Treatment

Like CD patients, DH patients have the same HLA haplotypes (DQ2 and DQ8) and following a GFD improves the symptoms [154]. Drug therapy with dapsone or sulfonamides is also a possible treatment [153].

### *3.3. Wheat Allergy*

Allergens cause allergic reactions, and wheat is one of the five most frequent foods causing them in children. After milk and eggs, wheat is the most common allergen in Japan, Germany, and Finland [159]. In children and adults, wheat allergy (WA) prevalence is approximately 1% depending on age and region [160,161]. In contrast to CD, distinct wheat components such as water-insoluble proteins (gliadin and glutenin) and water/salinesoluble proteins (albumin and globulin) contribute to the development of WA [11,162,163].

#### 3.3.1. IgE-Mediated Wheat Allergy

IgE-mediated WA is triggered by allergen ingestion (food allergy), inhalation (respiratory allergy), or skin contact (dermal allergy). The antigen is introduced by dendritic cells that trigger CD4+ T cells to differentiate into T helper type 2 (Th2) cells. These cells produce cytokines such as IL-4, IL-5, and IL-13 that stimulate B cells to produce IgE [142,164]. When a new exposure to wheat allergens occurs, the IgE antibodies that are bound to their high-affinity receptor (FcεRI) on basophils or mast cells, recognize specific epitopes in wheat allergens [165]. The recognition results in IgE-crosslinking that triggers the release of vasoactive mediators like histamine from mast cells or basophils, leading to allergic responses, including WA [166,167]. The most common symptoms of WA due to these mechanisms include gastrointestinal symptoms (nausea, abdominal pain, vomiting, diarrhea), dermal (itching, eczema, redness), respiratory (rhinitis, asthma), circulatory (flushing, angioedema), and cerebral (disturbed thinking, headache, dizziness) which typically manifest minutes to hours after exposure [164,168].

Wheat-dependent exercise-induced anaphylaxis (WDEIA) is a particular type of IgEmediated WA. This condition gives rise to severe anaphylactic reactions to wheat when intense exercise is practiced soon after being consumed [169]. Symptoms of WDEIA include angioedema, chest pain, diarrhea, dysphagia, dyspnea, flushing, headache, hoarseness, nausea, pruritus, and syncope [142,170].

Baker's asthma is also an IgE-mediated WA that develops after allergen inhalation, especially cereal flour dust present in the work environment, and affects 0.03–0.24% of pastry factory workers, cereal handlers, confectioners, and bakery workers. It is considered one of the most frequent occupational, cereal-induced allergic asthmas [171–173]. Consuming cooked wheat or products containing it does not manifest symptoms in these patients, but they may react after eating products contaminated with raw wheat flour [174].

IgE-mediated wheat allergens are widely distributed in wheat's different protein fractions. Currently, 28 allergens have been identified in wheat, according to WHO/IUIS Allergen Nomenclature Sub-Committee (Table 2).

The heat-resistant α-amylase/trypsin inhibitor is an allergen that binds to specific IgE and is involved in anaphylaxis, in some cases of WDEIA [175], and baker's asthma [176]. Wheat seeds highly express Tri a 37, which is a plant defence protein. It is also resistant to digestion and heat and can act as a powerful allergen. Individuals who have IgE antibodies against Tri a 37 have a high risk of severe allergic symptoms upon wheat intake [177,178]. ω-5-gliadin, also known as Tri a 19, is involved in anaphylactic reactions to wheat and WDEIA in children [179,180].


**Table 2.** Wheat proteins implicated in IgE-mediated wheat allergy. Source: www.allergen.org (accessed on 19 July 2021).
