Gluten allergies

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Template:Gluten sensitivity Gluten allergies are a group of allergies that have been connected to gluten sensitivity within humans. Globally, allergic diseases are growing in frequency, and among the allergens, wheat allergens have been identified as a more serious problem.[1] Typical symptoms are urticaria, atopic eczema/dermatitis syndrome.[2] Atypical allergic responses include anaphylaxis. Many conditions result from peripheral responses to ingested gluten[3]. Gluten is more frequently a cause of allergic aggrevation of rheumatoid arthritis and may also aggrevate other autoimmune diseases.[4]

## Contents

* 1 Background
* 1.1 Gluten as a dominant food allergen
* 2 Types of allergens
* 2.1 Intrinsic allergens
* 2.1.1 Classic gluten allergies
* 2.1.2 Allergies to other Triticeae proteins
* 2.2 Extrensic allergens
* 3 Types of reactions
* 3.1 Asthma, Anaphylaxis, Nasal Allergies
* 3.2 Urticaria, Atopy, Eczema
* 3.3 Autoimmune (Rheumatoid) arthritis
* 3.4 Neuropathies
* 4 References

## Background

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The frequencies of food allegies is on the rise in many global areas, particulary as people are living longer and transitting from indigenous foods to western diets. Wheat allergies are among the allergies more frequently encountered. Aside from the rapid increase in diagnosed gluten enteropathy, which are dominated by cellular responses α-gliadin, other wheat proteins also produce both evident and hidden allergic reactions. One clear example of bizarre types of reactions glutens can cause is exercise-induced anaphylaxis and asthma. Wheat dependent exercise induced anaphylaxis (WDEIA) is now believed to be induced by injested gluten that finds a way into the blood stream. This pathway is also believed responsible for some forms of wheat-allergy mediated eczema, however not neccesarily caused by the same allergen. Thus, allergic responses to gluten may not be evident at the site of initial contact. Recent studies have indicated that wheat allergies may be difficult to detect in the extracts commonly used for pin-prick or RAST testing, because these allergens are often hidden by the organization of proteins within the seeds. Isolation and purification of these proteins have revealled the targets of IgE. [5] While IgE may be a potent stimulator of mast cell responses and inflamatory reactions, some studies indicate there are several classes of responses, for example IgG1,IgG2, IgG4 that are associated with IgE.[6] thus indicating that some proportion of idiopathic gluten sensitivities may be a consequence of gluten allergies. Animal studies indicate that the agglutenins from wheat are also potent stimulators of other food allergies. More direct evidence comes from coeliac disease in which gliadins are a favored digestive target of tissue transglutaminase.

#### Gluten as a dominant food allergen

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Contact allergies typically result from antigen contact with the dermis and associated mucousal tissue. While personal hygeine products that contain gluten (see Wheat protein hydrolysates) are abundant, often ingested gluten is a probable cause atopic eczema & dermatitis syndrome. The allergic response is the infiltration of gluten proteins beyond the lumen of the small intestine. Exercise, drugs (aspirin and NSAIDs), food chemicals (MSG, sodium benzoate, food colorants) may play a role. Other wheat proteins may play a role such as lectins and agglutenation proteins. In addition, the innate peptide of alpha gliadin shows an ability to enter and signal cells in the GI tract (such as in coelia disease). Glaidin also alters natural killer cell/immature dendritic cell cross-talk and prevents the killing of gliadin-specific dendritic cells allowing in anti-gliadin IgE to increase.[7].

## Types of allergens

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### Intrinsic allergens

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#### Classic gluten allergies

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Prolamin allergies. Prolamins and the closely related glutelins, a recent study in Japan found that glutenins are a more frequent allergen, however gliadins are associated with the most severe disease. A proteomics based study found a γ-gliadin isoform gene.[5] Wheat dependent exercise induced anaphylaxis (WDEIA) is primarily mediated by ω-5 gliadin which is encoded by the Gli-1B gene derived from the Aegilops speltoides B genome within wheat.

Glutelin allergies. Glutenin (wheat glutelin) is a predominant allergen in wheat.[5] Nine subunits of LMW-glutinen have been found to bind to wheat allergy associated IgE.

#### Allergies to other Triticeae proteins

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Albumin and globulin. At present many of the allergens of wheat have not been characterized, the early studies found many to the albumin class[8]. A recent study in Europe confirmed the increased presense of allergies to amylase/trypsin inhibitors (serpins)[9][5] and lipid transfer protein (LPT).[10] but less reactivity to the globulin fraction[11] The allergies tend to differ between populations (Italian, Japanese, Danish or Swiss), indicating a potential genetic component to these reactivities.

Hydrolyzed Wheat Protein (Cosmetics) Allergy. Proteins are made of a chain of dehydrated amino acids. When enzymes cut proteins into pieces they add water back to the site at which they cut, called enzymatic hydrolysis, for proteins it is called proteolysis. The initial products of this hydrolysis are polypeptides and smaller products are called simply peptides. When proteins are cut into polypeptides, buried regions are exposed on the surface, and these buried regions can be antigenic. Such hydrolyzed Wheat protein is used as an additive in foods and cosmetics. The peptides are often 1 kD in size (9 amino acid residues in length) and may have improved allergenicity relative to wheat. [12] These wheat polypeptides can cause immediate contact urticaria in susceptible people.[13]

Malt allergies. Malt allergies are rare and directed toward the proteins in barley-malt.[14]

Grass allergies. 3 decades ago the major allergenic components of wheat allergies were examined in bakers. 40 allergens were detected, some cross-reacted with rye proteins and a few cross-reacted with grass pollens.[15] A later study showed that baker's allergy extend over a broad range of cereal grasses (wheat, durum wheat, triticale, cereal rye, barley, rye grass, oats, canary grass, rice, maize, sorghum and Johnson grass) though the greatest similarities were seen between wheat and rye [16] and that these allergies show cross reactivity between seed proteins and pollen proteins[17] including a prominent crossreactivity between the common environment rye pollen and wheat gluten[18][19]

Cryptic allergies. Recent studies show that detection of wheat allergens using whole wheat sources may not be adequate relative to using purified wheat proteins which are not commonly tested for.[10][5][20][21] The studies recommends that people with suspected Triticeae allergies be tested with isolated/purified extracts instead of whole extracts. While the scientific techniques are amicable for identification of previously unidentified allergens, these techniques are still not clinically useful. This may, also need to be extended to hydrolysates of those extracts.

### Extrensic allergens

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This group of allergens 'come along for the ride'. Appear as a result of growing, storing or preparation of wheat. Two of the most common are yeast and amylase reactivities.

Mite allergy. A second potential source of wheat sensitive allergies responses may not be caused by gluten or any wheat protein, but the mites and mite bits that contaminate Triticeae seeds derivatives.[22]

Food additives (pseudo-sensitivity to wheat). Colitis is a common element in gluten-sensitivity particularly elevated in coeliac disease. Studies of antibodies associated with colitis reveal that Crohn's disease and collagenous colitis have a high frequency of anti-yeast antibodies (ASCA), and 60% of celiacs also have high ASCA. ASCA are generally directed toward mannans in yeast, and lectin binding proteins in humans are protective against ASCA. Yeast is used to make bread, beer and yeast hydrolysates and therefore the reactivity to yeast might appear as gluten sensitivity. Another source of reaction is to fungal amylases used to increase sugar production in bread making for rising.

## Types of reactions

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### Asthma, Anaphylaxis, Nasal Allergies

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Exercise-induced anaphylaxis. Wheat gliadins and potentially oat avenins are associated with another disease, known as wheat- dependent exercise Induced Anaphylaxis (WDEIA) which is similar to Baker's Allergy as both are mediated by IgE responses.[23] In WDEIA, however, the ω-gliadins[24] or a high molecular weight glutenin subunit, and similar proteins in other Triticeae genera enter the blood stream during exercise where they cause acute asthmatic or allergic reaction.[25] One recent study of ω-gliadins demonstrated these gliadins are more similar to the bulk of oat avenins than α/β or γ gliadins but, so far, oat avenins have not been linked to WDEIA. Wheat may specifically induce WDEIA and certain chronic urticaria because the anti-gliadin IgE detects ω5-gliadins expressed by most of the Gli-B1 alleles but almost no responses prolamins extracted from rye or wheat/rye translocates. The Gli-B1 gene in wheat, Triticum aestivum comes from one of three progenitor species, Aegilops speltoides, indicating that nascent mutations on the B genome of wheat or from a small number of cultivated triticeae species.[26].

Recent study of WDEIA shows that both aspirin and exercise increase the presence of gliadin in the blood stream[3] and the chronic induced behavior may extend to NSAIDs, MSG, Benzoate and other synthetic chemical food additives.

Baker's Allergy. Baker's allergy has a ω-gliadin component and thioredoxin hB component.[27] In addition, a gluten-extrensic allergen has been identified as aspergillus amylase, added to flour to increase its baking properties.

Food induced Asthma. Wheat is a common cause.[28]

Allergic urticaria on the shin

### Urticaria, Atopy, Eczema

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Contact Sensitivity[29], Atopic Dermatitis[30], Eczema, and Urticaria appear to be related phenomena the cause is generally the believed to be the hydrophobic prolamin components of certain Triticeae, Aveneae cultivars, in wheat one of these proteins is ω-gliadin (Gli-B1 gene product). A study of mothers and infants on an allergen-free diet demonstrated that these conditions can be avoided if wheat sensitive cohort in the population avoid wheat in the first year of life[31]. As with exercise induced anaphylaxis aspirin (also: tartrazine, sodium benzoate, sodium glutamate (MSG), sodium metabisulfite, tyramine) may be sensitizing factors for reactivity.[32] From the Wheat Dependent Exercise Anaphylaxis studies it appears that aspirin and probably NSAIDs allow the entry of wheat proteins into the blood, where IgE reacts within allergens in the dermal tissues.

### Autoimmune (Rheumatoid) arthritis

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There appears to be an association of autoimmune rheumatoid arthritis (ARA) both with GSE and gluten allergies[33]. ARA in GSE/CD may be secondary to tTG autoimmunity. In a recent study in Turkey, 8 of 20 ARA patients had wheat reactivities on the RAST tests. When this allergic food and all other patient specific RAST+ foods were removed half of the patients had improved ARA by serological markers. In patients with wheat allergies, rye was effectively substituted.[4] This may indicate that some proportion of RA in GSE/CD is due to downstream effects of allergic responses. In addition, cross-reactive anti-beef-collagen antibodies (IgG) may explain some rheumatoid arthritis (RA) incidences.[34]

### Neuropathies

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Migraines. In the late 70s it was reported that people with migraines had reactions to food allergens, like ARA, the most common reaction was to wheat (78%), Orange, eggs, tea, coffee, chocolate, milk, beef, corn, cane sugar, and yeast. When 10 foods causing the most reactions were removed migranes fell precipitously, hypertension declined.[35] Some specific instances are attributed to wheat.[36]

Infantile Autism. Worsening of neurological symptoms in autistic patients with milk and wheat consumption has been reported.[37] However, a Swedish study reported a negative impact of a gluten free diet. [38]

Acute psychosis. Wheat and rye allergy (IgE) antibodies have also been found in acute psychosis patients.[39]

# References

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1. ↑ Mansueto P, Montalto G, Pacor ML; et al. (2006). "Food allergy in gastroenterologic diseases: Review of literature". World J. Gastroenterol. 12 (48): 7744–52. PMID 17203514.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
2. ↑ Perr HA (2006). "Novel foods to treat food allergy and gastrointestinal infection". Current allergy and asthma reports. 6 (2): 153–9. PMID 16566866.
3. ↑ 3.0 3.1 Morita E, Kunie K, Matsuo H (2007). "Food-dependent exercise-induced anaphylaxis". J. Dermatol. Sci. 47 (2): 109–17. doi:10.1016/ j.jdermsci.2007.03.004 Check `|doi=` value (help). PMID 17507204.CS1 maint: Multiple names: authors list (link)
4. ↑ 4.0 4.1 Karatay S, Erdem T, Kiziltunc A; et al. (2006). "General or personal diet: the individualized model for diet challenges in patients with rheumatoid arthritis". Rheumatol. Int. 26 (6): 556–60. doi:10.1007/s00296-005-0018-y. PMID 16025333.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
5. ↑ 5.0 5.1 5.2 5.3 5.4 Akagawa M, Handoyo T, Ishii T, Kumazawa S, Morita N, Suyama K (2007). "Proteomic analysis of wheat flour allergens". J. Agric. Food Chem. 55 (17): 6863–70. doi:10.1021/jf070843a. PMID 17655322.CS1 maint: Multiple names: authors list (link)
6. ↑ Pfeil T, Schwabl U, Ulmer WT, König W (1990). "Western blot analysis of water-soluble wheat flour (Triticum vulgaris) allergens". Int. Arch. Allergy Appl. Immunol. 91 (3): 224–31. PMID 1693911.CS1 maint: Multiple names: authors list (link)
7. ↑ Terrazzano G, Sica M, Gianfrani C; et al. (2007). "Gliadin Regulates the NK-Dendritic Cell Cross-Talk by HLA-E Surface Stabilization". J. Immunol. 179 (1): 372–81. PMID 17579058.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
8. ↑ Sutton R, Hill DJ, Baldo BA, Wrigley CW (1982). "Immunoglobulin E antibodies to ingested cereal flour components: studies with sera from subjects with asthma and eczema". Clin. Allergy. 12 (1): 63–74. PMID 7067068.CS1 maint: Multiple names: authors list (link)
9. ↑ Armentia A, Sanchez-Monge R, Gomez L, Barber D, Salcedo G (1993). "In vivo allergenic activities of eleven purified members of a major allergen family from wheat and barley flour". Clin. Exp. Allergy. 23 (5): 410–5. PMID 8334538.CS1 maint: Multiple names: authors list (link)
10. ↑ 10.0 10.1 Pastorello EA, Farioli L, Conti A; et al. (2007). "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. 144 (1): 10–22. doi:10.1159/000102609. PMID 17496422.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
11. ↑ Walsh BJ, Wrigley CW, Musk AW, Baldo BA (1985). "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. 76 (1): 23–8. PMID 3839248.CS1 maint: Multiple names: authors list (link)
12. ↑ Akiyama H, Sakata K, Yoshioka Y; et al. (2006). "Profile analysis and immunoglobulin E reactivity of wheat protein hydrolysates". Int. Arch. Allergy Immunol. 140 (1): 36–42. doi:10.1159/000092000. PMID 16534217.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
13. ↑ Laurière M, Pecquet C, Bouchez-Mahiout I; et al. (2006). "Hydrolysed wheat proteins present in cosmetics can induce immediate hypersensitivities". Contact Derm. 54 (5): 283–9. doi:10.1111/j.0105-1873.2006.00830.x. PMID 16689814.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
14. ↑ Figueredo E, Quirce S, del Amo A; et al. (1999). "Beer-induced anaphylaxis: identification of allergens". Allergy. 54 (6): 630–4. PMID 10435480.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
15. ↑ Blands J, Diamant B, Kallós P, Kallós-Deffner L, Lowenstein H (1976). "Flour allergy in bakers. I. Identification of allergenic fractions in flour and comparison of diagnostic methods". Int. Arch. Allergy Appl. Immunol. 52 (1–4): 392–406. PMID 65335.CS1 maint: Multiple names: authors list (link)
16. ↑ Baldo BA, Krilis S, Wrigley CW (1980). "Hypersensitivity to inhaled flour allergens. Comparison between cereals". Allergy. 35 (1): 45–56. PMID 6154431.CS1 maint: Multiple names: authors list (link)
17. ↑ Valero Santiago A, Amat Par P, Sanosa Valls J, Sierra Martínez P, Malet Casajuana A, García Calderón PA (1988). "Hypersensitivity to wheat flour in bakers". Allergologia et immunopathologia. 16 (5): 309–14. PMID 3228051.CS1 maint: Multiple names: authors list (link)
18. ↑ Donovan GR, Baldo BA (1990). "Crossreactivity of IgE antibodies from sera of subjects allergic to both ryegrass pollen and wheat endosperm proteins: evidence for common allergenic determinants". Clin. Exp. Allergy. 20 (5): 501–9. PMID 2253081.
19. ↑ Yazicioglu M, Oner N, Celtik C, Okutan O, Pala O (2004). "Sensitization to common allergens, especially pollens, among children with respiratory allergy in the Trakya region of Turkey". Asian Pac. J. Allergy Immunol. 22 (4): 183–90. PMID 15783130.CS1 maint: Multiple names: authors list (link) .
20. ↑ Harada S, Iijima M, Nakamura A, Yoshizaki Y, Matsuo H, Morita E (2007). "[Four cases of wheat-dependent exercise-induced anaphylaxis with negative gluten cap-rast score]". Arerugi (in Japanese). 56 (1): 41–8. PMID 17272957.CS1 maint: Multiple names: authors list (link) CS1 maint: Unrecognized language (link)
21. ↑ Battais F, Richard C, Szustakowski G; et al. (2006). "Wheat flour allergy: an entire diagnostic tool for complex allergy". Allergie et immunologie. 38 (2): 59–61. PMID 16711538.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
22. ↑ Sanchez-Borges M, Capriles-Hulett A, Fernandez-Caldas E; et al. (1997). "Mite-contaminated foods as a cause of anaphylaxis". J. Allergy Clin. Immunol. 99 (6 Pt 1): 738–43. PMID 9215239.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
23. ↑ Mittag D, Niggemann B, Sander I, Reese I, Fiedler EM, Worm M, Vieths S, Reese G. (2004). "Immunoglobulin E-reactivity of wheat-allergic subjects (baker's asthma, food allergy, wheat-dependent, exercise-induced anaphylaxis) to wheat protein fractions with different solubility and digestibility". Mol Nutr Food Res. 48 (5): 380–389. PMID 15672478.CS1 maint: Multiple names: authors list (link)
24. ↑ Matsuo H, Morita E, Tatham AS, Morimoto K, Horikawa T, Osuna H, Ikezawa Z, Kaneko S, Kohno K, and Dekio S. (2004). "Identification of the IgE-binding epitope in omega-5 gliadin, a major allergen in wheat-dependent exercise-induced anaphylaxis". J Biol Chem. 279 (13): 12135–12140. PMID 14699123.CS1 maint: Multiple names: authors list (link)
25. ↑ Matsuo H, Morimoto K, Akaki T, Kaneko S, Kusatake K, Kuroda T, Niihara H, Hide M, and Morita E. (2005). "Exercise and aspirin increase levels of circulating gliadin peptides in patients with wheat-dependent exercise-induced anaphylaxis". Clin Exp Allergy. 35 (4): 461–466. PMID 15836754.CS1 maint: Multiple names: authors list (link)
26. ↑ Denery-Papini S, Lauriére M, Branlard G; et al. (2007). "Influence of the allelic variants encoded at the Gli-B1 locus, responsible for a major allergen of wheat, on IgE reactivity for patients suffering from food allergy to wheat". J. Agric. Food Chem. 55 (3): 799–805. doi:10.1021/jf062749k. PMID 17263477.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
27. ↑ Weichel M, Glaser AG, Ballmer-Weber BK, Schmid-Grendelmeier P, Crameri R (2006). "Wheat and maize thioredoxins: a novel cross-reactive cereal allergen family related to baker's asthma". J. Allergy Clin. Immunol. 117 (3): 676–81. doi:10.1016/j.jaci.2005.11.040. PMID 16522470.CS1 maint: Multiple names: authors list (link)
28. ↑ Burr ML, Fehily AM, Stott NC, Merrett TG (1985). "Food-allergic asthma in general practice". Human nutrition. Applied nutrition. 39 (5): 349–55. PMID 4077572.CS1 maint: Multiple names: authors list (link)
29. ↑ Langeland T, Nyrud M (1982). "Contact urticaria to wheat bran bath: a case report". Acta Derm. Venereol. 62 (1): 82–3. PMID 6175150.
30. ↑ Barnetson RS, Wright AL, Benton EC (1989). "IgE-mediated allergy in adults with severe atopic eczema". Clin. Exp. Allergy. 19 (3): 321–5. PMID 2736432.CS1 maint: Multiple names: authors list (link)
31. ↑ Zeiger RS, Heller S, Mellon MH; et al. (1989). "Effect of combined maternal and infant food-allergen avoidance on development of atopy in early infancy: a randomized study". J. Allergy Clin. Immunol. 84 (1): 72–89. PMID 2754147.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
32. ↑ Van Bever HP, Docx M, Stevens WJ (1989). "Food and food additives in severe atopic dermatitis". Allergy. 44 (8): 588–94. PMID 2610332.CS1 maint: Multiple names: authors list (link)
33. ↑ Hvatum M, Kanerud L, Hällgren R, Brandtzaeg P (2006). "The gut-joint axis: cross reactive food antibodies in rheumatoid arthritis". Gut. 55 (9): 1240–7. doi:10.1136/gut.2005.076901. PMID 16484508.CS1 maint: Multiple names: authors list (link)
34. ↑ Dieterich W, Esslinger B, Trapp D, Hahn E, Huff T, Seilmeier W, Wieser H, and Schuppan D. (2006). "Cross linking to tissue transglutaminase and collagen favours gliadin toxicity in coeliac disease". Gut. 55 (4): 478–84. PMID 16188922.CS1 maint: Multiple names: authors list (link)
35. ↑ Grant EC (1979). "Food allergies and migraine". Lancet. 1 (8123): 966–9. PMID 87628.
36. ↑ Pascual J, Leno C (2005). "A woman with daily headaches". The journal of headache and pain : official journal of the Italian Society for the Study of Headaches. 6 (2): 91–2. doi:10.1007/s10194-005-0158-1. PMID 16362649.
37. ↑ Lucarelli S, Frediani T, Zingoni AM; et al. (1995). "Food allergy and infantile autism". Panminerva medica. 37 (3): 137–41. PMID 8869369.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
38. ↑ Sponheim E (1991). "[Gluten-free diet in infantile autism. A therapeutic trial]". Tidsskr. Nor. Laegeforen. (in Norwegian). 111 (6): 704–7. PMID 2008691.CS1 maint: Unrecognized language (link)
39. ↑ Rix KJ, Ditchfield J, Freed DL, Goldberg DP, Hillier VF (1985). "Food antibodies in acute psychoses". Psychological medicine. 15 (2): 347–54. PMID 4023138.CS1 maint: Multiple names: authors list (link)

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