This document summarizes research on wheat allergy. It finds that wheat allergy prevalence is approximately 0.4-1% in children and 0.3-0.5% in adults. Symptoms typically present as skin reactions, gastrointestinal issues, or respiratory symptoms. Wheat allergy often resolves by ages 6-7. Key wheat allergens include alpha-amylase inhibitors, lipid transfer proteins, gliadins and glutenins. Diagnosis involves tests for wheat-specific IgE or oral food challenges. Wheat allergy is associated with increased risk of developing respiratory allergies.

1. Wheat allergy PlaneeVatanasurkitt,MD

2. Topic outline Prevalence Manifestation : children, adult Natural history Wheat allergen Diagnosis Cross-reactivity with grass Processing on allergenicity of wheat allergen WDEIA: pathogenesis

3. prevalence 0.4-1 % of children Venter C. incidence of parentally reported and clinically diagnosed food allergy in the first year of life JACI 2006;117:1118-24 0.3-0.5 % of children 0-14 yr Roehr CC. food allergy and nonallergic food hypersensitivity in children and adolecent. Clin Exp Allergy 2004:34:1534-41

4. 0.4% in adult Vierk KA. Prevalence of self-reported food allergy in american adult and use of food label.JACI 2007;119:1504-1510

5. Natural history of wheat allergy From Johns Hopkins pediatric allergy clinic 1999-2006 total 5000 children 103 patient had symptomatic reaction to wheat and positive wheat IgE test result Keet et al .The natural history of wheat allergy :Ann Allergy Asthma immunol.2009;102:410-15

6. Keet et al .The natural history of wheat allergy :Ann Allergy Asthma immunol.2009;102:410-15

7. Keet et al .The natural history of wheat allergy :Ann Allergy Asthma immunol.2009;102:410-15

8. Rate of resolution Keet et al .The natural history of wheat allergy :Ann Allergy Asthma immunol.2009;102:410-15

9. Predictors of prognosis Wheat IgE level correlated with resolution of allergy and peak wheat IgE level predict rate of resolution Keet et al .The natural history of wheat allergy :Ann Allergy Asthma immunol.2009;102:410-15

10. Wheat allergy : study retrospective study ;350 children aged less than 7 yr with food hypersensitivity treated in the Department of Allergology, Helsinki University Central Hospital, Helsinki, Finland, between 1992 and 1998, were reviewed to identify patients with wheat hypersensitivity. Kotaniemi-Syrjanenet al. The prognosis of wheat hypersensitivity :Pediatr Allergy Immunol 2010: 21: e421–e428.

11. Kotaniemi-Syrjanenet al. The prognosis of wheat hypersensitivity :Pediatr Allergy Immunol 2010: 21: e421–e428.

12. Sensitization to wheat and gliadin, and other food 15/21 IgE mediated wheat hypersensitivity had positive SPT reaction to cow’s milk 18/21 had positive SPT to hen’s egg 25/28 wheat allergic children had challenge proven cow milk allergy Sensitization to giadin is associated with slower achievement of tolerance and increased risk of asthma Kotaniemi-Syrjanenet al. The prognosis of wheat hypersensitivity :Pediatr Allergy Immunol 2010: 21: e421–e428.

13. Risk factors for development respiratory allergy and asthma 62% had become sensitized to birch pollen 68% had symptoms of allergic rhinoconjunctivitis during follow up at median age 4.4 yr 89% of children positive SPT to both wheat and hen egg development allergic rhinitis later in childhood Kotaniemi-Syrjanenet al. The prognosis of wheat hypersensitivity :Pediatr Allergy Immunol 2010: 21: e421–e428.

14. Risk factors for development respiratory allergy and asthma Asthma was diagnosed in 12 [43%] at median age 1.9 yr Incidence of asthma 64% in gliadin sensitized children comparison with 21% in gliadin-negative children Kotaniemi-Syrjanenet al. The prognosis of wheat hypersensitivity :Pediatr Allergy Immunol 2010: 21: e421–e428.

15. Wheat allergy: a double-blind,Placebo-controlled study in adults 27 patients Age 14-60 years History suspected wheat allergy Method : DBPCFC raw and cooked wheat, SPT, Ig E JACI 2006;117:433-9

16. 14/27 [52%] had positive result for glass pollen Most subjects also report food allergy to other fruits and vegetables 13/27 [48%] positive to wheat DBPCFC 38% of challenge positive patients were grass pollen positive compared with 64% in the challenge negative group JACI 2006;117:433-9

17. JACI 2006;117:433-9

18. JACI 2006;117:433-9

19. JACI 2006;117:433-9

20. JACI 2006;117:433-9

21. Wheat allergy Low incidence <1 % presentation : skin > GI > RS Immediate reaction > delayed reaction age of tolerance 6-7 years Associated with development of allergic rhinoconjunctivitis Wheat allergy does occur in adult patient Sensitivity and specificity of SPT and specific IgE for wheat in diagnosis of wheat allergy are low

22. Allergen involved in wheat allergy Categorized in to four fraction on basis of solubility Water soluble: albumin Salt soluble : globulin Aqueous alcohol: gliadins Dilute alkali/acid : glutelins Pastorello EA et al. European patients: alpha-amylase inhibitors , lipid transferproteins and low molecular-weight glutenins. Allergenic molecules recognized by double blind, placebo-controlled food challenge. Int Arch Allergy Immunol 2007; 144:10 – 22.

23. Sera of 16 wheat challenge-positive patients and 6 patient with wheat anaphylaxis Immunobloting of three Osborne’s protein fraction Pastorello EA et al. European patients: alpha-amylase inhibitors , lipid transferproteins and low molecular-weight glutenins. Allergenic molecules recognized by double blind, placebo-controlled food challenge. Int Arch Allergy Immunol 2007; 144:10 – 22.

24. Raw wheat Cooked wheat Pastorello EA et al. European patients: alpha-amylase inhibitors , lipid transferproteins and low molecular-weight glutenins. Allergenic molecules recognized by double blind, placebo-controlled food challenge. Int Arch Allergy Immunol 2007; 144:10 – 22.

25. Albumin/globulin fraction of Raw wheat

26. Gliadin fraction of raw wheat

27. Glutenin fraction of raw wheat

29. In water/salt-soluble albumin/globulin Most important allergen are amylase/trypsin inhibitor subunit Responsible for classic food allergy in children with atopic dermatitis and adult Pastorello EA et al. European patients: alpha-amylase inhibitors , lipid transferproteins and low molecular-weight glutenins. Allergenic molecules recognized by double blind, placebo-controlled food challenge. Int Arch Allergy Immunol 2007; 144:10 – 22.

30. In water/ salt-insoluble gluten gliadinsare involved in WDEIA, some cases of atopic dermatitis and in anaphylaxis in adults and children. Among the gliadins, ώ-5 gliadin(Tri a 19) was identified as a major allergen of WDEIA JACI 1999; 103 :912 -17 J DermatolSci 2003; 33: 99 – 104.

31. Gliadin Four of seven B-cell epitopes of ώ -5 gliadinidentified in WDEIA (QQI PQQQ , QQF PQQQ , QQS PEQQ , and QQ SPQQQ ) were found to be dominant Battais et al. reported that IgE antibodies of patients with WDEIA and classic wheat allergy recognized sequential epitopes of repetitive domains of ώ -5 gliadin. J BiolChem 2004;279:12135-40 Allergy 2005;60:815-21

32. Glutenins Glutenins in the water/salt-insoluble fraction are polymeric proteins made up of subunits of HMW and low molecular weight (LMW) Three B-cell epitopes of HMW glutenin subunits from repetitive domains, QQPG Q, QQPG QGQQ,and QQS GQSGQ, were identified in a minor subgroup of WDEIA LMW glutenin subunit s are also involved in child and adult wheat immediate allergies , including WDEIA J Immunol 2005;175:8116-22

33. Non specific lipid transfer protein Wheat non specific lipid transfer protein (nsL TP) (Tri a 14) with a molecular weight of 9 kDa was recently identified as a new wheat allergen in nine out of 22 patients with wheat food allergy by IgEimmunoblotting followed by mass spectrometry, and was confirmed to have the biological activity in vivo by a positive SPT with purified wheat LTP Pastorello EA et al. European patients: alpha-amylase inhibitors , lipid transferproteins and low molecular-weight glutenins. Allergenic molecules recognized by double blind, placebo-controlled food challenge. Int Arch Allergy Immunol 2007; 144:10 – 22.

34. Non specific lipid transfer protein 28% of 60 patient with wheat food allergy shower IgE reaction with purified wheat LTP Wheat nsLTP has also been reported as an inhalant allergen in baker asthma Pastorello EA et al. European patients: alpha-amylase inhibitors , lipid transferproteins and low molecular-weight glutenins. Allergenic molecules recognized by double blind, placebo-controlled food challenge. Int Arch Allergy Immunol 2007; 144:10 – 22.

35. other Some studies using proteomic analysis showed that several other proteins, such as b -amylase, peroxidase, thioredoxin (Tri a 25 ), and serpin (serine protease inhibit or), were also able to bind IgE from patients with wheat food allergy.

36. Protein state and route of exposure to gluten structures probably orient pattern of epitope reactivity and wheat food allergy manifestion

37. Cross-reactivity of wheat allergens with grass

38. Cross-reactivity of wheat allergens with grass Jones et al. demonstrated clinically insignificant cross-reactivity between cereals and grasses in children with confirmed wheat allergy by oral challenge in US Pastorello et al. showed lack of cross-reactivity between α-amylase inhibitor and grass pollen allergen and between nsLTP and grass pollen allergens JACI1995;96:341-51 Int Arch Allergy Immunol 2007;144:10-22

39. Processing on allergenicity of wheat allergens

40. Immunoblotting of cooked wheat When heating Some patient lost their IgE binding capacity toward LTP

41. Diagnostic test for wheat allergy Using CAP system ,PPV less than 75% Poor capacity due to commercial test reagent are mixture of wheat/salt-soluble wheat protein which lack allergen from insoluble gliadin fraction Recently the role of ώ-5 gliadin for diagnosis of wheat allergy was highlighted

42. Diagnostic test for wheat allergy Maximum efficiency of ώ-5 gliadin for diagnosis WDEIA was 0.89kUa/l Sensitivity 78% specificity 96% Matsuo et al sensitivity and specificity of recombinant omega 5 gliadin-specific IgE measurement in WDEIA Allergy 2008;63:233-36

43. Sensitivity in 50 Japanese WDEIA By immunoCAP system Matsuo et al sensitivity and specificity of recombinant omega 5 gliadin-specific IgE measurement in WDEIA Allergy 2008;63:233-36

44. Diagnosis test for wheat allergy

45. diagnosis In vitro : specific IgE to 5 gliadin in immediate reaction to wheat In vivo : challenge test, SPT with purified and recombinant wheat allergen

46. Wheat-dependent ,Exercise-induced Anaphylaxis in thai children Three-day challenge protocol Open challenge for wheat day 1 Exercise challenge test day 2 Exercise challenge test after meal containing wheat on day 3

47. Open challenge for wheat The challenge protocol started with 1 gram of wheat. The amount was doubled every 30 minutes until a dose of 16 grams of wheat was reached (a cumulative dose of 31 grams)

48. Exercise challenge an exercise challenge was performed on a steady-state, motor-driven treadmill with slope and velocities adjusted to achieve 80 percent of the maximum predicted workload for the individual age of the patients. The exercise was then maintained at this level for 6 minutes. lung function test was performed before, immediately after and at 3, 5, 10, 15, 20, and 30 minutes after the exercise challenge

49. Exercise challenge after a meal containing wheat An exercise challenge test was performed within one hour after a meal containing at least 16 grams of wheat

51. Pathophysiological mechanism for food dependent exercise-induced anaphylaxis Exercise-induced change in plasma osmolarity Alteration in blood pH with exercise Tissue transglutaminase activity .IL-6 and exercise Redistribution of blood during exercise and mast cell heterogeneity Changes in gut permeability and exercise Paula Robson-ansley ,George Du Toit. pathophysiology diagnosis and management of exercise-induced anaphylaxis Current Opinion in allergy and clinical immunology 2010,10:312-317

52. Exercise-induced change in plasma osmolarity Recent research demonstrated that in vitro alteration in osmolarity can increase basophil activation and histamine releasability Barg et al. food dependent exercised induced anaphylaxis J InvestigAllergolClinImmunol 2008;18:312-315

53. Exercise-induced change in plasma osmolarity Barg et al. performed histamine releasing assays using a range of buffers 280, 340, 450 mOsm in FDEIA ,food allergy and healthy Demonstrated an increase histamine release in the FDEIA at 340 mOsm but not other group 340 mOsm are pathological and would not be achieved even vigorous exercise Barg et al. food dependent exercised induced anaphylaxis J InvestigAllergolClinImmunol 2008;18:312-315

54. Alteration in blood pH with exercise Optimal mast cell degranulation occur at a pH 7.0 During sub optimal exercise pH remain the same at rest but during very heavy exercise pH decrease and may be low as 7.0 in the arterial blood Saeki K.histamine release by inorganic from mast cell granules isoloated by different procedureJpn J pharmacol 1972;22:27-32 Hultman E. acid-base balance during exercised.Exec Sport Sci Rev 1980;8:41-128

55. Tissue transglutaminase activity IL-6,exercise During exercise IL-6 is actively produced within contracting skeletal muscle and central nervous system IL-6 increase expression of tTG Tissue transglutaminase enzyme may result in peptide aggregation that leads to increase IgEcrosslinking PalosuoK.transglutaminase-mediated cross linking of o peptic fraction of omega-5 gliadin enhance igE reactivity in wheat-dependent exercise induced anaphylaxis. JACI 2003 .111:1386-1392

56. Redistribution of blood during exercise and mast cell heterogeneity Exercise –induced redistribution of blood flow away from the viscera to skeletal muscle Gut tolerated peptide are redistributed to sensitized mast cell inducing EIA Paula Robson-ansley ,George Du Toit. pathophysiology diagnosis and management of exercise-induced anaphylaxis Current Opinion in allergy and clinical immunology 2010,10:312-317

57. Change in gut permeability and exercise Tight junction in GI tract can become relaxed Allerginic peptide having greater access to gut associated immune system Paula Robson-ansley ,George Du Toit. pathophysiology diagnosis and management of exercise-induced anaphylaxis Current Opinion in allergy and clinical immunology 2010,10:312-317

58. management If a diagnosis of FDEIA has been made then allergen should be avoid both prior to and after exercise Suggest a 3h avoidance prior to exercise and 1 h following exercise Recognition of prodromal manifestation of EIA is important to discontinue exercise at the earliest warning sign Emergency plan and medication Exercise with a companion who aware of the condition Paula Robson-ansley ,George Du Toit. pathophysiology diagnosis and management of exercise-induced anaphylaxis Current Opinion in allergy and clinical immunology 2010,10:312-317

59. summary Wheat allergy are low prevalence Important allergen in wheat :amylase/trypsin inhibitor subunit, ώ-5 gliadin,nsLTP Manifestation: skin ,GI,RS Diagnosis : challenge , IgE to ώ-5 gliadin in immediated reaction to wheat Treatment : avoid Prognosis : 50 % tolerance in age 6-7 years