Gluten

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Code: f79
Latin name: Common
Source material: Gluten from Wheat
Common names: Gluten, Tri a Gluten, Gliadin, Gamma-Gliadin, Omega-gliadin

Allergen Exposure

Geographical distribution

Gluten is the elastic rubbery protein present in Wheat, Rye, Barley and to a lesser degree in Oats. It binds the dough in bread and other baked goods. It contributes to consistency and sponginess.

Only Gluten from Wheat (and close family members), Barley, Rye and Oats may result in symptoms of coeliac disease (CD) in susceptible individuals. Although Oats contains Gluten, studies have reported that levels are too low to warrant exclusion by individuals with CD. In contrast, Wheat starch with a 0.3% protein level has an actual Gluten content of around 200 ppm (mg/Kg).

Environment

Food derived from Wheat, Barley and Rye contains gliadin and is toxic to individuals with CD. Because the type and proportion of prolamin proteins in grains vary, the kind of reaction (if any) they are likely to cause also varies. Corn, Rice, other cereal grains such as sorghum, millet, teff, ragi and Job's tears as well as Buckwheat, quinoa and amaranth can safely be ingested by a person with CD. Wheat, Rye, Barley, Spelt and kamut, however, should be avoided in CD. Although Oats contain Gluten, studies have reported that levels are too low to warrant exclusion by individuals with CD. However, there are concerns among some authorities on coeliac disease that even if Oats themselves are safe, they nonetheless may be contaminated with Wheat, Rye, or Barley (1).

Unexpected exposure

Some foods contain gliadin because they are direct derivatives from Wheat, such as glucose and maltose syrups. Also posing dangers are Wheat germ oil, and alcoholic beverages obtained from various gliadin-containing grains, such as beer made from Barley. In other foods, the residual Wheat proteins may derive from production practices; blue cheeses or mold-covered cheeses, for example, should not be allowed in a Gluten-free diet, since Penicillium inocula are grown on bread, and therefore are thought to contain residual gliadin (2).

Allergens

The Gluten allergen has been identified and characterized:

The gliadin and glutenin proteins form a "complex" and have been termed Gluten; i.e., Gluten is composed of gliadin and glutelin. Wheat flour contains between 7% and 12% Gluten proteins by weight. Gluten is also known as Tri a Gluten, Gliadin, Gamma-gliadin and Omega-gliadin. See Wheat f4 for details on the individual gliadins (e.g., Tri a alphabeta-gliadin, Tri a alpha-gliadin, Tri a beta-gliadin, Tri a omega-2 gliadin), and glutelin.

Gluten consists mainly of proteins (~ 90%), which can be divided into alcohol-soluble gliadins and alcohol-insoluble glutenins. 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 and are the major storage proteins in most cereal seeds (3-4). Prolamins consist of a heterogeneous mixture of proteins of a molecular weight 30-90 kDa (5). There are specific names for individual prolamins from different species: secalins from Rye, hordeins from Barley, zeins from Maize, and avenins from Oats.

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%

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 (6). 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.

The major difference between glutenins and gliadins is in their functionality. While gliadins are single polypeptide chains (monomeric proteins), the glutenins are multichained structures of polypeptides that are held together by disulfide bonds.

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 (7).

Another classification of the gluten proteins is based on the amino acid sequences and does not correspond precisely to the gliadin/glutenin classification for Wheat prolamins discussed above, which is based on the ability of the proteins to form inter-molecular disulphide bonds. In contrast, this further classification divides the proteins into 3 groups: sulphur-poor (S-poor), S-rich, and high-molecular-weight (HMW) prolamins.

The S-poor prolamins comprise the omega-gliadins of Wheat, the omega-secalins of Rye, and C hordeins of Barley. The S-rich prolamins are the major group of prolamins present in Wheat, Barley and Rye, accounting for approximately 80% of the total fractions. They comprise the alpha-gliadins, the gamma-gliadins and LMW glutenin subunits of Wheat, the gamma and B hordeins of Barley and the 40 kDa and 75 kDa gamma-secalins of Rye. The HMW subunits of Wheat glutenin play an important role in determining the breadmaking quality of Wheat. HMW prolamins are also present in Barley and Rye, where they are called D hordein and HMW secalins, respectively.

Early studies demonstrated that a number of Wheat allergens play diverse roles in allergy to Wheat (8-14). Although the albumin and globulin fractions are the most prevalent allergens in Wheat-allergic individuals, IgE binding has been demonstrated to the water/salt-insoluble fractions (gliadin and glutenin) of Wheat flour (5,15).

The alpha- and fast omega- are the most immuno-reactive gliadins, with the total glutenins also being highly immuno-reactive. The development of IgE antibodies to alpha-gliadin and total glutenins is to a moderate degree associated with the development of IgE antibodies to water/salt-soluble Wheat allergens and may be due to the presence of cross-reacting epitopes in the prolamins and the water/salt-soluble albumins/globulins, in particular enzyme inhibitors. The develop-ment of allergen-specific IgE to the majority of gliadins is independent of both the levels of total IgE and the development of IgE antibodies to water/salt-soluble proteins, suggesting that 2 or more populations of IgE may be involved in hypersensitivity to cereal prolamins: those which bind to epitopes homologous to those found in water/salt-soluble proteins, and those which bind to the -rich repetitive domains of prolamins (16).

Similarly, in a study assessing the allergenicity of the protein fractions extracted from Wheat flour with indicated solvents, the gliadins (ethanol) were the strongest allergens, followed by glutenins (acetic acid), albumins (water), and globulins (salt water). Of the gliadins, the alpha and beta fractions were most potent, followed by the gamma and omega types (17).

LMW glutenin, alpha-gliadin, and gamma-gliadin have been identified as allergens in Wheat-allergic patients (18). Alpha-gliadin and fast omega-gliadin have been reported to be the allergens associated with baker's asthma (5). Low-molecular-weight (LMW) glutenin, one of the water/salt-insoluble proteins, has been reported to be the major allergen for patients allergic to Wheat (19-20). Other researchers have shown that alpha-gliadin and -gamma-gliadin, in addition to LMW glutenin, are the allergens for patients with Wheat allergies (18).

Although glutenins usually occur in Wheat as polymers with molecular weights of up to 1000 kDa and are held together by disulphide bonds, low-molecular-weight glutenin subunits have been identified (4-16).

Individual types of gliadin found in Gluten have been characterised and may each individually or in various combinations result in sensitisation. For example, omega-5 gliadin (Tri a 19) from Wheat, a gliadin, also known as fast omega-gliadin, has been reported to be a major allergen in WDEIA (14,18,20-32). Approximately between 66% and 92% of Wheat-allergic patients are positive to this allergen. 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 (14). Further information on omega-5 gliadin will be found at Wheat f4 in this reference book, and recombinant omega-5 gliadin at rTri a 19; Omega-5 Gliadin f416 (Separate reference book).

Potential cross-Reactivity

Studies of Wheat allergens have reported various degrees of cross-reactivity. Wheat 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 (5). 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 (5).

Fast omega-gliadin is a major allergen among water/salt-insoluble proteins in the case of Wheat-dependent exercise-induced anaphylaxis in Japanese patients, and IgE against fast omega-gliadin cross-reacts to gamma-gliadin and slow omega-gliadin (32). 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 Wheat-dependent exercise-induced anaphylaxis 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 (24).

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 (33).

Clinical Experience

IgE-mediated reactions
Gluten is among the most important food components accounting for hypersensitivity reactions in children. Adverse reactions to Gluten protein include:

  1. Food allergy,
     
  2. Food-dependant exercise-induced asthma or anaphylaxis,
     
  3. Coeliac disease, a non-IgE-mediated enteropathy caused by gliadin.

The onset of adverse reactions in the first 2 conditions may be immediate, delayed, or both immediate and delayed (34).

Sensitisation and allergic reactions to distinct gliadins and glutelin are discussed in detail at Wheat f4.

Overview of food allergy to Gluten

The majority of IgE-mediated reactions to Wheat involve the albumin and globulin fractions. Gliadin and Gluten in Wheat, Barley and Rye may also induce IgE-mediated reactions. There is increasing evidence that components of gliadin are involved in baker's asthma. See Wheat f4, Barley f6 and Rye f5 for further information.

Sensitisation to Gluten by ingestion can lead to food allergy symptoms, whereas sensitisation by inhalation causes baker's asthma and rhinitis. For example, Wheat omega-5 gliadin (Tri a 19) has been shown to be a major allergen in children with immediate allergy to ingested Wheat (21).

Gluten-dependent exercise-induced anaphylaxis

The major allergen resulting in Gluten-dependant exercise-induced anaphylaxis (GDEIA) is a gliadin, a common and cross-reactive allergen found in Wheat, Barley and Rye. The condition is more commonly defined according to the predominant food involved, i.e., Wheat-, or Barley-, or Rye-dependant exercise-induced anaphylaxis. GDEIA is a severe IgE-mediated allergic reaction provoked by the combination of the ingestion of food containing Gluten with intensive physical exercise during the next few hours (26,28-30,35-39). Typical symptoms are generalised urticaria and severe allergic reactions such a shock or hypotension (14). GDEIA may occur to multiple food intake (40).

The involvement of Gluten in this condition has been suggested from studies of Wheat. Of the Wheat proteins, omega-5 gliadin (Tri a 19), one of the components of fast omega-gliadin, has been reported to be a major allergen in WDEIA (18). 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 (23). A study suggests that, in addition to IgE antibodies against omega-5 gliadin, IgA antibodies may be involved in the pathogenesis of WDEIA (27).

See Wheat f4 for more on this condition.

Atopic Dermatitis

Wheat, and in particular the Gluten component, may result in or exacerbate atopic dermatitis (AD) (41-42). The strong association between positive oral Wheat challenge and positive SPT with ethanol-soluble gliadin suggests that gliadin is an important allergen for Wheat-allergic children with AD (43).

SPT with a NaCl Wheat suspension and ethanol-soluble Wheat gliadin was performed on 18 Wheat challenge-positive or Wheat challenge-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 SPT positive for gliadin and that all had elevated Gluten-specific IgE levels. Those who were challenge-negative were negative with both SPT to gliadin and Gluten-specific IgE test. 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 test (43).

Other IgE-mediated food reactions

Gluten may be a "hidden allergen" (44).

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 (45). The prevalence of asthma among bakers has been shown to be around 10%, and the prevalence of cereal allergy 15-25% (46-47). Of those bakers who have cereal allergy, up to 35% experience asthma (48). 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 (49).

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 (50). 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, with the former shown in inhibition studies to be more reactive than the latter (51-53). However, further analyses have demonstrated that major IgE-binding proteins are found in other fractions (gliadin and glutenin) as well (53).

Other reactions

Non-IgE immune reactions to Gluten may result in coeliac disease.

Coeliac disease is widespread, occurring in 0.5-1% of the population. Coeliac disease is traditionally associated with European countries, particularly Scandinavia, but is now commonly seen in populations of European ancestry (North and South Americas, Australia), and in North Africa, the Middle East and South Asia (54). In adults, the prevalence appears to be 1 in 250-300, while in children it may be as high as 1 in 100 (54-55). The prevalence of coeliac disease among school children from India is not rare in Wheat-eating areas of North India (56).

CD disease may occur at any age. In infants, symptoms will usually appear only a few months after the introduction of foods containing Gluten into the diet (6-12 months); in adulthood, the onset is usually between 30-40 years (57). After onset, it is a life-long disorder. It tends to affect twice as many females as males.

CD is thought to be the result from an inappropriate T-cell-mediated immune response against ingested Gluten in genetically pre-disposed individuals. It is caused by IgA- and IgG-mediated immune responses, and approximately 90-95% of cases are linked to the HLA-DQ2 gene complex, while 5-10% are seen in those with HLA DQ8 gene complexes. Sensitisation and activation of the T-lymphocytes lead to inflammation and structural alteration of the mucosal lining. The enzyme tissue transglutaminase is one of the targets of the autoimmune response in coeliac sprue. The enzyme converts particular glutamine residues in Gluten peptides into glutamic acid, which results in a higher affinity of these peptides for HLA-DQ2 or HLA-DQ8 (negative charges are preferred at anchor positions in the peptide-binding groove of this molecule) (54,58-62).

 
Compiled by Dr Harris Steinman, harris@zingsolutions.com

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As in all diagnostic testing, the diagnosis is made by the physican based on both test results and the patient history.