f49 Apple

Allergens within Food of Plant Origin

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  • Latin name: Malus x domestica
  • Family: Rosaceae
  • Common names: Apple, Cultivated Apple
  • Source material: Peels from green apple
Food
A food, which may result in allergy symptoms in sensitised individuals.

Allergen Exposure

Geographical distribution
Apples are one of the most widely grown fruits in the Western Hemisphere. Early cultivation probably predates written history, and over 1000 varieties exist. Apples can be classified into four main groups: dessert, culinary, cider and ornamental. Varieties are also often grouped into summer and late-fall, according to the time of maturity. Apples are grown in temperate zones throughout the world. They are relatively easy to transport and store, and so are readily available throughout the year. Apples feature among the most familiar and common fruits in the West, ranking with Oranges and Bananas.
 
Environment
Readily edible varieties are all cultivated. Apples are most valued as a fresh dessert fruit, but also may be made into jams, jellies, vinegars, fresh juice, a puree called applesauce, a preserve called Apple butter, wines, ciders, brandies and pastries. They may also be baked, fried, stewed, dried, spiced, candied, or used in mincemeat or chutney. The fruit is a source of pectin. Pectin is a thickener in jams, etc., and a culture medium in laboratories. An edible oil (that is also used for illumination) can be obtained from the seed. Apples are a good source of vitamins A and C.

A ripe raw Apple is one of the easiest foods for the stomach to deal with, and reduces acidity. It is therefore common as a remedy for digestive complaints. The Apple is also an excellent dentifrice, the mechanical action of eating the fruit serving to clean both the teeth and the gums.

Apple leaves contain an antibacterial substance called phloretin, which is active in doses as low as 30 ppm. Apple contains over 266 volatile components that include alcohol, esters, aldehydes, ketones, ethers, acids, bases, acetals, and hydrocarbons (1).

Unexpected exposure
The hard wood is used for turnery, canes, tool handles, pipes and fuel.
 
Allergens
Early studies reported the presence of a number of allergenic proteins in Apple extracts: they were of 18, 31, 50, 38, 16, 14, and 13 kDa (2).
 
An allergen of approximately 60 kDa, cross-reacting with the major Mugwort pollen allergen Art v 1, along with Birch pollen, Timothy grass pollen, Peanuts, and Celery, has been isolated. The allergen appeared to be distinct from Bet v 1 and profilin and was thought to represent a novel cross-reactive allergen involved in oral allergy syndrome (3).
 
An allergen present in Apple was reported that was similar in size to a 35 kDa protein isolated from Birch pollen, a minor allergen that 10 -15% of Birch-pollen-allergic individuals are sensitised to. Cross-reactivity was demonstrated with proteins of comparable size from Litchi, Mango, Banana, Orange, Pear and Carrot. The 35 kDa protein was immunologically independent of the major Birch pollen allergen Bet v 1 (4).
 
A number allergens have been characterised:
  • Mal d 1, a 18 kDa heat-labile protein, a major allergen, was demonstrated to be a Bet v 1-homologue belonging to the PR 10 plant protection protein family (5-13). The isoforms Mal d 1a and Mal d 1b have also been characterised (14).
     
  • Mal d 2, a 31 kDa thaumatin-like protein (15).
     
  • Mal d 3, a 9 kDa Lipid Transfer Protein, a minor allergen (16-23).
     
  • Mal d 4, a 14 kDa protein, a profilin and major allergen (24).
A Bet v 6-related food allergen, a PCBER (Phenylcoumaran benzylic ether reductase) has been characterized (25).
 
The peel of Apple and other Rosaceae fruits has been reported to have a clinically relevant higher allergenicity than the pulp (26). The 18 and 31 kDa allergens, which are heat-labile and unstable in solution, experience almost complete elimination of allergenic potency with short heating (27).
 
Anecdotal reports from Apple-allergic patients hold that some Apple strains usually are highly allergenic (Granny Smith, Golden Delicious), whereas others (Jamba, Gloster, Boskop) are tolerated without any symptoms or with moderate symptoms (28). This may be true: the level of allergenic protein varies with the species of Apple and its ripeness; the IgE-binding potency depends on the occurrence of the 18-kDa allergen (28). The Mal d 1 content of Golden Delicious Apples was shown to rise considerably during maturation and storage (29).
 
Golden Delicious Apples had the greatest amount of the 18 kDa allergen (compared with Macintosh, Red Delicious, and Granny Smith). The l18 kDa allergen was found at levels in this order: Golden Delicious > Boskoop > Jamba. This would explain the different results to skin-specific IgE determinations to allergens from different Apple extracts (30). Other factors may influence the allergenicity or protein content of Apple. Apples in stores have been shown to have higher levels of allergen than freshly picked fruit. The amount of the 18 kDa allergen (Mal d 1) increased significantly when Apples were stored at 4 degrees C, but not under controlled exposure to oxygen and carbon dioxide (2).
 
Further, different Mal d 1 isoforms can be present within a single cultivar (5). The divergent allergenicity of Apple strains appears to depend on different expression levels of the major allergen. The introduction of a proline residue in position 111 of Mal d 1 and in position 112 of Bet v 1 present in Birch tree pollen resulted in a drastic reduction of allergenicity of both the pollen and the food allergen, obviously also removing the cross-reactive epitope (5).
 
On the basis of band intensity in SDS-PAGE studies, the mean amount of Mal d 1 present in mature Golden Delicious Apples has been estimated to be 1-5mg per 100g fresh weight. A bite of Apple of approximately 10g, which is able to elicit symptoms in Apple-allergic patients, represents 0.1-0.5 mg of the ingested major allergen (28).

Potential Cross-Reactivity

An extensive cross-reactivity among the different individual species of the Rosaceae family could be expected and in fact does occur frequently (31). For example, in a DBPCFC study, reactions to Peach occurred in 22 patients, to Apple in 6 and to Apricot in 5. The authors conclude that a positive skin- or serum-specific IgE test should not be taken as the only guide for multi-species dietary restrictions but that, nevertheless, the potential of clinical allergy to other Rosaceae should not be neglected (32).
 
Early studies reported cross-reactivity between Birch pollen and a number of foods, e.g., Apple, Pear, Celery, Carrot and Potato (33).
 
Subsequently a number of allergens or panallergens have been identified, and this has shed light on the causes and patterns (34).
 
Birch pollen is a significant cause of allergy in temperate climates, affecting 5-54% of the population in Western Europe. Patients allergic to Birch pollen are more often allergic to fresh fruits and vegetables than are patients allergic to other pollens (35). About 40-70% of Birch pollen-allergic patients show allergic symptoms after ingesting or handling raw fruits, especially Apple, due to cross-reactivity between an allergen present in the food and Bet v 1, the major Birch pollen allergen (36-41).
 
Type I allergic symptoms in the oropharyngeal mucosa, upon contact with plant-derived food in patients with pollen allergies, have been termed oral allergy syndrome (OAS). IgE cross-reactivity between pollen, in particular Birch pollen, and food allergens represents the molecular basis for this phenomenon. No one single allergen in a single source can of course be responsible, but rather one or a number of cross-reacting allergens in multiple sources. For example, in a study of patients with a history of oral allergy syndrome after eating Apple, 16/28 (57%) reacted to Bet v 1; among 20 polysensitised subjects presenting oral allergy syndrome after consumption of Apple, 4 reacted to Bet v 2 (20%). Among patients with IgE against both recombinant allergens, 6 (35.30%) presented symptoms of allergy after eating Apples (42).
 
In a Japanese study on oral allergy syndrome and pollen allergy, in 101 patients the most common allergen was Birch tree pollen. In 61% of Birch-allergic patients, a concomitant allergy to fruit or vegetable was reported. Apple was the most prevalent allergen (97%), followed by Peach (67%), Cherry (58%), Pear (40%), Plum (40%) and Melon (33%) (43). Similar results were reported from a study in Hokkaido. In patients with Birch pollen allergy, the higher the serum-specific IgE to Birch pollen, the higher was the incidence of hypersensitivity to Apple pulp (44).
 
Laboratory confirmation has demonstrated that the major cause of cross-reactivity between Birch pollen and Apple is biochemical and immunological similarity between the major allergens, Bet v 1 and Mal d 1, as demonstrated by serological and cellular immunoassays (5, 10, 45-46). Mal d 1, the major Apple allergen, has been shown through sequence comparison to Bet v 1, the major Birch pollen allergen, to have a 64.5% identity on the amino acid level and 55.6% identity on the nucleic acid level (11).
 
Clinical and laboratory evidence is supported by research demonstrating that patients who are Birch pollen- and Apple-allergic improve if desensitised to Birch pollen (47); and showing a marked reduction or a total disappearance of Apple-induced oral allergy syndrome after injection immunotherapy with Birch pollen extracts (48). These recent studies contradict an earlier study that reported a poorer response (47).
 
Allergy to Apple is commonly associated with Birch pollinosis because the two share homologous allergens. However, some patients have Apple allergy but no allergy to Birch pollen, suggesting that there are allergens in Apple that do not cross-react with Birch (20). Serum-IgE antibodies to Apple allergens were detected in 90% of patients with clinical Apple allergy, with similar allergens being demonstrated in 44% of patients with clinical Birch pollen allergy and in 5-10% of patients with other atopic allergies. RAST inhibition studies confirmed that Apple and Birch pollen allergens cross-react (49). In other words, Bet v 1 has all the allergenic epitopes of Mal d 1, but Mal d 1 is only a weak inhibitor of the IgE reactivity with the Major birch pollen allergen, probably due to the absence of some Bet v 1 epitopes on the fruit allergen. Other reasons for the latter observation have been proposed: there may be a lower association constant of Bet v 1-specific IgE to Mal d 1 epitopes; or Mal d 1 represents most of the allergenicity of Apple fruit; or the high lability of allergens during extraction or processing of Apple is probably not due to destruction of discontinuous epitopes, but to interactions with compounds from the fruit tissue, and most of these reactions are catalysed by enzymes (7).
 
Cross-inhibition assays have also reported the existence of common B-cell epitopes present on Dau c 1 in Carrot and Api g 1 in Celery, as well as on Bet v 1 (50).
 
In Mediterranean areas, oral allergy syndrome occurs independently of an associated Birch pollen allergy, and on occasion may present with no other associated pollen allergy. In a study to assess the possible association of OAS with London Plane tree (Platanus acerifolia) pollen allergy, 720 patients were selected on the basis of seasonal or perennial rhinitis, or asthma, or both; 61 (8.48%) were found to be sensitised to P. acerifolia pollen, and a food allergy was observed in 32 (52.45%). Food allergens most frequently implicated included Hazelnut, Peach, and Apple (51).
 
Allergy to Rosaceae fruits in patients without a related pollen allergy has been reported to result in a severe clinical entity; it was also reported that profilin- and Bet v 1-related structures are not involved in Rosaceae fruit allergy without pollinosis (52).
 
Other allergens or panallergens may also contribute to cross-reactivity between Birch pollen and Apple allergy.
 
A minor allergen present in Birch pollen and a similar protein present in Timothy pollen were shown to share common epitopes with antigens in Apple, Carrot and Celery tuber (53). This may have been the minor Birch pollen allergen Bet v 6 (phenylcoumaran benzylic ether reductase (PCBER)), which occurs in many foods including Apple, Peach, Orange, Litchi, Strawberry, Persimmon, Zucchini, and Carrot (25, 39). This allergen may also have been the 35 kDa protein isolated from Birch pollen, a minor allergen immunologically independent of the major Birch pollen allergen Bet v 1, to which 10 -15% of Birch pollen-allergic individuals are sensitised, and for which cross-reactivity was demonstrated with proteins of comparable size from Apple, Litchi, Mango, Banana, Orange, Pear and Carrot (4).
 
Lipid transfer proteins (LTPs) have been reported to be important, clinically relevant panallergens. One has been characterised in Apple and named Mal d 3. LTP from Artemisia pollen and Chestnut has been demonstrated to cross-react with allergens of Rosaceae fruits, but significant differences in specific IgE binding capacities were observed among members of the plant LTP family (17, 19, 22). Similarly, the LTP present in Peach and beer may cross-react with LTP from several other plant-derived foods (17, 54). 
 
Although cross-reactivity has been clearly established between Apple and Birch tree pollen, cross-reactivity may occur between Apple and other pollens. In a study, cross-allergenicity between Apple pulp and 5 pollen species (Birch, Japanese Cedar, Orchard grass, Mugwort and Ragweed), investigated by RAST inhibition, demonstrated that Apple pulp extract effectively inhibited RASTs to all the pollens except Japanese Cedar pollen (55). Similarly, a study reported on an association between grass pollen allergy and sensitisation to Tomato, Potato, Green Pea, Peanut, Watermelon, Melon, Apple, Orange and Kiwi (56). This may be as a result of a Group 4 grass pollen allergen, a 60 kDa glycoprotein which is recognised by 70% of patients sensitive to these pollens and is found in Timothy grass, Mugwort and Birch pollen, and in Peanut, Apple, Celery root, and Carrot. Group 4-related allergens thus occur in pollens of unrelated plants and in plant food and may therefore contribute to cross-reactivity in patients allergic to various pollens and plant food (57).
 
Allergy to Apple has been associated with Kiwi-allergic individuals (58).
 
Sensitisation to profilin and/or bromelain-type cross-reacting carbohydrate determinants (CCD), caused by pollen (Timothy grass, Mugwort) or Hymenoptera venom allergens, can elicit false-positive IgE antibodies against Natural Rubber Latex and Apple (59).
 
Minor allergenic determinants cross-reactive with Apple and Birch pollen epitopes have also been isolated in the pollen of the Apple tree (60). Apple seed allergens have been reported to cross-react with Birch pollen allergen(s) (61).

Clinical Experience

IgE-mediated reactions
Allergy to Apple has been documented for over 3 decades, and may frequently induce symptoms of food allergy in sensitised individuals, in particular oral allergy syndrome (24, 49, 62-67). Itching, tingling and other mild reactions on the oropharyngeal mucosa are the most common complaints after eating raw Apples, and angioedema, urticaria and shock are less common. Other symptoms may include rhinoconjunctivitis, asthma, laryngeal oedema, abdominal effects, pruritis and hand dermatitis (68).
 
In a Japanese study of sera of 4,797,158 patients collected in laboratories during 1994-1998, evaluation of specific IgE values of greater than 0.70 UA/ml showed that among food allergens, Apple had the highest response (69). Similarly, in a food hypersensitivity study of Finnish university students, among 172 subjects, Apple was a frequent (29.1%) cause of symptoms (70).
 
“Apple contact urticaria syndrome” and rhinitis are relevant phenomena. However, itching and tingling and other mild reactions on the oropharyngeal mucosa were reported in early studies to be the most common complaints after eating raw Apples (71). These became known as oral allergy syndrome, and Apple is the most frequently reported offending food in Birch-pollen-sensitive patients with OAS (30, 44, 72-81). Up to 70% of patients with Birch pollen allergy exhibit this syndrome. The most frequent and therefore best characterised pollen-fruit syndrome combines Apple allergy and tree pollen-induced allergy. Some studies have reported an extremely close association: in 196 Birch pollen-hypersensitive patients with oral allergy syndrome caused by different vegetable foods, 195 patients had Apple and/or Hazelnut allergy (82).
 
Oral allergy syndrome may occur following low-dose exposure to Apple, as demonstrated in a report of a 24-year-old-woman who experienced acute oedema of the lips with itching in the mouth after a kiss from her boyfriend who had just eaten a green Apple (83). 
 
In a study of 276 adult patients reporting asthma or rhinitis symptoms on eating or handling various foods, 24% were affected. Hazelnut, Apple and shellfish were the most often named (84).
 
The prevalence of atopy caused by Apple, Peach, and Hazelnut in patients with tree pollen allergy was evaluated. Skin prick tests for Apple, Peach, and Hazelnut were positive in 51 (64.6%), 61 (77.2%), and 71 (89.9%) patients, respectively. Granny Smith showed more positive skin reactions and a better agreement with clinical history than Golden Delicious. RAST for Apple, Peach, and Hazelnut was positive in 53 (68.8%), 13 (16.9%), and 31 (40.3%) patients, respectively (30).
 
Although not as common as allergy to Apple associated with pollen allergy, allergy to Rosaceae fruits in patients without a related pollen allergy is reported to be a severe clinical entity. Profilin- and Bet v 1-related structures are not involved (24) (85). Anaphylaxis to Apple has been reported, including that of a 23-year-old woman and a 14-year-old girl with 3-year and 7-year histories, respectively, of anaphylactic reactions to Apple pulp. In the first patient, eating raw Apples immediately elicited itching and tingling of the lips and mouth with severe oedema of the lips and tongue, irritation of the throat and slight colic in the upper abdomen. In the second, nausea and vomiting occurred after ingestion of Apples (55). Anaphylaxis may occur in association with other allergic manifestations such as contact urticaria (86). Anaphylaxis may be precipitated by Apple in association with exercise: this is food-dependant exercise-induced anaphylaxis (87-92).
 
In a study of 99 Finnish children with atopic dermatitis, Hen egg was the most common food allergen in children under 1 year of age. After that age, Apple, Carrot, Pea, and Soybean elicited positive reactions as often as egg (93). 
 
Contact urticaria, although uncommon, can occur following contact with Apple (94).
 
The authors of one study reported that oral challenge tests indicated an increase in clinical reactivity to Apples during the Birch pollen season in Birch-pollen allergic individuals (95).
 
Other reactions
All members of this genus contain the toxin hydrogen cyanide in their seeds and possibly also in their leaves, but almost never in their fruits. Hydrogen cyanide is the substance that gives almonds their characteristic taste, but it should be consumed only in very small quantities. Apple seeds do not normally contain very high quantities of hydrogen cyanide but even so should not be consumed in large quantities. In small quantities, hydrogen cyanide has been shown to stimulate respiration and improve digestion. In excess, however, it can cause respiratory failure and even death.
 
An anaphylactic reaction has been recorded to Apple juice containing acerola, the allergy reaction being to the acerola (96).
 
The acidity of Apple juice may result in bronchoconstriction in some individuals (97). 
 
Auriculotemporal syndrome (Frey’s syndrome, gustatory flushing) has occurred within minutes of eating Apple (98).
 
Compiled by Dr Harris Steinman, harris@zingsolutions.com

References:

    1. Dimick PS, Hoskin JC. Review of apple flavor--state of the art. Crit Rev Food Sci Nutr 1983;18(4):387-409
    2. Hsieh LS, Moos M Jr, Lin Y. Characterization of apple 18 and 31 kd allergens by microsequencing and evaluation of their content during storage and ripening. J Allergy Clin Immunol. 1995; 96(6 Pt 1): 960-70
    3. Heiss S, Fischer S, Muller WD, Weber B, Hirschwehr R, Spitzauer S, Kraft D, Valenta R. Identification of a 60 kd cross-reactive allergen in pollen and plant-derived food. J Allergy Clin Immunol. 1996;98(5 Pt 1):938-47
    4. Wellhausen A, Schoning B, Petersen A, Vieths S. IgE binding to a new cross-reactive structure:a 35 kDa protein in birch pollen, exotic fruit and other plant foods. Z Ernahrungswiss. 1996;35(4):348-55
    5. Son DY, Scheurer S, Hoffmann A, Haustein D, Vieths S. Pollen-related food allergy: cloning and immunological analysis of isoforms and mutants of Mal d 1, the major apple allergen, and Bet v 1, the major birch pollen allergen. Eur J Nutr. 1999;38(4):201-15
    6. Hoffmann-Sommergruber K, Vanek-Krebitz M, Ferris R, O'Riordain G, Susani M, Hirschwehr R, Ebner C, Ahorn H, Kraft D, Scheiner O, Breiteneder H. Isolation and cloning of Bet v 1-homologous food allergens from celeriac (Api g1) and apple (Mal d1). Adv Exp Med Biol. 1996;409:219-24
    7. Vieths S, Schoning B. Characterization of Mal d 1, the 18-kD major apple allergen, at the molecular level. Monogr Allergy. 1996;32:63-72
    8. Puehringer HM, Zinoecker I, Marzban G, Katinger H, Laimer M. MdAP, a novel protein in apple, is associated with the major allergen Mal d 1. Gene 2003;321:173-83
    9. Karamloo F, Scheurer S, Wangorsch A, May S, Haustein D, Vieths S. Pyr c 1, the major allergen from pear (Pyrus communis), is a new member of the Bet v 1 allergen family. J Chromatogr B Biomed Sci Appl 2001;756(1-2):281-293
    10. Holm J, Baerentzen G, Gajhede M, Ipsen H, Larsen JN, Lowenstein H, Wissenbach M, Spangfort MD. Molecular basis of allergic cross-reactivity between group 1 major allergens from birch and apple. J Chromatogr B Biomed Sci Appl. 2001;756(1-2):307-13.
    11. Vanek-Krebitz M, Hoffmann-Sommergruber K, Laimer da Camara Machado M, Susani M, Ebner C, Kraft D, Scheiner O, Breiteneder H. Cloning and sequencing of Mal d 1, the major allergen from apple (Malus domestica), and its immunological relationship to Bet v 1, the major birch pollen allergen. Biochem Biophys Res Commun. 1995;214(2):538-51
    12. Vieths S, Janek K, Aulepp H, Petersen A. Isolation and characterization of the 18-kDa major apple allergen and comparison with the major birch pollen allergen (Bet v I). Allergy. 1995;50(5):421-30
    13. Vieths S, Schoning B, Petersen A. Characterization of the 18-kDa apple allergen by two-dimensional immunoblotting and microsequencing. Int Arch Allergy Immunol. 1994;104(4):399-404
    14. Helsper JP, Gilissen LJ, van Ree R, America AH, Cordewener JH, Bosch D. Quadrupole time-of-flight mass spectrometry:a method to study the actual expression of allergen isoforms identified by PCR cloning. J Allergy Clin Immunol. 2002;110(1):131-8
    15. Krebitz M, Wagner B, Ferreira F, Peterbauer C, Campillo N, Witty M, Kolarich D, Steinkellner H, Scheiner O, Breiteneder H. Plant-based heterologous expression of Mal d 2, a thaumatin-like protein and allergen of apple (Malus domestica), and its characterization as an antifungal protein. J Mol Biol. 2003;329(4):721-30
    16. Garcia-Selles FJ, Diaz-Perales A, Sanchez-Monge R, Alcantara M, Lombardero M, Barber D, Salcedo G, Fernandez-Rivas M. Patterns of reactivity to lipid transfer proteins of plant foods and Artemisia pollen: an in vivo study. Int Arch Allergy Immunol. 2002;128(2):115-22
    17. Diaz-Perales A, Garcia-Casado G, Sanchez-Monge R, Garcia-Selles FJ, Barber D, Salcedo G. cDNA cloning and heterologous expression of the major allergens from peach and apple belonging to the lipid-transfer protein family. Clin Exp Allergy. 2002;32(1):87-92
    18. Pastorello EA, Pompei C, Pravettoni V, Brenna O, Farioli L, Trambaioli C, Conti A. Lipid transfer proteins and 2S albumins as allergens. Allergy. 2001;56 Suppl 67:45-7
    19. Asero R, Mistrello G, Roncarolo D, de Vries SC, Gautier MF, Ciurana CL, Verbeek E, Mohammadi T, Knul-Brettlova V, Akkerdaas JH, Bulder I, Aalberse RC, van Ree R. Lipid transfer protein:a pan-allergen in plant-derived foods that is highly resistant to pepsin digestion. Int Arch Allergy Immunol. 2000 May;122(1):20-32.
    20. Pastorello EA, Pravettoni V, Farioli L, Ispano M, Fortunato D, Monza M, Giuffrida MG, Rivolta F, Scibola E, Ansaloni R, Incorvaia C, Conti A, Ortolani C. Clinical role of a lipid transfer protein that acts as a new apple-specific allergen. J Allergy Clin Immunol. 1999;104(5):1099-106
    21. Sanchez-Monge R, Lombardero M, Garcia-Selles FJ, Barber D, Salcedo G. Lipid-transfer proteins are relevant allergens in fruit allergy. J Allergy Clin Immunol. 1999;103(3 Pt 1):514-9
    22. Diaz-Perales A, Lombardero M, Sanchez-Monge R, Garcia-Selles FJ, Pernas M, Fernandez-Rivas M, Barber D, Salcedo G. Lipid-transfer proteins as potential plant panallergens: cross-reactivity among proteins of Artemisia pollen, Castanea nut and Rosaceae fruits, with different IgE-binding capacities. Clin Exp Allergy. 2000;30(10):1403-10
    23. Asero R, Mistrello G, Roncarolo D, Amato S, Falagiani P. Analysis of the heat stability of lipid transfer protein from apple. J Allergy Clin Immunol. 2003 Nov; 112(5): 1009-11.
    24. van Ree R, Fernandez-Rivas M, Cuevas M, van Wijngaarden M, Aalberse RC. Pollen-related allergy to peach and apple: an important role for profilin. J Allergy Clin Immunol. 1995;95(3):726-34
    25. Karamloo F, Wangorsch A, Kasahara H, Davin LB, Haustein D, Lewis NG, Vieths S. Phenylcoumaran benzylic ether and isoflavonoid reductases are a new class of cross-reactive allergens in birch pollen, fruits and vegetables. Eur J Biochem. 2001;268(20):5310-20
    26. Fernandez-Rivas M, Cuevas M. Peels of Rosaceae fruits have a higher allergenicity than pulps. Clin Exp Allergy. 1999;29(9):1239-47
    27. Paschke A, Wigotzki M, Steinhart H. Alterations of allergenicity of fruits and vegetables during technological processing. [Abstract] 8th International Symposium on Problems of Food Allergy 2001,ch 11-13, Venice
    28. Vieths S, Jankiewicz A, Schoning B, Aulepp H. Apple allergy: the IgE-binding potency of apple strains is related to the occurrence of the 18-kDa allergen. Allergy. 1994;49(4):262-71
    29. Vieths S, Schoening B, Jankiewicz A.  Occurrence of IgE binding allergens during ripening of apple fruits Food Agric Immunol 1993;5:93-105
    30. de Groot H, de Jong NW, Vuijk MH, Gerth van Wijk R. Birch pollinosis and atopy caused by apple, peach, and hazelnut; comparison of three extraction procedures with two apple strains. Allergy. 1996;51(10):712-8
    31. Yman L. Botanical relations and immunological cross-reactions in pollen allergy. 2nd ed. Pharmacia Diagnostics AB. Uppsala. Sweden. 1982: ISBN 91-970475-09
    32. Rodriguez J, Crespo JF, Lopez-Rubio A, De La Cruz-Bertolo J, Ferrando-Vivas P, Vives R, Daroca P. Clinical cross-reactivity among foods of the Rosaceae family. J Allergy Clin Immunol. 2000;106(1 Pt 1):183-9
    33. Dreborg S, Foucard T. Allergy to apple, carrot and potato in children with birch pollen allergy. Allergy. 1983;38(3):167-72
    34. Grote M. Binding of antibodies against birch pollen antigens/allergens to various parts of apples as studied by immuno-gold electron microscopy. Immunobiology. 1988;176(3):290-300
    35. Osterballe M, Scheller R, Stahl Skov P, Andersen KE, Bindslev-Jensen C. Diagnostic value of scratch-chamber test, skin prick test, histamine release and specific IgE in birch-allergic patients with oral allergy syndrome to apple. Allergy 2003;58(9):950-3
    36. Jeep S, Pilz B, Baisch A, Kleine-Tebbe J, Ohnemus U, Kunkel G. Immunoblot studies in birch pollen-allergic patients with and without fruit hypersensitivity: part I: antibody pattern for birch pollen extract. J Investig Allergol Clin Immunol. 2001;11(4):255-63
    37. Asero R, Mistrello G, Roncarolo D, Amato S, Zanoni D, Barocci F, Caldironi G. Detection of clinical markers of sensitization to profilin in patients allergic to plant-derived foods. J Allergy Clin Immunol. 2003;112(2):427-32
    38. Jeep S, Pilz B, Baisch A, Kleine-Tebbe J, Ohnemus U, Kunkel G. Immunoblot studies in birch pollen-allergic patients with and without fruit hypersensitivity:part II:antibody pattern for fruit extracts. J Investig Allergol Clin Immunol. 2001;11(4):264-70
    39. Vieths S, Scheurer S, Ballmer-Weber B. Current understanding of cross-reactivity of food allergens and pollen. Ann N Y Acad Sci. 2002;964:47-68
    40. Kleine Tebbe J, Galleani M, et al. Basophil histamine release in patients with birch pollen hypersensitivity with and without allergic symptoms to fruits. Allergy 1992;47(6):618-23
    41. Wensing M, Akkerdaas JH, van Leeuwen WA, Stapel SO, Bruijnzeel-Koomen CA, Aalberse RC, Bast BJ, Knulst AC, van Ree R. IgE to Bet v 1 and profilin:cross-reactivity patterns and clinical relevance. J Allergy Clin Immunol. 2002;110(3):435-42
    42. Rossi RE, Monasterolo G, Operti D, Corsi M. Evaluation of recombinant allergens Bet v 1 and Bet v 2 (profilin) by Pharmacia CAP system in patients with pollen-related allergy to birch and apple. Allergy. 1996;51(12):940-5
    43. Gotoda H, Maguchi S, Kawahara H, Terayama Y, Fukuda S. Springtime pollinosis and oral allergy syndrome in Sapporo. Auris Nasus Larynx. 2001;28 Suppl:S49-52
    44. Yamamoto T, Asakura K, Kataura A. Hypersensitivity to apple pulp among patients with birch pollinosis in Hokkaido. [Japanese] Arerugi. 1993;42(11):1701-6
    45. Ebner C, Hirschwehr R, Bauer L, Breiteneder H, Valenta R, Ebner H, Kraft D, Scheiner O. Identification of allergens in fruits and vegetables:IgE cross-reactivities with the important birch pollen allergens Bet v 1 and Bet v 2 (birch profilin). J Allergy Clin Immunol. 1995;95(5 Pt 1):962-9
    46. Fritsch R, Bohle B, Vollmann U, Wiedermann U, Jahn-Schmid B, Krebitz M, Breiteneder H, Kraft D, Ebner C. Bet v 1, the major birch pollen allergen, and Mal d 1, the major apple allergen, cross-react at the level of allergen-specific T helper cells. J Allergy Clin Immunol. 1998;102(4 Pt 1):679-86
    47. Herrmann D, Henzgen M, Frank E, et al. Effect of hyposensitization for tree pollinosis on associated apple allergy. J Investig Allergol Clin Immunol 1995;5(5):259-67
    48. Asero R. Effects of birch pollen-specific immunotherapy on apple allergy in birch pollen-hypersensitive patients. Clin Exp Allergy. 1998 Nov;28(11):1368-73
    49. Bjorksten F, Halmepuro L, Hannuksela M, Lahti A. Extraction and properties of apple allergens. Allergy. 1980;35(8):671-7
    50. Hoffmann-Sommergruber K, O'Riordain G, Ahorn H, Ebner C, Laimer Da Camara Machado M, Puhringer H, Scheiner O, Breiteneder H. Molecular characterization of Dau c 1, the Bet v 1 homologous protein from carrot and its cross-reactivity with Bet v 1 and Api g 1. Clin Exp Allergy. 1999;29(6):840-7
    51. Enrique E, Cistero-Bahima A, Bartolome B, Alonso R, San Miguel-Moncin MM, Bartra J, Martinez A. Platanus acerifolia pollinosis and food allergy. Allergy. 2002;57(4):351-6
    52. Fernandez-Rivas M, van Ree R, Cuevas M. Allergy to Rosaceae fruits without related pollinosis. J Allergy Clin Immunol. 1997;100(6 Pt 1):728-33
    53. Halmepuro L, Lowenstein H. Immunological investigation of possible structural similarities between pollen antigens and antigens in apple, carrot and celery tuber. Allergy. 1985;40(4):264-72
    54. Asero R, Mistrello G, Roncarolo D, Amato S, van Ree R. A case of allergy to beer showing cross-reactivity between lipid transfer proteins. Ann Allergy Asthma Immunol. 2001;87(1):65-7
    55. Sakamoto T, Hayashi Y, Yamada M, Torii S, Urisu A. A clinical study of two cases with immediate hypersensitivity to apple-pulp and an investigation of cross-allergenicity between apple-pulp allergen and some other pollen allergens. [Japanese] Arerugi. 1989;38(7):573-9
    56. Caballero T, Martin-Esteban M. Association between pollen hypersensitivity and edible vegetable allergy: a review. J Investig Allergol Clin Immunol. 1998;8(1):6-16
    57. Grote M, Stumvoll S, Reichelt R, Lidholm J, Rudolf V. Identification of an allergen related to Phl p 4, a major timothy grass pollen allergen, in pollens, vegetables, and fruits by immunogold electron microscopy. Biol Chem. 2002; 383(9):1441-5
    58. Gall H, Kalveram KJ, Forck G, Sterry W. Kiwi fruit allergy: a new birch pollen-associated food allergy. J Allergy Clin Immunol. 1994;94(1):70-6
    59. Ebo D, Hagendorens M, Bridts C, De Clerck L, Stevens W. Sensitization to cross-reactive carbohydrate determinants and the ubiquitous protein profilin: mimickers of allergy. Clin Exp Allergy. 2004; 34(1): 137-144
    60. Berrens L, van Dijk AG, Houben GF, Hagemans ML, Koers WJ. Cross-reactivity among the pollen proteins of birch and apple trees. Allerg Immunol (Leipz). 1990;36(3):147-56.
    61. Lahti A, Bjorksten F, Hannuksela M. Allergy to birch pollen and apple, and cross-reactivity of the allergens studied with the RAST. Allergy. 1980;35(4):297-300
    62. Besler M, Ortolani C, Vieths S. Apple (Malus domestica) Internet Symposium on Food Allergens 2000;2(4):1-23
    63. Johnstone IL. Apple allergy. Br Med J. 1972;4(840):613
    64. Lahti A, Hannuksela M. Hypersensitivity to apple and carrot can be reliably detected with fresh material. Allergy. 1978;33(3):143-6
    65. Kennedy P. Acute reaction to apple-eating. Br Med J. 1978;2(6150):1501-2.
    66. Skamstrup Hansen K, Vestergaard H, Stahl Skov P, Sondergaard Khinchi M, Vieths S, Poulsen LK, Bindslev-Jensen C. Double-blind, placebo-controlled food challenge with apple. Allergy. 2001;56(2):109-17
    67. Kalyoncu AF, Demir AU, Kisacik G, Karakoca Y, Iskandarani A, Coplu L, Sahin AA, Baris YI. Birch pollen related food hypersensitivity: as a para-occupational syndrome. Allergol Immunopathol (Madr). 1995;23(2):94-5
    68. Hannuksela M, Lahti A. Immediate reactions to fruits and vegetables. Contact Dermatitis. 1977;3(2):79-84
    69. Kimura S. Positive ratio of allergen specific IgE antibodies in serum, from a large scale study. [Japanese] Rinsho Byori. 2001;49(4):376-80
    70. Mattila L, Kilpelainen M, Terho EO, Koskenvuo M, Helenius H, Kalimo K. Food hypersensitivity among Finnish university students: association with atopic diseases. Clin Exp Allergy. 2003;33(5):600-6
    71. Kremser M, Lindemayr W. Frequency of the so-called "apple allergy" ("apple contact urticaria syndrome") in patients with birch pollinosis. [German] Z Hautkr. 1983;58(8):543-52
    72. Ortolani C, Ispano M, Pastorello E, Bigi A, Ansaloni R. The oral allergy syndrome. Ann Allergy. 1988;61(6 Pt 2):47-52
    73. Halmepuro L, Vuontela K, Kalimo K, Bjorksten F. Cross-reactivity of IgE antibodies with allergens in birch pollen, fruits and vegetables. Int Arch Allergy Appl Immunol. 1984;74(3):235-40
    74. Helbling A, Important cross-reactive allergens. [German] Schweiz Med Wochenschr 1997;127(10):382-9
    75. Hernandez J, Garcia Selles FJ, Pagan JA, Negro JM. Immediate hypersensitivity to fruits and vegetables and pollenosis. [Spanish] Allergol Immunopathol (Madr). 1985;13(3):197-211
    76. Ishida T, Murai K, Yasuda T, Satou T, Sejima T, Kitamura K. Oral allergy syndrome in patients with Japanese cedar pollinosis. [Japanese] Nippon Jibiinkoka Gakkai Kaiho. 2000;103(3):199-205
    77. Asero R, Mistrello G, Roncarolo D, Casarini M, Falagiani P. Allergy to nonspecific lipid transfer proteins in Rosaceae:a comparative study of different in vivo diagnostic methods. Ann Allergy Asthma Immunol. 2001;87(1):68-71
    78. Asero R. Detection and clinical characterization of patients with oral allergy syndrome caused by stable allergens in Rosaceae and nuts. Ann Allergy Asthma Immunol. 1999;83(5):377-83
    79. Wuthrich B, Borga A, Yman L. Oral allergy syndrome to a jackfruit (Artocarpus integrifolia). Allergy. 1997;52(4):428-31
    80. Kazemi-Shirazi L, Pauli G, Purohit A, Spitzauer S, Froschl R, Hoffmann-Sommergruber K, Breiteneder H, Scheiner O, Kraft D, Valenta R. Quantitative IgE inhibition experiments with purified recombinant allergens indicate pollen-derived allergens as the sensitizing agents responsible for many forms of plant food allergy. J Allergy Clin Immunol. 2000;105(1 Pt 1):116-25
    81. Pastorello EA, Pravettoni V, Bigi A, Qualizza R, Vassellatti D, Schilke ML, Stocchi L, Tedeschi A, Ansaloni R, Zanussi C. IgE-mediated food allergy. Ann Allergy. 1987;59(5 Pt 2):82-9
    82. Asero R. Relevance of pollen-specific IgE levels to the development of Apiaceae hypersensitivity in patients with birch pollen allergy. Allergy. 1997;52(5):560-4
    83. Wuthrich B. Oral allergy syndrome to apple after a lover's kiss. Allergy. 1997;52(2):235-6
    84. Eriksson NE. Food sensitivity reported by patients with asthma and hay fever. A relationship between food sensitivity and birch pollen-allergy and between food sensitivity and acetylsalicylic acid intolerance. Allergy. 1978;33(4):189-96
    85. Fernandez Rivas M, van Ree R, Cuevas M. Allergy to Rosaceae fruits without related pollinosis. J Allergy Clin Immunol 1997;100(6 Pt 1):728-33
    86. Pigatto PD, Riva F, Altomare GF, Parotelli R. Short-term anaphylactic antibodies in contact urticaria and generalized anaphylaxis to apple. Contact Dermatitis. 1983;9(6):511
    87. Anibarro B, Dominguez C, Diaz JM, Martin MF, et al. Apple-dependent exercise-induced anaphylaxis. Allergy 1994;49:481-482
    88. Guinnepain MT, Eloit C, Raffard M, Brunet Moret MJ, et al. Exercise-induced anaphylaxis: useful screening of food sensitization. Ann Allergy 1996;77(6):491-6
    89. Anaut A, Iglesias A, Zapatero L, et al. Exercise-induced anaphylactic reaction to apple. Allergy 1994;49:67
    90. Mathelier-Fusade P, Vermeulen C, Leynadier F. Responsibility of food in exercise-induced anaphylaxis:7 cases. [French] Ann Dermatol Venereol. 2002;129(5 Pt 1):694-7
    91. Sanchez-Morillas L, Iglesias Cadarso A, Zapatero Remon L, Reano Martos M, Rodriguez Mosquera M, Martinez Molero MI. Exercise-induced anaphylaxis after apple intake. [Spanish] Allergol Immunopathol (Madr). 2003;31(4):240-3
    92. Anibarro B, Dominguez C, Diaz JM, Martin MF, Garcia-Ara MC, Boyano MT, Ojeda JA. Apple-dependent exercise-induced anaphylaxis. Allergy. 1994;49(6):481-2.
    93. Hannuksela M. Diagnosis of dermatologic food allergy. Ann Allergy. 1987;59(5 Pt 2):153-6
    94. Meynadier J, Meynadier JM, Guilhou JJ. Contact urticaria in atopic patients. Apropos of 2 cases. [French] Ann Dermatol Venereol. 1982;109(10):871-4
    95. Skamstrup Hansen K, Vieths S, Vestergaard H, Skov PS, Bindslev-Jensen C, Poulsen LK. Seasonal variation in food allergy to apple. J Chromatogr B Biomed Sci Appl. 2001;756(1-2):19-32
    96. Raulf-Heimsoth M, Stark R, Sander I, Maryska S, Rihs HP, Bruning T, Voshaar T. Anaphylactic reaction to apple juice containing acerola: cross-reactivity to latex due to prohevein. J Allergy Clin Immunol. 2002;109(4):715-6.
    97. Santucci TF Jr, Rourk MH Jr, Spock A. Apple juice challenge-pulmonary function test: a simple method to identify an acid-sensitive esophagus inducing bronchoconstriction. Ann Allergy 1990;64(2Pt1):135-42
    98. Zacharisen MC, George RA. Recurrent rash associated with food ingestion in a 5-year-old child. Ann Allergy Asthma Immunol 2003;90(6):599-603

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