rAna o 3, Cashew nut

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Code: f443
Latin name: Anacardium occidentale
Source material: rAna o 3 is a CCD-free recombinant protein.
Family: Anacardiaceae
Common names: 2S Albumin

Biological function: 2S Albumin, a storage protein.

Mw: 12.6 kDa

Clinical Utility

Cashew food allergy is associated with the presence of IgE directed against the major seed storage proteins in cashew, including the 13S globulin (legumin group) and 2S albumins, both of which represent major allergen classes in several plant seeds. Sensitisation to Ana o 3 indicates a primary cashew nut allergy and sensitisation to 2S albumins, such as Ana o 3, is known to be associated with systemic food reactions. (1, 2 3, 4)

Ana o 3, a 2S albumin, has been shown to be a major cashew-nut allergen, with 81% (21/26) of sera from patients with cashew allergy being reactive to Ana o 3.

Recombinant Ana o 3, like other recombinant nut allergens, can be used to assess patient reactivity (in particular to a very stable cashew allergen), characterise IgE binding epitopes, and study the effect of mutations on IgE binding. (5)

Allergen Exposure

See Cashew Nut, f202

Allergen description:

Ana o 3 is a 2S albumin, a storage protein. (6)

Storage proteins are classified into albumins (2S albumins or conglutins) and globulins, which in turn are divided into 7S globulins (vicilins) and 11S globulins (glycines and legumins). (7)

2S albumins are grouped in the prolamin super-family; other allergenic proteins included in this superfamily are the non-specific lipid transfer proteins, the alpha-amylase/trypsin inhibitors, and the prolamin storage proteins of cereals. (8)

2S albumins are a major group of seed-storage proteins, widely distributed in both mono- and di-cotyledonous plants. They have been reported as major food allergens in seeds of many plants. They are deposited in the protein bodies of developing seeds and are used by the plant as a source of nutrients during subsequent germination and seedling growth. (9) 2S albumins have a high sulphur-containing amino acid content. (10) 2S albumins are thought to sensitise directly via the gastrointestinal tract (GIT); and the high stability of their intrinsic protein structure despite the harsh conditions present in the GIT suggests that these proteins are able to cross the gut mucosal barrier, to sensitise the mucosal immune system and/or elicit an allergic response. (9) Similarly to other 2S albumins, cashew allergens strongly resist heat denaturation (roasting) and hydrolysis by digestive proteases (pepsin, trypsin), and thus display a high allergenic potency. (11) Other processes employed to little effect include autoclaving (121°C, up to 30 min), blanching (100°C, up to 10 min), microwave heating, dry roasting (up to 200°C for 15 min), gamma-irradiation, and pH (1, 3, 5, 7, 9, 11, and 13); demonstrating that Ana o 1, Ana o 2, and Ana o 3 are stable, regardless of the processing method to which the nut seeds are subjected. (9, 12)

2S albumins have been previously identified in Brazil nut (Ber e 1), Oriental mustard (Bra j 1), rapeseed (Bra n 1), black mustard (Bra ni 2S albumin), turnip (Bra r 1), pecan nut (Car i 1), chickpea (Cic a 2S Albumin), buckwheat (Fag e 10 kDa, Fag e 16 kDa), soya bean (Gly m 2S albumin), sunflower seed (Hel a 2S albumin), black walnut (Jug n 1), English walnut (Jug r 1), almond (Pru du 2S albumin), Castor bean (Ric c 1, Ric c 3), sesame seed (Ses i 1, Ses i 2), yellow mustard (Sin a 1), Arabian cotton (CS-1A), and upland cotton (Mat5-D).  (9)

2S albumins are also present in pistachio nut (Pis v 1), hazelnut (Cor a 14) and peanut. In peanut, Ara h 2, Ara h 6, and Ara h 7 are all 2S albumins.

Not all 2S albumins should be considered major allergens. In a recent study, none of the patients´ sera from 23 individuals allergic to soya bean was found to have IgE specifically against soya bean 2S albumins, suggesting that these proteins are not major allergens within the patient population analysed. (13)

Potential Cross-Reactivity

Despite the skeleton of cysteine residues of 2S albumins being highly conserved, a relatively low amino acid sequence homology, within and among plant species, has been demonstrated. (9) Overall, the degree of sequence homology of 2S allergens ranges from 14 to 40%, and does not reflect phylogenetic relationships, with the exception of 2S albumins belonging to the Brassicaceae family (i.e. Bra j 1, Bra n 1 and Sin a 1). (9)

Although 2S albumins have high structural homology, cross-reactivity seems to be uncommon in this protein family. (9)

For example, Ber e 1, a 2S albumin, a major allergen of Brazil nut, has been shown to have the following homology with 2S albumins from other tree and ground nuts: Ara h 2 (40%), Ara h 6 (48%), Ana o 3 (61%), Car i 1 (66%) and Jug r 1 (68%). (14) Yet in a study evaluating the ability of Brazil nut to react against other nuts (almond, hazelnut, pecan, cashew, walnut and peanut) or legumes (pea and chickpea), the cross-reactivity of antisera against all protein extracts tested was found to be negligible. (9, 15)

Cross-reactivity between 2S allergens has only been demonstrated in cases of high sequence homology, and seems to be linked to shared linear epitopes between allergens. For example, the 2S allergens from yellow mustard (Sin a 1) and rapeseed (Bra n 1) exhibit the highest sequence homology compared to other 2S proteins, and were recognized by IgE and IgG of sera of mustard-sensitive individuals as well as by immunoglobulins present in the serum of a rapeseed-hypersensitive patient. (9, 16)

The results of another study suggest that either Ses i 1 or Ses i 2 cross-reacts with a 2S albumin from poppy seed. (17)

A few studies have reported instances in which cross-reactivity between 2S albumins may be clinically relevant.

A high degree of IgE-binding cross-reactivity has been demonstrated between the cashew allergens and the corresponding allergens Pis v 1, Pis v 2 and Pis v 3 of the closely-related pistachio nut. (18, 19) Less frequent cross-reactions also occur with other tree nuts, like almond and hazelnut. Almost no cross-reaction was reported to occur between cashew and peanut. In most cases this cross-reactivity is of no clinical significance, and would simply reflect some phylogenetic relatedness among tree nuts. Cashew and pistachio belong to the same family of Anacardiaceae. (11)

Although no cross-reactivity has been demonstrated between cashew and peanut 2S albumins (11), the peanut allergens Ara h 6 and Ara h 7, also 2S albumins, show 59 and 35% amino acid sequence identity respectively to Ara h 2, a well-known major food allergen. (20) Inhibition assays have demonstrated significant cross-reactivity of Ara h 2 and Ara h 6 allergens. (21)

Cross-reactivity between 2S albumins of species from the Brassicaceae family, including oilseed rape, turnip rape and mustard, has recently been suggested. (22)

Serum from an individual allergic to mustard was demonstrated to display cross-reactivity between sunflower and mustard 2S albumins. (23)

Cashew nut allergic patients with sensitization to Ana o 3 should also be investigated for allergy to other nuts or seeds, such as pistachio, walnut and peanut, as co-existing allergies may occur. (24)

Clinical Experience

Cashew nut allergic patients have high risk of experiencing severe allergic reactions; the risk has been reported to be even higher than for peanut allergic patients (74 % vs. 30 %). (25, 26, 27)

Cashew nut allergy is potentially life-threatening and can start early in life and is rarely outgrown. Symptoms can be elicited upon first known exposure and the dose is often very low (e.g. smelling, touching without eating). (27, 28)

Incidents of hypersensitivity reaction to 2S food allergens have been described with increasing frequency. Although symptoms such as mild laryngeal irritation, urticaria and asthma have been reported, severe systemic symptoms including angioedema and anaphylaxis have been described. (9)

Cashew food allergy is associated with the presence of IgE directed against the major seed storage proteins in cashew, including the 13S globulin (legumin group) and 2S albumins, both of which represent major allergen classes in several plant seeds. (29) In a study evaluating the relevance of Ana o 3, an immunoblot analysis showed that 81% (21 of 26) sera from patients with cashew allergy were reactive to Ana o 3. (1)

Cashew nut allergic patients sensitized to Ana o 3 should avoid raw as well as roasted/heated cashew nuts. (30)

Compiled by Dr Harris Steinman, harris@allergyadvisor.com


  1. Robotham JM, Wang F, Seamon V, Teuber SS, Sathe SK, Sampson HA, Beyer K, Seavy M, Roux KH. Ana o 3, an important cashew nut (Anacardium occidentale L.) allergen of the 2S albumin family. J Allergy Clin Immunol 2005;115(6):1284-90.
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  6. International Union of Immunological Societies Allergen Nomenclature: IUIS official list http://www.allergen.org/ Accessed August 2013.
  7. García BE, Lizaso MT. Cross-reactivity syndromes in food allergy. J Investig Allergol Clin Immunol 2011;21(3):162-70.
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  9. Moreno FJ, Clemente A. 2S Albumin Storage Proteins: What Makes them Food Allergens? Open Biochem J 2008;2:16-28.
  10. Youle RJ, Huang AHC. Occurrence of low molecular weight and high cysteine containing albumin storage proteins in oilseeds of diverse species. Am J Botany 1981;68(1):44-8.
  11. Rougé P, Thibau F, Bourrier T, Saggio B, Culerrier R, Rancé F, Barre A. Signification clinique des allergènes croisants de la noix de Cajou (Anacardium occidentale) / Clinical significance of allergen cross-reactivity of cashew nuts. Revue Française d'Allergologie 2011;51(1):31-5.
  12. Venkatachalam M, Monaghan EK, Kshirsagar HH, Robotham JM, O'Donnell SE, Gerber MS, Roux KH, Sathe SK. Effects of processing on immunoreactivity of cashew nut (Anacardium occidentale L.) seed flour proteins. J Agric Food Chem 2008 Oct 8;56(19):8998-9005.
  13. Lin J, Shewry PR, Archer DB, Beyer K, Niggemann B, Haas H, Wilson P, Alcocer MJ. The potential allergenicity of two 2S Albumins from soybean (Glycine max): A protein microarray approach. Int Arch Allergy Immunol 2006;141(2):91-102.
  14. Jacquenet S, Renaudin J-M, Bihain B. Ber e 1, allergène majeur de la noix du Brésil : intérêt de l’allergène recombinant pour le diagnostic in vitro. Revue Française d'Allergologie 2009;49(6):462-5.
  15. Clemente A, Chambers SJ, Lodi F, Nicoletti C, Brett GM. Use of the indirect competitive ELISA for the detection of Brazil nut in food products. Food Control 2004;15(1):65-9.
  16. Monsalve RI, González de la Peña MA, López-Otín C, Fiandor A, Fernández C, Villalba M, Rodríguez R. Detection, isolation and complete amino acid sequence of an aeroallergenic protein from rapeseed flour. Clin Exp Allergy 1997;27(7):833-41.
  17. Asero R, Mistrello G, Roncarolo D, Antoniotti PL, Falagiani P. A case of sesame seed-induced anaphylaxis. Allergy 1999;54(5):526-7.
  18. Noorbakhsh R, Mortazavi SA, Sankian M, Shahidi F, Tehrani M, Jabbari AF, Behmanesh F, Varasteh A. Pistachio allergy-prevalence and in vitro cross-reactivity with other nuts. Allergol Int 2011;60(4):425-32.
  19. Hasegawa M, Inomata N, Yamazaki H, Morita A, Kirino M, Ikezawa Z. Clinical features of four cases with cashew nut allergy and cross-reactivity between cashew nut and pistachio. Allergol Int 2011;60(4):425-32.
  20. Kleber-Janke T, Crameri R, Appenzeller U, Schlaak M, Becker WM. Selective cloning of peanut allergens, including profilin and 2S albumins, by phage display technology. Int Arch Allergy Immunol 1999;119:265-74.
  21. Lehmann K, Schweimer K, Reese G, Randow S, Suhr M, Becker WM, Vieths S, Rösch P. Structure and stability of 2S albumin-type peanut allergens: implications for the severity of peanut allergic reactions. Biochem J 2006;395(3):463-72.
  22. Puumalainen TJ, Poikonen S, Kotovuori A, Vaali K, Kalkkinen N, Reunala T, Turjanmaa K, Palosuo T. Napins, 2S albumins, are major allergens in oilseed rape and turnip rape. J Allergy Clin Immunol 2006;117(2):426-32.
  23. Asero R, Mistrello G, Roncarolo D, Amato S. Allergenic similarities of 2S albumins. Allergy 2002;57(1):62-3.
  24. Maloney JM, Rudengren M, Ahlstedt S, Bock SA, Sampson HA.  The use of serum-specific IgE measurements for the diagnosis of peanut, tree nut, and seed allergy. J Allergy Clin Immunol 2008;122(1):145-51.
  25. Vetander M, Helander D, Flodstrom C, Ostblom E, Alfven T, Ly DH, Hedlin G, Lilja G, Nilsson C, Wickman M. Anaphylaxis and reactions to foods in children--a population-based case study of emergency department visits. Clin Exp Allergy 2012;42(4):568-77.
  26. de Silva IL, Mehr SS, Tey D, Tang MLK. Paediatric anaphylaxis: a 5 year retrospective review. Allergy 2008;63(8):1071-6.
  27. Clark AT, Anagnostou K, Ewan PW. Cashew nut causes more severe reactions than peanut: case-matched comparison in 141 children. Allergy 2007;62(8):913-6.
  28. 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.
  29. Teuber SS, Sathe SK, Peterson WR, Roux KH. Characterization of the soluble allergenic proteins of cashew nut (Anacardium occidentale L.). J Agric Food Chem 2002;50(22):6543-9.
  30. 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.


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