Wheat allergy.pdf

Wheat allergy
Suravat Homvises, MD.

Introduction
• Wheat (Triticum aestivum) may be considered the most important source of food globally
• Most food cultures serve wheat as an important part of daily meals, including bread, pasta,
breakfast cereal, semolina, bulgur, and couscous
Dramburg S, et al. Pediatr Allergy Immunol 2023;34 Suppl 28:e13854.

• In most countries, allergy to milk and egg are 2 most common food allergies but wheat comes
as third at least in Germany, Japan, and Finland
• Wheat allergy prevalence varies depending on the age and region from 0.4% to 4%
• Over the last 2-3 decades in Thailand, wheat has developed into another leading food that
causes allergic reactions in children
• Most typical clinical manifestations of wheat-induced food allergy include IgE-mediated food
allergy and celiac disease
Introduction
- Dramburg S, et al. Pediatr Allergy Immunol 2023;34 Suppl 28:e13854.
- Srisuwatchari W, et al. Asian Pac J Allergy Immunol 2022;40:263-8.

Allergen families
• Wheat belongs to Triticeae tribe of grass family Poaceae together with rye and barley
• Most allergenic proteins in wheat are members of the prolamin superfamily including
• Cereal prolamins (gliadins and glutenins) are seed storage proteins that are found in grains
of cereal grasses
• Bifunctional inhibitors (alfa-amylase/trypsin inhibitors)
• Wheat proteins have been broadly divided according to their solubility into
• Water-soluble albumins
• Salt-soluble globulins
• Insoluble prolamins: gliadins (soluble in aqueous alcohols) and glutenins

Albumin/
Globulin
Gliadin Glutenin

• Gliadins and glutenins are major storage proteins in wheat grain, also making wheat flour
suitable for baking
• No consensus definition of major and minor allergens of wheat
• Little is known of allergenicity
• Wheat is highly cross-reactive with other cereals, mainly rye and barley
• Oats belong to the same grass family but are more distantly related to wheat
• Children with challenge-proven wheat allergy usually tolerate ingested oats despite frequent
sensitization
• Cross-reactivity of wheat comes at least from sensitization to grass pollen
Allergen families

• Best characterized single wheat allergen is omega-5-gliadin (Tri a 19) which is major allergen for
wheat-dependent, exercise-induced anaphylaxis (WDEIA)
• Important allergen in early childhood wheat allergy with immediate onset symptoms and atopic
eczema and baker’s asthma/allergy
• Alpha-amylase inhibitors (AAI) and LTP (Tri a 14) are associated with both baker’s allergy and
food allergy
• Two studies demonstrated role of sensitization to low-molecular-weight (LMW) glutenin (Tri a 36)
and high-molecular-weight (HMW) glutenin (Tri a 26) with most typical type of childhood wheat
allergy
Allergen families

• Sera were obtained from 40 children (mean age 2.5 years) with suspected wheat allergy who
presented with atopic dermatitis and/or gastrointestinal and/or respiratory symptoms
• Wheat allergy was diagnosed with open or double-blinded, placebo-controlled oral wheat challenge
• Serum IgE antibodies to omega-5-gliadin were measured by ELISA
Palosuo K, et al. J Allergy Clin Immunol 2001;108:634-8.

• 16 (84%) children with immediate symptoms had IgE antibodies to
purified omega-5-gliadin
• In contrast, IgE antibodies to omega-5-gliadin were not detected in
any of the children with delayed or negative challenge test results
or in control children
• Diagnostic specificity and positive predictive value of omega-5-
gliadin ELISA were each 100% for immediate challenge reactions
Palosuo K, et al. J Allergy Clin Immunol 2001;108:634-8.

• 108 children (median age 1.5 years) with suspected wheat allergy underwent open or double-
blinded, placebo-controlled oral wheat challenges
• ImmunoCAP: Allergen-sIgE antibodies to wheat, gluten, gliadin, and total IgE
• Most of allergen components were essentially purified in microarray
Makela MJ, et al. Clin Exp Allergy 2014;44:1420-30.

• Allergens differentiating most effectively children with immediate reactions from those with no
reactions were AAIs, alpha-, beta-, and gamma-gliadins, HMW-glutenin subunit
• Positive IgE responses to ≥5 wheat allergens and strongly positive IgE responses to ≥3
wheat allergenic components gave moderate sensitivity with good specificity resulting with a
LR+ of 5.10 for immediate reactions in oral wheat challenge

• Patients who exhibited severe immediate reactions
(required epinephrine) in oral wheat challenge had
strongest IgE responsiveness against
• Gamma-gliadin (sensitivity 86%, specificity 92%,
LR+10.99, and LR-0.16 for strongly positive IgE
responsiveness, P<0.001)
• HMW-glutenin subunits (sensitivity 86%,
specificity 86%, LR+6.26, and LR-0.17 for
positive IgE responsiveness, P<0.001)

• 63 children with doctor’s diagnosis of wheat allergy confirmed sensitization to wheat and, on
wheat elimination diet, went through oral wheat challenges or had a convincing recent history of
wheat allergy
• IgE-ab to omega-5-gliadin, low molecular weight glutenin (LMW-glutenin), high molecular weight
glutenin (HMW-glutenin) and native gliadin preparation containing alpha-, beta-, gamma-, and
omega-gliadin (gliadin) were analyzed
Nilsson N, et al. Pediatr Allergy Immunol 2015;26:119-25.

• Levels of IgE-ab to wheat and four wheat components were significantly higher in wheat allergy
than in non-wheat allergy children (p < 0.001)
• ROC curves calculated show that HMW-glutenin test had largest AUC of 0.88, while AUCs
varied between 0.78 and 0.82 for the other wheat components tested
• Omega-5-gliadin was the test showing the highest specificity and best in discriminating between
children with WA from non-WA children

• Challenge positive children (n = 26) were divided into 2
severity groups (mild = severity score 1 and 2;
severe = score 4)
• Both severity groups had significantly higher levels of IgE-ab
to all four components as compared to non-WA
• Children with severe symptoms compared to mild symptoms
had significantly higher IgE-ab to gliadin, HMW-glutenin, and
LMW-glutenin but not to omega-5 gliadin
• Children with mild symptoms compared to non-WA had
significantly higher IgE-ab to omega-5 gliadin, HMW-glutenin,
and LMW-glutenin but not to gliadin

• 101 bakers with wheat flour allergy (40 German, 37 Dutch, and 24 Spanish) and 29 pollen-
sensitized control subjects with wheat-specific IgE but without occupational exposure
• All sera were tested for sIgE binding to 19 recombinant wheat single allergens and to the 2
cross-reactive carbohydrate determinants (CCDs)
Sander I, et al. J Allergy Clin Immunol 2015;135:1529-37.

• Of 101 bakers with work-related asthma, rhinitis and wheat flour
sensitization, or both
• 80% of bakers had specific IgE levels of 0.35 kUA/L or greater
• 91% of bakers had specific IgE levels of 0.1 kUA/L or greater
to at least one of the 21 allergens

• Most positive IgE test results in bakers were thiol reductase (Tri a 27), WDAI-0.19 (Tri a 28),
WTAI-CM1 (Tri a 29), SPILA (Tri a 39), thioredoxin (Tri a 25), peroxiredoxin (Tri a 32)

• Combination of IgE tests to 5 components, Tri a 27, Tri a 28, tetrameric alpha-amylase
inhibitor CM2 (Tri a 29.02), serine protease inhibitor–like allergen (Tri a 39), and 1-cys-
peroxiredoxin (Tri a 32), produced the maximal AUC 0.84
• This was still lower than AUC for wheat- or rye flour-specific IgE
AUC 0.84
AUC 0.89
AUC 0.88

• Cross-reactivity to grass pollen was proved for 9 components
• Cross-reactivity to rye flour was proved for 18 components

Leeds S, et al. Curr Opin Allergy Clin Immunol 2021;21:269-77.

Clinical manifestations
• (A) IgE-mediated form of wheat allergy
• (B) Wheat-dependent, exercise-induced anaphylaxis (WDEIA)
• (C) Baker’s allergy or asthma
• (D) Contact urticaria

(A) IgE-mediated form of wheat allergy
• Routes of sensitization: GI (or cutaneous) uptake of with subsequent or concomitant IgE
sensitization to stable proteins
• Age group: Infants/children/rarely adults
• Wheat allergens: Gliadins (omega-5-gliadin), HMW glutenins, LMW-glutenins, AAI’s
• Thermal stability: high
• Digestive stability: high
• Products: All wheat products

• Symptoms: Quick onset (minutes to 2 hours) of potentially severe systemic reactions with
various symptoms of anaphylaxis
• Mucosal (oropharyngeal), cutaneous (urticaria, angioedema, eczema flaring), airway related
(upper and lower airways), gastrointestinal and/or cardiovascular symptoms
• May be associated with delayed-type symptoms, which include worsening of atopic
dermatitis, and gastrointestinal symptoms such as stomach pain and diarrhea or loose stool
• Additional clinical features: Atopic eczema (infants with wheat allergy), reactions after other
cereals including rye and barley, rarely oats
• Medical diagnosis: Obvious and repeatable food allergic reaction to wheat
• Avoidance: No oral intake of wheat at significant amounts (milligram levels)
(A) IgE-mediated form of wheat allergy

(B) Wheat-dependent, exercise-induced anaphylaxis (WDEIA)
• Routes of sensitization: GI uptake with sensitization to especially omega-5-gliadin
• Age group: Adults/adolescents
• Wheat allergens: Omega-5-gliadin, LTP (Tri a 14)
• Thermal stability: high
• Digestive stability: high
• Products: Ingested wheat prior to exercise

• Symptoms: Quick onset urticaria, angioedema, and/or systemic symptoms of anaphylaxis
• Combination of food and exercise is necessary to elicit reaction
• Additional clinical features: Alcohol consumption enhances responsiveness
• Medical diagnosis: Symptoms and history, sensitization to omega-5-gliadin, challenge test
(some cases)
• Avoidance: No ingestion of wheat
- Ricci G, et al. Medicina (Kaunas) 2019;55.
(B) Wheat-dependent, exercise-induced anaphylaxis (WDEIA)

(C) Baker’s allergy or asthma
• One of the most common types of occupational asthma
• Routes of sensitization: Inhalation of wheat flour and dust during grain processing and
subsequent sensitization to water-soluble allergens
• Affected group: Exposed workers, typically Bakers
• Wheat allergens: Combination to Tri a 27, 28, 29, 39, 32 gives highest sensitivity and specificity
• Other allergens including AAI’s (Tri a 15 and 30), Tri a 21 and 33 common
• Products: Wheat flour and dust in air

• Symptoms: Airway symptoms (allergic rhinoconjunctivis and asthma symptoms) within few
hours of exposure
• Medical diagnosis: Allergic asthma and rhinoconjunctivitis due to wheat protein inhalation
• Avoidance: Occupational avoidance strategies in situations of large wheat protein exposure
(C) Baker’s allergy or asthma

(D) Contact urticaria
• Routes of sensitization: Use of local cosmetics on skin
• Age group: Adolescents/adults
• Wheat allergens: Hydrolyzed wheat protein (HWP)/gluten
• Allergen abundance: Common in cosmetics
• Products: Hydrolyzed gluten in cosmetics such as facial soap

• Symptoms: Typical urticaria after application of cream/soap
• Ingestion of foods containing deamidated gluten can cause systemic reactions (anaphylaxis)
• Additional clinical features: Usually patients do not have other types of wheat allergy
• Medical diagnosis: Obvious contact urticaria when using HWP containing products
• Avoidance: Cosmetics containing HWP, those with systemic reactions avoidance of HWP in food
(D) Contact urticaria

Other clinical manifestations
• Food protein-induced enterocolitis syndrome
• Non-IgE-mediated manifestation
• Infants develop vomiting, pallor, and lethargia 1–4 hours following ingestion of wheat in
absence of IgE-mediated skin or respiratory symptoms
• Eosinophilic esophagitis
• Irritable bowel syndrome and constipation are not associated with allergy
Ricci G, et al. Medicina (Kaunas) 2019;55.

Risk factors
• Atopic disorders often coexist, including atopic dermatitis (53–87%), asthma (48–75%),
allergic rhinitis (34–62%)
• 90% of infants have been reported to be allergic to other foods
• Cow’s milk and/or egg are more frequently associated with wheat allergy, less frequently
fish, soya, and nuts
• Sensitization to grasses is associated with increased risk for occurrence of sensitization to wheat
over time

• Timing of Initial Exposure and breastfeeding
• Delaying exposure to wheat until after 6 months was associated with a higher risk (>4
times) of developing wheat allergy
• 7 studies (5 observational, low to moderate quality, 2 RCTs, high quality)
• Earlier introduction of wheat or gluten most likely lowers the risk of wheat sensitization early
in life, but it does not affect the risk of wheat allergy
• Correlation between breastfeeding and wheat allergy is not clearly explained
Risk factors
- Chmielewska A, et al. J Paediatr Child Health 2017;53:889-96.

Exclusive breastfeeding
1. Longer BF was associated
with wheat allergy (2 studies)
and sensitization (1 study)
2. Longer exclusive BF was
associated lower risk of wheat
sensitization (1 study)
1
1
2
Early introduction of wheat
1. Early introduction was
associated with reduced risk of
wheat sensitization up to 5
years (1 study)
2. Introducing cereal ≥7 months
of age increased the risk of
wheat allergy (1 study)
3. No effect in RCTs (1 study)
1
2 Chmielewska A, et al. J Paediatr Child Health 2017;53:889-96.

1
3
Exclusive breastfeeding
1. Longer BF was associated
with wheat allergy (2 studies)
and sensitization (1 study)
2. Longer exclusive BF was
associated lower risk of wheat
sensitization (1 study)
Early introduction of wheat
1. Early introduction was
associated with reduced risk of
wheat sensitization up to 5
years (1 study)
2. Introducing cereal ≥7 months
of age increased the risk of
wheat allergy (1 study)
3. No effect in RCTs (1 study)
Chmielewska A, et al. J Paediatr Child Health 2017;53:889-96.

Investigations
• Skin prick test
• Commercial wheat extract or inhouse solution employing wheat flour can be used
• Sensitivity from 0.69 to 0.89
• Specificity from 0.64 to 0.77
• Positive predictive value from 0.56 to 0.86
• Negative predictive value from 0.76 to 0.97
• Very low specificity for all types of wheat allergy
• Improved by additional testing to omega-5 gliadin (dissolved in ethanol, in-house
preparation) or other gliadins

Investigations
• Specific IgE testing
• Whole wheat extract, Tri a 14, Tri a 19, gliadins
• Wheat extract has low specificity and high sensitivity: patterns A, B and C
• Omega-5 gliadin and gliadins (alpha, beta, gamma): patterns A and B
• Lipid transfer proteins (Tri a 14): patterns A and B
• AAIs, particularly dimeric 0.19, LMW and HMW glutenins, Tri a 37: patterns A and C

• Specific IgE testing to wheat extracts
• Specific IgE testing to omega-5-gliadin (Tri a 19)
Investigations
Ricci G, et al. Medicina (Kaunas) 2019;55.

• Oral food challenges
• IgE-mediated form of wheat allergy
• Various protocols with whole wheat can be used
• Start with low dose (1-50 mg) of wheat-specific protein
• WDEIA and Baker’s allergy or asthma
• History and IgE testing are enough for diagnosis
• Idiopathic anaphylaxis, carefully monitored exercise challenge with high readiness
treatment of anaphylaxis after wheat ingestion may be considered
• Some centers have used ASA or alcohol as additional provoking factor
• Contact urticaria
• Challenge on the skin with HWP containing cream
Investigations

Managements (Advice and avoidance)
• Level of avoidance can be titrated according to symptoms
• Those with anaphylaxis should avoid products even with small amounts of wheat
• Those with delayed symptoms and IgE-negative to wheat should be encouraged to use
maximal dose not eliciting symptoms
• WDEIA
• Avoidance of all gluten-containing wheat especially if co-factors present
• Baker’s allergy or asthma
• Avoidance of inhalation of wheat containing protein
• Contact urticaria
• Avoidance of cosmetics with hydrolyzed wheat protein Dramburg S, et al. Pediatr Allergy Immunol 2023;34 Suppl 28:e13854.

• All wheat allergic patients should be prescribed treatment for acute allergic reactions and be
given detailed treatment plan
• Those with delayed reactions or mild systemic reactions, antihistamine is enough
• Those with history of severe reactions, use of adrenaline autoinjector should be instructed
• WDEIA
• Adrenaline autoinjector
• Baker’s allergy or asthma
• Symptomatic treatment for rhinitis/asthma
Managements (Pharmacotherapy)

Wheat immunotherapy
Leeds S, et al. Curr Opin Allergy Clin Immunol 2021;21:269-77.

• Strategies in developing gluten-free products
• Hypoallergenic wheat lines
• Replacement of wheat with rice, soybean, or other gluten-free ingredient
Managements
Yano H. Foods 2023;12.

• Enzymic degradation: epitope degradation with specific enzymes
• Ion exchanger deamidation: deaminating amino groups of glutamine and/or asparagine within
epitopes by treating with cation exchange resin
• Thioredoxin treatment: dissociate disulfide bonds in gluten proteins (gliadin and glutenin)
Hypoallergenic wheat
Morita E, et al. Foods 2023;12.

Methods Major Outcomes and Limitations
Wheat lines with a reduced allergenicity
1BL/1RS translocation (Clement)
Significant reduction of omega-5-gliadin protein was presented using SDS-PAGE and immunoblotting with rabbit
polyclonal antibody. Low allergenicity was presented with IgE-immunoblotting using small numbers of WDEIA
patients’ sera. No oral challenge test was preformed in human.
1B/1R translocation (Pamier)
Significant reduction of omega-5-gliadin protein was determined by RP-HPLC. No significant difference in basophil
activation compared with conventional wheat line in WDEIA patients.
A genome diploid einkorn lacking B
chromosomes
Low allergenicity was presented in negative skin prick test and lack of IgE-immunoreactivity to omega-5-gliadin in
almost all WDEIA patients sensitized with omega-5-gliadin. No oral challenge test was performed in human.
Wheat line lacking all omega-gliadin encoding
loci Gli A1, Gli B1 and Gli D1 established using
traditional breeding (3xN)
Lack of omega-5-gliadin was determined using SDS-PAGE and RP-HPLC. Low reactivity to omega-5-gliadin was
presented using ELISA with several WDEIA patients’ sera. Significant IgE reactivity was presented to other gluten
proteins. No oral challenge test was performed in human.
Aneuploid wheat line lacking Gli-B1 locus
(1BS-18)
Lack of omega-5-gliadin protein was determined using RP-HPLC and immunoblotting with rabbit polyclonal
antibody. Low allergenicity was presented using guinea pig and rat wheat challenge models. Oral tolerance to
wheat was determined using rat models. No oral challenge test was performed in human.
Wheat line lacking Gli B1 and Glu B3 loci
established using double-haploid breeding
(DH20)
Low allergenicity was determined using IgE-immunoblotting with 14 WDEIA patients’ sera, immunoblot inhibition
assay and ELISA inhibition assay. No oral challenge test was performed in human.

Methods Major Outcomes and Limitations
Genetic engineering
Transgenic wheat lines with RNA interference
for ω5-gliadin (Butte 86)
Omega-5-gliadin protein was either undetectable or depleted in SDS-PAGE. Greatly reduced IgE-immunoreactivity
to omega-5-gliadin was presented in most of 11 WDEIA patients using IgE-immunoblotting. Small amount of
omega-5-gliadin protein derived from 1D chromosome remaind in the line. No oral challenge test was performed in
human.
Enzymic degradation
Two-step method to produce hypoallergenic
wheat using cellulase and actinase
Low allergenicity and immunotolerance effect were confirmed by clinical open studies. Thirteen of 15 children with
AD ingested cupcake made of the wheat without allergy symptom. Most children with wheat allergy associated with
AD became immunotolerance to normal wheat product after continuous intake of the cupcake.
Ion exchanger deamidation
Deamidation of gliadin using a cation
exchange resin
Low allergenicity was presented using IgE-immunoblotting with sera obtained from patients with High Serum IgE,
and a mouse model of wheat-gliadin allergy. No clinical study was performed in human.
Thioredoxin treatment
Reduced thioredoxin treatment of wheat
allergens
Low allergenicity was presented using ELISA with Serum IgE obtained from patients with wheat allergy, skin prick
test and CAP-FEIA inhibition assay. No oral challenge test was performed in human.

Prognosis
• Prognosis of IgE-mediated wheat allergy in children is generally favorable, with 45-69% of
children becoming tolerant by 6 years of age
• Retrospective cohort study included 83 children who had history of immediate-type allergic
reaction to wheat and were followed until 6 years of age
• Rates of tolerance acquisition at 3, 5, and 6 years of age were 20.5%, 54.2%, and 66.3%
Koike Y, et al. Int Arch Allergy Immunol 2018;176:249-54.

Risk factors for persistent wheat allergy
• History of anaphylaxis to all foods including wheat
• High level of wheat- or omega-5-gliadin-specific
IgE antibodies
Koike Y, et al. Int Arch Allergy Immunol 2018;176:249-54.

• Total of 81 children were enrolled (mean age of 7.0 ± 2.7 years at initiation of wheat OIT)
• Median follow-up duration was 2 years (IQR 1.2-3.0 years)
• Complicated cases: experienced frequent reactions (at least grade 2 or exercise-induced
reactions) or deviated from up-dosing protocol >> 26 patients (32.1%)
• Initial wheat-sIgEs were significantly higher in complicated cases (median of 192.3 vs 6.9 kUA/L)
• Initial omega-5-gliadin-sIgEs were significantly higher in complicated cases (median of 15.0 vs
1.6 kUA/L)
• Risk factors for complicated cases include higher omega-5-gliadin-sIgEs and anaphylaxis during
OFC (aOR 1.035 and 5.684, respectively)
Pacharn P, et al. Asian Pac J Allergy Immunol 2024.

Celiac disease
• Chronic immune-mediated enteropathy driven by dietary gluten, which is present in grains
including wheat, rye and barley
• Epidemiology
• Prevalence in general population can be high as 1.4% (95% CI: 1.1–1.7%)
• High-prevalence countries in Europe include Sweden, Finland, Turkey, the United Kingdom,
Italy, the Czech Republic and Portugal
Lindfors K, et al. Nat Rev Dis Primers 2019;5:3.

• Risk factors
• First-degree relative with celiac disease (2–20%)
• Type 1 diabetes mellitus (3–12%)
• Selective IgA deficiency (2–8%)
• Autoimmune thyroiditis (4–7%)
• Sjögren syndrome (4–12%)
• Down syndrome (5–12%)
• Addison disease (5%)
• Turner syndrome (3–4%)
• Williams syndrome (2–4%)
Celiac disease

Dietary gluten
• Gliadins and glutenins are particularly rich in proline and glutamine amino acids
• High proline content resistant to proteolytic processing by gastric and pancreatic enzymes
• Prolamin, proline and glutamine residues content in oats are substantially lower than cereals
(wheat, rye and barley)
• Various long gliadin peptides are generated in gastrointestinal tract and capable of activating
immune responses
Genetics
• HLADQ2 and HLA-DQ8 impart the strongest risk
• HLA explain only ~50% of the genetic variance in coeliac disease
Mechanisms

• Gluten peptides that result from incomplete digestion in gut lumen gain access to lamina propria
through epithelial barrier
• Generation of gluten-specific T cell responses
• Small intestinal mucosal gluten-specific CD4+ T cell responses and wheat gliadin and
transglutaminase 2 antibodies (encoded by TGM2)
• Glutamine residues are replaced by glutamic acid, which increases binding affinity of gluten
peptides to HLA-DQ2 or HLA-DQ8 molecules on APCs
• Gluten-specific CD4+ T cells recognize the HLA-presented gliadin peptides by cell surface T
cell receptors (TCRs) and secrete various cytokines, including IFN-gamma and IL-21
Mechanisms

• Generation of autoantibodies
• CD4+ T cell might provide help signals to both gluten-specific and TG2-specific B cells,
promoting activation and differentiation into plasma cells that secrete deamidated gliadin
peptides (DGPs) and TG2 antibodies
• Both antibody can be detected in the circulation of patients with celiac disease; in addition,
TG2-Abs are present in the small intestinal mucosa
• Antibodies are thought to increase the permeability of the epithelial barrier, allowing gliadin
peptides to access the lamina propria
Mechanisms

• Cytokines in intestinal mucosal immune response
• Cytokines including IFN-gamma and IL-21 produced by gluten-specific CD4+ T cells as
result of adaptive immune activation
• Innate immune responses are hallmarked by increased mucosal expression of IL-15, IL-18
and type I interferons, which produced by stressed intestinal epithelial and/or dendritic cells
• IL-15 inhibits Treg cells, promoting loss of oral tolerance and immune regulation, and by
licensing intraepithelial lymphocytes (IEL) to kill intestinal epithelial cells
Mechanisms

• Intraepithelial lymphocytes
• IELs is increased and their amount correlates with severity of mucosal atrophy
• IELs in mucosa display cytotoxic transformation, which induct intestinal epithelial cell
apoptosis driven by mechanisms involving Fas ligand, perforin, granzyme B and type II
integral membrane protein NKG2D
• Main ligand for NKG2D expressed IELs is stress-induced HLA class I molecule MICA
• Interaction of NKG2D and MICA directly induces intestinal epithelial cell death
Mechanisms

• Innate immune activation
• Enteric infections, including viral and bacterial pathogens (Campylobacter), could directly
induce release of innate immune cytokines and cause intestinal epithelial cell stress or pro-
inflammatory signature in APCs
• Non-gluten proteins such as alpha-amylase/trypsin inhibitors may be able to induce innate
immune responses via Toll-like receptor 4 (TLR4)-dependent mechanisms
• Environmental factors
• Intestinal dysbiosis
• Smoking
Mechanisms

Clinical manifestations
• Most common clinical presentation has
shifted to milder multi-organ manifestations
• Dermatitis herpetiformis, presents in up to
10% of adults, is the best characterized
extraintestinal manifestation and defined by
itching blisters, particularly on elbows, knees,
buttocks and scalp
• Diagnostic delays can reach up to 10 years
in resource-rich countries, and longer in
resource-poor countries

• EmAs (TG2 antibodies specific in endomysium) and TG2-Ab assays
• Excellent sensitivity (90–100%) and close to 100% specificity
• EmA has been regarded as gold-standard method
• Most accurate serological tests are for IgA isotype EmAs and TG2-Abs
• IgG isotype antibody tests are needed only in case of selective IgA deficiency
• DGP-specific antibodies may recognize some patients that are not detected by EmA and TG2-Ab
• First-generation anti-gliadin antibody assays, which use native gliadin peptides as antigen, are
considered inaccurate, and no longer recommended for diagnosis
Diagnosis

• Small intestine biopsy
• Small bowel mucosal villous atrophy, intraepithelial lymphocytosis and crypt hyperplasia
• Villous atrophy is not a specific pathognomic finding for celiac disease
• Additional diagnostic tools
• Detection of intestinal TG2-targeted coeliac IgA isotype autoantibody deposits in intestinal
mucosal tissue samples is helpful in unequivocal cases but requires frozen biopsy samples
• HLA typing is useful for exclusion of celiac disease
• Unlikely to arise in individuals who are not carrying either HLA-DQ2 or HLA-DQ8
• Quantification of inflammatory cells in small intestinal mucosa
• Increased number of CD3+ lymphocytes is not specific finding
Diagnosis

Small intestinal biopsy
Mucosal inflammation
with crypt hyperplasia
Normal Villous atrophy with
crypt hyperplasia

Husby S, et al. J Pediatr Gastroenterol Nutr 2012;54:136-60.

Managements
• Gluten-free diet
• All food based on or containing wheat, rye, barley and all cross-breeds of these cereals
• Primitive wheat varieties such as kamut, einkorn, spelt
• US FDA in 2013 issued regulations defining foods labelled ‘gluten free’ as containing
<20 parts per million (ppm) of gluten (equal to 20 mg per kg of food)
• Factors may associated with poor adherence
• Diagnosis in adolescence
• Lower socioeconomic status
• Local food culture
• Travelling and eating out in restaurants

Prognosis
• Celiac disease is associated with increased in enteropathy-associated T cell lymphoma, non-
Hodgkin lymphoma and adenocarcinoma of intestine
• Non-neoplastic complication is splenic hypofunction, which might predispose patients to
increased numbers of infections

References (1)
• Dramburg S, Hilger C, Santos AF, de Las Vecillas L, Aalberse RC, Acevedo N, et al. EAACI Molecular Allergology User's Guide 2.0. Pediatr Allergy Immunol 2023;34
Suppl 28:e13854.
• Ricci G, Andreozzi L, Cipriani F, Giannetti A, Gallucci M, Caffarelli C. Wheat Allergy in Children: A Comprehensive Update. Medicina (Kaunas) 2019;55.
• Srisuwatchari W, Vichyanond P, Jirapongsananuruk O, Visitsunthorn N, Pacharn P. Characterization of children with IgE-mediated wheat allergy and risk factors that
predict wheat anaphylaxis. Asian Pac J Allergy Immunol 2022;40:263-8.
• Palosuo K, Varjonen E, Kekki OM, Klemola T, Kalkkinen N, Alenius H, et al. Wheat omega-5 gliadin is a major allergen in children with immediate allergy to ingested
wheat. J Allergy Clin Immunol 2001;108:634-8.
• Makela MJ, Eriksson C, Kotaniemi-Syrjanen A, Palosuo K, Marsh J, Borres M, et al. Wheat allergy in children - new tools for diagnostics. Clin Exp Allergy
2014;44:1420-30.
• Nilsson N, Sjolander S, Baar A, Berthold M, Pahr S, Vrtala S, et al. Wheat allergy in children evaluated with challenge and IgE antibodies to wheat components. Pediatr
Allergy Immunol 2015;26:119-25.
• Sander I, Rihs HP, Doekes G, Quirce S, Krop E, Rozynek P, et al. Component-resolved diagnosis of baker's allergy based on specific IgE to recombinant wheat flour
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