) in mice. Mast cells sensitized with anti‐DNP‐IgE and subsequently stimulated by DNP‐HSA increased the release of β‐hexosaminidase enzyme and histamine, indicative of mast cell degranulation. This induction was diminished by nontoxic resveratrol at 1–25 μM. Western blot analysis showed that 1–25 μM resveratrol dose‐dependently mitigated the induction of FcεRI responsible for the IgE binding onto mast cells. Protein expression levels of Syk, PLCγ and PKC, all involved in allergic responses, were enhanced in activated mast cells and such levels were dampened by resveratrol. Furthermore, the Evans blue staining was evident in the ear of IgE‐mediated mice, which was diminished by oral administration of 10 mg/kg resveratrol. Edema, a usual component of most allergic reactions, apparent in the ear and dorsal skin was alleviated by resveratrol administration to IgE‐mediated mice. Taken together, the anti‐allergic responses of resveratrol suggest possible therapeutic strategies in preventing allergic diseases possibly through inhibiting mast cell degranulation and ameliorating passive cutaneous anaphylaxis.

The rate of epinephrine administration associated with allergy skin testing in a suburban allergy practice from 1997 to 2010.

Allergy skin testing is considered a safe method for testing for IgE-mediated allergic responses although anaphylactic events can occur. Reported rates of anaphylaxis per patient are not consistent and range from 0.008 to 4%. The aim of this study was to determine the rate of epinephrine use associated with allergy skin-prick testing (SPT) and intradermal testing (IDT) in a suburban practice over 13 years. This retrospective chart review used billing and procedure coding records during the time period from January 1997 to June 2010 to identify encounters where epinephrine was administered after SPT or IDT. Patient encounters with procedure codes for skin testing plus either parenteral epinephrine, corticosteroid, antihistamine, or i.v. fluid administration were identified. These patient charts were reviewed to determine if epinephrine was administered, whether systemic reactions developed, and rates of epinephrine administration were calculated. There were 28,907 patient encounters for SPT and 18,212 for IDT. Epinephrine was administered in six patient encounters (0.02%) where SPT was performed; no IDT encounters led to epinephrine administration. There were no fatalities. Allergy skin testing to a variety of allergens, when administered by well-trained personnel, is a safe procedure. This study, involving the largest population to date, showed a rate of systemic reactions requiring epinephrine of 20 per 100,000 SPT visits. No epinephrine was given after IDT.

Oral allergy syndrome and risk of food-related anaphylaxis: a cross-sectional survey analysis

Background Oral Allergy Syndrome (OAS) is an IgE-mediated allergic response to fresh fruits, nuts and vegetables caused by cross-reactivity between pollen allergens and structurally similar food proteins. Alder pollen is a prominent allergen in coastal British Columbia, present at high levels from FebruaryApril. We hypothesized that this exposure may lead to increased prevalence of Alder pollen allergy and OAS. We sought to determine our population-based prevalence, cross-reactivity patterns, and incidence of food-related anaphylaxis.

Proteomic Approach to Evaluate Mechanisms That Contribute to Food Allergenicity: Comparative 2D-DIGE Analysis of Radioallergosorbent Test Positive and Negative Patients

Proteomic profiles of RAST+ subjects with severe food allergies and RAST− subjects were compared using 2D-DIGE analysis to obtain candidate biomarkers specific to food allergies. Our analysis highlighted 52 proteins that were differentially expressed between the RAST+ and RAST− groups of which 37 were successfully identified that include chondroitin sulfates, zinc finger proteins, C-type lectins, retinoic acid binding proteins, heat shock proteins, myosin, cytokines, mast cell expressed proteins, and MAP kinases. Biological network analysis tool Metacore revealed that most of these regulated proteins play a role in immune tolerance, hypersensitivity and modulate cytokine patterns inducing a Th2 response that typically results in IgE-mediated allergic response which has a direct or indirect biological link to food allergy. Identifying unique biomarkers associated with certain allergic phenotypes and potentially cross-reactive proteins through bioinformatics analyses will provide enormous insight into the mechanisms that underlie allergic response in patients with food allergies.

A mixture of three prebiotics does not affect vaccine specific antibody responses in healthy term infants in the first year of life

BackgroundPrevious studies have shown, that prebiotics can modulate the immune response in infants at risk for allergy, leading to a lower incidence of atopic dermatitis. Few studies have evaluated the effect of prebiotic carbohydrates alone on the vaccine-specific antibody response as a marker for the development of the immune system in healthy infants not at risk for allergy. AimThis study evaluates the effect of adding a specific prebiotic mixture of short chain galacto-oligosaccharides (scGOS)/long chain fructo-oligosaccharides (lcFOS) ratio 9:1 and pectin-derived acidic oligosaccharides (pAOS) to formula feeding on the specific immunoglobulin responses to Haemophilus influenza type b (Hib) and tetanus immunization in healthy non-atopic infants during the first year of life. MethodsThis substudy has been embedded in a multinational multicenter RCT (n=1130 children) to evaluate the effect of study prebiotics on the incidence of fever episodes during the first year of life. The study prebiotics were administered throughout the first year of life. This is a substudy on the vaccine-specific immunoglobulin responses to Hib and tetanus immunizations. Only data of the Dutch children, 80 in the prebiotics group and 84 in the control group, were used for this substudy. They all followed the national vaccination schedule leading to a homogeneous group. Blood was sampled at 6 and 12months of age. ResultsHib immunizations: median values did not differ between groups at the age of 6 and 12months. At the age of 12months, 34 out of 37 (91.9%) infants in the prebiotics group and 31 out of 34 infants (91.2%) in the control group had Hib antibody levels >1.0μg/ml.Tetanus immunizations: median values did not differ between groups at the age of 6 and 12months and were above the cut-off value of 0.1IU/ml in all infants in both the prebiotics and the control group. ConclusionNo effect of prebiotics supplementation on vaccination specific antibody levels was found in children up to the age of 12months; the vaccine specific antibody levels in infants fed the study prebiotics or a control diet were similar during the first year of life. We hypothesize that this specific prebiotic mixture, which resembles the composition of oligosaccharides in human milk, mainly promotes Th1 and Treg dependent immune responses and induces a down regulation of IgE-mediated allergic responses, while the desired vaccine-specific serum antibody responses remain intact.

A Comparison of Techniques for Evaluating IgE-Mediated Allergies

Skin prick testing remains the most popular way to confirm an IgE-mediated allergic response. This study was performed to compare the accuracy and sensitivity of two skin testing modalities (serial endpoint titration and skin prick testing with 2 different in vitro assays). In 52 atopic patients serial endpoint titration showed a higher degree of sensitivity in evaluating skin response in less sensitive reactors. At higher degrees of reactivity in individual patients there was good correlation between the 3 modalities. Identifying patients who are less sensitive reactors is important, so that they can be started on immunotherapy. In fact, an informal survey of low-reacting patients treated with immunotherapy showed a high degree of success.

The ethyl acetate extract of Cordyceps militaris inhibits IgE-mediated allergic responses in mast cells and passive cutaneous anaphylaxis reaction in mice

Cordyceps militaris has been used as a traditional herbal medicine for treating allergy in East Asia. We investigated the anti-allergic efficacy of Cordyceps militaris and its mechanism of action. β-Hexosaminidase release of mast cells, a key parameter of degranulation, was evaluated. Anti-allergic potential of Cordyceps militaris was studied using passive cutaneous anaphylaxis (PCA) in vivo. The anti-allergic mechanism of Cordyceps militaris was investigated by immunoblotting analysis, RT-PCR and other biological approaches in mast cells. GSCM EtOAc extract (GSCME) inhibited antigen-induced degranulation with a IC50 value (28.5 μg/ml) in RBL-2H3 cells and antigen-induced passive cutaneous anaphylaxis (PCA) response with a ED50 value (665 mg/kg) in vivo. The release of interleukin (IL-4) and tumor necrosis factor (TNF-α were decreased by GSCME in RBL-2H3 cells. In order to elucidate the anti-allergic mechanisms of GSCME in mast cells, we examined the activated levels of signaling molecules. GSCME inhibited the phosphorylation Syk, ERK, p38 and JNK expression. Identified genistein, daidzein, genistein 7-O-β-d-glucoside 4″-O-methylate, genistein 4'-O-β-d-glucoside 4″-O-methylate, glycitein 7-O-β-d-glucoside 4″-O-methylate, daidzein 7-O-β-d-glucoside 4″-O-methylate and adenosine in GSCME, inhibited antigen-induced degranulation in RBL-2H3 cells. Our study suggests that GSCME might be used as a therapeutic agent for allergic diseases.

The hair dyes PPD and PTD fail to induce a TH2 immune response following repeated topical application in BALB/c mice

1,4-Phenylenediamine (PPD) and the structurally-related 1,4-toluenediamine (PTD) are frequently used oxidative hair dye precursors that can induce a delayed-type hypersensitivity reaction known as contact allergy. Very rare cases of Type 1 (IgE-mediated) allergic responses associated with PPD or PTD have been reported among hair dye users. As part of an effort to determine if repeated dermal exposure to the dyes could induce a T-helper-2 (TH2) response, we used a dermal exposure regimen in mice reported to identify a TH2 response. Ear swelling was evident at post-final exposure to PPD and PTD, indicating that an immune response was observed. However, cytokine mRNA after repeated topical exposure to these two chemicals showed no shift in the expression toward the typical TH2 cytokines interleukin (IL)-4 and IL-10 compared to the TH1 cytokine interferon (IFN)-γ. Consistent with these cytokine profiles, no concomitant increase in total serum IgE antibody titer or in B220+IgE+ lymphocytes in lymph nodes and skin application site skin was detected. In contrast, using an identical exposure regimen, animals topically exposed to the known respiratory (Type 1) allergen toluene 2,4-diisocyanate (TDI) showed significant expression of IL-4 and IL-10 mRNA compared to IFNγ as well as an increase in total serum IgE and in B220+IgE+ cells in lymph nodes and skin application site. The data generated are consistent with the pattern of adverse reactions to hair dyes seen clinically, which overwhelmingly is of delayed rather than immediate-type hypersensitivity. Although current animal models have a limited ability to detect rare TH2 responses to contact allergens, the present study results support the view that exposure to hair dyes is not associated with relevant TH2 induction.

Reduction of Total IgE by Targeted Coengagement of IgE-BCR and FcgRIIb with Fc-Engineered Antibodies

RATIONALE: An IgE-mediated allergic response requires allergen-specific B-cell differentiation into IgE-producing plasma cells. We created XmAb7195, an omalizumab (Xolair) -related anti-IgE antibody Fc engineered for high affinity to human FcγRIIb, to coengage IgE-BCR and FcγRIIb and prevent activation and terminal differentiation of IgE+ B cells. Our hypothesis is that XmAb7195 will not only sequester free IgE, but will suppress its production and reduce total IgE.

A Novel Imidazo[1,5-b]isoquinolinone Derivative, U63A05, Inhibits Syk Activation in Mast Cells to Suppress IgE-Mediated Anaphylaxis in Mice

Mast cells play a pivotal role in IgE-mediated allergic responses. Development of specific inhibitors against FcεRI-associated proximal signaling molecules in mast cells may represent a promising therapeutic strategy for allergic diseases. We examined whether a novel synthetic compound, 3-butyl-1-chloro-8-(2-methoxycarbonyl)phenyl-5H-imidazo[1,5-b]isoquinolin-10-one (U63A05), could suppress antigen-stimulated degranulation and cytokine secretion in mast cells and IgE-mediated passive cutaneous anaphylaxis (PCA) in mice. U63A05 reversibly and dose-dependently inhibited degranulation of rat basophilic leukemia (RBL)-2H3 mast cells and bone marrow–derived mast cells (BMMCs) stimulated by antigen (IC50 values for RBL-2H3 and BMMCs were 4.1 and 4.8 μM, respectively). The secretion of inflammatory cytokines was also suppressed in antigen-stimulated mast cells. However, degranulation by thapsigargin, a typical calcium inducer, was not inhibited by U63A05. U63A05 exerts its inhibitory effect, to the same extent as in degranulation, on the activating phosphorylation of Syk and downstream signaling molecules, including LAT and SLP-76. Further downstream, the activating phosphorylations of Akt, Erk1/2, p38, and JNK were also inhibited. Finally, antigen-stimulated PCA was dose-dependently suppressed in mice (ED50, 26.3 mg/kg). Taken together, the results suggest that U63A05 suppresses the activation of mast cells and the mast cell–mediated allergic response through the inhibition of Syk activation in mast cells.

Ethyl acetate extract of Psidium guajava inhibits IgE-mediated allergic responses by blocking FcεRI signaling

Psidium guajava (P. guajava) is an important food crop and medicinal plant with antioxidant, anti-inflammatory, and anti-allergic activities, supporting its traditional uses. However, its precise effects remain unknown. We investigated the effects of P. guajava ethyl acetate extract (PGEA) on IgE-mediated allergic responses in rat mast RBL-2H3 cells. PGEA reduced antigen (DNP–BSA)-induced release of β-hexosaminidase and histamine in IgE-sensitized RBL-2H3 cells. In addition, it inhibited antigen-induced IL-4 and TNF-α mRNA expression and protein production in IgE-sensitized RBL-2H3 cells. PGEA also suppressed antigen-induced COX-2 mRNA and protein expression in these cells, as well as antigen-induced activation of NFAT and reactive oxygen species. Moreover, it inhibited antigen-induced activation of NF-κB and degradation of IκB-α. To identify the mechanisms underpinning the inhibition of degranulation and cytokine production by PGEA, we examined the activation of intracellular FcεRI signaling molecules. PGEA suppressed antigen-induced phosphorylation of Syk, LAT, Gab2, and PLCγ2 but not Lyn, and inhibited antigen-induced phosphorylation of downstream signaling intermediates including MAP kinases and Akt. Collectively, the anti-allergic effects of PGEA in vitro suggest its possible therapeutic application to inflammatory allergic diseases, in which its inhibition of inflammatory cytokine production and FcεRI-dependent signaling events in mast cells may be hugely beneficial.

IgE-mediated allergic responses (PP-021)

IgE-mediated allergic responses (PP-021)

IgE-mediated allergic responses (WS-021)

IgE-mediated allergic responses (WS-021)

Peanut-induced intestinal allergy is mediated through a mast cell–IgE–FcεRI–IL-13 pathway

Although implicated in the disease, the specific contributions of FcepsilonRI and IL-13 to the pathogenesis of peanut-induced intestinal allergy are not well defined. We sought to determine the contributions of FcepsilonRI, IL-13, and mast cells to the development of intestinal mucosal responses in a murine model of peanut-induced intestinal allergy. Sensitized wild-type (WT), FcepsilonRI-deficient (FcepsilonRI(-/-)), and mast cell-deficient (Kit(W-sh/W-sh)) mice received peanut orally every day for 1 week. Bone marrow-derived mast cells (BMMCs) from WT, FcepsilonRI(-/-), IL-4(-/-), IL-13(-/-), and IL-4/IL-13(-/-) mice were differentiated and transferred into WT, FcepsilonRI(-/-), and Kit(W-sh/W-sh) recipients. BMMCs from WT and UBI-GFP/BL6 mice were differentiated and transferred into WT and Kit(W-sh/W-sh) mice. Blockade of IL-13 was achieved by using IL-13 receptor alpha2 (IL-13Ralpha2)-IgG fusion protein. FcepsilonRI(-/-) mice showed decreased intestinal inflammation (mast cell and eosinophil numbers) and goblet cell metaplasia and reduced levels of IL4, IL6, IL13, and IL17A mRNA expression in the jejunum. Transfer of WT BMMCs to FcepsilonRI(-/-) recipients restored their ability to develop intestinal allergic responses unlike transfer of FcepsilonRI(-/-), IL-13(-/-), or IL-4/IL-13(-/-) BMMCs. FcepsilonRI(-/-) mice exhibited lower IL-13 levels and treatment of WT mice with IL-13 receptor alpha2 prevented peanut-induced intestinal allergy and inflammation. These data indicate that the development of peanut-induced intestinal allergy is mediated through a mast cell-dependent IgE-FcepsilonRI-IL-13 pathway. Targeting IL-13 might be a potential treatment for IgE-mediated peanut-induced allergic responses in the intestine.

Inhibition of B Cell Receptor-Mediated B Cell Activation and IgE secretion by Coengagement of Surface IgE and FcγRIIb with Fc-Engineered Antibodies

RATIONALE: An IgE-mediated allergic response requires allergen-specific B-cell differentiation into IgE-producing plasma cells. B-cell activation is suppressed by BCR coengagement with inhibitory receptor FcγRIIb; therefore, we reasoned that an anti-IgE IgG engineered for high Fc domain affinity to FcγRIIb would coengage IgE-BCR and FcγRIIb, specifically deactivating IgE+ B cells. We describe XmAb6728 as a novel therapeutic based on omalizumab (Xolair) that binds the same epitope of soluble IgE but also uniquely suppresses IgE+ B cells.

Impaired activation of mast cells upon IgE-mediated antigen stimulation in a stroke-prone spontaneously hypertensive rat strain, SHRSP.Z

We investigated IgE-mediated allergic responses in a metabolic syndrome model rat strain, SHRSP.Z, which develops obesity and hypertension to cast light on the relationship between metabolic disturbances and allergic responses. IgE-mediated cutaneous anaphylactic responses were severely attenuated in this strain regardless of the presence of fa/ fa mutation, compared with the parental WKY/Izm strain. Furthermore, in the peritoneal mast cells of both the SHRSP.Z and SHRSP/Izm strains, IgE-mediated activation, such as degranulation and protein tyrosine phosphorylation, was severely impaired whereas no significant differences were found in morphology and number of peritoneal mast cells. Immunoblot analyses revealed that phosphorylation levels of Syk upon IgE-mediated antigen stimulation were significantly decreased and basal expression of linker for activation of T cells (LAT) was down-regulated in peritoneal mast cells of the SHRSP strains. These results suggest that attenuated cutaneous allergic responses in the SHRSP.Z strain might be attributed to impaired FcɛRI-mediated signal transduction in mast cells.

Subepithelial dendritic B cells in orofacial granulomatosis

Orofacial granulomatosis (OFG) is a chronic, disfiguring, granulomatous inflammation of the lips and oral mucosa. The pathogenesis is unknown, but it has been linked previously to Crohn's disease (CD) and more recently to dietary sensitivity. The oral mucosa is an immunologically responsive site associated with the generation of protective mucosal and systemic immune responses to vaccination and also hyperresponsiveness to allergens in some individuals. Classically, immune responses in oral mucosa are considered to be mediated by mucosa-associated lymphoid tissues (MALT), secondary lymphoid follicles that are intimately associated with epithelia. Immunohistochemistry was used to investigate the inflammatory infiltrate in OFG and control tissue samples. Polymerase chain reaction (PCR), cloning of PCR products, and sequencing were used to characterize the local immunoglobulin gene profile in OFG. We describe large, active, dendritic B cells in oral mucosa that were not associated with any organized lymphoid tissues in the local subepithelial microenvironment. They express activation induced cytidine deaminase, which is essential for immunoglobulin gene diversification by somatic hypermutation and class switch recombination. IgE is also expressed by these B cells. They do not align with any other previously described B-cell subset in secondary lymphoid tissues in terms of morphology, proliferative activity, or phenotype. These subepithelial dendritic B cells may contribute to the immune responsiveness of the oral mucosa, including IgE-mediated allergic responses. In patients with OFG, further understanding of the role these cells play in oral immunity may lead to novel therapeutic possibilities.