t215 Bet v 1

Summary

Bet v 1 is a protein of molecular weight 17 kDa. It is a major allergen of birch pollen. Up to 95% of patients sensitized to birch have been reported to respond to Bet v 1. Various studies have shown that the prevalence of sensitization to Bet v1 varies geographically. In a European study, the lowest prevalence was observed in Portugal (6.8%) and the highest in Denmark (57.4%). The prevalence of the allergy has been aggravated due to increasing pollution and industrialization in countries. Bet v 1 allergen has been reported as a predictor of allergic rhinitis (AR) and asthma. Immunotherapy with birch pollen extract has been recommended for patients identified solely with Bet v 1 sensitization. Allergen immunotherapy may improve allergy to pollen from order Fagales and associated oral allergy syndrome by using with Bet v 1 or extract from birch pollen. Studies have shown extensive cross-reactivity of Bet v 1 with Fagales tree pollens such as hazel, beech, oak, and alder and plant foods such as apple, cherry, peach, etc.

Epidemiology

Worldwide distribution

A European study performed in 14 countries stated that the percentage of birch allergic patients ranged between 6.8%‐57.4%. with the lowest prevalence in Portugal and highest in Denmark. (1, 2). A retrospective study conducted in Italy on patients suspected of allergic rhinitis (AR) reported Bet v 1 sensitization varied from 53% to 95%, based on the area(2, 3).

A study conducted on patients sensitive to trees in Europe reported Bet v 1 and Bet v 2 (profilin) combination impeded binding of IgE to extracts from oak, hornbeam, alder, and hazel by an average of 72% to88%. The study indicates that Bet v 1 and Bet v 2 together comprise 82% of the IgE epitopes seen in Fagales pollens. Thus, showing the birch pollen's dominance derived allergens within the homologous birch group, such as birch, hazel, alder, oak, chestnut, beech, hornbeam (2, 4). (2, 4). In another study, the usage of Bet v 1, together with natural birch extract, exhibited patients' identification with an allergy to homologous birch trees (hazel and alder) with a 99.2% sensitivity (2, 5).

In a study of the adolescent in the Austrian population, 16.3% of participants showed Bet v 1 Immunoglobulin E (IgE) reactivity  (2, 6). In a German study of children and adolescent population, 14.1% were Bet v 1 sensitized. In Denmark and Switzerland's general population, the prevalence of sensitization to birch pollen was 13.7% and 7.9%, respectively(2, 7, 8). A  molecular diagnostics study in the Czech Republic on pollen sensitized patients sera (n =826) showed that 54.2% were Bet v 1 sensitized (2, 9). In another study in Germany on adult population  (n=260) allergic to tree pollen (Birch, hazel and alder), 92% were positive to IgE anti- Bet v 1(2, 5, 10).

A study comprised 650 allergic individuals diagnosed through the patient's allergy history and skin prick testing analyses in Zimbabwe's urban areas. Among these, 50 allergic patients to pollens (n =25) and mites were subjected to IgE reactivity testing. The study analyzed the Zimbabwe patient population against pollens, and mites showed different IgE reactivity profiles than allergic patients from Austria (central Europe). The study exhibited among the birch allergic patients 95% in Austria and 0% in Zimbabwe showed IgE reactivity towards Bet v 1. The same study also observed that 10% of patients in Austria and 100% in Zimbabwe showed IgE reactivity towards Bet v 2 (11).

In a Chinese study, sera samples (n=203) from patients suffering from allergic rhinitis (AR) or asthma were analyzed after testing with specific IgE against Bet v (birch) and Bet v 1. The study stated 16.7% (n= 34) of these sera exhibited specific IgE to Bet v and among these 82.4% (n= 28) specific IgE to Bet v 1. Bet v 1 was concluded as the major allergen from birch (12).  

Environmental Characteristics

Source and tissue

IUIS lists Bet v 1 as a major allergen from birch (Betula verrucosa) pollen. Bet v 1 Birch pollen's recombinant allergen components are accessible for allergen-specific IgE antibody testing(13). Bet v 1 is identified in > 90.0% of patients allergic to birch pollen IgE antibodies (14). 

Risk factors

Industrialization in countries has increased the prevalence of allergies. And pollution may be one of the contributing factors. It can initiate allergen nitration exogenously (in the air) or endogenously (in inflamed lung tissue). A study explored this impact and concluded that nitration of Bet v 1.0101 could be an aiding factor in the surge in allergy from birch pollen(15).

Clinical Relevance

Specific molecules

Bet v 1 is a protein of the pathogenesis‐related class 10 (PR‐10) family with a molecular weight of 17kDa(16). In about 95% of patients allergic to birch pollen, IgE reactivity to Bet v1 can be seen, and approximately 60% of the patients are known to be solely sensitized to Bet v1(17). The Bet v 1 sensitization profiles differ among geographical areas, as observed in the studies provided above (Epidemiology Section above). Bet v 1 has been recommended as a marker allergen in diagnosing patients with genuine sensitization to birch pollen. Therefore to classify patients with genuine sensitization to birch pollen and verify the diagnosis of birch pollen allergy prior to initiating immunotherapy with the birch pollen extract, utilization of Bet v1 has been recommended (18). Thus, under specific immunotherapy guidelines for allergen-specific immunotherapy (AIT), patients who are only reactive to Bet v 1 are advised to be treated with birch pollen extract. Studies on cross-reactivity have shown patients showing specific-IgE reactivity to Bet v 1 are sensitized to birch pollen, tree pollen of order Fagales (hazel, alder, hornbeam, oak) and are allergic to plant-based foods. The extract from birch pollen has an abundant quantity of Bet v 1 content. AIT with Bet v 1 or birch pollen extract may facilitate in improving allergy to pollen from order Fagales and related oral allergy syndrome (17, 18).

Cross-reactive molecules

Among the amino acid compositions of Bet v 1 (birch), Car b 1(hornbeam), and Aln g 1(alder), strong identity has been observed. With 79% to 83% amino acid sequence identity found for Car b 1, Aln g 1, and Cor a 1(hazel) compared with Bet v 1. 58% amino acid sequence identity with Bet v 1was found in Que a 1(oak). The major allergens of chestnut (Cas s 1) and beech (Fag s 1)  displayed a 75% and 69%  (N‐terminal) amino acid sequence homology with Bet v 1(2).

Members of the Bet v 1-related food proteins are apple (Mal d 1), pear (Pyr c 1), strawberry (Fra a 1), cherry (Pru av 1), apricot (Pru ar 1), kiwi (Act d 8), peach (Pru p 1), carrot (Dau c 1), celery (Api g 1), soybean (Gly m 4), hazelnut (Cor a 1), and peanut (Ara h 8). Due to the high degree of sequence similarity and highly similar tertiary structure, cross-reactivity occurs between the amino acid sequences of these molecules and Bet v 1, the major allergen from birch pollen (2, 14). 

Prevention and Therapy

Experimental trials

A significant decrease in allergic symptoms with immunotherapy products comprising only recombinant or purified Bet v 1 in birch allergic patients has been proven through clinical trials(2, 19, 20). In a study, Bet v 1.0102 (Bet v 1d) was examined as a hypoallergenic isoform of Bet v 1 and a prospective candidate for allergen-specific immunotherapy (16).

Molecular Aspects

Biochemistry

Bet v 1 comprises various isoforms with a molecular mass of about 17.5 kDa (16). Bet v 1 folds into a curved seven-stranded antiparallel β-sheet, two short α-helices and an extended C-terminal helix creating an enlarged inner cavity, usual for the PR-10 protein family. Bet v 1 structures present in the protein database (PDB) display small differences, with backbone pair-wise average value of the distance of  1.5 - 2 Å between atoms(16). Bet v 1 Secondary structure elements form hydrophobic pockets acting as storage or carrier proteins. Bet v 1 isoforms allergenicity is not affected by ligands. X-ray crystallography discovered that Bet v 1 ligand interaction might increase the size of the hydrophobic pocket, thus modifying the protein surface (21).

A study investigated the possible consequences of nitration of Bet v 1 (nitro-Bet v 1.0101) as higher levels of IgE antibodies. The study showed a robust T-cell proliferation was observed even with a low concentration of nitro-Bet v 1.0101. Other observations studied due to nitration of Bet v 1.0101 were oligomerization, low susceptibility to endolysosomal degradation, and alteration to cytokine secretion of dendritic cells. The study concludes the nitration of the major birch pollen allergen Bet v 1 modifies allergens' immunological and biochemical properties. Thus, the tested molecular findings show that pollution potentially enhances the incidences of allergy. (15)

Isoforms, epitopes, antibodies

B-cell epitopes composed of amino acid residues found on the allergen's molecular surface are IgE binding sites (22). Isoforms of  Bet v 1 can be grouped into three classes with molecules showing IgE-binding activities high (isoforms a[Bet v 1.0101], e [Bet v 1.0103], and j[Bet v 1.0106]), intermediate (isoforms b[Bet v 1.0201], c[Bet v 1.0202], and f[Bet v 1.0104]), and low/no (d[Bet v 1.0102], g[Bet v 1.0105], and l[Bet v 1.0107]). (21, 23). The current Bet v 1 proper names of isoallergens are provided in the IUIS list (23). The most abundantly found isoforms from Bet v 1  are Bet v 1a (50% to 70%), Bet v 1b (3% to 20%),  Bet v 1d (20%), Bet v 1f (2% to 8%), and Bet v 1j (~1%). Sequence and allergenicity of isoforms Bet v 1m and Bet v 1b are nearly indistinguishable (Bet v 1.0201, 98.1% identity). Bet v 1 isoforms sequence of d, g, and l are highly similar to Bet v 1a (95.6%, 95.0%, 94.3% identity, respectively). A study shows the serum IgE binding to equimolar amounts of surface-coated Bet v 1a, Bet v 1d, and Bet v 1m  (21).

An experiment with sera from individuals' allergic to birch pollen indicated that Bet v 1.0101 (Bet v 1 a) could cause a high level of IgE antibody production, which may result in type I allergic reactions (16, 24). Moreover, Bet v 1.0102 (Bet v 1d) activates IgG4 expression (16, 24).  

Cross-reactivity

The Bet v 1 molecular surface has a space-filling model with a surface-exposed amino acid.  Cross-reactive B-cell epitopes are usually situated in this area and cause symptoms that patients allergic to birch pollen experience when they come in contact with pollens from associated trees such as hornbeam, alder and hazel (22).

Fruits and vegetables with similar three-dimensional structures to Homologous PR-10 proteins can stimulate allergic cross-reactions with Bet v 1-specific IgE antibodies, such as apples, peaches, cherries,  and others(16). The structural conformation and the epitope repertoire recognized by the specific IgE antibodies determines the degree of birch pollen-related food cross‐reactivity in an individual patient. This contact causes inflammatory reactions like itching of the throat, lips, and tongue, sometimes accompanied by swelling of the lips and tongue. (14). The study stated that 20% of birch pollen (Bet v 1) sensitized patients developed an oral allergy syndrome (OAS). Among these patients suffering from OAS also showed symptoms such as rhino-conjunctivitis (75%), asthma (20%), and chronic urticaria (12%). In these patients the most frequent triggers were observed from cherry (16.0%), plum (16.0%), persimmon (20.0%), kiwi (20.0%), nuts (36.0%), peach (56.0%), and Apple (68.0%) (14).

Diagnostic Relevance

Disease Severity

Studies have reported Bet v 1 allergen as a predictor of allergic rhinitis (AR) and asthma (25). Birch pollen–derived allergens is the dominant allergen within the homologous group. This dominance has been exhibited in inhibition tests of patients sensitive to trees in Europe. A combination of recombinant Bet v 1 and Bet v 2 inhibits the binding of IgE to extracts from oak, hazel, hornbeam, and alder by an average of 72%‐88%, implying that Bet v 1 and Bet v 2 together contain 82% of the IgE epitopes in Fagales pollens. Moreover, utilizing Bet v 1 combined with natural birch extract has been shown to distinguish patients with AR sensitive to homologous trees with a 99.2% sensitivity( 2).

Diluted isoforms Bet v 1a, Bet v 1d, and Bet v 1m have been used for determining cross-linking of membrane-bound human IgE by IgE-Bet v 1 isoform interaction (26).

Exposure

The main exposure route for this allergen is through inhalation (airway) (23).

Compiled By

Author: Turacoz Healthcare Solutions

Reviewer: Dr. Magnus Borres

Last reviewed: November 2020