t216 Bet v 2

Summary

Bet v 2 is a profilin protein of 13–14.4 kDa molecular weight and is a minor allergen of birch (Betula verrucosa) pollen. Approximately 10% of patients allergic to birch have reported having a response towards Bet v 2. Recombinant Bet v 4 is used for allergen-specific IgE antibody testing. Profilin allergen functions as an actin-binding protein and is known to be highly cross-reactive. Various pollens other than Birch (Bet v 2) contain profilin allergens like timothy grass (Phl p 12) and the olive tree (Ole e 2). Experimental trials have shown individuals allergic to profilin have known to be polysensitized to multiple allergen sources. This makes diagnosing through specific-IgE testing for allergen components and recognizing patient-tailored immunotherapy important in such individuals. High cross-reactivity is observed with profilins present in other grass and tree pollen allergens such as timothy grass, mugwort, olive and others. Cross-reactivity is also detected with plant foods, like apple, celery, cherry, hazelnut, grass, latex, and others.

Epidemiology

Worldwide distribution

A European GA2LEN study, conducted in 14 countries reported the percentage of patients sensitized to birch, ranged 6.8%‐57.4%.(1, 2)

Bet v 2 (profilin) is recognized by Immunoglobulin E (IgE) antibodies in about 10% of birch sensitized individuals. (3). A study showed Finland had 2%, Sweden 12%, Austria 30%, France 20%, Italy 33% and Switzerland 43% percentage of birch pollen–sensitive patients with specific IgE to the recombinant birch pollen allergens Bet v 2. Bet v 2 sensitization appears to be more prevalent in southern European regions. (2, 4)

A comparative study was conducted with atopic patients suffering from allergic rhinitis, asthma and atopic dermatitis in Uganda and German. In atopic patients’ sera from Uganda (n=83) and Germany (n=97) sensitization to Bet v 2 was reported to be 26% and 24% respectively (5). 

Environmental Characteristics

Source and tissue

IUIS lists Bet v 2 as a minor allergen from Betula verrucosa birch pollen. Recombinant allergen components, Birch pollen profilin is available for allergen-specific IgE antibody testing. Bet v 2 is a protein of 13–14.4 kDa belonging to the family of profilins. Profilins are homologous proteins found in all eukaryotic cells(4). Birch pollen recombinant allergen Bet v 2 (profilin) has been purified after being expressed in Escherichia coli by pharmaceutical companies. Originally, cDNA encodes the isoforms which are represented on Bet v2 and these are isolated by IgE immuno-screening. A study shows one of the methods to use Bet v 2 for SPTs is by dissolving in sterile 0.9% sodium chloride at 5 µg/mL and 20 µg/mL concentrations (6).

Clinical Relevance

Specific molecules

Bet v 2 contains many of the Fagales pollen specific-IgE epitopes. Therefore may substitute natural tree pollen extracts for diagnosis and for patient-tailored immunotherapy of tree pollen allergy (6).  

Cross-reactive molecules

A study showed birch, alder, hornbeam, hazel, and oak pollen contain allergens that share IgE epitopes with Bet v 1 and Bet v 2. A combination of Bet v 1 and Bet v 2 can be reported on an average for 82% of tree pollen-specific IgE.(6).

Profilin is responsible for the cross-reactions between birch (Bet v 2), mugwort (Art v 4) and celery (Api g 4). (7) Another study showed subjects with positive IgE to Bet v 2 had also reactivity to latex (Hev b 8), timothy grass (Phl p 12), olive tree (Ole e 2), and mugwort (Art v 4) pollen allergens. (7, 8). A study showed Bet v 2 (profilin) sensitized patients were also sensitized to Phl p 12 (grass pollen profilin). (9).

Bet v 2 has been found to be cross-reactive with profilin allergens of almond (Pru du 4), apple (Mal d 4), celery(Api g 4), cherry (Pru av 4), hazelnut (Cora 2), kiwi (Act d 9), peanut (Ara h 5), Peach (Pru p 4), pear (Pyr c 4), potato (Sola t 8), soybean (Gly m 3) and walnut (Jug r 5). Bet v 2 and food allergens cross-reactivity is due to the presence of profilin proteins in food (2). 

Prevention and Therapy

Experimental trials

Profilin allergen such as from birch (Bet v 2) and timothy grass (Phl p 12) is highly cross-reactive in various plant-based pollen sources. In an allergic patient due to cross-reactivity with such other allergen sources may lead to the detection of specific-IgE (sIgE) during testing. Currently, standardized major allergen extracts are used for immunotherapies. Thus, for a profilin-reactive patient, this type of standard therapy may not be beneficial. IgE towards profilin in an allergic patient undergoing therapy should be monitored as it may be indicative of an increasing range of patient sensitivity towards other allergen sources (polysensitization) (10).

Sera from 12 patients allergic to grass pollen suffering from allergic rhinitis and conjunctivitis was used for sIgE testing. High levels of SIgE towards Bet v 2 comparable to timothy grass pollen sIgE levels were observed. Even with such a reaction towards birch allergen the patients should undergo grass pollen-specific immunotherapy and not birch(11). In such cases, if initial diagnoses through sIgE testing are not performed, primary sensitization testing through natural pollen extracts may lead to misdiagnoses. 

Molecular Aspects

Biochemistry

Birch allergen Bet v 2 is a profilin that performs actin-binding and controls cell division, differentiation, and growth. Profilins have been found to be highly cross-reactive allergens showing cross-reactivity with latex and food due to high sequence conservation. They have been named as pan-allergens due to the wide-spread cross-reactivity (12). 

Isoforms, epitopes, antibodies

Bet v 2 have major IgE -reactive epitopes clustered on the N- and C-terminal α-helices and on a protein, segment containing two strands of the β-sheet. A change in the orientation of the N-terminal α helix in Bet v 2 has been found. This change in orientation alters the topography of one of the hydrophobic patches on the surface of the molecule, which is involved in the binding of proline-rich ligands. The common epitope areas are in regions with conserved sequence and secondary structure. These epitope areas overlap with the natural profilin ligand binding sites, showing that the ligand-free native profilin act across-sensitizing agent. (13)

A study was conducted with sera from 102 tree sensitive patients from different parts of Europe (Austria, France, Sweden, and Switzerland). The sera were preabsorbed with recombinant Bet v 1 and Bet v 2 prior to exposure to alder, hornbeam, oak, hazel, and birch pollen extract. The study reported 82% of Fagles-specific IgE were pre-absorbed with the two recombinant allergens. Thus, indicated that together Bet v 1 and Bet v 2 contain 82% of the IgE epitopes present in Fagales pollens. The study stated combination of recombinant Bet v 1 and Bet v 2 (from birch pollen extract) inhibited IgE binding to extracts of alder, hornbeam, hazel, and oak pollens by an average of 72%‐88%.(2, 6)

Cross-reactivity

A study regarding IgE binding showed Bet v 2 and Phl p 12 (timothy grass allergen) are fully cross-reactive. The study detected IgE units against Bet v 2 in the majority of patients like IgE units directed against Phl p 12. It is found that in patients with IgE to Bet v 2 and Phl p 12, both profilin allergens able to induce basophil activation to a similar extent.(9)

Profilin in general is involved in a wide range of cross-reactivities among plants, and patients sensitized to it react with a variety of plants and foods. Due to structural similarity, the cross-reactivity of IgE is considered to occur, rather than of amino acid sequence similarity. (7)

Diagnostic Relevance

Disease Severity

A study examined patients with seasonal allergic rhinitis (SAR) against birch or timothy pollen. For IgE activity, recombinant allergens of birch (Bet v 1, Bet v 2, Bet v 4) and of timothy grass  (Phl p 1/p 5b, Phl p 7, and Phl p 12) were tested against natural extracts of birch (t3) and timothy grass (g6). The study stated no difference was found in health-related quality of life (HRQL) between patients sensitized solely against major versus minor allergens in birch-allergic patients. In SAR minor allergen sensitization plays an important role (14).

Individuals sensitized to both profilin such as Bet 2, Phl p 12 and porcelains such as Bet v 4 and Phl p 7 will show positive results to almost all allergenic sources. This may cause a serious issue in diagnosing and administrating correct allergen-specific immunotherapy. In a study conducted on 106 patients were suspected of airborne and showed a positive response to Bet v 2 and/or Phl p 7. Only 9 showed hypersensitivity to both profilin and polcalcin. Out of these 7 reacted to multiple sIgE testing for sensitization to primary sources like mugwort, ragweed, birch, olive, etc (15). 

Exposure

The main exposure route for this allergen is through inhalation (airway) (16).

Compiled By

Author: Turacoz Healthcare Solutions

Reviewer: Dr. Magnus Borres

Last reviewed: November 2020