Cor a 1
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. According to a systematic review, this allergy accounts for about 17-100% of the total tree nut allergies in Europe. Further, hazelnut allergy as well as sensitization is also frequent outside Europe, in countries such as India, Russia, Israel, Australia, Mexico and South Africa.
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.
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. There is over 97% cross-reactivity between birch pollen Bet v 1 and Cor a 1. 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. 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.
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.
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. 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.
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.
The prevalence of sensitization to Cor a 1 increase with age. 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.
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. 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.
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. 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.
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. 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. Further, moderate-to-strong correlation was observed among both the allergens in another study, conducted among 82 hazelnut-allergic individuals in Finland.
Cross-reactivity among PR-10 allergens is high, due to sequence homology. 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, and highly correlated, as reported by a study conducted in the US, where a correlation coefficient of 0.82 was found. Allergen multiplex investigations reveal complex patterns of Cor a 1 and other PR-10 sensitization.
Diagnostics
Disease Severity
As exposed above, Cor a 1 sensitization is associated with milder symptoms in hazelnut-allergic patients in Europe. Quantitative data support this view, with a Japanese study suggesting that high levels of Cor a 1 IgE are associated with tolerance to hazelnut. 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). 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.
AIT Prescription
Cor a 1 sensitization has been proposed as a predictive marker of better AIT efficacy.
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.
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. 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.
References
- Barni S, Mori F, Piccorossi A, Sarti L, Pucci N, Maresca M, et al. Low-Dose Oral Food Challenge with Hazelnut: Efficacy and Tolerability in Children. International archives of allergy and immunology. 2019;178(1):97-100.
- Calamelli E, Trozzo A, Di Blasi E, Serra L, Bottau P. Hazelnut Allergy. Medicina (Kaunas, Lithuania). 2021;57(1).
- McWilliam V, Koplin J, Lodge C, Tang M, Dharmage S, Allen K. The Prevalence of Tree Nut Allergy: A Systematic Review. Current Allergy and Asthma Reports. 2015;15(9):54.
- Botha M, Basera W, Facey-Thomas HE, Gaunt B, Gray CL, Ramjith J, et al. Rural and urban food allergy prevalence from the South African Food Allergy (SAFFA) study. The Journal of allergy and clinical immunology. 2019;143(2):662-8.e2.
- Elizur A, Appel MY, Nachshon L, Levy MB, Epstein-Rigbi N, Golobov K, et al. NUT Co Reactivity - ACquiring Knowledge for Elimination Recommendations (NUT CRACKER) study. Allergy. 2018;73(3):593-601.
- Fedorova OS, Ogorodova LM, Fedotova MM, Evdokimova TA. [The prevalence of food allergy to peanut and hazelnut in children in Tomsk Region]. Voprosy pitaniia. 2014;83(1):48-54.
- Mahesh PA, Wong GW, Ogorodova L, Potts J, Leung TF, Fedorova O, et al. Prevalence of food sensitization and probable food allergy among adults in India: the EuroPrevall INCO study. Allergy. 2016;71(7):1010-9.
- McWilliam V, Peters R, Tang MLK, Dharmage S, Ponsonby AL, Gurrin L, et al. Patterns of tree nut sensitization and allergy in the first 6 years of life in a population-based cohort. The Journal of allergy and clinical immunology. 2019;143(2):644-50.e5.
- Ruiz Segura LT, Figueroa Pérez E, Nowak-Wegrzyn A, Siepmann T, Larenas-Linnemann D. Food allergen sensitization patterns in a large allergic population in Mexico. Allergologia et immunopathologia. 2020:In press.
- Costa J, Mafra I, Carrapatoso I, Oliveira MB. Hazelnut Allergens: Molecular Characterization, Detection, and Clinical Relevance. Critical reviews in food science and nutrition. 2016;56(15):2579-605.
- Hofmaier S, Hoffmann-Sommergruber K, Breiteneder H. Important Allergenic Molecules and their Characteristics. In: Matricardi PM, Kleine-Tebbe J, Hoffmann HJ, Valenta R, Ollert M, editors. EAACI Molecular Allergology User's Guide: Using Molecular Allergology in the Clinical Practice. Zutich, Switzerland: The European Academy of Allergy and Clinical Immunology (EAACI); 2016. p. 365-74.
- Scala E, Asero R, Niederberger V. Tree Pollen Allergy. In: Matricardi PM, Kleine-Tebbe J, Hoffmann HJ, Valenta R, Ollert M, editors. EAACI Molecular Allergology User's Guide: Using Molecular Allergology in the Clinical Practice. Zutich, Switzerland: The European Academy of Allergy and Clinical Immunology (EAACI); 2016. p. 71-83.
- Biedermann T, Winther L, Till SJ, Panzner P, Knulst A, Valovirta E. Birch pollen allergy in Europe. Allergy. 2019;74(7):1237-48.
- Datema MR, Zuidmeer-Jongejan L, Asero R, Barreales L, Belohlavkova S, de Blay F, et al. Hazelnut allergy across Europe dissected molecularly: A EuroPrevall outpatient clinic survey. The Journal of allergy and clinical immunology. 2015;136(2):382-91.
- De Knop KJ, Verweij MM, Grimmelikhuijsen M, Philipse E, Hagendorens MM, Bridts CH, et al. Age-related sensitization profiles for hazelnut (Corylus avellana) in a birch-endemic region. Pediatr Allergy Immunol. 2011;22(1 Pt 2):e139-49.
- Brandström J, Nopp A, Johansson SG, Lilja G, Sundqvist AC, Borres MP, et al. Basophil allergen threshold sensitivity and component-resolved diagnostics improve hazelnut allergy diagnosis. Clin Exp Allergy. 2015;45(9):1412-8.
- Masthoff LJ, van Hoffen E, Mattsson L, Lidholm J, Andersson K, Zuidmeer-Jongejan L, et al. Peanut allergy is common among hazelnut-sensitized subjects but is not primarily the result of IgE cross-reactivity. Allergy. 2015;70(3):265-74.
- Bernstein DI, Würtzen PA, DuBuske L, Blaiss MS, Ellis AK, Weber RW, et al. Allergy to oak pollen in North America. Allergy and asthma proceedings. 2021;42(1):43-54.
- Elisyutina O, Fedenko E, Campana R, Litovkina A, Ilina N, Kudlay D, et al. Bet v 1-specific IgE levels and PR-10 reactivity discriminate silent sensitization from phenotypes of birch allergy. Allergy. 2019;74(12):2525-8.
- Kim JH, Kim SH, Park HW, Cho SH, Chang YS. Oral Allergy Syndrome in Birch Pollen-Sensitized Patients from a Korean University Hospital. Journal of Korean medical science. 2018;33(33):e218.
- Li JD, Du ZR, Liu J, Xu YY, Wang RQ, Yin J. Characteristics of pollen-related food allergy based on individual pollen allergy profiles in the Chinese population. The World Allergy Organization journal. 2020;13(5):100120.
- Buyuktiryaki B, Cavkaytar O, Sahiner UM, Yilmaz EA, Yavuz ST, Soyer O, et al. Cor a 14, Hazelnut-Specific IgE, and SPT as a Reliable Tool in Hazelnut Allergy Diagnosis in Eastern Mediterranean Children. J Allergy Clin Immunol Pract. 2016;4(2):265-72.e3.
- Flinterman AE, Akkerdaas JH, den Hartog Jager CF, Rigby NM, Fernandez-Rivas M, Hoekstra MO, et al. Lipid transfer protein-linked hazelnut allergy in children from a non-Mediterranean birch-endemic area. The Journal of allergy and clinical immunology. 2008;121(2):423-8.e2.
- Valcour A, Lidholm J, Borres MP, Hamilton RG. Sensitization profiles to hazelnut allergens across the United States. Ann Allergy Asthma Immunol. 2019;122(1):111-6.e1.
- Jacob T, von Loetzen CS, Reuter A, Lacher U, Schiller D, Schobert R, et al. Identification of a natural ligand of the hazel allergen Cor a 1. Sci Rep. 2019;9(1):8714.
- Knol EF, Wickman M. Tree Nut and Seed Allergy. In: Matricardi PM, Kleine-Tebbe J, Hoffmann HJ, Valenta R, Ollert M, editors. EAACI Molecular Allergology User's Guide: Using Molecular Allergology in the Clinical Practice. Zutich, Switzerland: The European Academy of Allergy and Clinical Immunology (EAACI); 2016. p. 245-54.
- van Ree R, Aalberse RC. Allergens and the Allergenic Composition of Source Materials. In: Matricardi PM, Kleine-Tebbe J, Hoffmann HJ, Valenta R, Ollert M, editors. EAACI Molecular Allergology User's Guide: Using Molecular Allergology in the Clinical Practice. Zutich, Switzerland: The European Academy of Allergy and Clinical Immunology (EAACI); 2016. p. 11-20.
- Faber MA, De Graag M, Van Der Heijden C, Sabato V, Hagendorens MM, Bridts CH, et al. Cor a 14: missing link in the molecular diagnosis of hazelnut allergy? International archives of allergy and immunology. 2014;164(3):200-6.
- Scala E, Abeni D, Cecchi L, Guerra EC, Locanto M, Pirrotta L, et al. Molecular Recognition Profiles and Clinical Patterns of PR-10 Sensitization in a Birch-Free Mediterranean Area. International archives of allergy and immunology. 2017;173(3):138-46.
- Datema MR, van Ree R, Asero R, Barreales L, Belohlavkova S, de Blay F, et al. Component-resolved diagnosis and beyond: Multivariable regression models to predict severity of hazelnut allergy. Allergy. 2018;73(3):549-59.
- Hofmann C, Scheurer S, Rost K, Graulich E, Jamin A, Foetisch K, et al. Cor a 1-reactive T cells and IgE are predominantly cross-reactive to Bet v 1 in patients with birch pollen-associated food allergy to hazelnut. The Journal of allergy and clinical immunology. 2013;131(5):1384-92.e6.
- Guhsl EE, Hofstetter G, Lengger N, Hemmer W, Ebner C, Fröschl R, et al. IgE, IgG4 and IgA specific to Bet v 1-related food allergens do not predict oral allergy syndrome. Allergy. 2015;70(1):59-66.
- Uotila R, Röntynen P, Pelkonen AS, Voutilainen H, Kaarina Kukkonen A, Mäkelä MJ. For hazelnut allergy, component testing of Cor a 9 and Cor a 14 is relevant also in birch-endemic areas. Allergy. 2020;75(11):2977-80.
- Breiteneder H, Kleine-Tebbe J. PR-10 like Allergens. In: Matricardi PM, Kleine-Tebbe J, Hoffmann HJ, Valenta R, Ollert M, editors. EAACI Molecular Allergology User's Guide: Using Molecular Allergology in the Clinical Practice. Zutich, Switzerland: The European Academy of Allergy and Clinical Immunology (EAACI); 2016. p. 299-310.
- Aglas L, Soh WT, Kraiem A, Wenger M, Brandstetter H, Ferreira F. Ligand Binding of PR-10 Proteins with a Particular Focus on the Bet v 1 Allergen Family. Curr Allergy Asthma Rep. 2020;20(7):25.
- Lüttkopf D, Müller U, Skov PS, Ballmer-Weber BK, Wüthrich B, Skamstrup Hansen K, et al. Comparison of four variants of a major allergen in hazelnut (Corylus avellana) Cor a 1.04 with the major hazel pollen allergen Cor a 1.01. Mol Immunol. 2002;38(7):515-25.
- Inoue Y, Sato S, Takahashi K, Yanagida N, Yamamoto H, Shimizu N, et al. Component-resolved diagnostics can be useful for identifying hazelnut allergy in Japanese children. Allergology international : official journal of the Japanese Society of Allergology. 2020;69(2):239-45.
- Nilsson C, Berthold M, Mascialino B, Orme M, Sjölander S, Hamilton R. Allergen components in diagnosing childhood hazelnut allergy: Systematic literature review and meta-analysis. Pediatr Allergy Immunol. 2020;31(2):186-96.