Background Most birch pollen-allergic patients develop allergic cross-reactions to the major allergen found in apples Mal d1, known as pollen-related food allergy (prFA). This is due to a strong clinically relevant homology between the major allergen in birch Bet v 1 and Mal d 1. Daily apple consumption induces oral tolerance in prFA, but its effect on the inhalational allergy has not been investigated. Objectives As continuous apple consumption might also mitigate the inhalational allergy, this study aimed to uncover apple cultivars suitable for treatment of birch pollen rhinoconjunctivitis and apple allergy in a controlled and established dosage. Methods Patients (n = 52) with birch pollen allergy and prFA to apples were subjected to a prick-to-prick test (SPT) with 23 cultivars (red-fleshed, old traditional and new commercial). By SPT, the apple parts flesh, peel equatorial and peel apical near the stalk were compared for their reactivity. One apple cultivar of each allergenicity class (low, middle and high) was subsequently tested in an oral provocation test (OPT). Results According to the SPTs, we provide a ranking of all 23 cultivars. Red-fleshed apples displayed the lowest reactivity, followed by old and new cultivars. Four cultivars showed disagreement from their allergenicity class: Santana and Pink Ladyâ, new cultivars that provoked only low to moderate. In contrast, White Rosemary and Goldparm€ ane, two old cultivars, induced strong reactions. Skin reactivity increased from flesh to peel to stalk, and SPT results could predict the severity of prFA of each allergenicity class. Conclusions Herein, we propose a treatment protocol for allergen immunotherapy to birch pollen and prFA with daily apple consumption. Red-fleshed, old and the new cultivars Santana and Pink Ladyâ provoke less allergic reactions and are suitable for initial induction. After a controlled and well-tolerated increase of intake, also moderate and finally high allergenic apple cultivars should be integrated into treatment of birch pollen allergenic patients.

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Background Seventy percent of patients suffering from birch pollen allergy (BPA) develop a pollen‐related food allergy (prFA), especially to apples, due to a clinically relevant cross‐reactivity between the major allergen in birch Bet v 1 and Mal d 1 in apples. Therefore allergen‐specific immunotherapy with fresh apples (AITA) could be a promising natural treatment of both BPA and prFA. Objective To assess the clinical efficacy of immunotherapy by daily apple consumption for patients with BPA and prFA. Methods A daily defined increasing amount of selected cultivars (Red Moon®, Pink Lady®, Topaz, Golden Delicious) was continuously consumed by 16 patients (12 female; median age; 50; range, 23–68 years), leading to increased intake of allergen over a period of at least 8 months. Specific IgE and IgG4 to Bet v 1 and Mal d 1, conjunctival and oral provocation tests, skin reactivity, and the average daily rhinoconjunctivitis combined symptom and medication score (CSMS) were measured during the peak birch pollen season. Results After 8 months of therapy, patients showed increased tolerance to apples (p < .001) and a decreased skin reactivity to apples. Oral allergy syndrome to other birch prFA than apple also decreased (p < .05). Moreover, daily rhinoconjunctivitis CSMS declined by 34% (p < .001), as did conjunctival reactivity to birch pollen extract by 27% (p < .01), while specific IgG4 to Mal d 1 and Bet v 1 increased (p < .01).

PR-10 proteins constitute a major cause of food allergic reactions. Birch-pollen-related food allergies are triggered by the immunologic cross-reactivity of IgE antibodies with structurally homologous PR-10 proteins that are present in birch pollen and various food sources. While the three-dimensional structures of PR-10 food allergens have been characterized in detail, only a few experimental studies have addressed the structural flexibility of these proteins. In this study, we analyze the millisecond-timescale structural flexibility of thirteen PR-10 proteins from prevalent plant food sources by NMR relaxation-dispersion spectroscopy, in a comparative manner. We show that all the allergens in this study have inherently flexible protein backbones in solution, yet the extent of the structural flexibility appears to be strikingly protein-specific (but not food-source-specific). Above-average flexibility is present in the two short helices, α1 and α2, which form a V-shaped support for the long C-terminal helix α3, and shape the internal ligand-binding cavity, which is characteristic for PR-10 proteins. An in-depth analysis of the NMR relaxation-dispersion data for the PR-10 allergen from peanut reveals the presence of at least two subglobal conformational transitions on the millisecond timescale, which may be related to the release of bound low-molecular-weight ligands from the internal cavity.

The protein Mal d 1 is responsible for most allergic reactions to apples (Malus domestica) in the northern hemisphere. Mal d 1 contains a cysteine residue on its surface, with its reactive side chain thiol exposed to the surrounding food matrix. We show that, in vitro, this cysteine residue is prone to spontaneous chemical modification by ascorbic acid (vitamin C). Using NMR spectroscopy and mass spectrometry, we characterize the chemical structure of the cysteine adduct and provide a three-dimensional structural model of the modified apple allergen. The S-ascorbylated cysteine partially masks a major IgE antibody binding site on the surface of Mal d 1, which attenuates IgE binding in sera of apple-allergic patients. Our results illustrate, from a structural perspective, the role that chemical modifications of allergens with components of the natural food matrix can play.