Table of Contents

f428 Cor a 1 Scientific Information Summary Epidemiology Environmental Characteristics Clinical Relevance Molecular Aspects Diagnostic Relevance Compiled By

Component

f428 Cor a 1

f428 Cor a 1 Scientific Information

Type:

Component

Name; WHO/IUIS:

Cor a 1

Biological function:

PR-10 protein

Allergen code:

f428

Source Material:

Located in reproductive tissues, such as pollen, fruits and seeds Native sourced from the nuts or pollens of Corylus avellana

Other Names :

Bet v 1-like, Fagales group I, PR-10 protein

Summary

Cor a 1 is a heat-labile molecular allergen present in the kernels as well as in the pollen of hazel plants (Corylus avellana). It is a member of the pathogenesis-related (PR)-10 family of proteins that is also known as Fagales group I or Bet v 1-like proteins. There are two isoforms or isoallergens of Cor a 1: Cor a 1.01, the PR-10 allergen of hazel pollen, and Cor a 1.04, the PR-10 allergen of hazelnut. Over 97% of cross-reactivity has been reported between birch pollen Bet v 1 and Cor a 1. Thus, sensitization to Cor a 1 is mainly related to exposure and sensitization to Betulaceae and Fagaceae tree pollen. Also, the prevalence of sensitization to Cor a 1 increase with age. Ingested Cor a 1 is rapidly denatured because of gastrointestinal acidity and enzymatic digestion, losing its allergenic properties. Thus, Cor a 1-related symptoms are usually limited to oral allergy syndrome (OAS). Cor a 1.04 sensitization has been linked with OAS, oral itching, oral mucosal irritation, or angioedema of lips, tongue, or throat, mostly affecting older children and adults. Cor a 1 sensitization is associated with milder symptoms in hazelnut-allergic patients, while it is considered to be protective against moderate and severe clinical presentations. Cor a 1 immunoglobulin E (IgE) has low diagnostic accuracy for the identification of moderate-to-severe allergic reactions to hazelnuts in children. Sensitization to Cor a 1 has been proposed as a predictive marker of better allergen immunotherapy efficacy. Bet v 1 and Cor a 1 also show significant cross-reaction with PR-10 proteins from alder pollen (Aln g 1), apple (Mal d 1) and peach (Pru p 1).

Epidemiology

Worldwide distribution

Hazelnut allergy (Corylus avellana) is the most common tree nut allergy in Europe (1, 2). According to a systematic review, this allergy accounts for about 17-100% of the total tree nut allergies in Europe (3). Further, hazelnut allergy as well as sensitization is also frequent outside Europe, in countries such as India, Russia, Israel, Australia, Mexico and South Africa (4-9).

Cor a 1 is the hazelnut PR-10 allergen, a member of the pathogenesis-related (PR)-10 family which is also known as Fagales group I or Bet v 1-like proteins. There are two isoforms, or isoallergens, of Cor a 1: Cor a 1.01, the PR-10 allergen of hazel pollen, and Cor a 1.04, the PR-10 allergen of hazelnut (10, 11).

High sequence identity among allergens of the PR-10 family explains frequent pollen-food cross-reactivity in areas of Betulaceae and Fagaceae tree pollination from the birch (Betula verrucosa) homologous group (12, 13). There is over 97% cross-reactivity between birch pollen Bet v 1 and Cor a 1 (14, 15). Further, a study also reported that sensitization to Cor a 1 and birch are highly correlated (Spearman coefficient=0.98, p<0.0001) in hazelnut-sensitized subjects (16). As an example, among 161 hazelnut-sensitized patients from the Netherlands, 86% were sensitized to Cor a 1 and 87% were sensitized to Bet v 1 (17).

Sensitization to Betulaceae and Fagaceae tree pollen and Bet v 1-like allergens with food cross-reactivity is also reported in Russia, China, Korea, and the United States (18-21).

The prevalence of Cor a 1 sensitization in subjects with hazelnut sensitization or allergy decreases with decrease in regional exposure to Bet v 1 and homologous pollen allergens. As an example, in Turkey, IgE to Cor a 1 was detectable in 7.3% (4 out of 55) of patients who were sensitized to hazelnut (22). Similarly, the prevalence of Cor a 1 among hazelnut-sensitized patients ranged from 36% to 73% in different regions of the United States (US).

In the EuroPrevall study conducted from 2005 to 2010 among 731 hazelnut-sensitized individuals in 12 European centers, sensitization to Cor a 1 reached an overall prevalence of 74.3%, confirming it as a major hazelnut allergen (i.e., exhibiting IgE reactivity in > 50% of allergic patients) in all participating centers, except for the Southern centers, such as Athens and Madrid (14).

Sensitization to Cor a 1 in the absence of sensitization to Bet v 1 is uncommon but a possible finding, even in the birch group pollination area (14, 23).

The prevalence of sensitization to Cor a 1 increase with age (14, 24). As an example, in a study conducted in Belgium, sensitization to Cor a 1.04 was found in 18% of preschool children, 50% of school-age children and 90% of adults with hazelnut allergy (15).

Environmental Characteristics

Source and tissue

Cor a 1 is a molecular allergen present in the kernels as well as in the pollen of hazel plants. It is a ribonuclease belonging to the PR-10 family, mainly involved in defense mechanism and stimulus-specific responses (10).

The molecule can be generated by recombinant expression systems. Cor a 1 and its isoallergens are expressed in Escherichia coli and further characterized by mass spectrometry and nano-ultra performance liquid chromatography (25).

Cor a 1, similar to other PR-10 allergens, is a labile protein, easily degraded by heating, cooking, acidity, and digestion in the gastrointestinal tract (26). Cor a 1 susceptibility to enzymatic degradation can result in partial loss of the allergen during the process of allergenic extract preparation (27).

Risk factors

Sensitization to Cor a 1 is mainly related to exposure and sensitization to Betulaceae and Fagaceae tree pollen (10, 12).

Clinical Relevance

Disease severity

Ingested Cor a 1 is rapidly denatured as a result of gastrointestinal acidity and enzymatic digestion, losing its allergenic properties. Thus, Cor a 1-related symptoms are usually limited to oral allergy syndrome (OAS). In fact, when sensitization to Cor a 1 isoforms is assessed separately, hazel pollen Cor a 1.01 and hazelnut Cor a 1.04 sensitization may behave differently. Cor a 1.04 sensitization was linked with OAS, oral itching, oral mucosa irritation, or angioedema of lips, tongue, or throat, mostly affecting older children and adults (28, 29). However, Cor a 1.01 sensitization, even in birch-free areas such as central and southern Italy, was associated to respiratory symptoms, rhino-conjunctivitis or asthma, and its peak prevalence was seen in patients aged 14 to 65 (Scala, Abeni et al. 2017).

Sensitization to multiple hazelnut molecular allergens is frequent, however, the EuroPrevall study demonstrated a statistically significant protective effect of Cor a 1 sensitization through the inverse association of its prevalence with moderate and severe clinical presentations (30). In this study, Cor a 1 sensitization was present in 80.4% of patients with OAS symptoms, in 72.4% of those with moderate symptoms, and in 59.4% of those with severe symptoms (p=0.002). Similar data were obtained in a study conducted in the US on 10,503 hazelnut-allergic individuals, suggesting that they were less likely to develop severe symptoms owing to Cor a 1 sensitization (24).

Cross-reactive molecules

Cross-reactivity between Cor a 1 and Bet v 1 has shown to be clinically relevant and mediated by IgE antibodies as well as T-cells (31). As an example, high prevalence of cross-sensitization (71%) between Cor a 1 and Bet v 1 was reported in an Austrian study, conducted among 35 birch-pollen-allergic patients (32). Further, moderate-to-strong correlation was observed among both the allergens in another study, conducted among 82 hazelnut-allergic individuals in Finland (33).

Cross-reactivity among PR-10 allergens is high, due to sequence homology (34). Therefore, co-sensitization is frequent, e.g. 80% between Cor a 1 and the peanut PR-10 Ara h 8 in a study from the Netherlands (17), and highly correlated, as reported by a study conducted in the US, where a correlation coefficient of 0.82 was found (24). Allergen multiplex investigations reveal complex patterns of Cor a 1 and other PR-10 sensitization (29).

Molecular Aspects

Biochemistry

The PR-10 proteins are cytosolic proteins having 154-163 amino acids with a molecular weight of 17 kDa. They are mostly involved with defense mechanisms in plants. They share a common tertiary structure with seven antiparallel β-sheets enrolled around a central hydrophobic or amphipathic cavity for ligand binding. Different ligands have been proposed, among which flavonoids (10, 35).

These allergens are heat-labile proteins, labile at low pH and lacking proteolytic resistance. Thus, dry-heat processes like roasting reduce their allergenicity. Further, autoclaving (121℃ or 138℃, 15 or 30 min) also reduces the allergenicity of these allergens (10).

Isoforms, epitopes, antibodies

Cor a 1 comprises four isoallergens, namely Cor a 1.01, Cor a 1.02, Cor a 1.03 and Cor a 1.04 with a molecular weight of 17 kDa and 160-161 amino acids. These four proteins are termed isoallergens, because of comparable molecular weight and biological function, with approximately 67% of sequence homology. Cor a 1.01 is mainly identified in hazel pollens, Cor a 1.02 and Cor a 1.03 in hazel leaves, whereas Cor a 1.04 is found in hazelnut (10).

The isoallergen Cor a 1.01 has four isoforms, Cor a 1.0101, Cor a 1.0102, Cor a 1.0103 and Cor a 1.0104, with ~95% sequence similarity among the isoforms. Also, the isoallergen 1.04 exists in four polymorphic isoforms or variants i.e., Cor a 1.0401 to Cor a 1.0404, with 97%-99% amino acid sequence similarly (10). The IgE reactivity of these isoforms follows the order, Cor a 1.0401>1.0402>1.0403>1.0404 (36).

Cross-reactivity

Cor a 1.04 and Bet v 1.01 share 67.3% amino acid sequence similarity. Interestingly, the sequence identity is higher with Cor a 1.04 (66-67%) from hazelnut as compared to Cor a 1.01 (61-65%) from hazel pollen (25).

The IgE-binding of Cor a 1 and Ara h 8 (peanut) was found to be correlated, due to 53% of amino acid sequence similarity (17). In a study conducted on 526 Italian PR-10 positive patients, cross-reactivity among various PR-10 proteins was assessed. The findings reported a significant Spearman correlation coefficient for Cor a 1.04 with Aln g 1 (alder), Mal d 1 (apple) and Pru p 1 (peach). The amino-acid sequence homology between Cor a 1.04 and other PR-10 proteins, retrieved from the UNIPROT database (www.uniprot.org), was 52.1% for Act d 8 (kiwi), 36.6% for Api g 1 (celery), 52.8% for Ara h 8, 56.5% for Gly m 4 (soybean), 62.1% for Mal d 1, 63.9% for Pru p 1, 65.8% for Aln g 1 and 67.1% for Bet v 1, respectively (29).

Diagnostic Relevance

Disease Severity

As exposed above, Cor a 1 sensitization is associated with milder symptoms in hazelnut-allergic patients in Europe (30). Quantitative data support this view, with a Japanese study suggesting that high levels of Cor a 1 IgE are associated with tolerance to hazelnut (37). Further, Cor a 1 sensitization may be high in birch-endemic areas due to primary sensitization to Bet v 1, which is manifested as mild OAS in adults. While in children, Cor a 1 sensitization is not found to be related to primary hazelnut allergy (moderate-to-severe symptoms) (2, 24, 30). Thus, Cor a 1 IgE has low diagnostic accuracy for the identification of moderate-to-severe allergic reactions to hazelnuts in children as suggested in a systematic review (38).

AIT Prescription

Cor a 1 sensitization has been proposed as a predictive marker of better AIT efficacy (34).

Compiled By

Author: Turacoz Healthcare Solutions

Reviewer: Dr. Christian Fischer

Last reviewed: March 2021

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