Celiac Disease and Sensitization to Wheat, Rye, and Barley: Should We Be Concerned?

BACKGROUND: Concomitance of celiac disease (CD) and IgE-mediated wheat allergy is described in some case reports. The objective was to evaluate the frequency of sensitization to wheat, rye, barley, and malt in children and adolescents with CD. METHODS: Measurement of serum levels of specific IgE to wheat, rye, barley, and malt (ImmunoCAP; sensitization IgE ≥0.35 kUA/L) in CD patients followed in specialized clinics to verify allergy history, general characteristics, small bowel biopsy characteristics, compliance with gluten-free diet (GFD), and occurrence of symptoms in case of noncompliance. RESULTS: We evaluated 74 patients; the median of age and age at diagnosis of CD were 8.6 years (5.0-12.8) and 3.6 years (1.6-7.0), respectively. Median time of GFD was 3.5 years (1.4-5.8). History of asthma occurred in 17.3% of subjects, allergic rhinitis in 13.5%, and AD in 5.4%. Frequency of sensitization was 4% for wheat, 10.8% for rye, 5.4% for barley, and 2.7% for malt. There was no association between wheat sensitization and age at diagnosis, time of GFD, small bowel biopsy characteristics, allergy history, and gluten consumption. There was no relationship between sensitization to wheat and occurrence of immediate symptoms when not complying with GFD. CONCLUSION: In conclusion, the frequency of sensitization to wheat, rye, barley, and malt in CD patients was 4, 10.8, 5.4, and 2.7%, respectively. Therefore, to ensure that cutaneous and respiratory contact with wheat is safe, we advise patients with CD to investigate their sensitivity to wheat, rye, and barley because not all patients with CD are allergic to these cereals.

Minimal Lesions of the Small Intestinal Mucosa: More than Morphology.

Minimal lesions of the small bowel are mucosal changes characterized by an increased number of intraepithelial lymphocytes (with or without crypt hyperplasia) and normal villous architecture. Such changes are associated with a wide spectrum of conditions, ranging from food intolerances to infections, and from drugs to immune diseases, with different clinical profiles and manifestations, which complicates the formulation of a differential diagnosis. Patient history, symptom evaluation, and histopathology are the diagnostic features needed to establish a correct diagnosis. Physicians should assist pathologists in formulating a precise morphological evaluation by taking well-oriented small intestinal biopsies and collecting informative clinical findings that inform histopathology. In this current clinical controversy, the authors provide the reader with an appraisal of the small intestine minimal lesions through a careful analysis of the major conditions (e.g., celiac disease and other non-celiac disorders) responsible for such changes and their differential diagnosis. Also, we acknowledge that some of the diseases detailed in this article may progress from an early minimal lesion to overt mucosal atrophy. Thus, the timing of the diagnosis is of paramount importance.

TNF-α, IL-17, and IL-22 production in the rectal mucosa of nonceliac wheat sensitivity patients: role of adaptive immunity.

In recent years, a new gluten- or wheat-related disease has emerged, a condition labeled "nonceliac gluten sensitivity" (NCGS) or "nonceliac wheat sensitivity" (NCWS). NCWS pathogenesis is still uncertain and attributed to very different mechanisms. We aimed to study the different T-lymphocyte subsets in the rectal mucosa of NCWS patients to demonstrate the possible contribution of adaptative immune response. Twelve patients (11 women, 1 man, age range 23-61 yr, median 32 yr) with a definitive diagnosis of NCWS were recruited at random for the present study. They underwent rectal endoscopy with multiple mucosal biopsies at the end of a double-blind placebo-controlled (DBPC) wheat challenge when they reported the reappearance of the symptoms. As controls we included 11 "healthy patients", sex- and age-matched with the patients who underwent colonoscopy evaluation for rectal bleeding due to hemorrhoids. Cells freshly obtained from rectal tissue were stained to detect anti-CD45, anti-CD3, anti-CD4, and anti-CD8. Furthermore, intracellular staining was performed with anti-tumor necrosis factor (TNF)-α, anti-interleukin (IL)-17, and anti-IL-22. Production of TNF-α by CD45+, CD3+, CD4+, and CD8+ cells, as well as of IL-17 by CD4+ cells, was higher in the rectal tissue of NCWS patients than in controls. On the contrary, IL-22 production by CD8+ cells was lower in NCWS patients than in the controls. In NCWS patients diagnosed by DBPC wheat challenge, there is a complex immunological activation, with a significant role for the adaptive response.NEW & NOTEWORTHY Nonceliac wheat sensitivity (NCWS) is a syndrome characterized by symptoms triggered by gluten intake. The pathogenesis is still uncertain. Studies have shown a role for innate immunity. We demonstrated that production of TNF-α by CD45+, CD3+, CD4+, and CD8+ cells and of IL-17 by CD4+ cells is higher in the rectal tissue of NCWS patients than in controls. We clearly demonstrated that in patients with NCWS there is a significant role for the adaptive response.

Wheat Consumption Leads to Immune Activation and Symptom Worsening in Patients with Familial Mediterranean Fever: A Pilot Randomized Trial.

We have identified a clinical association between self-reported non-celiac wheat sensitivity (NCWS) and Familial Mediterranean Fever (FMF). Objectives: A) To determine whether a 2-week double-blind placebo-controlled (DBPC) cross-over wheat vs. rice challenge exacerbates the clinical manifestations of FMF; B) to evaluate innate immune responses in NCWS/FMF patients challenged with wheat vs. rice. The study was conducted at the Department of Internal Medicine of the University Hospital of Palermo and the Hospital of Sciacca, Italy. Six female volunteers with FMF/NCWS (mean age 36 ± 6 years) were enrolled, 12 age-matched non-FMF, NCWS females, and 8 sex- and age-matched healthy subjects served as controls. We evaluated: 1. clinical symptoms by the FMF-specific AIDAI (Auto-Inflammatory Diseases Activity Index) score; 2. serum soluble CD14 (sCD14), C-reactive protein (CRP), and serum amyloid A (SSA); 3. circulating CD14+ monocytes expressing interleukin (IL)-1ß and tumor necrosis factor (TNF)-α. The AIDAI score significantly increased in FMF patients during DBPC with wheat, but not with rice (19 ± 6.3 vs. 7 ± 1.6; p = 0.028). sCD14 values did not differ in FMF patients before and after the challenge, but were higher in FMF patients than in healthy controls (median values 11357 vs. 8710 pg/ml; p = 0.002). The percentage of circulating CD14+/IL-1ß+ and of CD14+/TNF-α+ monocytes increased significantly after DBPC with wheat vs. baseline or rice challenge. Self-reported NCWS can hide an FMF diagnosis. Wheat ingestion exacerbated clinical and immunological features of FMF. Future studies performed on consecutive FMF patients recruited in centers for auto-inflammatory diseases will determine the real frequency and relevance of this association.

Thermal treatment reduces gliadin recognition by IgE, but a subsequent digestion and epithelial crossing permits recovery.

Wheat is one of the most important crops in the world in terms of human nutrition. With regards to health, some individuals exhibit wheat-related disorders such as food allergy to wheat (FAW). In this disorder, gluten is involved, particularly the gliadins which are among the main proteins responsible for FAW. Food processing, as well as digestibility and intestinal transport are key factors to consider since they may affect the allergenic potential of food allergens. Wheat is always consumed after heat processing and this step may impact epitope accessibility by inducing aggregation and may irreversibly destroy conformational epitopes. Our aim was to investigate the effects of heating and digestion on the structure of well-known allergens (total gliadins and α-gliadins) and their capacity to maintain their allergenic potential after crossing an intestinal barrier. The sizes of the processed (heated and heated/digested) proteins were characterized by laser light scattering and chromatographic reverse phase. The IgE-binding capacities of native and processed proteins were checked using a dot blot with sera from wheat allergenic patients. Furthermore, the abilities of these samples to cross the intestinal barrier and to induce mast cell degranulation were investigated by combining two in vitro cellular models, Caco-2 and RBL-SX38. The heat treatment of total gliadins and α-gliadins induced the production of large aggregates that were hardly recognized by IgE of patients in dot-blot. However, after limited pepsin hydrolysis, the epitopes were unmasked, and they were able to bind IgE again. Native proteins (gliadins and α-type) and processed forms were able to cross the Caco-2 cells in small amount. Permeability studies revealed the capacity of α-gliadins to increase paracellular permeability. In the RBL assay, the total native gliadins were able to trigger cell degranulation, but none of their processed forms. However after crossing the CaCo-2 monolayer, processed gliadins recovered their degranulation capacity to a certain extent. Total native gliadins remained the best allergenic form compared to α-type.

Towards reducing the immunogenic potential of wheat flour: omega gliadins encoded by the D genome of hexaploid wheat may also harbor epitopes for the serious food allergy WDEIA.

BACKGROUND: Omega-5 gliadins are a group of highly repetitive gluten proteins in wheat flour encoded on the 1B chromosome of hexaploid wheat. These proteins are the major sensitizing allergens in a severe form of food allergy called wheat-dependent exercise-induced anaphylaxis (WDEIA). The elimination of omega-5 gliadins from wheat flour through biotechnology or breeding approaches could reduce the immunogenic potential and adverse health effects of the flour. RESULTS: A mutant line missing low-molecular weight glutenin subunits encoded at the Glu-B3 locus was selected previously from a doubled haploid population generated from two Korean wheat cultivars. Analysis of flour from the mutant line by 2-dimensional gel electrophoresis coupled with tandem mass spectrometry revealed that the omega-5 gliadins and several gamma gliadins encoded by the closely linked Gli-B1 locus were also missing as a result of a deletion of at least 5.8 Mb of chromosome 1B. Two-dimensional immunoblot analysis of flour proteins using sera from WDEIA patients showed reduced IgE reactivity in the mutant relative to the parental lines due to the absence of the major omega-5 gliadins. However, two minor proteins showed strong reactivity to patient sera in both the parental and the mutant lines and also reacted with a monoclonal antibody against omega-5 gliadin. Analysis of the two minor reactive proteins by mass spectrometry revealed that both proteins correspond to omega-5 gliadin genes encoded on chromosome 1D that were thought previously to be pseudogenes. CONCLUSIONS: While breeding approaches can be used to reduce the levels of the highly immunogenic omega-5 gliadins in wheat flour, these approaches are complicated by the genetic linkage of different classes of gluten protein genes and the finding that omega-5 gliadins may be encoded on more than one chromosome. The work illustrates the importance of detailed knowledge about the genomic regions harboring the major gluten protein genes in individual wheat cultivars for future efforts aimed at reducing the immunogenic potential of wheat flour.

In extremis diagnosis of celiac disease and concomitant wheat allergy.

Celiac disease (CD) and concomitant wheat allergy are not commonly described in the literature. Both can have almost the same treatment consisting of a gluten-free or wheat-free diet. On the other hand, they are based on totally different pathogenetic mechanisms and can be easily underdiagnosed, particularly CD. We describe a peculiar case of a young female patient affected by wheat allergy whose serological and histological data were not diagnostic for CD. Organ culture system successfully detected specific antibodies for CD in duodenal biopsy supernatant, supporting the diagnosis of CD.

Celiac Disease and Wheat Allergy: A Growing Association?

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.

Gluten sensitivities and the allergist: Threshing the grain from the husks.

"Gluten sensitivity" has become commonplace among the public. Wheat allergy (WA) and celiac disease (CD) are well-defined entities, but are becoming a fraction of individuals following a gluten-free diet (GFD). Wheat allergy has a prevalence of <0.5%. Wheat, specifically its omega-5 gliadin fraction, is the most common allergen implicated in food-dependent, exercise-induced anaphylaxis. CD is a non-IgE hypersensitivity to certain cereal proteins: gluten in wheat, secalin in rye, hordein in barley, and to a lesser extent avenin in oat. It is a rare disease, with an estimated prevalence that varied widely geographically, being higher in Northern Europe and the African Saharawi region than in South-East Asia. In addition to suggestive symptoms, serologic testing has high diagnostic reliability and biopsy is a confirmatory procedure. Patients with CD have extra-intestinal autoimmune comorbid conditions more frequently than expected. A third entity is nonceliac gluten sensitivity, which has been created because of the increasing number of subjects who claim a better quality of life or improvement of their variety of symptoms on switching to a GFD. The phenomenon is being fueled by the media and exploited by the industry. The lack of a specific objective test has been raising substantial controversy about this entity. Allergists and gastroenterologists need to pay attention to the multitudes of individuals who elect to follow a GFD. Many such subjects might have WA, CD, or another illness. Providing them with appropriate evaluation and specific management would be of great advantages, medically and economically.

A chimeric IgE that mimics IgE from patients allergic to acid-hydrolyzed wheat proteins is a novel tool for in vitro allergenicity assessment of functionalized glutens.

BACKGROUND: Acid-hydrolyzed wheat proteins (acid-HWPs) have been shown to provoke severe allergic reactions in Europe and Japan that are distinct from classical wheat allergies. Acid-HWPs were shown to contain neo-epitopes induced by the deamidation of gluten proteins. However, products with variable rates of deamidation can be found. OBJECTIVES: In this work, we studied the effect of the extent of wheat proteins deamidation on its allergenicity. A recombinant chimeric IgE was produced and compared to patients' IgE for its capacity to assess the IgE-mediated triggering potential of acid-HWPs. METHODS: Sera from acid-HWP allergic patients were analyzed via ELISA and a functional basophil assay for their IgE reactivity to wheat proteins with different deamidation levels. A chimeric mouse/human IgE (chIgE-DG1) specific for the main neo-epitope, QPEEPFPE, involved in allergy to acid-HWPs was characterized with respect to its functionality and its reactivity compared to that of patients' IgE. RESULTS: Acid-HWPs with medium (30%) and high (50-60%) deamidation levels displayed a markedly stronger IgE binding and capacity to activate basophils than those of samples with weak (15%) deamidation levels. The monoclonal chIgE-DG1 allowed basophil degranulation in the presence of deamidated wheat proteins. ChIgE-DG1 was found to mimic patients' IgE reactivity and displayed the same ability to rank acid-HWP products in a degranulation assay. CONCLUSION: Increasing the deamidation level of products from 15% to 60% resulted in an approximately 2-fold increase in their antigenicity and a 100-fold increase in their eliciting potential. The chimeric ChIgE-DG1 may be a useful tool to evaluate functionalized glutens for their allergenic potential. By mimicking patient sera reactivity, chIgE-DG1 also provided data on the patients' IgE repertoire and on the functionality of certain repeated epitopes in gluten proteins.

Polyphenol Interactions Mitigate the Immunogenicity and Allergenicity of Gliadins.

Wheat allergy is an IgE-mediated disorder. Polyphenols, which are known to interact with certain proteins, could be used to reduce allergic reactions. This study screened several polyphenol sources for their ability to interact with gliadins, mask epitopes, and affect basophil degranulation. Polyphenol extracts from artichoke leaves, cranberries, apples, and green tea leaves were examined. Of these extracts, the first three formed insoluble complexes with gliadins. Only the cranberry and apple extracts masked epitopes in dot blot assays using anti-gliadin IgG and IgE antibodies from patients with wheat allergies. The cranberry and artichoke extracts limited cellular degranulation by reducing mouse anti-gliadin IgE recognition. In conclusion, the cranberry extract is the most effective polyphenol source at reducing the immunogenicity and allergenicity of wheat gliadins.

Characterization of a hypoallergenic wheat line lacking ω-5 gliadin.

BACKGROUND: There is no curative treatment for wheat-dependent exercise-induced anaphylaxis (WDEIA). ω-5 Gliadin is one of the dominant allergens affecting WDEIA patients. The use of ω-5 gliadin-free wheat flour in the regular diet is considered one of the prophylactic approaches against the elicitation of allergic symptoms and sensitization to ω-5 gliadin. We sought to find hypoallergenic bread wheat (or common wheat) that lacked the genes encoding ω-5 gliadin and to evaluate its in vitro allergenicity. We also aimed to evaluate the sensitization ability of one of the selected hypoallergenic wheat lines by using a possible animal model of wheat allergy. METHODS: We screened the deletion lines of bread wheat by western blotting to ascertain common wheat lines lacking the ω-5 gliadin locus. The deletion lines we used have partial deficiency of chromosome 1B (Endo and Gill, 1996). To assess sensitization ability of gluten from the selected deletion line, guinea pigs were fed with either the gluten from the selected deletion line or commercially available gluten, and allergic score was evaluated after challenging the same gluten preparations. RESULTS: We found that a deletion line 1BS-18 had the least deficiency of chromosome 1B among the deletion stocks lacking the ω-5 gliadin locus. The challenge test using the guinea pigs revealed that the symptoms induced by application of the 1BS-18 gluten were much less than that of commercially available gluten. CONCLUSIONS: The deletion line 1BS-18, which lacked the ω-5 gliadin locus, is likely to have a low sensitization capacity in the guinea pig. The use of the wheat products of the 1BS-18 line in daily life may provide a feasible solution for the onset of wheat allergy.

Evaluation of the cross-reactivity of antigens in Glupearl 19S and other hydrolysed wheat proteins in cosmetics.

BACKGROUND: In Japan, over 2000 users of a facial soap containing Glupearl 19S (GP19S), a hydrolysed wheat protein (HWP), developed immediate-type systemic wheat allergy (HWP-IWA), and ∼70% of them developed associated contact urticaria. OBJECTIVES: We investigated whether HWP-IWA patients cross-react with other HWPs, and analysed HWP antigenic characteristics. METHODS: We used 10 types of HWP that are commercially available as cosmetic ingredients, and 16 subjects with HWP-IWA. We performed an enzyme-linked immunosorbent assay (ELISA) to evaluate the reactivity to each HWP, and western blotting to evaluate the characteristics of the antigens by using HWP-IWA patients' serum IgE antibodies. We also performed prick tests with the HWPs. RESULTS: The patients reacted to four other HWPs in addition to GP19S, according to ELISA, and this was confirmed by strong reactions in the prick tests to the same four types of HWP. Smears of antigens with molecular weights ranging from the high range to the low range were seen on western blotting with the four HWPs that showed strong reactions in the ELISA and prick tests. CONCLUSIONS: HWP-IWA patients cross-react with other HWPs. The antigens that they cross-reacted to had a molecular weight distribution similar to that of GP19S present in the HWPs.

Selection of lactic acid bacteria strains for the hydrolysis of allergenic proteins of wheat flour.

BACKGROUND: Wheat flour is one of the most common causative agents of food allergy. The study presents the selection and characterization of lactic acid bacteria (LAB) strains capable of hydrolyzing/modifying allergenic proteins of wheat flour. Hydrolysis of wheat proteins was determined with sodium dodecyl sulfate-polyacrylamide gel electrophoresis and immunoblotting with sera from patients with food allergy to gluten. RESULTS: The analysis of electrophoretic profiles of protein extracted from sourdough shows the capability of selected LAB strains for proteolytic degradation of wheat proteins that belong to two factions: albumin/globulin (hydrolysis of 13 polypeptides with a molecular weight between 103 and 22 kDa); and gliadin (seven polypeptides with a molecular weight between 39 and 24 kDa). All analyzed strains were capable of hydrolyzing some IgE-binding epitopes of wheat allergens. The lack of such changes in control samples indicates that they were induced rather by the proteolytic activity of bacterial strains than endogenous enzymes of wheat flour. The gluten proteins were susceptible to hydrolysis by sequential digestion with pepsin and trypsin. CONCLUSION: The selected strains exhibit proteolytic activity, which leads to a reduction in allergenicity of wheat sourdoughs. These strains may be applied as specific starter cultures to prepare bakery products of special nutritional use. © 2015 Society of Chemical Industry.

Non-celiac gluten sensitivity and rheumatic diseases.

Celiac disease is an autoimmune systemic disease having among its clinical manifestations frequent symptoms common to rheumatologic diseases such as musculoskeletal pain, asthenia, and cognitive fatigue. It is associated with other autoimmune diseases like Sjögren disease. It is a well-characterized disease with specific diagnostic tests. Non-celiac gluten sensitivity is an emerging entity with symptoms similar to celiac disease, but without specific diagnostic tests. The concept of non-celiac gluten sensitivity and its diagnostic problems are reviewed, and the hypothesis of its association with fibromyalgia, spondyloarthritis, and autoimmune conditions is proposed. Clinical observations supporting the hypothesis are described, highlighting the benefit of treating non-celiac gluten sensitivity.

Cutaneous Manifestations of Non-Celiac Gluten Sensitivity: Clinical Histological and Immunopathological Features.

BACKGROUND: The dermatological manifestations associated with intestinal diseases are becoming more frequent, especially now when new clinical entities, such as Non-Celiac Gluten Sensitivity (NCGS), are identified. The existence of this new entity is still debated. However, many patients with diagnosed NCGS that present intestinal manifestations have skin lesions that need appropriate characterization. METHODS: We involved 17 patients affected by NCGS with non-specific cutaneous manifestations who got much better after a gluten free diet. For a histopathological and immunopathological evaluation, two skin samples from each patient and their clinical data were collected. RESULTS: The median age of the 17 enrolled patients affected by NCGS was 36 years and 76% of them were females. On the extensor surfaces of upper and lower limbs in particular, they all presented very itchy dermatological manifestations morphologically similar to eczema, psoriasis or dermatitis herpetiformis. This similarity was also confirmed histologically, but the immunopathological analysis showed the prevalence of deposits of C3 along the dermo-epidermal junction with a microgranular/granular pattern (82%). CONCLUSIONS: The exact characterization of new clinical entities such as Cutaneous Gluten Sensitivity and NCGS is an important objective both for diagnostic and therapeutic purposes, since these are patients who actually benefit from a GFD (Gluten Free Diet) and who do not adopt it only for fashion.

Non-celiac gluten sensitivity: a work-in-progress entity in the spectrum of wheat-related disorders.

Non-celiac gluten sensitivity is an undefined syndrome with gastrointestinal and extra-intestinal manifestations triggered by gluten in patients without celiac disease and wheat allergy. The pathogenesis involves immune-mediated mechanisms requiring further research. Symptoms disappear in a few hours or days after gluten withdrawal and recur rapidly after gluten ingestion. Besides gluten, other wheat proteins as well as fermentable oligo-, di-, mono-saccharides and polyols (FODMAPs) may contribute to this syndrome. This syndrome occurs mainly in young women, being rare in children. Its prevalence ranges from 0.6% to 6%, based on primary or tertiary care center estimates. No biomarker is available, but half of patients tests positive for IgG anti-gliadin antibodies, which disappear quickly after gluten-free diet together with symptoms. Also, genetic markers are still undefined. Although currently limited to a research setting, double-blind, placebo-controlled, cross-over trial strategy is recommended to confirm the diagnosis. Treatment is based on dietary restriction with special care to nutrient intake.

Eighteen cases of wheat allergy and wheat-dependent exercise-induced urticaria/anaphylaxis sensitized by hydrolyzed wheat protein in soap.

BACKGROUND: Glupearl 19S, an acid-hydrolyzed wheat protein (HWP), is used widely in Japan as a moisturizing ingredient in facial soaps. Since 2010, there has been an increasing number of reports of contact urticaria and wheat allergy resulting from the use of products containing this substance. CASE REPORTS: Sixty-one patients who had used HWP-containing facial soap visited our hospital. Thirty-five of these experienced urticaria or anaphylaxis after consuming wheat-containing food. RESULTS: Eighteen of the 35 patients tested positive to 0.01% Glupearl 19S solution. Wheat-specific IgE and serum gluten-specific IgE were higher in the patients with HWP allergy than in non-HWP allergy patients. Among the patients who tested positive to Glupearl 19S on the skin prick test, nine experienced HWP-wheat-dependent exercise-induced anaphylaxis, and four experienced food-dependent anaphylaxis. Moreover, four of these patients not only experienced food-dependent anaphylaxis but also a worsening of the symptoms during exercise. DISCUSSION: The clinical symptomology was so variable that the patients were classified into six groups. We found that patients with HWP allergy tended to manifest symptoms of both HWP-wheat-dependent exercise-induced anaphylaxis and contact urticaria. The etiology of hydrolyzed wheat protein allergy is unknown. Patients with a history of these symptoms need to be informed about the risk of consuming wheat-containing foods and the importance of excluding such items from their diet.

Acid hydrolysis of wheat gluten induces formation of new epitopes but does not enhance sensitizing capacity by the oral route: a study in "gluten free" Brown Norway rats.

BACKGROUND: Acid hydrolyzed wheat proteins (HWPs) are used in the food and cosmetic industry as emulsifiers. Cases of severe food allergic reactions caused by HWPs have been reported. Recent data suggest that these reactions are caused by HWPs produced by acid hydrolysis. OBJECTIVES: To examine the sensitizing capacity of gluten proteins per se when altered by acid or enzymatic hydrolysis relative to unmodified gluten in rats naïve to gluten. METHODS: High IgE-responder Brown Norway (BN) rats bred on a gluten-free diet were sensitized without the use of adjuvant to three different gluten products (unmodified, acid hydrolyzed and enzymatic hydrolyzed). Rats were sensitized by intraperitoneal (i.p.) immunization three times with 200 µg gluten protein/rat or by oral dosing for 35 days with 0.2, 2 or 20 mg gluten protein/rat/day. Sera were analyzed for specific IgG and IgE and IgG-binding capacity by ELISA. IgE functionality was measured by rat basophilic leukemia (RBL) assay. RESULTS: Regardless of the route of dosing, all products had sensitizing capacity. When sensitized i.p., all three gluten products induced a strong IgG1 response in all animals. Acid hydrolyzed gluten induced the highest level of specific IgE but with a low functionality. Orally all three gluten products induced specific IgG1 and IgE but with different dose-response relations. Sensitizing rats i.p. or orally with unmodified or enzymatic hydrolyzed gluten induced specific IgG1 responses with similar binding capacity which was different from that of acid hydrolyzed gluten indicating that acid hydrolysis of gluten proteins induces formation of 'new' epitopes. CONCLUSIONS: In rats not tolerant to gluten acid hydrolysis of gluten enhances the sensitizing capacity by the i.p. but not by the oral route. In addition, acid hydrolysis induces formation of new epitopes. This is in contrast to the enzymatic hydrolyzed gluten having an epitope pattern similar to unmodified gluten.