nCor a 9, Hazelnut

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Code: f440
Latin name: Corylus avellana
Source material: nCor a 9 is purified from a hazelnut extract
Family: Betulaceae
Common names: 11S Globulin

ImmunoCAP allergen components:

rCor a 1 - f428
rCor a 8 - f425
nCor a 9 - f440
rCor a 14 - f439

Allergen: Cor a 9 (1-8).

Biological function: An 11S globulin

Mw: Approximately 35-40 kDa

Clinical Utility

Sensitisation to Cor a 9 (an 11S globulin storage protein) has been reported to be associated with severe hazelnut allergy in children and adults , both in the United States and in Europe. (1, 3, 9-11). Hazelnut components provide improved risk assessment in hazelnut allergic patients, and sensitization to Cor a 9 indicates a primary hazelnut allergy.

Allergen Exposure

See Hazelnut, f17

Allergen Description

Cor a 9 is a 35-40 kDa protein, an 11S globulin-like protein, a seed storage protein found in a variety of seeds including soybean, broad bean, yellow mustard seed, pecan, etc.

The 11S globulins, also known as legumins, are classified as part of the Cupin superfamily. The legumins are large (300-450 kDa), generally hexameric, non-glycosylated members of a complex family of proteins. Individual subunits are found both as intact precursor proteins (50-60 kDa) and as processed acidic (30-40 kDa) and basic (20 kDa) subunits that generally remain covalently associated in seeds. (12, cited in 13) Legumins are composed of 2 polypeptide chains of different molecular masses and amino acid sequences (heterodimeric form, composed of a 20- to 40-kDa chain plus a 20- to 25-kDa chain), which are linked together by one disulfide bridge. (14) The legumins are related to each other structurally and are believed to share ancestors in common with vicilin-like 7S proteins. (12, cited in 13)

In addition to Cor a 9, several other legumins (11S globulin seed storage protein family members) have been identified as food allergens. These include Ara h 3 and Ara h 4 of the peanut, the soybean G1 and G2 glycinins, Ana o 2 of cashew nut, Sin a 2 of mustard, tree nuts (almond, pistachio and walnut) and possibly a legumin from buckwheat. (1, 14-16)

Fresh and roasted (10 min at 170°C) hazelnuts generally contain a higher amount of intact hazelnut proteins than older (>6 months) raw hazelnuts stored at room temperature. The time of storage of raw hazelnuts has been shown to be inversely related to the amounts of Cor a 9 and IgE-binding proteins. (17). Cor a 9 sensitized patients are likely to react both to raw and roasted hazelnuts (18).

Cor a 9 is an abundant seed storage proteins in hazelnut. Notably, Cor a 9 is a pollen-independent hazelnut allergen.

Potential Cross-Reactivity

The homology between the 11S globulins ranges from 45 to 50% [36-41% identity]. Interestingly, one known IgE-binding epitope of Ara h 3 (peanut) shares 67% of amino acids with the corresponding area of the newly identified Cor a 9. The amino acids that differ were previously shown not to be critical for IgE binding in Ara h 3. (1) However, despite reported data, there is still little evidence of IgE-cross reactivity involving 11S globulins. For example, Sin a 2 from mustard shares IgG epitopes with allergenic 11S globulins from tree nuts (almond, hazelnut, pistachio and walnut), but not from peanut. (15,16) The 11S globulin Sin a 2 is a marker to predict severity of symptoms in mustard-allergic patients. (15) The possibility of cross-reactivity between the 11S globulins in buckwheat, poppy and hazelnut was raised in a study of a 7-year-old boy who developed a grade III anaphylactic reaction after consumption of a cake containing buckwheat flour. (19) Some studies have shown that 11S globulins are involved in cross-reactivity between coconut and walnut. (15)

Clinical Experience

Hazelnut (Corylus avellana) allergy varies from rather mild oral allergy symptoms to potentially life-threatening anaphylaxis, and exhibits geographic and age-related variations. (9) This is suggested by a number of studies.

In Antwerp, Belgium, (young) children predominantly exhibit sensitisation to hazelnut storage proteins Cor a 9 and Cor a 11 that is unrelated to birch pollen allergy, and is generally associated with a more severe clinical outcome on consumption on raw and processed hazelnut. In contrast, adults predominantly present with an oral allergy syndrome, due to extensive cross-reactivity between the labile Cor a 1.04 and Bet v 1, the major allergen from birch (Betula verrucosa) pollen. (9)

Cor a 9 was recognised by serum IgE from 86% (12/14) of patients with hazelnut allergy with systemic reactions. IgE reactivity to Cor a 1.04 was detected in 50% (7/14) of hazelnut-allergic patients. (1)

Attempts have been made to elucidate the relevance of the individual hazelnut allergens. A study assessing sensitisation to the components rCor a 1, rCor a 8, nCor a 9, and rCor a 14 in a population of hazelnut-sensitised children and adults from a birch-endemic area concluded that sensitisation to Cor a 9 and Cor a 14 was highly specific for patients with objective symptoms in double-blind, placebo-controlled food challenges (DBPCFCs) as a marker for a more severe hazelnut-allergic phenotype. A group of 161 hazelnut-sensitised patients were included in the study: 40 children and 15 adults with objective symptoms on DBPCFCs, and 24 adults with a convincing objective history, were compared with 41 children and 41 adults with no or subjective symptoms on DBPCFCs (grouped together). IgE levels to hazelnut extract were significantly higher in children with objective symptoms than with no or subjective symptoms. In 13% of children and 49% of adults with hazelnut allergy with objective symptoms, only sensitisation to rCor a 1.04 was observed, and not to other water-soluble allergens. Sensitisation to rCor a 8 was rare, in contrast to rCor a 1. Sensitisation to nCor a 9, rCor a 14, or both was strongly associated with hazelnut allergy with objective symptoms. IgE levels to either nCor a 9 of 1 kUA/L or greater, or rCor a 14 of 5 kUA/L or greater (children), and IgE levels to either nCor a 9 of 1 kUA/L or greater or rCor a 14 of 1 kUA/L or greater (adults), had a specificity of greater than 90%, and accounted for 83% of children and 44% of adults with hazelnut allergy with objective symptoms. (3) Both children and adults without birch pollinosis had significantly higher IgE levels to nCor a 9 than those with birch pollinosis. Levels of IgE to rCor a 14 were also higher in adults without than those with a history of allergic symptoms to birch pollinosis, and no such difference was observed for IgE to rCor a 14 among children. IgE to nCor a 9 had better capacity than IgE to rCor a 14 to identify children with objective symptoms in DBPCFCs. (3)

A study that assessed sensitisation to hazelnut components in different age groups of hazelnut-allergic patients, and infants with atopic dermatitis (AD) sensitised to hazelnut in a birch-endemic region, examined sera from 80 hazelnut-allergic patients: 33 infants under 1 year of age with AD, healthy controls, and 29 birch pollen-allergic but hazelnut-tolerant individuals. IgE reactivity to Cor a 1.01, Cor a 1.04, Cor a 8, and Cor a 9 were also evaluated. Forty patients (22 preschool children, 10 schoolchildren, and 8 adults) with systemic reactions on consumption of hazelnut were sensitised to Cor a 11 (respective rates of 36%, 40%, and 12.5%). Forty patients (6 preschool children, 10 schoolchildren, and 24 adults) reported oral allergy syndrome, but only 2 of them (of preschool age) were sensitized to Cor a 11. Two (8%) of the AD infants sensitised to hazelnut showed IgE reactivity to Cor a 11. This reactivity was not observed in any of the AD infants without sensitisation to hazelnut, in any of the birch-pollen allergic patients without hazelnut allergy, or in any of the healthy control individuals. Sensitization to Cor a 11 in a birch-endemic region is predominantly found in children with severe hazelnut allergy; a finding that is consistent with observations concerning sensitisation to Cor a 9. (8)

Researchers have pointed out that allergy to hazelnut can be severe, and can occur at a young age. The pattern of hazelnut sensitisation in infants with atopic dermatitis (AD) was investigated in Belgium utilising the sera of 34 infants, all under 1 year of age and with AD. From the 29 infants with a sensitisation to at least one food allergen, 20 demonstrated IgE reactivity to hazelnut. Twelve (60%) of the children with IgE reactivity to hazelnut demonstrated sensitisation to Cor a 9. In these infants, no sensitisation to Cor a 1, the homologue of the major birch pollen allergen Bet v 1 (Birch), or the lipid transfer protein (Cor a 8) from hazelnut was demonstrable. Half of the children sensitised to Cor a 9 demonstrated IgE reactivity to its homologue in peanut (Ara h 3), from which five were also sensitised to Gly m 6 from soy. None of the infants with AD without IgE reactivity to hazelnut demonstrated sensitisation to Cor a 1, 8, or 9. (10)

The prevalence of sensitisation to Cor a 9 has been shown by other authors to differ between age groups: 65% of preschool children, 50% of schoolchildren, and 17% of adults with a severe reaction to hazelnut recognised nCor a 9. (10,11) This age-related effect was also observed in another study where 83% of the children and 36% of the adults with hazelnut allergy with objective symptoms were sensitised to nCor a 9. Sensitisation to rCor a 14 also showed an age-related prevalence: 70% of children and 39% of adults with hazelnut allergy with objective symptoms were rCor a 14 sensitised. (3) 

 

Compiled by Dr Harris Steinman
harris@allergyadvisor.com

References

  1. Beyer K, Grishina G, Bardina L, Grishin A, Sampson HA. Identification of an 11S globulin as a major hazelnut food allergen in hazelnut-induced systemic reactions. J Allergy Clin Immunol 2002;110(3):517-23.
  2. Hansen KS, Ballmer-Weber BK, Sastre J, Lidholm J, Andersson K, Oberhofer H, Lluch-Bernal M, Ostling J, Mattsson L, Schocker F, Vieths S, Poulsen LK. Component-resolved in vitro diagnosis of hazelnut allergy in Europe. J Allergy Clin Immunol 2009;123(5):1134-41.
  3. Masthoff LJ, Mattsson L, Zuidmeer-Jongejan L, Lidholm J, Andersson K, Akkerdaas JH, Versteeg SA, Garino C, Meijer Y, Kentie P, Versluis A, den Hartog Jager CF, Bruijnzeel-Koomen CA, Knulst AC, van Ree R, van Hoffen E, Pasmans SG. Sensitization to Cor a 9 and Cor a 14 is highly specific for a hazelnut allergy with objective symptoms in Dutch children and adults. J Allergy Clin Immunol 2013;132(2):393-9.
  4.  International Union of Immunological Societies Allergen Nomenclature: IUIS official list http://www.allergen.org. Accessed June 2013.
  5.  Rigby NM, Marsh J, Sancho AI, Wellner K, Akkerdaas J, van Ree R, Knulst A, Fernández-Rivas M, Brettlova V, Schilte PP, Summer C, Pumphrey R, Shewry PR, Clare Mills EN. The purification and characterisation of allergenic hazelnut seed proteins. Mol Nutr Food Res 2008;52(S2):S251-S261.
  6. Guo F, Kothary MH, Wang Y, Yu X, Howard AJ, Fu TJ, Zhang YZ. Purification and crystallization of Cor a 9, a major hazelnut allergen. [Spanish] Acta Crystallogr Sect F Struct Biol Cryst Commun 2009;65(Pt 1):42-6.
  7. Robotham JM, Hoffman GG, Teuber SS, Beyer K, Sampson HA, Sathe SK, Roux KH. Linear IgE-epitope mapping and comparative structural homology modeling of hazelnut and English walnut 11S globulins. Mol Immunol 2009;46(15):2975-84.
  8. Verweij MM, Hagendorens MM, Trashin S, Cucu T, De Meulenaer B, Devreese B, Bridts CH, De Clerck LS, Ebo DG. Age-dependent sensitization to the 7S-vicilin-like protein Cor a 11 from hazelnut (Corylus avellana) in a birch-endemic region. J Investig Allergol Clin Immunol 2012;22(4):245-51.
  9. Ebo DG, Verweij MM, Sabato V, Hagendorens MM, Bridts CH, De Clerck LS. Hazelnut allergy: a multi-faced condition with demographic and geographic characteristics. Acta Clin Belg 2012;67(5):317-21.
  10. Verweij MM, Hagendorens MM, De Knop KJ, Bridts CH, De Clerck LS, Stevens WJ, Ebo DG Young infants with atopic dermatitis can display sensitization to Cor a 9, an 11S legumin-like seed-storage protein from hazelnut (Corylus avellana). Pediatr Allergy Immunol 2011;22(2):196-201.
  11. De Knop KJ, Verweij MM, Grimmelikhuijsen M, Philipse E, Hagendorens MM, Bridts CH, De Clerck LS, Stevens WJ, Ebo DG. Age-related sensitization profiles for hazelnut (Corylus avellana) in a birch-endemic region. Pediatr Allergy Immunol 2011 Feb;22(1 Pt 2):e139-e149.
  12.  Casey R. Distribution and some properties of seed globulins. in Shewry PR (ed): Seed Proteins. Boston, Kluwer Academic. 1999:159-69.
  13. Wang F, Robotham JM, Teuber SS, Sathe SK, Roux KH. Ana o 2, a major cashew (Anacardium occidentale L.) nut allergen of the legumin family. Int Arch Allergy Immunol 2003;132(1):27-39.
  14. Rodin J, Sjodahl S, Josefsson LG, Rask L. Characterization of a Brassica napus gene encoding a cruciferin subunit: estimation of sizes of cruciferin gene families. Plant Mol Biol 1992;20(3):559-63.
  15. Sirvent S, Akotenou M, Cuesta-Herranz J, Vereda A, Rodriguez R, Villalba M, Palomares O. The 11S globulin Sin a 2 from yellow mustard seeds shows IgE cross-reactivity with homologous counterparts from tree nuts and peanut. Clin Transl Allergy 2012;2(1):23.
  16. Barre A, Jacquet G, Sordet C, Culerrier R, Rouge P. Homology modelling and conformational analysis of IgE-binding epitopes of Ara h 3 and other legumin allergens with a cupin fold from tree nuts. Mol Immunol 2007;44(12):3243-55.
  17. Dooper M, Plassen C, Holden L, Moen L, Namork E, Egaas E. Antibody binding to hazelnut (Corylus avellana) proteins: the effects of extraction procedure and hazelnut source. Food Agric Immunol 2008;19(3):229-240.
  18. Hansen KS, Ballmer-Weber BK, Lüttkopf D, Skov PS, Wüthrich B, Bindslev-Jensen C, Vieths S, Poulsen LK. Roasted hazelnuts--allergenic activity evaluated by double-blind, placebo-controlled food challenge. Allergy 2003;58(2):132-8.
  19. Varga EM, Kollmann D, Zach M, Bohle B. Anaphylaxis to buckwheat in an atopic child: a risk factor for severe allergy to nuts and seeds? Int Arch Allergy Immunol 2011;156(1):112-6.

 

As in all diagnostic testing, the diagnosis is made by the physican based on both test results and the patient history.