t225 Bet v 6

Summary

Bet v 6, a minor allergen of birch pollen, is an Isoflavone reductase (IFR) protein of 35 kDa molecular weight. Around 10-15% of birch sensitized patients have shown IgE-reactivity to Bet v 6. As per studies, the prevalence of Bet v 6 sensitivity may vary across geographical regions, depending on the tested population's diversity. Bet v 6 shares amino acid sequence similarity with IFR and its homolog (IFRH) protein from various plants. Birch sensitized individuals sensitive to Bet v 6 may suffer from allergic symptoms like skin reactions, respiratory allergy (asthma), gastrointestinal reactions, conjunctivitis, and pollen-related oral allergy (swelling and itching of the tongue, lip, and/or throat). Bet v 6 has exhibited cross-reactivity with proteins from various plant-based food (like apple, carrot, banana, pear, peach, nectarine, peanut, walnut, celery, tomato) and other tree or grass pollens (like Japanese cedar, poplar, pine).

Epidemiology

Worldwide distribution

In northern and central European countries, pollen from birch has been a significant source of aeroallergen-mediated allergic reactions among sensitive populations (1). 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 (2). In a Germany study, among birch pollen allergens, Bet v 6 (formerly known as Bet v 5) had 10-15% prevalence in the allergic population and was one of the allergens known to be cross-reactive with other similar food allergens (3, 4).

According to a study conducted on 217 sera obtained from Austrian patients allergic to birch pollen, 18% of the sera exhibited IgE reactivity to Bet v 6 allergen (5).

A European study was conducted on sera collected from carrot-allergic (n=49) patients and pollen-allergic patients tolerant to carrot (n =71). Birch pollen sensitization rate was reported as 90% and 67% in carrot allergic patients from Denmark (n=20) and Spain (n=9), respectively. Among these, Bet v 6 was recognized in 20% of Danish and 11% of Spanish patients. Out of the 71 pollen-allergic patients in the control group, 76% were sensitized to birch pollen extract. None of the patients in the control group showed IgE reactivity to Bet v 6 allergen. All carrot-allergic patients reported oral allergy symptoms like oral mucosa itching after ingestion of carrot. Some patients also reported responses like skin reactions, respiratory symptoms, gastrointestinal symptoms, and conjunctivitis (6).

In a Germany based study on 1,064 patients with sensitization to birch pollen extract (t3), 5.4% (study group, 57/1064) showed no IgE reactivity towards Bet v 1, 2, and 4 allergens. Only 2 (4%) of these patients showed IgE reactivity to Bet v 6 (t225) allergen. While from 57 birch allergic patients in the control group, 3 (5%) were Bet v 6-positive. Among these five Bet v 6- positive patients, 3 reported asthma-like symptoms. The study concluded that though Bet v 6 has been hypothesized to be a source of trigger for food allergies in patients sensitized to birch pollen, none of the participating patients reported any oral allergy syndrome (OAS) symptoms. (7).

The variety of Bet v 6 reactivity may be due to heterogeneity in the tested patient population geographically. Overall, Bet v 6 is one of the minor allergens from birch pollen which may induce allergic reactions among sensitive individuals. 

Environmental Characteristics

Source and tissue

The International Union of Immunological Societies (IUIS) has listed Bet v 6, an Isoflavone reductase (IFR) protein, a minor allergen from Betula verrucosa, birch pollen (8, 9). This IFR protein has been known to be immunologically independent of Bet v1, which is considered a major allergen of birch pollen (7).

Clinical Relevance

Disease severity

Bet v 6 may induce pollen-related oral allergy or OAS in a small part of the population of patients suffering from birch pollen allergy. The OAS symptoms may include swelling and itching of the tongue, lip, and/or throat (1, 10).

A German study reported IgE binding to 35 kDa molecular weight protein (which is Bet v 6 allergen) in 12% (9/76) of the birch pollen allergic patients’ sera (4).

Another study was conducted in Germany with sera from 27 birch allergic patients in the study group and one non-allergic control subject. 32% (9/28) of the sera were observed to bind with the recombinant Bet v 6 allergen (formerly known as Bet v 5) (1).

A study reported Bet v 6-positive in around 4.4% (5/114) of total birch allergic patients from both the study and control group. OAS symptoms were not detected in any of these patients. A high prevalence of perennial asthmatic symptoms was observed in Bet v 6-positive individuals (7).

Cross-reactive molecules

Bet v 6, a minor allergen, is known to be cross-reactive with pollen and proteins from various plant-based food such as fruits, vegetables, and spices (8).

A study analyzed 8 patients showing IgE-reactivity against allergen from birch (Bet v 6) and pear (Pyr c 5). 6 out of 8 (75%) patients suffered from oral allergy syndrome (OAS) to fresh pear and various other fruits, nuts, and vegetables such as peach, nectarine, peanut, walnut, celery, tomato, etc.(10).

Molecular Aspects

Biochemistry

Bet v 6, previously known as Bet v 5, is characterized as a minor allergen. Studies have shown Bet v 6 amino acid sequence identity of 55-58% with Isoflavone reductase (IFR) and a high level of sequence identity of 60-80% with its homolog (IFRH) protein from various plants (1).

Bet v 6 contains 307 amino acid residues with a molecular mass of 34.1 kDa (~35 kDa) and a pI of 6.7. The reductase protein types, IFR, IFRH, phenylcoumaran benzylic ether reductase (PCBER), and pinoresinol-lariciresinol reductase (PLR), consist of a glycine-rich motif that enables binding to NADPH. The motif is like the P-loop motif from Bet v 1 allergen family, which is unrelated to the reductase family (3).

The IFR protein is usually engaged in producing pterocarpan phytoalexins through chiral isoflavones synthesis from achiral precursors with the NADPH-dependent reduction process's assistance. The phytoalexins produced are then utilized by the plant for their defense response against fungal pathogens (1).

Studies have shown PCBER enzymatic activity in Bet v 6 and Pyr c 5, which are reductase allergens from birch and pear, respectively. Both the allergens can catalyze the NADPH- dependent reduction of lignans (3). 

Isoforms, epitopes, antibodies

Two isoforms, Bet v 6.0101 and bet v 6.0102, are listed in the IUIS database (9).

Cross-reactivity

Bet v 6 is identified as a food cross-reactive protein. Studies have reported 35 kDa protein from birch pollen, is cross-reactive with similar proteins from plant-based food like apple, lychee, pear, mango, carrot, orange, and banana (7).

Studies have shown Bet v 6 and Pyr c 5 allergens from birch and pear respectively to possess similar IgE-binding characteristics. Similar homologous reductase protein might also be present in other vegetables and fruits such as carrot, zucchini, persimmon, orange, apple, and peach. Further, analysis of the extracts from persimmon, orange, apple, and pear have revealed Bet v 6-like cross-reactive epitopes (3).

A study analyzing the degree of amino acid sequence identity with Bet v 6 reported 79% identity with pear (Pyr c 5), 80% with poplar, 76% with potato, 76% with Arabidopsis thaliana (mouseear cress), 67% with loblolly pine, 66% with tobacco, 60% with corn, 58% with pea, 57% with alfalfa, and 55% with chickpea (1).

A major cause of seasonal pollinosis in Japan was found to be Japanese cedar pollen, where more than 10% of the allergic individuals suffer from this allergy. The recombinant Bet v 6 (formerly known as Bet v 5) allergen exhibited an IgE binding frequency of 76% (19/25) in Japanese cedar pollen allergic patients. An isoflavone reductase-like homolog protein with high IgE-binding frequency is identified in Japanese cedar pollen (11). 

Diagnostic Relevance

Disease Severity

Studies have shown that specific-IgE against the cross-reacting allergen like Bet v 6, (considered as a panallergen) is not detectable in young children below 6 years of age. In contrast, Bet v 6 sensitization can be evident among older patients. This reactivity might be contributed by ‘molecular spreading’, an immunological phenomenon of the development of sensitization with aging (7).

Cross-reactivity

Though few studies mentioned Bet v 6 cross-reactivity with plants as a source for food allergies, the degree of this occurrence is yet to be determined (7). 

Exposure

This allergen's primary exposure route is through the airway (inhalation) (9). 

Compiled By

Author: Turacoz Healthcare Solutions

Reviewer: Dr. Christian Fischer

Last reviewed: January 2021