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Introduction: Wheat is the most important cereal for human nutrition but its high consumption is associated to an increasing complaint of wheat-related disorders, many of which are allergic in nature and different in respect to the involved allergens. In this study, we compared the clinical aspects of wheat allergy presented by patients sensitized to Tri a 19 in respect to those presented by patients sensitized to Tri a 14. Methods: With this aim, we selected patients sensitized to 1 or both of the 2 allergens, and among these we identified those who were really wheat allergic and reactive on the basis of a standardized methodology. We evaluated the clinical features such as the kind and severity of symptoms, the coexistence of triggering factors such as physical exercise and NSAIDs and alcohol consumption, and the association with other allergens and with various immunologic parameters. Wheat allergy in Tri a 19 sensitized patients was confirmed through a questionnaire while the patients sensitized to Tri a 14 underwent wheat challenge with 100 g of pasta followed by exercise on a treadmill. Results: Seventy-nine patients sensitized to Tri a 14 and 40 patients sensitized to Tri a 19 were recruited. The 2 sensitizations were independent with a significant inverse relation (p < 0.00001). The Tri a 19 sensitized patients presented, in respect to the Tri a 14 sensitized ones, an older age (p = 0.0017), a higher risk to be wheat allergic (p < 0.0001), a higher severity of the reactions (p < 0.00001) and a higher association with some cofactors, namely alcohol (p < 0.0005) and physical exercise (p = 0.003). On the contrary, Tri a 14 sensitization was associated with atopy (p < 0.0001), with a higher probability of patients being asymptomatic (p < 0.0001) and being sensitized to other foods, in particular to nuts and cereals (p < 0.00001). Conclusions: Sensitization to Tri a 19 or Tri a 14 determines different clinical pictures. In particular, sensitization to Tri a 19 implies a higher probability of severe reactions, even dependent on daily triggers, while that to Tri a 14 implies a higher cross-reactivity with other foods but it's more frequently asymptomatic, making a food challenge necessary to prevent useless food avoidance. [ABSTRACT FROM AUTHOR]

Background: Wheat lipid transfer protein (LTP; Tri a 14) and ω5-gliadin have been described as major allergens in wheat allergy (WA) and relevant in wheat-induced anaphylaxis, frequently associated with cofactors. Objective: The objective of this study was to compare tools currently available in routine diagnosis to detect Tri a 14 sensitization, its clinical relevance, and cosensitization to ω5-gliadin and other LTPs. Methods: One hundred eighteen adults sensitized to rTri a 14 by ImmunoCAP® (cutoff ≥0.1 kUA/L) identified among 210 LTP allergic patients were included. We evaluated (1) wheat skin prick test (SPT), (2) specific IgE (sIgE) to wheat, rTri a 14, rTri a 19, peach, apple, walnut, hazelnut, and peanut LTPs using ImmunoCAP® and microarray ImmunoCAP®ISAC (cutoff ≥0.3I SU), and (3) wheat-related symptoms. Results: Wheat SPT and sIgE were positive in 31% and 85% of subjects, respectively. rTri a 14 by microarray was detected in 25%. Eight percent showed cosensitization to ω5-gliadin. Thirty percent referred symptoms (gastrointestinal [13%], urticaria [11%], and anaphylaxis [8%]). Cofactors (45%) were significantly associated with systemic reactions. Conclusion: WA due to Tri a 14 is frequently related with systemic reactions and because are frequently related to cofactors, the culprit may not be suspected. Together with the poor performance to identify Tri a 14 sensitization of the current routine diagnostic tools based on the analysis of whole wheat extract, such as wheat SPT or sIgE, there is a high risk that WA may be overlooked. Thus, when WA is suspected, sIgE Tri a 14 assessment is recommended, together with wheat and ω5-gliadin, preferably in the singleplex format, and carefully evaluated considering ≥0.1 kUA/L as a cutoff. [ABSTRACT FROM AUTHOR]

Background: Wheat is known as the most widely consumed food all over the world. Although many types of wheat allergy have been recognized, their treatment still has a long way to go due to the complex pathogenesis. Oral immunotherapy (OIT) is under investigation for the treatment of wheat allergies. Previous studies have demonstrated that OIT using intact wheat allergens can induce tolerance, but is accompanied by a high risk of anaphylactic reactions. Objectives: Our objective was to prepare modified wheat allergens with hypoallergenic and tolerance-inducing properties to reduce adverse effects during immunotherapy. Methods: Wheat gliadin was degraded by hydrolysis with pepsin and trypsin, and then the hydrolysate was deamidated with hydrochloric acid. The IgE-binding capacity and T cell reactivity of the degraded gliadins were evaluated in vitro. Pepsin-digested gliadin (peptic-GLI) was applied in a mouse model to investigate whether it would induce oral tolerance. Results: Degradation with pepsin decreased IgE-binding capacity and maintained T cell reactivity. Oral administration of peptic-GLI to mice before sensitization and challenge with gliadin could significantly suppress the production of IgE, IgG1, and type 2 T helper cytokines. Moreover, the development of anaphylactic reactions and allergic responses of the small intestine induced by gliadin challenge were inhibited by oral administration of peptic-GLI. Conclusions: The findings of this study indicate that peptic-GLI with low allergenicity and potential for tolerance induction may become useful in wheat immunotherapy with less adverse effects. [ABSTRACT FROM AUTHOR]

Background: Wheat IgE-mediated food allergy in children is one of the most frequent food allergies in westernized countries, affecting between 0.4 and 1% of children. Although 95% predictive decision points have been determined for major allergens such as peanut, egg, and milk, the diagnostic performances of wheat-specific IgE (sIgE) and wheat component testing are not well established. Objectives: The aim of this study was to determine sIgE decision point cutoffs in children with IgE-mediated wheat allergy and provide a review of the literature. Method: A retrospective review of wheat oral food challenges was performed at the pediatric allergy unit of the University Hospitals of Geneva between 2004 and 2019. Performance characteristics for wheat and ω-5 gliadin sIgE were calculated and positive and negative OFC data were compared using the Mann-Whitney U test. Results: A wheat sIgE cutoff of 2.88 kUA/L had a sensitivity of 95% (negative decision point), whereas a cutoff of 78.1 kUA/L had a specificity of 95% (positive decision point). When giving equal weight to sensitivity and specificity, the optimal cutoff point for wheat sIgE was 12 kUA/L, which gave a specificity of 70% and a sensitivity of 66.67%. Conclusions: These findings suggest a high positive decision point for wheat sIgE (78.1 kUA/L). This reinforces the importance of considering OFC in children with IgE-mediated wheat allergy to confirm diagnosis even in patients with relatively high wheat sIgE values, as there is a risk of falsely mislabeling these patients as allergic. [ABSTRACT FROM AUTHOR]

Background: Diagnosing both celiac disease (CD) and wheat allergy (WA) might be challenging due to the increasingly popular gluten-free diets. Objectives: This study investigates the value of anti-tissue transglutaminase IgA (tTGIgA) and wheat-specific IgE (WIgE), and identifies clinical and serological features associated with CD and WA. Method: Serological markers of autoimmunity and allergy along with medical charts of patients assessed for tTGIgA and WIgE between 2010 and 2016 were evaluated. Results: During the last years, an increasing number of patients have been tested for tTGIgA, while the number of positive results decreased linearly. Among the 2,965 patients included, 128 patients showed at least once a positive tTGIgA. All patients with tTGIgA levels higher than the 12-fold upper normal limit had CD. The ratio of tTGIgA/total IgA did not perform better as a diagnostic test for CD compared to tTGIgA. tTGIgA and anti-nuclear antibodies were significantly associated. WA was only rarely investigated, particularly in adults. However, positive WIgE were found in nearly 50% of the cases. WIgE and tTGIgA values were negatively correlated. Conclusions: tTGIgA were increasingly tested, while the rate of positive results decreased in recent years, possibly reflecting the impact of current alimentary trends on clinical practice. Associated autoimmune disease was frequently found in CD. High levels of tTGIgA accurately predicted CD diagnosis. WA was rarely investigated and deserves more attention, in particular in children with atopic background. WA does not seem to be associated with CD. [ABSTRACT FROM AUTHOR]

Background: Wheat allergy is the third most common food allergy that develops during infancy in Japan. To identify factors associated with persistent wheat allergy, we assessed the rate of tolerance acquisition among Japanese children aged less than 6 years with an immediate-type wheat allergy using the oral food challenge (OFC) method. Methods: This retrospective cohort study included 83 children (born in 2005–2006) who had a history of immediate-type allergic reaction to wheat and were followed until 6 years of age. The subjects were divided to form “tolerant” (n = 55; tolerance acquired by 6 years of age) and “allergic” (n = 28; tolerance not acquired by 6 years of age) groups based on their OFC results. Results: The rates of tolerance acquisition to 200 g of udon noodles at 3, 5, and 6 years of age were 20.5% (17/83), 54.2% (45/83), and 66.3% (55/83), respectively. The total number of anaphylactic reactions experienced prior to 3 years of age in response to all foods (p < 0.01) and to wheat (p = 0.043) was significantly higher in the allergic than in the tolerant group. Wheat- and ω-5 gliadin-specific immunoglobulin E (IgE) levels were significantly higher in the allergic group than in the tolerant group (p < 0.01), and wheat-specific IgE levels were more likely to increase after infancy in the allergic group. Conclusions: A history of anaphylaxis to all foods including wheat and/or a high level of wheat- or ω-5 gliadin-specific IgE antibodies were identified as risk factors for persistent wheat allergy. [ABSTRACT FROM AUTHOR]

Background: Wheat allergy and other immune-mediated disorders triggered by wheat proteins are growing at an alarming rate for reasons not well understood. A mouse model to study hypersensitivity responses to salt-soluble wheat protein (SSWP) extract is currently unavailable. Here we tested the hypothesis that SSWP extract from wheat will induce sensitization as well as allergic disease in mice. Methods: Female BALB/cJ mice were weaned onto a plant protein-free diet. The mice were injected a total of 4 times with an SSWP (0.01 mg/mouse) fraction extracted from durum wheat along with alum as an adjuvant. Blood was collected biweekly and SSWP-specific IgE (SIgE) and total IgE (TIgE) levels were measured using ELISA. Systemic anaphylaxis upon intraperitoneal injection with SSWP was quantified by hypothermia shock response (HSR). Mucosal mast cell degranulation was measured by the elevation of mMCP-1 in the blood. The mice were monitored for dermatitis. Skin tissues were used in histopathology and for measuring cytokine/chemokine/adhesion molecule levels using a protein microarray system. Results: Injection with SSWP resulted in time-dependent SIgE antibody responses associated with the elevation of TIgE concentration. Challenge with SSWP elicited severe HSR that correlated with a significant elevation of plasma mMCP-1 levels. Sensitized mice developed facial dermatitis associated with mast cell degranulation. Lesions expressed significant elevation of Th2/Th17/Th1 cytokines and chemokines and E-selectin adhesion molecule. Conclusion: Here we report a mouse model of anaphylaxis and atopic dermatitis to SSWP extract that may be used for further basic and applied research on wheat allergy. [ABSTRACT FROM AUTHOR]

Introduction: Celiac disease and wheat allergy (WA) are infrequent diseases in the general population, and a combination of the 2 is particularly rare. Celiac disease occurs in around 1% of the general population and WA in around 1% of all children. Case Report: We report 2 patients with celiac disease and a gluten-free diet who developed WA consistent in anaphylaxis and an eyelid angioedema, respectively, through accidental wheat exposure. A serum study and an intestinal biopsy confirmed celiac disease. Both patients were studied with a skin prick test and serum-specific IgE, with a diagnosis of WA. Discussion: In patients with celiac disease, the trace amounts of cereals present in gluten-free food could act as a sensitization factor, and probably patients with persistent symptoms (despite a gluten-free diet) are experiencing WA symptoms rather than celiac disease symptoms. The number of patients diagnosed with celiac disease has increased in the recent decades: the association between celiac disease and WA, exceedingly rare to date, could increase as well, prompting special attention to the possibility of inadvertent intake of cereals. [ABSTRACT FROM AUTHOR]

Background: Non-celiac gluten sensitivity (NCGS) is a recently recognized disorder, characterized by the occurrence of symptoms following gluten ingestion. It is often self-diagnosed by the patient, but should be confirmed by the response to a gluten-free diet, followed by a gluten challenge. Celiac disease (CD) and wheat allergy (WA) must first be ruled out. Aims: (1) to determine the frequency of visits performed for symptoms self-perceived as gluten-related; (2) to assess in this cohort, the proportion of patients satisfying the diagnostic criteria for NCGS. Methods: A two-year prospective study including all consecutive patients complaining of gluten-related symptoms. NCGS was diagnosed on the basis of the disappearance of the symptoms within 6 months of a gluten-free diet, followed by their reappearance with the reintroduction of gluten in the diet for 1 month. Results: Three hundred and ninety two patients complaining of gluten-related symptoms were enrolled; 26 of these (6.63%) were affected by CD, 2 (0.51%) by WA and 27 were diagnosed with NCGS (6.88%). The remaining 337 patients (85.96%) did not experience any change of symptoms with a gluten-free diet. The PPV of the gluten-related symptom was found to be 7%. Conclusion: Eighty six percent of patients reporting gluten-related symptoms have neither NCGS, nor CD, nor WA. Self-perceived gluten-related symptoms are rarely indicative of the presence of NCGS. © 2015 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background: Wheat is a common food causing allergy which has implications on the quality of life. The diagnosis of IgE-mediated wheat allergy is based on the clinical history and presence of IgE antibodies (IgE-Ab) in skin or blood, and the results of an oral food challenge which is time consuming and associated with risks. An improved diagnostic workup is needed for wheat allergy. The objective was to examine the relationship between wheat challenge, CD-sens and IgE-Ab to related allergens in wheat-allergic children and investigate if a combination of different markers could enhance the prediction of challenge outcome. Method: Twenty-four children (aged 1-15 years) with a wheat allergy diagnosis underwent an open wheat challenge. CD-sens and IgE-Ab to wheat, hydrolyzed wheat protein (HWP), ω-5 gliadin and timothy grass were analyzed and related to the challenge outcome. Results: A positive challenge was seen in 12/24 children. Children reacting to the challenge had higher IgE-Ab concentrations to wheat, ω-5 gliadin and HWP (p < 0.01) and a tendency to higher wheat CD-sens values (p = 0.08) than nonreacting children. Combining wheat CD-sens >150 and IgE-Ab to wheat >20 kUA/l, or ω-5 gliadin >0.1 kUA/l predicted the challenge outcome in 83% of the patients. Most children with IgE-Ab to wheat also had IgE-Ab to timothy. Seven of 9 challenge-positive children had a positive CD-sens to HWP and IgE-Ab to HWP >8 kUA/l. Conclusion: Combining CD-sens and IgE-Ab to wheat or wheat components could be useful in the diagnosis and follow-up of wheat-allergic children. Copyright © 2013 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background: Adults suffering from wheat-dependant, exercise-induced anaphylaxis (WDEIA) develop IgE directed against wheat ω5-gliadins (major allergens for this allergy) and against wheat low-molecular weight glutenin subunits (LMW-GS). However, the ability of LMW-GS to trigger an inflammatory response is still unknown. It also remains to be determined if IgE from these patients bind the same epitopes on LMW-GS and ω5-gliadins or if the epitopes are independent. Methods: WDEIA patients were selected and skin prick tests (SPTs) were performed on them using commercial gluten, wheat flour extracts, prolamin fractions and a purified natural LMW-GS P42. The IgE-binding ability of natural and recombinant wheat prolamins was verified by immunoblot experiments. Cross-reactivity between LMW-GS and ω5-gliadins was studied by immunoblot inhibition experiments, using purified natural ω5-gliadin as an inhibitor. Results: Patients developed positive SPTs with natural LMW-GS fractions and/or with the purified LMW-GS P42. Natural and recombinant LMW-GS were highly reactive with patient IgE in immunoblot experiments, as was ω5-gliadin. However, differences in reactivity were evident within the LMW-GS group. Except for one recombinant LMW-GS (P73), IgE cross-reactivity between LMW-GS and natural ω5-gliadin was only partial. Conclusion: LMW-GS are able to promote local inflammation and they share common epitopes with ω5-gliadins. The nature of these epitopes is discussed. LMW-GS also carried specific epitopes, completely independent from the ω5-gliadin epitopes. Thus, LMW-GS behaved partly as independent allergens. Copyright © 2010 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background: Dietary intake of wheat causes hypersensitivity reactions in patients suffering from IgE-mediated food allergy and coeliac disease. Aim: To study the expression of IgE- and IgA-reactive antigens during wheat seed maturation and in different wheat cultivars. Methods: Summer wheat was grown in a glasshouse and seeds were harvested at defined maturation stages. Mature seeds were obtained from 13 different defined cultivars. Protein extracts were prepared from different maturation stages and cultivars with a standardized procedure based on seed weight and analysed by IgE and IgA immunoblotting using sera from clinically defined patients suffering from wheat allergy or coeliac disease. Results: With a few exceptions the expression of IgE- and IgA-reactive wheat antigens increased during wheat seed maturation. Wheat cultivars could be identified in which the expression of certain IgE- and IgA-reactive components was strongly reduced or not detectable. Conclusions: The expression of IgE- and IgA-reactive antigens depends on wheat seed maturation and varies in different wheat cultivars. Copyright © 2009 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background: Antigenic profiles obtained by ELISA with IgE from patients with wheat food allergy (WFA) established that major allergens are albumins/globulins (AG) for children suffering from atopic eczema/dermatitis syndrome (AEDS), ω5-gliadins for adults suffering from wheat-dependent exercise-induced anaphylaxis (WDEIA), anaphylaxis or urticaria and low-molecular-weight (LMW) glutenin subunits for patients with anaphylaxis. We aimed to characterize a new mast cell transfectant for its ability to degranulate with wheat proteins and patient sera and compare these results to those obtained by ELISA. Methods: Thirty sera from patients with WFA were tested: 14 with AEDS (group 1) and 16 with WDEIA, anaphylaxis or urticaria (group 2). An IgE Fc receptor (FcεRI) humanized rat RBL-2H3 line was established by transfection with cDNAs encoding α-, β- and γ-subunits for the human IgE receptor. Results: A humanized RBL clone was selected for its capacity to express mRNA α-, β- and γ-subunits of FcεRI, to bind allergen-specific human IgE and to degranulate. In group 1, sera induced enhanced degranulation with AG extract, but rarely reacted with gliadins and glutenins. In group 2, half of the sera showed degranulation with LMW glutenins whereas the AG fraction and lipid transfer proteins were rarely positive. ω5-Gliadins did not appear as a major allergen in degranulation assays, although functional allergen-specific IgE was measurable in appreciable amounts. Conclusion: Our data demonstrate that in wheat food allergen evaluation, correlation exists between mast cell degranulation and IgE measurements, depending on the type of allergen. Therefore, the biological activity of some allergen types may also be affected by other parameters. Copyright © 2008 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background: Three main problems hamper the identification of wheat food allergens: (1) lack of a standardized procedure for extracting all of the wheat protein fractions; (2) absence of double-blind, placebo-controlled food challenge studies that compare the allergenic profile of Osborne’s three protein fractions in subjects with real wheat allergy, and (3) lack of data on the differences in IgE-binding capacity between raw and cooked wheat. Methods: Sera of 16 wheat-challenge-positive patients and 6 patients with wheat anaphylaxis, recruited from Italy, Denmark and Switzerland, were used for sodium dodecyl sulfate-polyacrylamide gel electrophoresis/immunoblotting of the three Osborne’s protein fractions (albumin/globulin, gliadins and glutenins) of raw and cooked wheat. Thermal sensitivity of wheat lipid transfer protein (LTP) was investigated by spectroscopic approaches. IgE cross-reactivity between wheat and grass pollen was studied by blot inhibition. Results: The most important wheat allergens were the α-amylase/trypsin inhibitor subunits, which were present in all three protein fractions of raw and cooked wheat. Other important allergens were a 9-kDa LTP in the albumin/globulin fraction and several low-molecular-weight (LMW) glutenin subunits in the gluten fraction. All these allergens showed heat resistance and lack of cross-reactivity to grass pollen allergens. LTP was a major allergen only in Italian patients. Conclusions: The α-amylase inhibitor was confirmed to be the most important wheat allergen in food allergy and to play a role in wheat-dependent exercise-induced anaphylaxis, too. Other important allergens were LTP and the LMW glutenin subunits. Copyright © 2007 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background: Wheat is involved in different forms of respiratory, food and contact allergy. The IgE of patients generally reacts with various flour proteins. It is not known if antigenic relationships could explain some of these reactions and if proteins could be involved in different pathologies. Methods: Two sera were selected as representative of patients with either wheat-dependent exercise-induced anaphylaxis (WDEIA) or hypersensitivity to hydrolyzed wheat proteins (HHWP). Their IgE specificity was studied with wheat, barley and rye proteins, using immunoblot, and immunoblot inhibition with recombinant γ-3 hordein. This protein was chosen for its cross-reactivity with ω-5 gliadin, a major allergen in WDEIA. Results: The IgE from both sera strongly reacted with natural and recombinant γ-3 hordein but displayed different patterns of reactivity with wheat, barley and rye proteins. Those from the WDEIA patient showed expected reactions with ω-5 gliadin, γ-35 and γ-75 secalins, but also with wheat low-molecular-weight glutenin subunits (LMW-GS), and not with C hordeins. On the contrary, IgE from a HHWP patient reacted with C hordeins, various ω gliadins, and γ-75 secalin, but very weakly with γ-35 secalin and LMW-GS. Recombinant γ-3 hordein inhibited strongly but not totally the WDEIA patient’s IgE binding to prolamins. No such inhibition could be observed for the HHWP patient’s IgE. Conclusions: At least part of the reactions of prolamins with the IgE from the WDEIA patient was due to antigenic homologies. The occurrence of cross-reacting carbohydrates was unlikely. These common IgE epitopes were not involved in the pathology of the HHWP patient. Copyright © 2006 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background: Dietary intake of wheat can cause two distinct immunologically mediated diseases with severe gastrointestinal manifestations, coeliac disease (CD) and IgE-mediated food allergy. The pathomechanisms underlying these diseases are different, but the profile of the target antigens in wheat has not been compared for the two diseases. Methods: We compared IgA- and IgE-reactive antigens in wheat using sera from patients with coeliac disease (n = 35) and food allergy to wheat (n = 16) by one- and two-dimensional immunoblotting. Furthermore, the IgG subclass (IgG1–IgG4) reactivity to wheat antigens was studied by enzyme-linked immunosorbent assay. Results: IgA antibodies from CD patients and IgE antibodies from allergic patients recognised distinct profiles of wheat antigens. Furthermore, the IgG subclass responses to wheat antigens were different in CD and wheat-allergic patients. Conclusion: This study thus demonstrates that wheat contains antigens/epitopes which are preferentially recognised by CD patients, whereas others elicit IgE-mediated food allergy. This finding suggests that the nature of a food antigen may influence the quality of the pathological immune response in the gut and has implications for the diagnosis and therapy of hypersensitivity to wheat. Copyright © 2005 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]