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Allergen Encyclopedia
Table of Contents

Component

f425 Cor a 8

f425 Cor a 8 Scientific Information

Type:

Component

Name; WHO/IUIS:

Cor a 8

Biological function:

Non-specific lipid transfer protein

Allergen code:

f425

Source Material:

Seed storage proteins Native sourced from the seed extracts of Corylus avellana

Other Names :

Lipid transfer protein

Whole Allergen: Hazelnut
Related Allergens: f440 Cor a 9, f428 Cor a 1, f439 Cor a 14

Summary

Cor a 8, a non-specific lipid transfer protein (nsLTP), is an important pan-allergen found in hazelnuts (Corylus avellana). It is a PR-14 (Pathogenesis-Related family 14) protein, that belongs to the prolamin superfamily and has a molecular weight of 9 kDa. Cor a 8 is highly heat-stable and resistant to gastrointestinal digestion. The prevalence of sensitization to Cor a 8 among hazelnut-allergic patients is higher in non-birch endemic regions, like the Mediterranean, while rare in Northern or Western Europe. Cor a 8 sensitization has been initially associated with severe reactions in children and adults from birch-endemic regions. However, it has been reported recently that Cor a 8 sensitization could be clinically silent, found in hazelnut-tolerant patients, or associated with mild symptoms, such as oral allergy to hazelnut as well. Cor a 8-sIgE levels are not helpful in differentiating reactive or non-reactive patients among hazelnut-sensitized individuals. Thus, it may not serve as good diagnostic marker for hazelnut allergy. Sensitization to Cor a 8 is usually associated to other nsLTPs, such as Pru p 3 (peach) and Jug r 3 (walnut). Besides, it shows high degree of sequence similarity with other LTP of peanut (Ara h 9), walnut (Jug r 3) and some Rosaceae fruits. Further, peach allergy (Pru p 3) may serve as a diagnostic marker for hazelnut allergy (Cor a 8) in Mediterranean areas as Pru p 3 may serve as a primary sensitizer for Cor a 8 in these regions.

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 8, a non-specific lipid transfer protein (nsLTP), is an important pan-allergen of hazelnut. The prevalence of sensitization to Cor a 8 among hazelnut-allergic patients is higher in non-birch endemic regions, like the Mediterranean. Cor a 8 allergen may be associated with severe reactions upon challenge with hazelnuts in children and adults from birch-endemic and non- birch-endemic regions (10-13).

In a large study conducted among 731 hazelnut-sensitized individuals across 12 European centers, sensitization to Cor a 8 was found to be most prevalent in Mediterranean regions like Athens (83%, 15 out of 18), followed by Madrid (36%, 4 out of 11), while rare in Northern or Western Europe (<15%) (14). This pattern of prevalence was confirmed by numerous studies in hazelnut-allergic patients across Europe, which can be summarized as 65 – 85% in Spain and Greece, 47% in Italy (which comprises both birch-endemic and non-birch-endemic regions), 15% in Switzerland, 5% in Denmark (15-17).

Among 55 hazelnut-allergic children in Turkey, 42% (23 out of 55) were sensitized to Cor a 8 (18). Further, Cor a 8 sensitization was found in 22.2% (2 out of 9) of hazelnut-allergic children in a study conducted in Japan (19).

The prevalence of Cor a 8 sensitization in hazelnut-sensitized patients ranged from 8% to 17% in different regions of the United States (US), without significant age-related variation. Of note, the geographical variation in the prevalence of Cor a 8 sensitization as observed in Europe was not found in the US (20).

Environmental Characteristics

Source and tissue

Cor a 8 is an allergen component present in the seeds of hazel tree (Corylus avellana) (10).

Cation exchange chromatography and/or size-exclusion chromatography are some techniques that are used for purification of natural Cor a 8 from defatted hazelnut extract. The molecule can be generated by recombinant expression systems. Cor a 8 can be expressed in Escherichia coli (bacteria) or Pichia pastoris (yeast) (21, 22).

Clinical Relevance

Disease severity

Although Cor a 8 sensitization was initially described in association with severe reactions in children and adults from birch-endemic regions (23-25), it was subsequently demonstrated that Cor a 8 sensitization can be clinically silent, found in hazelnut-tolerant patients, or associated with mild symptoms such as oral allergy to hazelnut (11). 

In a study conducted in Belgium, sensitization to Cor a 8 was found in 17% of hazelnut-allergic patients showing systemic reactions (asthma, angioedema, rhino-conjunctivitis, hypotension or gastrointestinal symptoms) after consumption of hazelnut, while it was not found in the hazelnut-tolerant patients (24). A study conducted in the Netherlands (birch-endemic region) among hazelnut-sensitized individuals also reported sensitization to Cor a 8 to be a significant risk factor for the development of objective symptoms (generalized urticaria, angioedema, diarrhea, vomiting, rhino-conjunctivitis or bronchoconstriction).

Furthermore, a study conducted among 57 hazelnut-allergic patients and 62 control subjects with pollen allergy from Denmark, Switzerland and Spain revealed that the median IgE levels were significantly higher in hazelnut-allergic patients than in control subjects. Also, Cor a 8-sIgE levels depicted the best sensitivity and specificity, especially in the Mediterranean region like Spain (16).

Sensitization to multiple hazelnut molecular allergens is frequent as a study in the Netherlands among 161 hazelnut-sensitized patients found no statistical difference in the Cor a 8 sensitization among patients with severe or non-severe symptoms to hazelnut ingestion (25). The EuroPrevall study also demonstrated that the prevalence of Cor a 8 sensitization was not statistically different among the patients showing mild, moderate or severe clinical presentations (26).

However, in a recent study in Japan among 9 hazelnut-allergic children and 82 hazelnut tolerant children, Cor a 8 sensitization was found to be more frequent in hazelnut-tolerant than hazelnut-allergic children (19).

Furthermore, similar to other nsLTPs, the clinical expression of Cor a 8 sensitization can be modified by the presence of cofactors, mainly exercise and the intake of non-steroidal anti-inflammatory drugs (27).

Cross-reactive molecules

Sensitization to Cor a 8 is usually associated to other nsLTP and notably Pru p 3 (peach) (28). Pru p 3 is immunodominant and a probable primary sensitizer to Cor a 8, especially in non-birch endemic areas. (10, 14, 23).

Cor a 8 is cross-reactive to other tree nut nsLTPs, such as Jug r 3 from walnut (14).

Molecular Aspects

Biochemistry

The nsLTP family of proteins, also known as PR-14 (Pathogenesis-Related family 14), belongs to the prolamin superfamily (29). These small-sized monomeric proteins contain eight cysteine motifs, bridged by four disulfide linkages, four alpha-helices, and a lipid-binding cavity. The function of these proteins is to transport different wide varieties of lipids through membranes, in addition to plant defense against fungi and bacteria. Two subfamilies of nsLTP exists, namely nsLTP 1 (9kDa) and nsLTP 2 (7 kDa) (10, 21).

Cor a 8 is the nsLTP type I identified in the seeds of hazelnut. It is a 115 amino acid protein with a molecular weight of 9 kDa (10).

This allergen is resistant to food-processing techniques (high temperatures and pH changes) and gastrointestinal environment (gastric and intestinal enzymes). However, the allergenicity of Cor a 8 is affected, while being subjected to very high temperatures as well as wet processing (121℃ [15 minutes] and 138℃ [30 minutes] in an autoclave) (10). The IgE binding to Cor a 8 was also reduced by hot air or infrared roasting at 140℃, that was completely lost at 170℃ by roasting in both conditions (30).

Cor a 8 is not optimally retained in allergenic extracts at neutral pH, explaining under-estimation or even false negative results reported with skin prick tests (31, 32).

Isoforms, epitopes, antibodies

As of March 9, 2021, only one isoform, Cor a 8.0101, has been identified and officially published by the World Health Organization (WHO) and International Union of Immunological Societies (IUIS) Allergen Nomenclature (10, 33).

Cross-reactivity

Cross-reactivity among nsLTPs is lower than that seen with other plant pan-allergens, such as PR-10 and profilin families, due to a moderate degree of sequence conservation (34, 35).

Clinically relevant cross-reactivity between Cor a 8 and other nsLTPs involve mainly peanut, walnut, and Rosaceae fruit. Sequence similarity of Cor a 8 with the peanut nsLTP Ara h 9 and walnut LTP Jug r 3 was found to be 55% and 60% respectively (36, 37). There is a marked correlation (correlation coefficient=0.6 to 0.7) between IgE sensitization against Cor a 8 and against Ara h 9, as demonstrated in Europe (37) and in the US (20). Furthermore, a strong correlation between Cor a 8 and Jug r 3 (walnut, correlation coefficient=0.7) was noted in the study conducted in the US (20).

Regarding Rosaceae fruits, the highest Cor a 8 sequence similarity is with Pru du 3 (almond, 60%), followed by Mal d 3 (apple) and Pru ar 3 (apricot) at 59%, Pru av 3 (cherry, 58%), Pru p 3 (peach, 56%) and Pyr c 3 (pear, 54%), supporting IgE cross-reactivity among these allergens (10). Pru p 3 was found to be the most closely related structure to Cor a 8 and shared protein epitopes accountable for IgE-cross-reactivity (21). Furthermore, a variety of other nsLTPs share significant sequence similarity with Cor a 8 such as rice (48%), barley (43%) and maize (48%) (21). The clinical relevance of these data is supported by cohort studies. As an example, the EuroPrevall study (731 hazelnut-sensitized individuals in 12 European centers) demonstrated significant correlation of Cor a 8-sIgE with IgE to various food allergenic extracts, such as peach, apple, walnut, lentil and corn, whereas a weak correlation existed between Cor a 8-sIgE and IgE to pollens, such as mugwort, Chenopodium, plane tree, and Parietaria pollen (14). 

Diagnostic Relevance

Disease Severity

In areas with low prevalence rates for Cor a 8 sensitization, Cor a 8-sIgE may not be helpful for the diagnosis of hazelnut allergy, such as in a Flemish cohort of hazelnut-allergic individuals. The study reported Cor a 8 sensitization in 16% of patients with generalized reactions, while it was only 3% in patients presenting with oral allergy syndrome (38).

According to a study conducted on 64 hazelnut-sensitized patients in Turkey, Cor a 8-sIgE was found in 42.9% (12 out of 28) and 40.7% (11 out of 27) of reactive and non-reactive patients, respectively. However, the median IgE levels were comparable between reactive and nonreactive-sensitized patients (p=0.874), and hence could not differentiate clinical hazelnut allergy (18).

A study conducted on 91 hazelnut-sensitized children in Japan demonstrated that Cor a 8 may not serve as a good diagnostic marker for hazelnut allergy in Japan, unlike it being a useful marker in the Mediterranean region (19).

Cross-Reactivity

Peach allergy (Pru p 3) may serve as a diagnostic marker for hazelnut allergy (Cor a 8) in Mediterranean areas (15).

Exposure

The main route of exposure is through ingestion (14).

Compiled By

Author: Turacoz Healthcare Solutions

Reviewer: Dr. Christian Fischer

 

Last reviewed: March 2021

References
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