Wheat

• Common Wheat – Triticum aestivum L.
• Club Wheat – T. aestivum compactum
• Durum Wheat, Macaroni Wheat – T. durum
• Spelt Wheat – T. spelta L.
• Rivet Wheat – Triticum turgidum L.
• Emmer Wheat – T. dicoccoides
• Poulard Wheat – T. turgidum L.
• Polish Wheat – T. polonicum L.
• Persian Wheat – T. carthlicum Nevski
• Oriental Wheat – T. turanicum Jakubz.
• Einkorn Wheat – T. monococcum L.
• Wild Einkorn Wheat – T. boeoticum Boiss

Allergen Exposure

Expected exposure
Wheat is one of the major cereal grains belonging to the grass family (Poaceae or Gramineae) and is a staple food item in most diets worldwide.

Wheats are freely tillering, usually robust grasses 60 - 120 cm tall. The inflorescence has a typical single spike on each node. There are very many distinct types of Wheat that have been named as species. They are separable into three groups – diploid, tetraploid and hexaploid, according to the number of sets of chromosomes. The most important Wheats today are hexaploids, having 6 sets. These Wheats are in most cases larger and higher-yielding than diploids and tetraploids, and they also adapt to a wider range of climates.

The hexaploid Triticum aestivum is by far the most important of all Wheat species, the highest yielding and the widest ranging, as well as the one most suited to bread making. Its centre of origin is thought to be somewhere south of the Caspian sea, but its rise to prominence came only after Wheat cultivation had spread to more humid areas. During the last 2,000 years, it has come to replace almost all other species and has spread to almost all parts of the world where Wheat can be grown.

All varieties pf Wheat contain soluble and insoluble (gluten) proteins. The softer Wheat with the lowest protein content is used for biscuits, cakes and pastry. This is T. aestivum and the varieties closest to it. Harder Wheat with higher protein content is used for bread, semolina, cous-cous, macaroni and pasta. T. durum (Durum wheat) is a source of Italian pasta, Indian chappatis and Chinese noodles.

Environment
Common Wheat, the best known and most widely cultivated of the Wheats, is cultivated for the grain and used whole or ground. It is processed into Wheat berries or kernels, Wheat bran, Wheat flakes, flour, and Wheat germ. Finely ground, it is the source of flour for the world's softer bread-stuffs, such as cakes. Harder Wheat, on the other hand, is much better suited for breads, and for pastas and other products that need to maintain texture and flavour under the stress of heat. Wheat also is the source of alcoholic beverages such as beer, and the industrial alcohol is made into synthetic rubber and explosives. Bran and germ from flour milling are also important in livestock feed, and the grain itself is fed to livestock whole or coarsely ground. Wheat starch is used for pastes and sizing textiles. The straw is made into mats, carpets, and baskets, and is used for packing material, cattle bedding, and paper manufacturing. Some Wheat is cut for hay. Wheat is sometimes grown for pasture.

Unexpected exposure
See under Environment.

Allergens

Wheat, like all other foods, contains a number of proteins: over 300 have been matched to established protein database information (1), and some have been identified as allergens. The types and proportions of proteins in a cereal have a major impact on the quality and end use properties of the cereal. The major proteins in Wheat vary in proportion according to the type of Wheat, and this variability is one reason reactions to different Wheat products are not consistent.

Wheat protein can be classified into different proteins:

• albumins (water-soluble; not similar to egg or milk albumin)
   
• globulins (salt-soluble, water-insoluble)
   
• glutens (composed of gliadin and glutelin, the water/salt-insoluble wheat proteins)

Glutens can be further divided into:

• gliadins (28-42%; the major prolamin protein in Wheat, soluble in 70-90% alcohol)
   
• glutenins (42-62.5%; the major glutelin proteins in Wheat, soluble in dilute acid or alkali solutions)

Wheat flour contains between 7% and 12% gluten proteins by weight. All gluten proteins are high in proline and glutamine contents, and that is the predominant basis for calling them prolamins. Cereal prolamins have no known function apart from storage. Prolamins consist of a heterogeneous mixture of proteins of a molecular weight 30-90 kDa (2). There are specific names for individual prolamins from different species: secalins from Rye, hordeins from Barley, zeins from Maize, and avenins from Oats.

The 70% ethanol-soluble gliadins of a single Wheat grain can be separated into up to 50 components and are a heterogeneous mixture of single-chained polypeptides. They are divided into 4 groups, here in descending order of mobility in accordance with acid-PAGE studies: alpha-, beta-, gamma-, and omega-gliadins (3). Their molecular weight ranges from around 30 to 75 kDa.

The 70% ethanol-insoluble glutenins are divided into high-molecular-weight (HMW) and low-molecular-weight (LMW) glutenins.

Another way of classify the prolamins is by sequence information into three groups: sulphur-poor (S-poor), sulphur-rich (S-rich), and high-molecular-weight (HMW) prolamins. The S-poor prolamins comprise the omega-gliadins. The S-rich prolamins are the major group of prolamins in Wheat and they comprise the alpha-gliadins, the gamma-gliadins and LMW glutenins. The HMW prolamins play an important role in determining the bread making quality of Wheat. HMW prolamins are also present in Barley and Rye, where they are called D hordein and HMW secalins, respectively.

The following is a list of the type of prolamin in each grain and the percentage that the prolamin contributes to the grain's protein content:

        Wheat:      Gliadin          69%

        Corn:         Zein              55%

        Barley:       Hordein    46-52%

        Sorghum:   Kafirin           52%

        Rye:          Secalinin   30-50%

        Millet:        Panicin          40%

        Oats:         Avenin           16%

        Rice:          Orzenin           5%

Data suggest that the different prolamins may share regions of amino acid sequence homology with each other and with some of the water/salt soluble albumin/globulin proteins (4).

Early studies demonstrated that a number of Wheat allergens play diverse roles in allergy to Wheat: their sizes include 12, 15, 16, 17, 21, 26, 27, 30, 33, 38, 47 and 69 kDa (5-10).

The water/salt-soluble albumins and globulins are important proteins contributing to immediate hypersensitivity reactions (such as baker's asthma) to Wheat protein in those exposed in an occupational setting (6-7,11) In such cases, these proteins exhibit about 70% to 80% of the allergen-specific IgE-binding activity (7,12-13). They are also important in atopic dermatitis (13-14). Nevertheless, although up to 70 different IgE-binding proteins can be demonstrated to exist in the water/salt-soluble Wheat fraction, only a few of these allergens have been identified and characterised on a molecular basis (15). To the latter belong various 14- to 17-kDa proteins of the alpha-amylase/trypsin inhibitor family, including subunits of the tetrameric alpha-amylase inhibitor (9), 2 highly homologous dimeric alpha-amylase inhibitors (9,15-17) the monomeric alpha-amylase inhibitor (9,16) and a homologue to a barley trypsin inhibitor (16). In a study, the highest in vivo allergenic activity was shown to a glycosylated subunit CM 16* of the tetrameric alpha-amylase inhibitor, with skin reactivity detected to this allergen in 14 of 31 patients allergic to Wheat flour. A 36 kDa Wheat glycoprotein with peroxidase activity and similarity to a Barley seed-specific peroxidase has also been isolated from 6 of 10 patients with Wheat allergy and baker's asthma demonstrating specific IgE to this enzyme (70).

Other proteins in the water/salt-soluble fraction, such as peroxidase, glycerin-aldehyde-3-phosphate dehydro-genase, serpin (a serine proteinase inhibitor), and triosephosphate isomerase, have been regarded as major allergens in patients with baker's asthma, but great inter-individual variation of IgE-binding patterns of Wheat flour proteins in baker's asthma has been shown (16,18-19). Other Wheat allergens similar to the 27 kDa acyl-CoA oxidase variants of Rice and Barley or to 39 kDa fructose-bisphosphate-aldolase in Maize and Rice have been identified in pooled sera from Wheat-allergic individuals, but their frequency of sensitisation was not evaluated (15,18,20).

Although the albumin and globulin fractions are the most prevalent allergens in Wheat-allergic individuals, IgE binding has been demonstrated to both gliadin and glutenin fractions (13).

LMW glutenin, alpha-gliadin, and gamma-gliadin have been identified as allergens in Wheat-allergic patients (21). Alpha-gliadin and omega-gliadin (e.g. fast omega-gliadin) have been reported to be the allergens associated with baker's asthma (2). LMW glutenin has been reported to be the major allergen for patients allergic to Wheat (22-23). Other studies have shown that alpha-gliadin and gamma-gliadin, in addition to LMW glutenin, are allergens for patients with Wheat allergies (21).

The following allergens have been identified and characterised:

• Tri a 12, a profilin, an actin-binding protein, found in Wheat seed and pollen (24-27).
   
• Tri a 14, a lipid transfer protein, resulting in allergic reactions via ingestion, skin contact, and inhalation of Wheat flour (24,28-32).
   
• Tri a 18, a hevein-like protein (24-25).
   
• Tri a Gluten, also known as Gluten, Gliadin, Gamma-gliadin, Omega-gliadin (21,23,33-46).
   
• Tri a Chitinase, a chitinase (47).
   
• Tri a Bd 17K, an alpha-amylase inhibitor CM16 (48-49).
   
• Tri a 25, a thioredoxin (24-25,50-51).
   
• Tri a 26, a glutenin.
   
• Tri a aA/TI, an alpha-amylase / trypsin inhibitor, an approximately 14-15 kDa low-molecular-weight (LMW) allergen, resulting in allergic reactions via ingestion, and inhalation of Wheat, e.g., as flour (5,9,16,52-54).
   
• Tri a Bd36K, a peroxidase purified from Wheat albumin and an inhalant allergen. A 36 kDa protein (19).
   
• Tri a LMW Glu, a glutenin (24,34,46,55-60).
   
• Tri a Germin, a germin (61).
   
• Tri a Peroxidase, a peroxidase (62).
   
• Tri a TPIS, a triosephosphate isomerase, an allergen via inhalation in bakers (63).
   
• Tri a alphabeta Gliadin, a gliadin, also known as gliadin or gluten, resulting in allergic reactions via inhalation of Wheat, e.g., as flour (64).
• Tri a alpha Gliadin, a gliadin, also known as gliadin, gluten (2,21,25,33-35,46,55,60,65-66).
   
• Tri a beta Gliadin (2,34,46,60,65-66).
   
• Tri a gamma Gliadin (2,21,33-34,41-42,46,55,57,60,65).
   
• Tri a omega-2 Gliadin (2,33-34,37,46,55, 65-66).

The following allergens have been characterised in Wheat pollen: Tri a 1, Tri a 2, Tri a 3, Tri a 4, Tri a 5, Tri a CBP and Tri a 12. Tri a 12, a profilin, is also found in Wheat seed. (See Cultivated wheat g15.)

Tri a 14, a lipid transfer protein, has been shown to be heat-stable and to lack cross-reactivity to grass pollen allergens. In a study of sera of 16 Wheat challenge-positive patients and 6 patients with Wheat anaphylaxis recruited from Italy, Denmark and Switzerland, LTP was a major allergen only in Italian patients (58). In a study of 40 patients with occupational baker's asthma resulting from Wheat flour inhalation, IgE antibodies to Tri a 14 was found in 60% of 40, and the purified allergen elicited positive skin reactions in 62% of 24 of these patients. Tri a 14 and Peach LTP, Pru p 3, showed a sequence identity of 45%, but the low cross-reactivity between the 2 allergens detected in several individual sera reflected great differences in their 3-dimensional IgE-binding regions (28).

Tri a Gluten is composed of gliadin and glutelin, i.e., the gliadin and glutenin proteins form a "complex" and have been termed Gluten. Originally thought to be a single protein, gliadin is now known to consist of a number of isoforms or unique proteins, e.g., Tri a alphabeta Gliadin, Tri a alpha Gliadin, Tri a beta Gliadin and Tri a omega-2 Gliadin. See below for individual descriptions. Wheat flour contains between 7% and 12% Gluten proteins by weight. By definition, Gluten is found only in Wheat, although the term is commonly used to refer to any similar prolamin protein in any grain that is harmful to a person with coeliac disease. Other grains such as Rye, Barley, Oats and triticale (a Wheat-Rye hybrid) each contain their own prolamin, which causes the same intestinal damage in coeliac disease that gliadin causes. This is due to the similarity in protein structure. See Gluten f79.

Enzymatic hydrolysis of Wheat gluten demonstrated that the polymeric glutenin and monomeric gliadin in the gluten complex showed different behaviour after enzymatic hydrolysis: the monomeric protein (gliadin) and soluble glutenin were prone to enzymatic hydrolysis, while insoluble glutenin was resistant to enzymatic hydrolysis (67).

Tri a 19 (omega 5-gliadin) has been reported to cause sensitisation for between approximately 66% and 92% of Wheat-allergic patients. It has been reported to be a major allergen in Wheat-dependent exercise-induced anaphylaxis (WDEIA) (33).

Tri a 25, a thioredoxin, was reported to be an allergen in 8 out of 17 patient sera. The authors speculated that this family of allergens might play a role in the maintenance of allergic inflammation in baker's asthma (25). A more recent publication questioned whether this protein is a true allergen, since it had been found that thioredoxin alleviates the allergic response and that there was no evidence that thioredoxin acted as an allergen (68).

Tri a 26, a glutenin subunit, and Wheat omega-5 gliadin have been reported as major allergens in Wheat-dependent exercise-induced anaphylaxis. In a study, 29 of 30 patients with Wheat-dependent exercise-induced anaphylaxis had IgE antibodies to these epitope peptides. Twenty-five patients with atopic dermatitis who had IgE antibodies to Wheat and/or Gluten had very low or nonexistent levels of epitope peptide-specific IgE antibodies, suggesting that measurement of IgE levels specific to omega-5 gliadin (Tri a 19) and Tri a 26 is useful for the assessment of patients with Wheat-dependent exercise-induced anaphylaxis (55).

Tri a aA/TI is an alpha-amylase/trypsin inhibitor. This glycosylated form of alpha-amylase inhibitor may be more potent than the non-glycosylated form (8-9). This is a sensitising allergen whether it is ingested or inhaled, having been implicated as a major allergen associated with baker's asthma (9), and, less commonly, with food allergy (69). In particular, the subunits of the tetrameric alpha-amylase inhibitor, CM2, CM3 and CM16, are known to be major allergens for baker's asthma. In Japanese patients with atopic dermatitis, serum IgE bound only to CM3 and not to CM2 or CM16, suggesting that CM3 may be involved in both atopic dermatitis and baker's asthma (52).

Tri a Bd 36K, a peroxidase, is an allergen via inhalation (19).

Tri a LMW Glu appears to be a major allergen. In sera of 28 patients with food allergy to Wheat, 60% of sera were shown to have IgE antibodies against alpha- and beta-gliadins and LMW glutenin subunits (Tri a LMW Glu); 55% against gamma-gliadins; 48% against omega-gliadins; and 26% against HMW glutenins (46).

Tri a Germin is a germin, a glycoprotein expressed in many plants in response to biotic and abiotic stress. Wheat germin (expressed in transgenic tobacco plants) bound IgE from 6 of 12 patients sensitised to Wheat, and elicited skin- reactions in 4 out of 5 cases (61).

Tri a Peroxidase occurs in Wheat (T. aestivum). This 36 kDa seed-specific peroxidase is found specifically in T. monococcum but is also present in flour from diploid, tetraploid (pasta) and hexaploid (bread) Wheats. Sensitisation occurs via inhalation. Sera from 6 out of 10 patients hypersensitive to Wheat flour were shown to have IgE antibodies directed to this allergen (70). This allergen is one of the most reactive with some patients' sera (14).

Tri a TPIS, a triosephosphate isomerase, is an allergen via inhalation, mainly in bakers (63).

Tri a alphabeta Gliadin has been shown to be present in sera of 12% of bakers with occupational asthma, and it was demonstrated that water-insoluble proteins might also represent causative allergens (64).

Tri a alpha Gliadin, an alpha-gliadin, appears to be a major allergen and was reported to be present in 60% of sera of 28 patients with food allergy to Wheat (46). In a study of patients with WDEIA, IgE antibodies to alpha-gliadin were demonstrated in 13 of 18. The study also demonstrated cross-reactivity between this allergen and gamma-gliadin, suggesting that treatment with a Gluten-free diet, i.e., a diet excluding Wheat, Rye, and Barley, is indicated for all patients with WDEIA (35).

Tri a beta Gliadin, a beta-gliadin, was reported to be present in 60% of sera of 28 patients with food allergy to Wheat (46).

Tri a gamma Gliadin, a gamma-gliadin, was reported to be present in 55% of sera of 28 patients with food allergy to Wheat (46). In a study of 4 male Japanese patients, aged 39 to 53, with WDEIA, gamma-gliadin appeared to be a dominant allergen, causing the anaphylactic symptoms in these patients (41).

Tri a omega-2 Gliadin is an omega-gliadin. Among the allergens of the gliadin group, the omega-5 gliadin, a component of fast omega-gliadin, is a major allergen of Wheat-dependent exercise-induced anaphylaxis/asthma (WDEIA) (33-35,38,41-42,45,71). In a study to determine IgE binding against a panel of purified gluten proteins by using sera from 15 patients with WDEIA, approximately 80% of the patients reacted to fast omega-gliadin, strongly confirming that this allergen is a predominant allergen for WDEIA (33). The sera of all of these 15 patients also reacted to slow omega-gliadin, LMW, and HMW glutenin, apart from the strong reactivity to fast omega-gliadin (33). See also rTri a 19; Omega-5 Gliadin f416.

Omega-5 gliadin is also an allergen for children with an immediate-type allergy to Wheat (38). Transglutaminase-mediated cross-linking of a pepsin-trypsin-digested omega-5 gliadin was shown to cause a marked increase in IgE-binding both in vitro and in vivo. (36) Allergen-specific IgE shows fast omega-gliadin cross-reacting with gamma-gliadin and slow omega-gliadin (34,41-42). Gamma-70 and gamma-35 secalins in Rye and gamma-3 hordein in Barley cross-react with omega-5 gliadin (37). Fast gamma-gliadin is also called 1B-type omega-gliadin (72). Fast omega gliadins, which correspond to omega-5 gliadins, have also been suspected to be allergenic in bakers' asthma (2).

Potential cross-reactivity

An extensive cross-reactivity among the different individual species of the genus could be expected (73). Studies have also reported various degrees of cross-reactivity among different Wheat allergens. Water/salt-soluble proteins were reported to cross-react with alpha-gliadin and total glutenins, the water/salt-soluble proteins sharing cross-reacting epitopes with water/salt-insoluble proteins. The authors suggested that the development of IgE antibodies to alpha-gliadin may in part depend on the presence of cross-reacting antibodies to water/salt-soluble Wheat allergens (2). Clear cross-reactivity was also reported between gliadin and other fractions; the authors concluded that identical epitopes are found in several different allergenic molecules of the cereal flours despite their different solubility (2).

Fast omega-gliadin is a major allergen among water/salt-insoluble proteins in the case of WDEIA in Japanese patients, and IgE against fast omega-gliadin cross-reacts to gamma-gliadin and slow omega-gliadin (34). Further studies have reported that gamma-70 and gamma-35 secalins in Rye and gamma-3 hordein in Barley cross-react with omega-5 gliadin, suggesting that Rye and Barley may elicit symptoms in patients with Wheat-dependent exercise-induced ana-phylaxis. In immunoblotting, anti-omega-5 gliadin antibodies bound to 70 kDa and 32 kDa proteins in Rye and to a 34-kDa protein in Barley, but not to proteins in Oats. These proteins were identified as Rye gamma-70 secalin, Rye gamma-35 secalin and Barley gamma-3 hordein, respectively. In ELISA studies, 21/23 (91%) patients with WDEIA showed IgE antibodies to purified gamma-70 secalin, 19/23 (83%) to gamma-35 secalin and 21/23 (91%) to gamma-3 hordein. Skin prick testing gave positive reactions to gamma-70 secalin in 10/15 (67%) patients, to gamma-35 secalin in 3/15 (20%) patients and to gamma-3 hordein in 7/15 (47%) patients (37).

Considerable similarity has been reported among the major allergenic protein of maturing Rice seeds, Barley trypsin inhibitor, and Wheat alpha-amylase inhibitor (74).

Although extensive cross-reactivity can be expected among the varieties of Wheat, Einkorn wheats, particularly T. monococcum, are suspected to be less toxic than bread and pasta Wheats to patients with coeliac disease (75). Most lines of Einkorn wheats have been reported to lack the highly allergenic components of the alpha-amylase inhibitor family, but their flour/salt-soluble extracts show levels of IgE-binding similar to those of bread and pasta Wheats. Putative major allergens with molecular sizes from 20 to 60 kDa in Einkorn Wheats are responsible for the latter result (76).

Laboratory investigation has reported that Wheat flour allergens were immunologically partially identical to antigens of Rye flour and of common grass pollen (77-78). Further RAST inhibition experiments showed cross-reactivity between grain extracts of Wheat, Rye, Barley and Oats, suggesting that the bran layers of cereal grains are at least as allergenic as the flour (79). Cross-reactivity has been reported not only among the flours of Wheat, Rye, Barley and Oats, but also Corn and Rice, as shown by RAST inhibition tests (80). Synthetic Lol p 5 from Rye grass recognised proteins of other clinically important grass pollens, including Wheat, further indicating the presence of cross-reactivity at the level of allergenic epitope (81).

A putative class I chitinase recognised by sera from patients with Latex-fruit allergy was described in Chestnut, Cherimoya, Passion fruit, Kiwi, Papaya, Mango, Tomato, and Wheat flour extracts (47).

A lipid transfer protein, found in Spelt, was reported to be highly homologous to other LTPs from Wheat, Barley, Rice, Maize and Peach (29-30).

Clinical Experience

IgE-mediated reactions
Wheat is among the 6 most important food items accounting for hypersensitivity reactions in children.

Special adverse reactions to Wheat protein include:

1. Baker's asthma (an IgE-mediated reaction to inhaled flour from Wheat and other grains)
    
2. Coeliac disease, a non-IgE-mediated enteropathy caused by Wheat gliadin, and
    
3. Wheat-dependant exercise-induced asthma or anaphylaxis.

The onset of adverse reactions may be immediate, delayed, or both immediate and delayed (17). Differences in the specific allergens, the routes of sensitisation, and the end-organ responsiveness have not been completely understood or elucidated. Wheat hypersensitivity has been reported in both occupational and non-occupational settings and may occur to Wheat or Wheat flour (7,82-84).

Overview of food allergy to Wheat
Hypersensitivity reactions to ingested Wheat protein have been commonly reported, including by investigators performing blinded food challenges in children (17,85). In Japan, for example, Wheat is reported to be the food allergen causing the most reactions (86). Hypersensitivity reactions to ingested Wheat protein typically occur within an hour after Wheat ingestion and include gastrointestinal, respiratory and cutaneous symptoms (87). Adverse reactions typically occur within an hour after Wheat ingestion and include cutaneous, gastro-intestinal, and respiratory symptoms. Affected individuals are usually sensitised during infancy (88) and unlike in Peanut and shellfish allergy, the clinical reactivity typically resolves before adulthood.

Sensitisation to Wheat by ingestion can lead to food allergy symptoms and WDEIA, whereas sensitisation by inhalation can cause baker's asthma and rhinitis. Wheat omega-5 gliadin (Tri a 19) has been shown to be a major allergen in children with immediate allergy to ingested Wheat. Of 40 children with suspected Wheat allergy who presented with atopic dermatitis and/or gastro-intestinal and/or respiratory symptoms, after oral Wheat challenge, 19 children (48%) had immediate reactions and 8 children (20%) had delayed hypersensitivity symptoms. Sixteen (84%) of those with immediate symptoms had IgE antibodies to omega-5 gliadin. In contrast, IgE antibodies to omega-5 gliadin were not detected in any of the children with delayed or negative challenge test results. Skin prick testing with omega-5 gliadin was positive in 6 of 7 children with immediate challenge symptoms and negative in 2 children with delayed challenge symptoms (38). In a study, 60% of 28 patients with food allergy to Wheat had IgE antibodies directed against alpha- and beta-gliadins and LMW glutenin subunits, 55% of the affected group to gamma-gliadins, 48% to omega-gliadins and 26% to HMW glutenins. Further analysis also showed that 67% of patients had IgE antibodies to the albumin/globulin fraction (46).

Anaphylaxis
Wheat exposure may result in life-threatening anaphylactic reactions. (89) Minute residual Wheat protein may be responsible. A Wheat-allergic boy experienced systemic urticaria and angioedema within 40 minutes after the ingestion of 9 g of packed rice crackers which contained a trace quantity of Wheat protein, 1.50 µg/g. Three of 8 other kinds of processed rice crackers were contaminated by Wheat protein, with levels ranging from 0.26 to 1.13 µg/g. The authors concluded that approximately 13.5 µg of Wheat protein can elicit a systemic adverse reaction in highly sensitive Wheat-allergic individuals (90).

According to an analysis of a group of 580 patients in France with reactions to food, 60 presented with severe, near-fatal reactions. The foods most frequently incriminated in anaphylactic reactions were Celery (30%), crustaceans (17%), fish (13%), Peanuts (12%), Mango (6%), and Mustard (3%). Sensitisation to foods in the group tested was as follows: Wheat (39%), Peanuts (37%), Crab (34%), Celery (30%), and Soy (30%) (91).

Anaphylaxis to Wheat flour was also described in a 9-month-old child who had eaten cereal baby food. The allergens responsible were attributed to the Wheat alpha-amylase inhibitor subunits CM3 and CM16. CM2, CM3 and CM16 were found to be involved in baker's asthma (92).

Nonsteroidal anti-inflammatory drugs enhanced allergic reactions in a patient with Wheat-induced anaphylaxis (93).

Anaphylaxis has also been reported to Wheat isolates (60).

Wheat-dependent exercise-induced anaphylaxis (WDEIA)

WDEIA is a severe IgE-mediated allergic reaction provoked by the combination of Wheat or Wheat flour ingestion with intensive physical exercise during the next few hours (39,41-43,86,94-98). Typical symptoms are generalised urticaria and severe allergic reactions such a shock or hypotension (33). Wheat allergy is common in children but rare in adults, but Wheat-dependant exercise-induced anaphylaxis is common across the spectrum (99). Eighteen patients were described who had experienced recurrent episodes of generalised urticaria during exercise, 17 patients in association with collapse and 15 patients with an anaphylactic reaction. The symptoms appeared only when the patients had eaten food containing Wheat before exercise (35). WDEIA may occur to multiple food intake (100).

The threshold amount of ingested Wheat resulting in WDEIA has not yet been elucidated, but in a report of a 24-year-old Japanese woman who suffered for 2 years from attacks of urticaria, dyspnoea and syncope associated with exercise after the ingestion of Wheat, symptoms were induced following the ingestion of 64 g of bread, but not 45 g (101). Although ingestion of Wheat alone may result in WDEIA, there is a report of a 14-year-old boy who was shown to develop food-dependant exercise-induced anaphylaxis only on provocation testing with simultaneous intake of Wheat and umeboshi, but not when each food was eaten singly (102). A study reports on a 48-year-old female who developed urticaria, angioedema, dyspnoea and loss of consciousness after a restaurant meal. A second episode occurred. These reactions could be elicited in the ward only with a combination of Wheat flour, ethanol, additives and exercise (99).

Food-dependent exercised-induced cholinergic urticaria to Wheat occurring in a 24-year-old woman has been described (103).

Of the Wheat proteins, omega-5 gliadin (Tri a 19), one of the components of fast omega-gliadin, has been reported as a major allergen in WDEIA (19). Although the mechanism is not fully understood, a study reports that omega-5 gliadin-derived peptides are cross-linked by tissue transglutaminase (tTG), which causes a marked increase in IgE binding both in vitro and in vivo. Activation of tTG, during exercise, in the intestinal mucosa of patients with WDEIA could lead to the formation of large allergen complexes capable of eliciting anaphylactic reactions (36). A study suggests that, in addition to IgE antibodies against omega-5 gliadin, IgA antibodies may be involved in the pathogenesis of WDEIA (40).

Although omega-5 gliadin is the predominant allergen in WDEIA and is a component of gluten, in a study of patients with WDEIA, some were reported to be negative in IgE antibody tests for gluten, suggesting unreliable sensitivity of the test for the diagnosis of WDEIA; the findings implied that the measurement of IgE antibodies to gluten is not always satisfactory for the screening as well as diagnosis of WDEIA (33).

Pre-treatment with sodium bicarbonate appears to inhibit the reappearance of anaphylactic symptoms following Wheat ingestion and exercise provocation (104).

Although this is not an instance of WDEIA, a male athlete is described who suffered respiratory arrest following a run through a Wheat field, a run which had caused Wheat pollen to be released. He had multiple wheals on both legs and complained of severe breathlessness before collapsing. The authors suggest that it was possible that the symptoms were triggered either by the running itself, inhalation of allergens other than Wheat pollen, skin abrasions caused by contact with Wheat stalks, or a combination of these factors (105).

Atopic Eczema
Wheat allergy may result in or exacerbate atopic eczema (85,106).

In 34 children with atopic dermatitis, 33 were SPT-positive with Wheat, and 18 with Oats. Positive IgE antibody tests to Wheat and Oats could be detected in 32 and 30 samples respectively. SPT with Rice, Corn, Millet or Buckwheat was positive in 16/34 patients (10). The strong association between positive oral Wheat challenge and positive skin reactivity with ethanol-soluble gliadin suggests that gliadin is an important allergen in Wheat-allergic children with AD (107).

SPT with a NaCl Wheat suspension and ethanol-soluble Wheat gliadin was performed on 18 Wheat-challenge-positive or -negative children with AD, 6 adult AD patients with suspected cereal allergy, and 1 adult with Wheat-dependent exercise-induced urticaria/anaphylaxis. It was reported that 13 of the AD children were Wheat-challenge-positive, that 11 were positive for gliadin SPT, and that all had elevated gluten-specific IgE. Those who were challenge-negative were negative with both gliadin SPT and gluten-specific IgE. Four of the adult patients responded to a cereal-free diet, although only 2 of them appeared to be positive with gliadin SPT and gluten-specific IgE determinations (107).

Ocular-type atopic dermatitis belongs to the most severe end of the spectrum of AD, and IgE antibodies to Rice and Wheat were significantly higher in this form of AD. The authors suggest that food antigens may contribute to severe AD, resulting in ocular complications (108).

Allergic contact dermatitis from hydrolyzed Wheat protein in cosmetic cream has been reported (109).

Other cutaneous reactions
Chronic urticaria to ingestion of Wheat has been reported (110).

Other IgE-mediated food reactions
A significant association has been reported between recurrent serous otitis media and food allergy in 81 of 104 patients. An elimination diet resulted in a significant amelioration of the disease in 86% of the patients, and a challenge diet provoked recurrence of symptoms in 94%. The highest frequency was seen with Cow's milk, Wheat, egg, Peanut, Soy and Maize, and <10% frequency was seen with Orange, Tomato, Chicken and Apple (111).

Allergy to Wheat may also result in eosinophilic esophagitis (112).

Wheat may be a "hidden allergen" (113).

Baker's asthma
Baker's asthma is a frequent allergy in the baking industry. In Germany, approximately 1,800 bakers annually claim compensation for baker's asthma (114). The prevalence of asthma among bakers has been shown to be around 10%, and the prevalence of cereal allergy 15-25% (115-116). Of those bakers who have cereal allergy, up to 35% experience asthma (78). In Japan in recent years, the number of patients suffering from baker's asthma caused by bread Wheat has been increasing, and includes not only people engaged in food industries, but also those who live near a factory producing Wheat flour products (117).

Several protein components of salt extracts of Wheat flour weighing from 10 to 100 kDa have been identified as major IgE-binding proteins in occupational asthma (118). Allergen-specific IgE antibodies to a number of flour components have been demonstrated in allergic bakers' sera with the strongest reactivities occurring to water-soluble Wheat albumins and globulins, the former being shown in inhibition studies to be more reactive than the latter (12-13,119). However, further analyses have demonstrated that major IgE-binding proteins are found in other fractions (gliadin and glutenin) as well. (13) Therefore, it is no surprise that serum IgE antibodies from different allergic bakers have markedly different specificities and bind to numerous Wheat proteins (119). The major allergens are reported to be 15, 17, and 47 kDa allergens of Wheat (6) the 15 kDa Wheat allergen belonging to the alpha-amylase/trypsin inhibitor family (5,82). In ingested cereal allergy and atopic dermatitis, the IgE responses have appeared more poly-specific, being directed against over 30 individual bands of Wheat, Rye and Barley in IgE immunoblotting (10,14). Wheat flour peroxidase has also been reported to be a prominent allergen associated with baker's asthma (70). Several water-soluble Wheat molecules exhibit identical epitopes (120). Wheat flour proteins are allergens for 60% to 70% of bakers with workplace-related respiratory symptoms. Nevertheless, a great inter-individual variation of IgE-binding patterns of Wheat flour proteins occurs in baker's asthma (18).

Although baker's asthma (121-123) is an occupational hypersensitivity disease primarily caused by the inhalation of flour proteins, which are mainly derived from Wheat, the disease may also be caused by flour proteins from Rye, Barley or Soya (83-84). However, the allergens involved in baker's asthma are not limited to cereal allergens. Exposure possibilities in a bakery range from mould and mite contaminants to several additive agents used in the baking. For example, in a study of bakers with workplace-related respiratory symptoms, sensitisation to Wheat flour was demonstrated in 64%, to Rye flour in 52%, to Soy flour in 25%, and to alpha-amylase in 21% (114).

Cereal alpha- and beta-amylases may be more important allergens than fungal alpha-amylase. IgE antibody determination analysis showed that 29 of 30 subjects with inhalant-induced cereal allergy had IgE antibodies to cereal amylases, but that only 16 were positive to fungal alpha-amylase; RAST inhibition showed little cross-reactivity between cereal and fungal alpha-amylases (124).

Other occupational conditions
Occupational exposure to Wheat or Wheat dust may result in a number of other allergic conditions besides baker's asthma, and may involve animal workers, bakers and bakery, food industry, and mill workers.

In bakers, rhinitis, itching, skin eruptions, ocular symptoms (including tearing, itching and conjunctival injection) and respiratory symptoms (including cough and sputum production) have been reported. In a study, 44.4% of affected individuals were shown to have Wheat flour-specific IgE (125).

Occupational protein contact dermatitis has been described (126).

Cereal flours are used in the wood industry to improve the quality of the glues necessary to produce veneer panels. Three individuals were found to be allergic to cereal alpha-amylase inhibitors found in Wheat, which are important occupational allergens responsible for baker's asthma (127).

Asthma can be related to exposure to cereal flour contained in animal formula feeds (128).

Other reactions
Non-IgE immune reactions to gluten may result in coeliac disease. Even low levels of immuno-reactive gliadin (0.75 mg/100 g) found in Wheat starch may affect these individuals. In one study, the majority of the patients with coeliac disease (11 of 17) who had never consumed Wheat starch previously developed symptoms, which resolved within weeks of discontinuing the offending product (129).

In an Indian study, 39 children suffering from Wheat harvest-period respiratory allergy, along with randomly selected controls, were investigated for allergy symptoms. Of the allergic children, 81% had skin reactivity to antigen of Wheat threshing dust, 30% to fungal antigens, 14% to Wheat dust antigens and none to Wheat plant antigens (130).

Various Wheat and Soy protein sources, including the Soy protein isolates used to make infant formulas, may be related to juvenile or insulin-dependent diabetes mellitus (131-132).

Compiled by Dr Harris Steinman, harris@zingsolutions.com.

References

1. Skylas DJ, Mackintosh JA, Cordwell SJ, Walsh BJ, Harry J, Blumenthal C, Copeland L, Wrigley CW, Rathmell WG. Proteome Approach to the Characterisation of Protein Composition in the Developing and Mature Wheat-grain Endosperm.
   J Cereal Sci 2000;52:169-88
2. Sandiford CP, Tatham AS, Fido R, Welch JA, Jones MG, Tee RD, Shewry PR, Newman Taylor AJ. Identification of the major water/salt insoluble wheat proteins involved in cereal hypersensitivity.
   Clin Exp Allergy 1997;27(10):1120-9
3. Tatham AS, Shewry PR. The conformation of wheat gluten proteins. The secondary structures and thermal stabilities of alpha-, beta-, gamma- and omega-gliadins.
   J Cereal Sci 1985; 3:103-13
4. Shewry PR, Lafiandra D, Salcedo G et al.
   N-terminal amino acid sequences of chloroform/methanol-soluble proteins and albumins from endosperms of wheat, barley and related species.
   FEBS Letts 1984;175:359-63
5. Gomez L, Martin E, Hernandez D, Sanchez-Monge R, Barber D, del Pozo V, de Andres B, Armentia A, Lahoz C, Salcedo G, et al. Members of the alpha-amylase inhibitors family from wheat endosperm are major allergens associated with baker's asthma. FEBS Lett 1990;261(1):85-8
6. Pfeil T, Schwabl U, Ulmer WT, Konig W. Western blot analysis of water-soluble wheat flour (Triticum vulgaris) allergens. Int Arch Allergy Appi Immunol 1990:91:224-31
7. Sandiford CP, Tee RD, Newman-Taylor AJ. Identification of crossreacting wheat, rye, barley and soya flour allergens using sera from individuals with wheat-induced asthma. Clin Exp Allergy 1995;25(4):340-9
8. Sanchez-Monge R, Gomez L, Barber D, Lopez-Otin C, Armentia A, Salcedo G. Wheat and barley allergens associated with baker's asthma. Glycosylated subunits of the alpha-amylase-inhibitor family have enhanced IgE-binding capacity.
   Biochem J 1992;281(Pt 2):401-5
9. Armentia A, Sanchez Monge R, et al. In vivo allergenic activities of eleven purified members of a major allergen family from wheat and barley flour.
   Clin Exp Allergy 1993;23(5):410-5
10. Varjonen E, Vainio E, Kalimo K, Juntunen-Backman K, Savolainen J. Skin-prick test and RAST responses to cereals in children with atopic dermatitis. Characterization of IgE-binding components in wheat and oats by an immunoblotting method.
    Clin Exp Allergy 1995; 25:1100-7
11. Franken J, Stephan U, Neuber K, Bujanowski-Weber J, et al. Characterization of allergenic components of rye and wheat flour (Secale, Triticum vulgaris) by western blot with sera of bakers: their effects on CD23 expression. Int Arch Allergy Appl Immunol 1991;96(1):76-83
12. Baldo, BA, Wrigley, CW. IgE antibodies to wheat flour components.
    Clin Allergy 1978;8:109-24
13. Walsh BJ, Wrigley CW, Musk AW, Baldo BA. A comparison of the binding of IgE in the sera of patients with bakers' asthma to soluble and insoluble wheat-grain proteins.
    J Allergy Clin Immunol 1985;76:23-8
14. Varjonen E, Savolainen J, et al. IgE-binding components of wheat, rye, barley and oats recognized by immunoblotting analysis with sera from adult atopic dermatitis patients. Clin Exp Allergy 1994;24(5):481-9
15. Posch A, Weiss W, Wheeler C, Dunn MJ, Gorg A. Sequence analysis of wheat grain allergens separated by two-dimensional electrophoresis with immobilized pH gradients. Electrophoresis 1995 Jul;16(7):1115-9
16. Amano M, Ogawa H, Kojima K, Kamidaira T, Suetsugu S, et al. Identification of the major allergens in wheat flour responsible for baker's asthma.
    Biochem J 1998;330(Pt 3):1229-34
17. Rasanen L, Lehto M, et al. Allergy to ingested cereals in atopic children.
    Allergy 1994;49(10):871-6
18. Sander I, Flagge A, Merget R, Halder TM, Meyer HE, Baur X. Identification of wheat flour allergens by means of 2-dimensional immunoblotting.
    J Allergy Clin Immunol 2001;107(5):907-13
19. Yamashita H, Nanba Y, Onishi M, Kimoto M, Hiemori M, Tsuji H. Identification of a wheat allergen, Tri a Bd 36K, as a peroxidase. Biosci Biotechnol Biochem 2002;66(11):2487-90
20. Weiss W, Huber G, Engel KH, Pethran A, Dunn MJ, Gooley AA, Gorg A. Identification and characterization of wheat grain albumin/globulin allergens.
    Electrophoresis 1997;18(5):826-33
21. Maruyama N, Ichise K, Katsube T, Kishimoto T, Kawase S, Matsumura Y, Takeuchi Y, Sawada T, Utsumi S. Identification of major wheat allergens by means of the Escherichia coli expression system.
    Eur J Biochem 1998;255(3):739-45
22. Watanabe M, Tanabe S, Suzuki T, Ikezawa Z, Arai S. Primary structure of an allergenic peptide occurring in the chymotryptic hydrolysate of gluten. Biosci Biotechnol Biochem 1995;59(8):1596-7
23. Tanabe S, Arai S, Yanagihara Y, Mita H, Takahashi K, Watanabe M A major wheat allergen has a Gln-Gln-Gln-Pro-Pro motif identified as an IgE-binding epitope. Biochem Biophys Res Commun 1996;219(2):290-3
24. International Union of Immunological Societies Allergen Nomenclature: IUIS official list http://www.allergen.org/List.htm 2007
25. Weichel M, Vergoossen NJ, Bonomi S, Scibilia J, Ortolani C, Ballmer-Weber BK, Pastorello EA, Crameri R. Screening the allergenic repertoires of wheat and maize with sera from double-blind, placebo-controlled food challenge positive patients. Allergy 2006;61(1):1-135
26. van Ree R, Voitenko V, van Leeuwen WA, Aalberse RC. Profilin is a cross-reactive allergen in pollen and vegetable foods. Int Arch Allergy Immunol 1992;98(2):97-104
27. Rihs HP, Rozynek P, May-Taube K, Welticke B, Baur X. Polymerase chain reaction based cDNA cloning of wheat profilin: a potential plant allergen. Int Arch Allergy Immunol 1994;105(2):190-4
28. Palacin A, Quirce S, Armentia A, Fernandez-Nieto M, Pacios LF, Asensio T, Sastre J,
    az-Perales A, Salcedo G. Wheat lipid transfer protein is a major allergen associated with baker's asthma. J Allergy Clin Immunol 2007;120(5):1132-8
29. Robino A, Pravettoni V, Farioli L, Trambaioli C, Conti A, Pastorello EA. Occupational sensitisation caused by spelt: a case report [Poster] 8th International Symposium on Problems of Food Allergy, Venice. 2001, March 11-13
30. Asero R, Mistrello G, Roncarolo D, de Vries SC, Gautier MF, Ciurana CL, Verbeek E, Mohammadi T, Knul-Brettlova V, Akkerdaas JH, et al. Lipid transfer protein: a pan-allergen in plant-derived foods that is highly resistant to pepsin digestion. Int Arch Allergy Immunol 2000;122(1):20-32
31. Pastorello EA, Farioli L, Robino AM, Trambaioli C, Conti A, Pravettoni V. A lipid transfer protein involved in occupational sensitization to spelt. [Letter] J Allergy Clin Immunol 2001;108(1 Pt 1):145-6
32. Capocchi A, Fontanini D, Muccilli V, Cunsolo V, Saviozzi F, Saletti R, Foti S, Galleschi L. Tetraploid and hexaploid wheats express identical isoforms of nsLTP1.
    J Agric Food Chem 2006;54(6):2372-7
33. Matsuo H, Morita E, Tatham AS, Morimoto K, Horikawa T, Osuna H, Ikezawa Z, Kaneko S, Kohno K, Dekio S. Identification of the IgE-binding epitope in omega-5 gliadin, a major allergen in wheat-dependent exercise-induced anaphylaxis.
    J Biol Chem 2004;279(13):12135-40
34. Morita E, Matsuo H, Mihara S, Morimoto K, Savage AW, Tatham AS. Fast omega-gliadin is a major allergen in wheat-dependent exercise-induced anaphylaxis.
    J Dermatol Sci 2003;33(2):99-104
35. Palosuo K, Alenius H, Varjonen E, Koivuluhta M, et al. A novel wheat gliadin as a cause of exercise-induced anaphylaxis. J Allergy Clin Immunol 1999;103(5 Pt 1):912-7
36. Palosuo K, Varjonen E, Nurkkala J, Kalkkinen N, Harvima R, Reunala T, Alenius H. Transglutaminase-mediated cross-linking of a peptic fraction of omega-5 gliadin enhances IgE reactivity in wheat-dependent, exercise-induced anaphylaxis. J Allergy Clin Immunol 2003;111(6):1386-92
37. Palosuo K, Alenius H, Varjonen E, Kalkkinen N, Reunala T. Rye gamma-70 and gamma-35 secalins and barley gamma-3 hordein cross-react with omega-5 gliadin, a major allergen in wheat-dependent, exercise-induced anaphylaxis.
    Clin Exp Allergy 2001;31(3):466-73
38. Palosuo K, Varjonen E, Kekki OM, Klemola T, Kalkkinen N, Alenius H, Reunala T. Wheat omega-5 gliadin is a major allergen in children with immediate allergy to ingested wheat. J Allergy Clin Immunol 2001;108(4):634-8
39. Varjonen E, Vainio E, Kalimo K. Life threatening anaphylaxis caused by allergy to gliadin and exercise.
    Clin Exp Allergy 1997;27:162-6
40. Lehto M, Palosuo K, Varjonen E, Majuri ML, Andersson U, Reunala T, Alenius H. Humoral and cellular responses to gliadin in wheat-dependent, exercise-induced anaphylaxis. Clin Exp Allergy 2003;33(1):90-5
41. Morita E, Kameyoshi Y, Mihara S, Hiragun T, Yamamoto S. gamma-Gliadin: a presumptive allergen causing wheat-dependent exercise-induced anaphylaxis. [Letter] Br J Dermatol 2001;145(1):182-4
42. Morita E, Yamamura Y, Mihara S, Kameyoshi Y, Yamamoto S. Food-dependent exercise-induced anaphylaxis: a report of two cases and determination of wheat-gamma-gliadin as the presumptive allergen.
    Br J Dermatol 2000;143(5):1059-63
43. Gall H, Steinert M, Peter RU. Exercise-induced anaphylaxis to wheat flour.
    Allergy 2000;55(11):1096-7
44. Matsuo H, Dahlstrom J, Tanaka A, Kohno K, Takahashi H, Furumura M, Morita E. Sensitivity and specificity of recombinant omega-5 gliadin-specific IgE measurement for the diagnosis of wheat-dependent exercise-induced anaphylaxis.
    Allergy 2008;63(2):233-6
45. Matsuo H, Kohno K, Morita E. Molecular cloning, recombinant expression and IgE-binding epitope of omega-5 gliadin, a major allergen in wheat-dependent exercise-induced anaphylaxis.
    FEBS J 2005;272(17):4431-8
46. Battais F, Pineau F, Popineau Y, Aparicio C, Kanny G, Guerin L, Moneret-Vautrin DA, Denery-Papini S. Food allergy to wheat: identification of immunogloglin E and immunoglobulin G-binding proteins with sequential extracts and purified proteins from wheat flour.
    Clin Exp Allergy 2003;33(7):962-70
47. Diaz-Perales A, Collada C, Blanco C, Sanchez-Monge R, et al. Cross-reactions in the latex-fruit syndrome: A relevant role of chitinases but not of complex asparagine-linked glycans. J Allergy Clin Immunol 1999;104(3 Pt 1):681-7
48. Yamashita H, Kimoto M, Hiemori M, Okita M, Suzuki K, Tsuji H. Sandwich enzyme-linked immunosorbent assay system for micro-detection of the wheat allergen, Tri a Bd 17 K. Biosci Biotechnol Biochem 2001;65(12):2730-4
49. Kimoto M, Yoshikawa M, Takahashi K, Bando N, Okita M, Tsuju H. Identification of allergens in cereals and their hypoallergenization. I. Screening of allergens in wheat and identification of an allergen, Tri a Bd 17K. Ann Report Interdiscipl Res Inst Environ Sci 1998;17:53-60
50. Weichel M, Glaser AG, Ballmer-Weber BK, Schmid-Grendelmeier P, Crameri R. Wheat and maize thioredoxins: a novel cross-reactive cereal allergen family related to baker's asthma. J Allergy Clin Immunol 2006;117(3):676-81
51. Brant A. Baker's asthma. Curr Opin Allergy Clin Immunol 2007;7(2):152-5
52. Kusaba-Nakayama M, Ki M, Iwamoto M, Shibata R, Sato M, Imaizumi K. CM3, one of the wheat alpha-amylase inhibitor subunits, and binding of IgE in sera from Japanese with atopic dermatitis related to wheat.
    Food Chem Toxicol 2000;38(2-3):179-85
53. Buonocore V, De Biasi M-G, Giardina P, Poerio E, Silano V. Purification and properties on a-amylase tetrameric inhibitor from wheat kernel.
    Biochem Biophys Acta 1985;831:40-8
54. Buonocore V, Petrucci T, Silano V. Wheat protein inhibitors of alpha-amylase. Phytochemistry 1977;16:811-20
55. Matsuo H, Kohno K, Niihara H, Morita E. Specific IgE determination to epitope peptides of {omega}-5 Gliadin and High molecular weight glutenin subunit Is a useful tool for diagnosis of wheat-dependent exercise-induced anaphylaxis.
    J Immunol 2005;175(12):8116-22
56. Snégaroff J, Branlard G, Bouchez-Mahiout I, Laudet B, Tylichova M, Chardot T, Pecquet C, Choudat D, Raison-Peyron N, Vigan M, Kerre S, Laurière M. Recombinant proteins and peptides as tools for studying IgE reactivity with low-molecular-weight glutenin subunits in some wheat allergies.
    J Agric Food Chem 2007;55(24):9837-45
57. Akagawa M, Handoyo T, Ishii T, Kumazawa S, Morita N, Suyama K. Proteomic analysis of wheat flour allergens.
    J Agric Food Chem 2007;55(17):6863-70
58. Pastorello EA, Farioli L, Conti A, Pravettoni V, Bonomi S, Iametti S, Fortunato D, et al. Wheat IgE-mediated food allergy in European patients: alpha-amylase inhibitors, lipid transfer proteins and low-molecular-weight glutenins. Allergenic molecules recognized by double-blind, placebo-controlled food challenge. Int Arch Allergy Immunol 2007;144(1):10-22
59. Nakamura A, Tanabe S, Watanabe J, Makino T. Primary screening of relatively less allergenic wheat varieties. J Nutr Sci Vitaminol (Tokyo) 2005;51(3):204-6
60. Leduc V, Moneret-Vautrin DA, Guerin L, Morisset M, Kanny G. Anaphylaxis to wheat isolates: Immunochemical study of a case proved by means of double-blind, placebo-controlled food challenge.
    J Allergy Clin Immunol 2003;111(4):897-9
61. Jensen-Jarolim E, Schmid B, Bernier F, Berna A, Kinaciyan T, Focke M, Ebner C, Scheiner O, Boltz-Nitulescu G. Allergologic exploration of germins and germin-like proteins, a new class of plant allergens. Allergy 2002;57(9):805-10
62. Watanabe J, Tanabe S, Sonoyama K, Kuroda M, Watanabe M. IgE-reactive 60 kDa glycoprotein occurring in wheat flour. Biosci Biotechnol Biochem 2001;65(9):2102-5
63. Rozynek P, Sander I, Appenzeller U, Crameri R, Baur X, Clarke B, Bruning T, Raulf-Heimsoth M. TPIS--an IgE-binding wheat protein. Allergy 2002;57(5):463
64. Bittner C, Grassau B, Frenzel K, Baur X. Identification of wheat gliadins as an allergen family related to baker's asthma.
    J Allergy Clin Immunol 2008;121(3):744-9
65. Lauriere M, Pecquet C, Boulenc E, Bouchez-Mahiout I, Snegaroff J, Choudat D, Raison-Peyron N, Vigan M, Branlard G. Genetic differences in omega-gliadins involved in two different immediate food hypersensitivities to wheat. Allergy 2007;62(8):890-6
66. Battais F, Mothes T, Moneret-Vautrin DA, Pineau F, Kanny G, Popineau Y, Bodinier M, Denery-Papini S. Identification of IgE-binding epitopes on gliadins for patients with food allergy to wheat.
    Allergy 2005;60(6):815-21
67. Wang JS, Zhao MM, Zhao QZ, Bao Y, Jiang YM. Characterization of hydrolysates derived from enzymatic hydrolysis of wheat gluten.
    J Food Sci 2007;72(2):C103-7
68. Buchanan BB, Frick OL. Thioredoxin and food allergy. J Allergy Clin Immunol 2007;119(2):513-4;author reply 514-5
69. James JM, Sixbey JP, Helm RM, Bannon GA, Burks AW. Wheat alpha-amylase inhibitor: a second route of allergic sensitization.
    J Allergy Clin Immunol 1997;99(2):239-44
70. Sanchez-Monge R, Garcia-Casado G, Lopez-Otin C, Armentia A, Salcedo G. Wheat flour peroxidase is a prominent allergen associated with baker's asthma.
    Clin Exp Allergy 1997;27(10):1130-7
71. Seilmeier W, Valdez I, Mendez E, Wieser H. Comparative investigations of gluten proteins from different wheat species. II. Characterization of omega-gliadins.
    Eur Food Res Technol 2001;212:355-63
72. DuPont FM, Vensel WH, Chan R, Kasarda DD. Characterization of the 1B-Type omega-Gliadins from Triticum aestivum Cultivar Butte. Cereal Chem 2000;77:607-14
73. Yman L. Botanical relations and immuno-logical cross-reactions in pollen allergy. 2nd ed. Pharmacia Diagnostics AB. Uppsala. Sweden. 1982: ISBN 91-970475-09
74. Izumi H, Adachi T, Fujii N, Matsuda T, Nakamura R, Tanaka K, Urisu A, Kurosawa Y. Nucleotide sequence of a cDNA clone encoding a major allergenic protein in rice seeds. Homology of the deduced amino acid sequence with members of alpha-amylase/trypsin inhibitor family.
    FEBS Lett 1992;302(3):213-6
75. Borghi B, Castagna R, Corbellini M, Henu M, Salamini F. Breadmaking quality of Einkorn wheat (Triticum monococcum spp. monococcum). Cereal Chem 1996;73208-14
76. Sanchez-Monge R, Garcia-Casado G, Malpica JM, Salcedo G. Inhibitory activities against heterologous alpha-amylases and in vitro allergenic reactivity of Einkorn wheats. Theor Appl Genet 1996;93:745-50
77. Bjorksten F, Backman A, Jarvinen KA et al. Immunoglobulin E specific to wheat and rye flour proteins. Clin Allergy 1977;7:473-83
78. Blands J, Diamant B, Kallos P, Kallos-Deffner L, Lowenstein H. Flour allergy in bakers. I. Identification of allergenic fractions in flour and comparison of diagnostic methods.
    Int Arch Allergy Appi Immunol 1976; 52:392-406
79. Baldo BA, Krilis S, Wrigley CW. Hypersensitivity to inhaled flour allergens. Comparison between cereals.
    Allergy 1980;35:45-56
80. Block G, Tse KS, Kijek K, Chan H, Chan-Yeung M. Baker's asthma. Studies of the cross-antigenicity between different cereal grains. Clin Allergy 1984; 14:177-85
81. Suphioglu C, Blaher B, Rolland JM, McCluskey J, Schappi G, Kenrick J, Singh MB, Knox RB. Molecular basis of IgE-recognition of Lol p 5, a major allergen of rye-grass pollen. Mol Immunol 1998;35(5):293-305
82. Franken J, Stephan U, Meyer H, Konig W. Identification of alpha amylase inhibitor as a major allergen of wheat flour. Int Arch Allergy Appi Immunol 1994;104:171-4
83. Garcia-Casado G, Armentia A, Sanchez-Monge R, et al. A major baker's asthma allergen from rye flour is considerably more active than its barley counterpart.
    FEBS Lett 1995;364(1):36-40
84. Bush RK, Schroeckenstein D, Meier-Davis S, Balmes J, Rempel D. Soybean flour asthma: detection of allergens by immunoblotting.
    J Allergy Clin Immunol 1988;82(2):251-5
85. Sampson HA, Ho DG Relationship between food-specific IgE concentrations and the risk of positive food challenges in children and adolescents.
    J Allergy Clin Immunol 1997;100(4):444-51
86. Dohi M, Suko M, Sugiyama H, Yamashita N, et al. Food-dependant exercise-induced anaphylaxis; a study on 11 Japanese cases.
    J Allergy Clin Immunol 1991;87:34-40
87. Armentia A, Rodriguez R, Callejo A, Martin-Esteban M, Martin-Santos JM, Salcedo G, Pascual C, Sanchez-Monge R, Pardo M. Allergy after ingestion or inhalation of cereals involves similar allergens in different ages. Clin Exp Allergy 2002;32(8):1216-22
88. Sampson HA. Food allergy.
    J Allergy Clin Immunol 1989;84:1062-7
89. Vichyanond P, Visitsuntorn N, Tuchinda M. Wheat-induced anaphylaxis.
    Asian Pac J Allergy Immunol 1990;8:49-52
90. Matsumoto T, Miyazaki T. Systemic urticaria in an infant after ingestion of processed food that contained a trace quantity of wheat. Ann Allergy Asthma Immunol 2004;93(1):98-100
91. Andre F, Andre C, Colin L, Cacaraci F, Cavagna S. Role of new allergens and of allergens consumption in the increased incidence of food sensitizations in France. Toxicology 1994;93(1):77-83
92. Zapatero L, Martinez MI, Alonso E, Salcedo G, Sanchez-Monge R, Barber D, Lombardero M. Oral wheat flour anaphylaxis related to wheat alpha-amylase inhibitor subunits CM3 and CM16. Allergy 2003;58(9):956
93. Shirai T, Matsui T, Uto T, Chida K, Nakamura H. Nonsteroidal anti-inflammatory drugs enhance allergic reactions in a patient with wheat-induced anaphylaxis.
    Allergy 2003;58(10):1071
94. Perkins DN, Keith PK. Food- and exercise-induced anaphylaxis: importance of history in diagnosis.  Ann Allergy Asthma Immunol 2002;89:15-23
95. Armentia A, Martin Santos JM, Blanco M, et al. Exercise-induced anaphylactic reaction to grain flours. Ann Allergy 1990;65:149-51
96. Murakami R, Nakahara I, Kanemoto H, Suzuki T, Kasahara K, et al. Case of food-dependent exercise-induced anaphylaxis caused by wheat. [Japanese] Nippon Naika Gakkai Zasshi 1997
97. Guinnepain MT, Eloit C, Raffard M, Brunet Moret MJ, et al. Exercise-induced anaphylaxis: useful screening of food sensitization. Ann Allergy 1996;77(6):491-6
98. Mathelier-Fusade P, Vermeulen C, Leynadier F. Responsibility of food in exercise-induced anaphylaxis: 7 cases. [French] Ann Dermatol Venereol 2002;129(5 Pt 1):694-7
99. Fiedler EM, Zuberbier T, Worm M. A combination of wheat flour, ethanol and food additives inducing FDEIA.
    Allergy 2002;57(11):1090-1
100. Caffarelli C, Cataldi R, Giordano S, Cavagni G. Anaphylaxis induced by exercise and related to multiple food intake.
     Allergy Asthma Proc 1997;18(4):245-8
101. Hanakawa Y, Tohyama M, et al. Food-dependent exercise-induced anaphylaxis: a case related to the amount of food allergen ingested .
     Br J Dermatol 1998;138(5):898-900
102. Aihara Y, Kotoyori T, Takahashi Y, Osuna H, Ohnuma S, Ikezawa Z. The necessity for dual food intake to provoke food-dependent exercise-induced anaphylaxis (FEIAn): A case report of FEIAn with simultaneous intake of wheat and umeboshi.
     J Allergy Clin Immunol 2001;107(6):1100-5
103. Napoli D, Neeno T. Wheat dependent exercise-induced cholinergic urticaria. AAAAI 56th Annual Meeting 2000;March 3-8
104. Katsunuma T, Iikura Y, et al. Wheat-dependent exercise-induced anaphylaxis: inhibition by sodium bicarbonate.
     Ann Allergy 1992;68(2):184-8
105. Swaine IL, Riding WD. Respiratory arrest in a male athlete after running through a wheat field. Int J Sports Med 2001;22(4):268-9
106. Burks AW, James JM, Hiegel A, et al. Atopic dermatitis and food hypersensitivity reactions. J Pediatr 1998;132(1):132-6
107. Varjonen E, Vainio E, Kalimo K Antigliadin IgE – indicator of wheat allergy in atopic dermatitis. Allergy 2000;55(4):386-91
108. Uchio E, Miyakawa K, Ikezawa Z, Ohno S Systemic and local immunological features of atopic dermatitis patients with ocular complications.
     Br J Ophthalmol 1998;82(1):82-7
109. Sanchez-Perez J, Sanz T, Garcia-Diez A. Allergic contact dermatitis from hydrolyzed wheat protein in cosmetic cream.
     Contact Dermatitis 2000;42(6):360
110. Kanny G, Chenuel B, Moneret-Vautrin DA. Chronic urticaria to wheat.
     Allergy 2001;56(4):356-7
111. Nsouli TM, Nsouli SM, Linde RE, O'Mara F, Scanlon RT, Bellanti JA. Role of food allergy in serous otitis media.
     Ann Allergy 1994;73(3):215-9
112. Spergel JM, Beausoleil JL, Mascarenhas M, Liacouras CA. The use of skin prick tests and patch tests to identify causative foods in eosinophilic esophagitis.
     J Allergy Clin Immunol 2002;109(2):363-8
113. Steinman HA. Hidden Allergens in Foods.
     J Allergy Clin Immunol 1996;98(2):241-50
114. Baur X, Degens PO, Sander I. Baker's asthma: still among the most frequent occupational respiratory disorders. J Allergy Clin Immunol 1998;102(6 Pt 1):984-97
115. Savolainen J. Baker's Asthma: diversity of allergens. [Editorial] Clin Exp Allergy 1997;27:1111-3
116. Armentia A, Martin-Santos JM, Quintero A. et al. Baker's asthma: prevalence and evaluation of immunotherapy with a wheat flour extract. Ann Allergy 1990; 65:265-72
117. Kamidaira T, Suetsugu S, Umeda H. Clinical and immunologic studies on patients with baker's asthma. [Japanese] Arerugi 1986;35(1):47-59
118. Sandiford CP. Cereal-induced occupational asthma. Clin Exp Allergy 1996;26(2):128-31
119. Sutton R, Skerritt JH, Baldo BA, Wrigley CW. The diversity of allergens involved in baker's asthma. Clin Allergy 1984;14:93-107
120. Theobald K, Thiel H, Kallweit C, Ulmer W, Konig W. Detection of proteins in wheat flour extracts that bind human IgG, IgE, and mouse monoclonal antibodies.
     J Allergy Clin Immunol 1986; 78:470-7
121. Prichard MG, Ryan G, Musk AW. Wheat flour sensitization and airways disease in urban bakers. Brit J Ind Med 1984;41:450-4
122. De Zotti R, Larese F, Bovenzi M, Negro C, Molinari S. Allergic airway disease in Italian bakers and pastry makers.
     Occup Environ Med 1994; 51:548-52
123. Valero Santiago A, Amat Par P, Sanosa Vails J et al. Hypersensitivity to wheat flour in bakers.
     Allergol et Immunopathol 1988; 16:309-14
124. Sandiford CP, Tee RD, Taylor AJ. The role of cereal and fungal amylases in cereal flour hypersensitivity.
     Clin Exp Allergy 1994; 24:549-57
125. Matsumura Y, Niitsuma T, Ito H. A study of factors contributing to bakers' allergy symptoms. Arerugi 1994;43(5):625-33
126. Iliev D, Wüthrich B. Occupational protein contact dermatitis with type I allergy to different kinds of meat and vegetables.
     Int Arch Occup Environ Health. 1998;71(4):289-92
127. Lopez-Rico R, Moneo I, Rico A, Curiel G, Sanchez-Monge R, Salcedo G. Cereal alpha-amylase inhibitors cause occupational sensitization in the wood industry.
     Clin Exp Allergy 1998;28(10):1286-91
128. Valdivieso R, Pola J, Zapata C, Puyana J, Cuesta J et al. Farm animal feeders: another group affected by cereal flour asthma.
     Allergy 1988;43(6):406-10
129. Chartrand LJ, Russo PA, Duhaime AG, Seidman EG. Wheat starch intolerance in patients with celiac disease.
     J Am Diet Assoc 1997;97(6):612-8
130. Lavasa S, Kumar L, Kaushal SC, Ganguli NK. Wheat threshing dust – a "new allergen" in April-May nasobronchial allergy. Indian Pediatr 1996;33(7):566-70
131. Kitts D, Yuan Y, Joneja J, Scott F, Szilagyi A, Amiot J, Zarkadas M. Adverse reactions to food constituents: allergy, intolerance, and autoimmunity. Can J Physiol Pharmacol 1997;75(4):241-54
132. MacFarlane AJ, Burghardt KM, Kelly J, Simell T, Simell O, Altosaar I, Scott FW. A type 1 diabetes-related protein from wheat (Triticum aestivum). cDNA clo