Wheat allergy

WHEAT ALLERGY

Planee Vatanasurkitt,MD

TOPIC OUTLINE

Prevalence Manifestation : children, adult Natural history Wheat allergen Diagnosis Cross-reactivity with grass Processing on allergenicity of wheat

allergen WDEIA: pathogenesis

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

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

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

RATE OF RESOLUTION

age Rate of resolution

4 yrs 29%

8 yrs 56%

12 yrs 65%


PREDICTORS OF PROGNOSIS

Wheat IgE level correlated with resolution of allergy and peak wheat IgE level predict rate of resolution

Peak wheat IgE Median age of tolerance

<20kU/L 31 months

20-49 kU/L 54 months

>50 kU/L 145 months


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.Kotanie mi-Syrjanen et al. The prognosis of wheat hypersensitivity

:Pediatr Allergy Immunol 2010: 21: e421–e428.

Kotanie mi-Syrjanen et al. The prognosis of wheat hypersensitivity :Pediatr Allergy Immunol 2010: 21: e421–e428.

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 asthmaKotanie mi-Syrjanen et al. The prognosis of wheat hypersensitivity

:Pediatr Allergy Immunol 2010: 21: e421–e428.

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


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


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

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

JACI 2006;117:433-9

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

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.

Sera of 16 wheat challenge-positive patients and 6 patient with wheat anaphylaxis

Immunobloting of three Osborne’s protein fraction



Raw wheat Cooked wheat



Albumin/globulin fraction of Raw wheat

Gliadin fraction of raw wheat

Glutenin fraction of raw wheat

Albumin/globulin

Nonspecific LTPAlpha-Amylase/trypsin inhibitorGlobulinPeroxidaseSerpin

Gliadins Alpha-Amylase/trypsin inhibitorGamma-GliadinAlpha-gliadingluteninLMW

Glutenin Alpha-Amylase/trypsin inhibitorpuroindolinTritinLMW gluteninGranule-bound glycogen syntaseBeta- amylase

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



IN WATER/ SALT-INSOLUBLE GLUTEN

gliadins are 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 Dermatol Sci 2003; 33: 99 – 104.

GLIADIN

Four of seven B-cell epitopes of ώ -5 gliadin identified 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.Allergy 2005;60:815-21

J Biol Chem 2004;279:12135-40

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

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 IgE immunoblotting 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.

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



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.

Albumin/globulin

Water/salt insoluble gluten

Glutenin Nonspecific lipid transfer protein

Amylase/trypsin inhibitor

Gliadin High molecular weight Low molecular weight

Classic food allergyAtopic dermatitisWDEIA

Classic food allergyWDEIA

Immediated reaction

Inhalant allergen in baker’s asthma

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

CROSS-REACTIVITY OF WHEAT ALLERGENS WITH GRASS

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

PROCESSING ON ALLERGENICITY OF WHEAT ALLERGENS

Immunoblotting of cooked wheat

When heating Some patient lost their IgE binding capacity toward LTP

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

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

SENSITIVITY IN 50 JAPANESE WDEIA

Specific IgE to rώ5 gliadin

80%

Specific igE to wheat 48%

Specific IgE to gluten 56%

B cell epitope peptide of ώ5 gliadin

76%

B cell epitope of HMW glutenin

22%

By immunoCAP system

Matsuo et al sensitivity and specificity of recombinant omega 5 gliadin-specific IgE measurement in WDEIA

Allergy 2008;63:233-36

DIAGNOSIS TEST FOR WHEAT ALLERGY

In germany ,US studyMost patient have history of atopic dermatitis

No correlation with level of ώ5 gliadin specific IgE and outcome of oral wheat challenge

Ito et al High concentration of IgE specific to ώ5 gliadin had high risk of failing wheat challege

DIAGNOSIS

In vitro : specific IgE to 5 gliadin in immediate reaction to wheat

In vivo : challenge test, SPT with purified and recombinant wheat allergen

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

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)

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

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

PATHOPHYSIOLOGICAL MECHANISM FOR FOOD DEPENDENT EXERCISE-INDUCED ANAPHYLAXIS

1. Exercise-induced change in plasma osmolarity

2. Alteration in blood pH with exercise3. Tissue transglutaminase activity .IL-6

and exercise4. Redistribution of blood during exercise

and mast cell heterogeneity5. Changes in gut permeability and

exercisePaula Robson-ansley ,George Du Toit.pathophysiology diagnosis and management of exercise-induced anaphylaxisCurrent Opinion in allergy and clinical immunology 2010,10:312-317

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 anaphylaxisJ Investig Allergol Clin Immunol 2008;18:312-315

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 exerciseBarg et al. food dependent exercised induced

anaphylaxisJ Investig Allergol Clin Immunol 2008;18:312-315

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

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 IgE crosslinking

Palosuo K.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

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 anaphylaxisCurrent Opinion in allergy and clinical immunology 2010,10:312-317

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 anaphylaxisCurrent Opinion in allergy and clinical immunology 2010,10:312-317

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

conditionPaula Robson-ansley ,George Du Toit.pathophysiology diagnosis and management of exercise-induced anaphylaxisCurrent Opinion in allergy and clinical immunology 2010,10:312-317

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

Wheat allergy

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