nGliadin, Wheat

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Code: f98
Latin name: Triticum aestivum
Family: Poaceae
Sub family: Pooideae
Tribe: Triticeae
Common names: Gliadin

ImmunoCAP allergen components:

rTri a 14 Wheat
rTri a 19 - f416

Allergen: Gliadin is purified from a wheat extract and consists of 4 native, highly purified (99%) gliadins: α-, β-, g- and ω-gliadins (including ω-5 gliadin).

(α = alpha, β = beta, g = gamma, ω = omega)

Biological function: Gliadins

Mw: alpha-gliadin (40 kDa); gamma-gliadin (65 kDa)

Clinical Utility

Wheat-dependent, exercise-induced anaphylaxis (WDEIA) is characterised by anaphylactic reactions after wheat ingestion and physical exercise. IgE antibodies to recombinant omega 5-gliadin (Tri a 19) are detectable in a majority of WDEIA patients; the additional determination of alpha, beta and gamma gliadin improves the diagnostic value of diagnosing WDEIA, in particular in omega 5-gliadin-negative patients. (1)

Gamma- and omega 5-gliadin have also been shown to be of importance in food allergy to wheat, and may be of benefit in identifying severe wheat allergy. (2, 3)

Gliadin may be of benefit in assessing patients sensitised to hydrolysed wheat proteins (used particularly in cosmetics). (1, 4, 5)

Allergen Exposure

See Wheat, f4

Allergen Description

n-Gliadin is a natural, non-recombinant mix of alpha, beta, gamma and omega gliadins (fast omega-gliadin and slow omega-gliadin), purified to 99%. Pure omega 5-gliadin (Tri a 19) (fast omega-gliadin) is also available as a recombinant allergen.

Wheat proteins are classified into water/salt-soluble proteins and water/salt-insoluble glutens. The former is comprised of albumins, globulins, and several inhibitors, e.g. alpha-amylase inhibitor. The latter group is collectively termed ‘gluten’ and comprises gliadins and glutenins. Gliadins are classified into alpha/beta-, gamma-, and omega-gliadins, according to their electrophoretic mobility: alpha/beta-gliadins (fast), gamma-gliadins (intermediate), and omega-gliadins (omega-2 and omega-5 gliadin) (slow). (1, 2, 6)

Fig. 1  Classification of wheat gluten proteins.

Adapted from Tatham AS, Shewry PR. Allergens to wheat and related cereals. Clin Exp Allergy 2008;38(11):1712-26.

 

Omega-gliadins can be divided into fast omega-gliadin and slow omega-gliadin. (7) Fast omega-gliadin is also called 1B-type omega-gliadin (8) or omega 5-type gliadin. (9, 10) Omega 5-gliadin, a component of fast omega-gliadin, has been identified as a major allergen in WDEIA. (7, 11) Omega 5-gliadin has also been shown to be a relevant allergen in children with an immediate-type severe allergy to wheat. (7) Of the gliadins, alpha and fast omega are reported to be the most allergenic. (12)

Specifically, omega 5-gliadin (Tri a 19) has been described as a major allergen in WDEIA, and specific IgE antibodies to recombinant omega-gliadin are detectable by ImmunoCAP® (f416) in approximately 80% of WDEIA patients. (1)

Immediate contact and food hypersensitivity to hydrolysed wheat proteins (IHHWP) (wheat protein hydrolysates), particularly present in cosmetic products, has been described. (4) In patients sensitised to hydrolysed wheat proteins, omega 5-gliadin seems not to be the major allergen; instead, other gliadins or glutenins are proposed to be relevant. (4)

Potential Cross-Reactivity

IgE against fast omega-gliadin cross-reacts to gamma-gliadin and slow omega-gliadin. (13)

Gamma 70-secalin and gamma 35-secalin in rye, and gamma 3-hordein in barley, have been reported to cross-react with omega 5-gliadin: (14) therefore, treatment with a gluten-free diet – i.e. a diet excluding wheat, rye, and barley – is indicated for all patients with WDEIA. (11)

IHHWP patients have experienced allergic reactions similar to WDEIA patients as a result of sensitisation to gamma 3-hordein, (15) a barley prolamin that cross-reacts with omega 5-gliadins. (16)

Clinical Experience

In general, water- or salt-soluble proteins have been identified as allergens in baker's asthma, (17) whereas water/salt-insoluble proteins are allergens for wheat-dependent, exercise-induced anaphylaxis (WDEIA); (18) although in contrast, a study reported that alpha-gliadin and fast omega-gliadin (water/salt-insoluble wheat proteins) are the allergens associated with baker’s asthma. (12)

WDEIA is a rare but potentially severe form of food allergy. (19, 20) It is clinically characterised by anaphylactic reactions ranging from urticaria to respiratory, gastrointestinal, or cardiovascular symptoms that occur usually 1 to 4 hours after wheat ingestion followed by physical exercise. Co-factors such as aspirin or alcohol intake, infections, stress, or female sex hormones or menstruation can substitute for or synergise with exercise in eliciting an immediate-type hypersensitivity reaction after ingestion of wheat. (21)

Omega 5-gliadin has been shown to be useful for the in vitro diagnosis of WDEIA, (7, 11, 13, 22, 23, 24) allowing the diagnosis to be confirmed in 82% of Japanese patients. (25) HMW glutenin has been described as the second major allergen in WDEIA, and 97% of Japanese WDEIA patients could be diagnosed by determination of specific IgE to omega 5-gliadin and HMW glutenin. (26) However, HMW glutenin – although targeting IgE antibodies in WDEIA patients – is not necessarily positive in all WDEIA patients; as demonstrated in a study of WDEIA patients in which none of three omega 5-gliadin-negative individuals showed reactivity to this allergen, but all three displayed specific IgE against alpha/beta- or gamma-gliadin. The authors concluded that in their patient population, alpha/beta- or gamma-gliadins appeared to be of higher relevance as IgE-reactive proteins than HMW glutenin, (1) furthermore concluding that therefore, the additional determination of alpha-, beta- and gamma-gliadin improves the diagnostic value of diagnosing WDEIA – in particular in omega 5-gliadin-negative patients.

The role of alpha/beta- or gamma-gliadins as allergens in wheat-allergic patients and in some cases of WDEIA has been suggested previously. (2, 27) In a study of four male Japanese patients, aged 39 to 53 years of age, with WDEIA, binding to gluten was inhibited to a large part by purified gamma-gliadin, suggesting that gamma-gliadin was a dominant allergen causing the anaphylactic symptoms in these patients. (2) Alpha-gliadin and gamma-gliadin have been identified as allergens in European patients with WDEIA. (2)

A recent study assessed the benefit of assessing alpha-, beta-, gamma- and omega-gliadin in 17 patients with conventional WDEIA: a combination of wheat intake and exercise as eliciting factors was reported by 12/17 patients, while in 3 patients, additional factors (aspirin, alcohol, or infection) were required, and in 2 patients, aspirin or alcohol intake provoked WDEIA in the absence of exercise also. Specific IgE to wheat (f4) was positive in 59% and to recombinant omega 5-gliadin (Tri a 19, f416) in all but three patients (82%). Positive IgE reactivity (>0.35 kUA/l) to alpha/beta/gamma-gliadin was identified in 14/17 (82%) patients, including the three patients negative to omega 5-gliadin. (1) Further assessment of wheat gliadins using highly purified native alpha/beta-gliadin and gamma-gliadin reported IgE reactivity to alpha/beta-gliadin in 9/17 (53%), to gamma-gliadin in 13/17 (76%), and to wheat LTP in 1/17 of this group. Interestingly, in one patient with WDEIA confirmed by provocation test and IgE antibodies to alpha/beta/gamma-gliadin, gamma-gliadin was identified as the only IgE-reactive allergen. (1) In the control group, raised specific IgE to gamma-gliadin was demonstrated in one food-allergic individual and none other of the control group for alpha/beta-gliadin or high molecular weight (HMW) glutenin, indicating specificity for the detection of IgE antibodies to alpha/beta- or gamma-gliadin and HMW glutenin of at least 97.5%.  (1)

Detailed analysis of the study indicated that gamma-gliadin was the only IgE-reactive gliadin in two of three omega 5-gliadin-negative patients: specific IgE was absent for all wheat allergens except gamma-gliadin alone, suggesting that this allergen may elicit WDEIA. For this patient, WDEIA was confirmed twice by oral provocation, with exercise and aspirin as augmentation factors. The second patient had a history of baker′s asthma and WDEIA, and reacted with gamma-gliadin, alpha-amylase inhibitor dimer, and wheat lipid transfer protein (LTP). The third patient was shown to have specific IgE to alpha/beta-gliadin, with lower levels for omega 5-gliadin and gamma-gliadin. (1)

Other studies of wheat-allergic individuals have demonstrated heterogenous sensitisation to a range of proteins found in wheat; including sensitisation to individual gliadins, though less specific-IgE sensitisation appears to occur to beta-, gamma-, fast omega-, and slow omega-gliadin. (12)

In a study of the sera of 28 patients with food allergy to wheat, 60% were shown to have specific-IgE antibodies against alpha- and beta-gliadins and LMW glutenin subunits, 55% to gamma-gliadins, 48% to omega-gliadins, and 26% to HMW glutenins. (28)

In an early study assessing relevant wheat proteins in WDEIA, patient sera from 18 individuals with WDEIA were evaluated. In ELISA, all 18 patients showed elevated IgE levels to a novel, gamma-like gliadin (subsequently identified as omega 5-gliadin), and 13 of the patients showed elevated IgE levels to the alpha-gliadin. (11)

Cosmetics containing hydrolysed wheat proteins (HWP) can induce rare but severe allergic reactions. Nine patients were studied, all females without wheat allergy, but with contact urticaria to HWP-containing cosmetics. Six of these also experienced generalised urticaria or anaphylaxis (i.e. food allergy) to foods containing HWP, although they were able to eat normal bread, pasta and pastries (IHHWP). All patients had low to moderate levels of specific IgE to wheat flour (f4) or gluten (f79). Serum IgE reacting with gliadins was observed only in patients with associated food allergy. Sensitivity to HWP and tolerance to unmodified wheat proteins extracted from grains were confirmed using SPT. Immunoblotting showed that IgE from all patients reacted with almost all HWP tested. Reactions generally occurred with large random peptide aggregates. IgE also reacted with unmodified grain proteins, contrasting with the skin-test results. They always reacted with salt-soluble proteins, but reacted variably with gluten proteins. No reaction occurred with gliadins in patients without associated immediate hypersensitivity to food containing HWP.

These results demonstrated the role of hydrolysis on the allergenicity of wheat proteins, through either skin or digestive routes. The authors suggested that at least part of the epitopes involved pre-exist in unmodified wheat proteins, and that the aggregation of peptides bearing these epitopes and others created by hydrolysis, along with the increased solubility and the route of exposure, were possible contributors to the allergenicity of HWP. (5) Furthermore, serum IgE reacting with gliadins was observed only in patients with associated food allergy. (5)

In a subsequent study, the 4 IHHWP patients with associated food allergy displayed similar clinical symptoms to those of WDEIA patients, following wheat food intake. Both types of patients displayed generalised urticaria or anaphylaxis, which generally involved anti-omega-gliadin IgE. The main differences were the negativity of skin-prick tests using normal, unmodified wheat products, their positivity with HWP, and the apparent absence of associated effort in the cases of IHHWP patients. Of the four patients sensitised to HWP, none reacted to omega 5-gliadins. (29) The authors concluded that the IgE epitopes involved in IHHWP and WDEIA were different, suggesting that the protein state and the route of exposure were to very similar gluten structures, but probably dependent on the pattern of epitope reactivity. In other words, the authors suggested that the antigens involved in IHHWP associated with food allergy, and in WDEIA, are very similar – but different, corresponding to specific omega 1-2 and to omega 5-gliadins respectively. (29) No IgE cross-reactions were observed between these antigen groups.

 

Compiled by Dr Harris Steinman, harris@allergyadvisor.com

References

  1. Hofmann SC, Fischer J, Eriksson C, Bengtsson Gref O, Biedermann T, Jakob T. IgE detection to α/β/γ-gliadin and its clinical relevance in wheat-dependent exercise-induced anaphylaxis. Allergy 2012;67(11):1457-60.
  2. 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.
  3. Daengsuwan T, Palosuo K, Phankingthongkum S, Visitsunthorn N, Jirapongsananuruk O, Alenius H, Vichyanond P, Reunala T. IgE antibodies to omega-5 gliadin in children with wheat-induced anaphylaxis. Allergy 2005;60(4):506-9.
  4. Fukutomi Y, Itagaki Y, Taniguchi M, Saito A, Yasueda H, Nakazawa T, Hasegawa M, Nakamura H, Akiyama K. Rhinoconjunctival sensitization to hydrolyzed wheat protein in facial soap can induce wheat-dependent exercise-induced anaphylaxis. J Allergy Clin Immunol 2011;127(2):531-3.
  5. Lauriere M, Pecquet C, Bouchez-Mahiout I, Snegaroff J, Bayrou O, Raison-Peyron N, Vigan M. Hydrolysed wheat proteins present in cosmetics can induce immediate hypersensitivities. Contact Dermatitis 2006;54(5):283-9.
  6. Tatham AS, Shewry PR. Allergens to wheat and related cereals. Clin Exp Allergy 2008;38(11):1712-26.
  7. 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.
  8. 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.
  9. Kasarda DD, Autran JC, Lew E J-L, Nimmo CC, Shewry RP. N-terminal amino acid sequences of ω-gliadins and ω-secalins: Implications for the evolution of prolamin genes. Biochim Biophys Acta 1983;747:138-50.
  10. 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.
  11. Palosuo K, Alenius H, Varjonen E, Koivuluhta M, Mikkola J, Keskinen H, Kalkkinen N, Reunala T. A novel wheat gliadin as a cause of exercise-induced anaphylaxis. J Allergy Clin Immunol 1999;103(5 Pt 1):912-7.
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  15. Snégaroff J, Bouchez-Mahiout I, Pecquet C, Branlard G, Laurière M. Study of IgE antigenic relationships in hypersensitivity to hydrolyzed wheat proteins and wheat-dependent exercise-induced anaphylaxis. Int Arch Allergy Immunol 2006;139(3):201-8.
  16. 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.
  17. Savolainen J. Baker's Asthma: diversity of allergens. [Editorial] Clin Exp Allergy 1997;27:1111-3.
  18. Varjonen E, Vainio E, Kalimo K. Life threatening anaphylaxis caused by allergy to gliadin and exercise. Clin Exp Allergy 1997;27:162-6.
  19. NIAID-Sponsored Expert Panel, Boyce JA, Assa'ad A, Burks AW, Jones SM, Sampson HA, Wood RA, Plaut M, Cooper SF, Fenton MJ, Arshad SH, Bahna SL, Beck LA, Byrd-Bredbenner C, et al. Guidelines for the diagnosis and management of food allergy in the United States: report of the NIAID-sponsored expert panel. J Allergy Clin Immunol 2010;126(6 Suppl):S1-58.
  20. Morita E, Matsuo H, Chinuki Y, Takahashi H, Dahlström J, Tanaka A. Food-dependent exercise-induced anaphylaxis -importance of omega-5 gliadin and HMW-glutenin as causative antigens for wheat-dependent exercise-induced anaphylaxis-. Allergol Int 2009;58(4):493-8.
  21. Fischer J, Schuck E, Biedermann T. Wheat-dependent exercise-induced anaphylaxis exclusively during menstruation. Allergy 2010;65(10):1347-8.
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  27. 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.
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  29. 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.

 

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