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t220 Bet v 4

t220 Bet v 4 Scientific Information




Bet v 4

Route of Exposure:


Biological function:

Calcium-binding Proteins

Allergen code:


Source Material:

Birch pollens – Silver Birch Tree allergen components

Other Names :

Polcalcin, CBP


Bet v 4 is a polcalcin protein of 9.3 kDa molecular weight and is a minor allergen of birch (Betula verrucosa) pollen. Approximately 20% of the patients allergic to birch have reported having a response towards Bet v 4. Recombinant Bet v 4 is used for allergen-specific IgE antibody testing. Studies have shown prevalence of polysensitization to Bet v 1, Bet v 2 and/or Bet v 4 allergens in birch allergic individuals. Polcalcin allergen functions as a calcium binding protein and is known to be highly cross-reactive. Various pollens other than Birch (Bet v 4) contain polcalcin allergen like timothy grass (Phl p 7) and alder (Aln g 4). Experimental trials have shown individuals allergic to polcalcin have known to be allergic to multiple pollens. Individuals allergic to maize, timothy grass, mugwort and olive pollen have shown sensitivity to Bet v 4 allergen. Cross-reactivity between Bet v 4 and other food allergens has not been reported. This may be due to the absence of polcalcin allergen from plant-based foods. As Bet v 4 (polcalcin) is known as a predictor for pollen polysensitization, it can be used for diagnosis and treatment purposes for patients.


Worldwide distribution

Birch pollen’s minor allergen Bet v 4 (Polcalcin) responds to serum Immunoglobulin E (IgE)  in 20% pollen sensitized patients (1). A study showed Finland had 5%, Sweden 8%, Austria 11%, France 6%, Italy 27% and Switzerland 7% of individuals allergic to birch pollen with specific IgE to recombinant Bet v 4.(2, 3)

A study was conducted on Czech Republic’s population; both children (n=107) and adults (n=71) allergic to birch pollen for the presence of IgE antibodies specific to Bet v 1, Bet v 2 and Bet v 4. The results reported 17.8% of children and 9.9% of adults showed the presence of specific IgE against Bet v 4 allergen. (4)

 A Japanese study conducted on sera from 40 birch allergic patients reported only 2.5% of the individuals had specific IgE against Bet v 4. (5)

Another study conducted on a population (n=854) suspected of allergic rhinitis in Italy showed the percentage of individuals sensitized to Bet v 4 ranged between 3.72% to 14.41% depending on the region. (6)


Environmental Characteristics

Source and tissue

Bet v 4 has been listed by IUIS as a minor allergen from Betula verrucosa, birch pollen.(7) Recombinant allergen components, birch pollen polcalcin is available for allergen specific IgE antibody testing. In Escherichia coli as a nonfusion protein Bet v 4 is expressed and purified essentially with the use of immobilized metal affinity chromatography. (1, 3)

Risk factors

In one study, adults and children population allergic to birch with a diagnosis of allergic asthma, dermatitis or anaphylactic shock, sensitization towards more than one birch pollen allergen has been reported. The study showed polysensitization for Bet v 1, Bet v 2 and Bet v 4 was 2.8% in adults and 10.3% in children, for Bet v 1 and Bet v 4 was 4.2% in adults and 4.7% in children and for Bet v 2 and Bet v 4 was 1.4% in adult and 0.9% in children. (4)

Detection methods

A study developed Bet v 4-specific sandwich enzyme-linked immunosorbent assay (ELISA). Utilizing ELISA, 30 samples of birch pollen allergen products were tested and 0.2 to 4.4 μg/ml of Bet v 4 was detected.(8)

Clinical Relevance

Specific molecules

Bet v 4 has a molecular weight of 9.3 kDa and is characterized as an intracellular pollen protein. It biologically functions as a calcium-binding protein and contains two Ca 2+ binding sites. These binding sites are targeted by the specific IgE antibodies for Bet v 4 (4).

Polcalcin is a two EF-hand calcium-binding pollen allergen. Polcalcin allergen Bet v 4 from birch is highly cross-reactive. (9)

Cross-reactive molecules

Many pollens have been reported to have polcalcin allergens, such as Bet v 4 (birch), Aln g 4 (alder), Ole e 3 (olive), Cyn d 7 (Bermuda grass), Fra e 3 (ash), Bra n 1, 2 (rapeseed), Bra r 1, 2 (turnip rape), Phl p 7 (timothy grass). These allergens also contain cross-reactive IgE epitopes (9).

An immunoblot study exhibited the cause of reactivity towards birch and ragweed pollens was due to cross-reactivity between polcalcin allergen from birch (Bet v 4) and ragweed cross-reacting to the polcalcin allergen from timothy grass (Phl p 7) (9).

Prevention and Therapy

Experimental trials

A study showed patient sensitized to polcalcin allergen (like Bet v 4 or Phl p 7) showed no reaction to major allergens from birch (Bet v 1) and ragweed (Amb a 1). In such patient immunotherapy must be carefully considered as they might not benefit from birch or ragweed pollen extract-based immunotherapy. This is needed as patients cross-sensitized against polcalcin allergens are known to have sensitivity to multiple pollens. The same study has reported that individuals getting birch pollen-specific immunotherapy may develop antibodies against Bet v 4. (9)

Molecular Aspects


Bet v 4 IgE recognition depends upon the protein-bound calcium. The N-terminal of Bet v 4 provides the main support to facilitate IgE binding. It has been experimentally shown that in absence of protein-bound calcium in Bet v 4 IgE-epitopes decreases its capacity to bind. (1) The Bet v 4 allergen is extremely homologous with other calcium-binding proteins due to the two calcium-binding domains. The C-terminus, N-terminus and the section within the two calcium-binding areas of Bet v 4 demonstrate substantial sequence identity with the other pollen proteins containing two EF-hand. (1)

Isoforms, epitopes, antibodies

It has been found a necessary factor to maintain Bet v 4 IgE-epitopes are protein-bound calcium. Through experiments, it has been shown that recombinant and natural Bet v 4 share IgE-epitopes. (1)


A study showed within timothy grass and maize pollen allergic patient population sensitization to Bet v 4 pollen was reported to be 5-10%. While among patients suffering from mugwort and olive allergy sensitization to Bet v 4 was found to be 25-55%. Thus on an average 20% of the patients affected by plant-based allergy showed IgE reactivity towards Bet v 4. (1)

A study has stated that due to IgE cross-reactivity between allergens Phl p 7 (timothy grass) and homologous protein within Bet v 4 (birch) an immediate skin reaction against an extract from birch pollen may occur. (9)

A study has shown that Bet v 4 is known not to cross-react with food allergens. (10). This might be due to the absence of polcalcin allergen from plant-based foods. (9)

Diagnostic Relevance

Disease Severity

Pollen containing polcalcin allergen are found to be predictors for pollen polysensitization.(9)

Bet v 4 can be used for diagnosis or treatment purposes for polyvalent plant allergic patients as it is an important cross-reactive plant allergen.(1)


The main exposure route for this allergen is through inhalation (airway). (7)

Compiled By

Author: Turacoz Healthcare Solutions

Reviewer: Dr. Magnus Borres


Last reviewed: October  2020

  1. Twardosz A, Hayek B, Seiberler S, Vangelista L, Elfman L, Grönlund H, et al. Molecular Characterization, Expression inEscherichia coli, and Epitope Analysis of a Two EF-Hand Calcium-Binding Birch Pollen Allergen, Bet v 4. Biochemical and biophysical research communications. 1997;239(1):197-204.
  2. Biedermann T, Winther L, Till S, Panzner P, Knulst A, Valovirta E. Birch pollen allergy in Europe. Allergy. 2019;74(7):1237-48.
  3. Movérare R, Westritschnig K, Svensson M, Hayek B, Bende M, Pauli G, et al. Different IgE reactivity profiles in birch pollen-sensitive patients from six European populations revealed by recombinant allergens: an imprint of local sensitization. International archives of allergy and immunology. 2002;128(4):325-35.
  4. Sekerková A, Poláčková M. Detection of Bet v1, Bet v2 and Bet v4 specific IgE antibodies in the sera of children and adult patients allergic to birch pollen: evaluation of different IgE reactivity profiles depending on age and local sensitization. International archives of allergy and immunology. 2011;154(4):278-85.
  5. Shirasaki H, Yamamoto T, Koyanagi Y, Watanabe N, Himi T. Detection of specific IgE antibodies in sera of Japanese birch-allergic patients using recombinant allergens Bet v 1, Bet v 2 and Bet v 4. Allergology International. 2008;57(1):93-6.
  6. Ciprandi G, Comite P, Mussap M, De Amici M, Quaglini S, Barocci F, et al. Profiles of birch sensitization (Bet v 1, Bet v 2, and Bet v 4) and oral allergy syndrome across Italy. J Investig Allergol Clin Immunol. 2016;26(4):244-8.
  7. Allergen-Nomenclature. Bet v 4 2019 [27-10-2020]. Available from:
  8. Dehus O, Zimmer J, Döring S, Führer F, Hanschmann K-M, Holzhauser T, et al. Development and in-house validation of an allergen-specific ELISA for quantification of Bet v 4 in diagnostic and therapeutic birch allergen products. Analytical and bioanalytical chemistry. 2015;407(6):1673-83.
  9. Kazemi-Shirazi L, Niederberger V, Linhart B, Lidholm J, Kraft D, Valenta R. Recombinant marker allergens: diagnostic gatekeepers for the treatment of allergy. International archives of allergy and immunology. 2002;127(4):259-68.
  10. Vieths S, Scheurer S, BALLMER‐WEBER B. Current understanding of cross‐reactivity of food allergens and pollen. Annals of the New York Academy of Sciences. 2002;964(1):47-68.