f49 Apple

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• Latin name: Malus x domestica
• Family: Rosaceae
• Common names: Apple, Cultivated apple, Crabapple
• Source material: Peel from green Apple

Synonymes: M. domestica, M. communis, M. pumila, M. sylvestris

Allergen Exposure

• Mal d 1, a 18 kDa heat-labile protein, a major allergen, a Bet v 1 homologue (PR 10) protein family member (6-30).
   
• Mal d 2, a 31 kDa thaumatin-like protein (6,15,18-19,22,25,31-34).
   
• Mal d 3, a 9 kDa lipid transfer protein, a minor allergen (6,15,19,22,24-25,35-50).
   
• Mal d 4, a 14 kDa protein, a profilin and a major allergen (6,15,19,22,24,33,51-54).

A Bet v 6-related food allergen, a PCBER (Phenylcoumaran benzylic ether reductase) (55-56).

An isoflavone reductase (IFR) allergen has been described (57).

A novel putative allergen, a glyceraldehyde-3-phosphate dehydrogenase, has been detected; of 7 Apple-allergic patients, 71% reacted to this protein (58).

As in the case of other allergens, sensitisation to Apple allergens follows a heterogenous pattern: for example, in a study to determine the pattern of recognition of individual major and minor allergens among subjects with a positive in vitro diagnosis for Apple allergy, the following frequencies were found:

• nMal d1 (87%),
• rMal d2 (57%),
• nMal d3 (31%),
• nMal d4 (29%) (59).

The peel of Apple and other Rosaceae fruits has been reported to have a clinically relevant higher allergenicity than the pulp (60). The 18 and 31 kDa allergens, which are heat-labile and unstable in solution, experience almost complete elimination of allergenic potency with short heating (61). Mal d 1 and Mal d 2 are distributed throughout the Apple pulp and peel, while Mal d 3 is restricted to the peel. Different Apple cultivars show markedly different expression of major allergens (25). Interestingly, Mal d 1 and Mal d 3 and their homologues have been detected in Rosaceae pollen. Although the pollen load of Rosaceae is rather low as a rule, there is confirmed evidence for temporary peaks, indicating that allergen exposure for sensitised individuals is likely (62).

Anecdotal reports from Apple-allergic patients hold that some Apple strains tend to be highly allergenic (Granny Smith, Golden delicious), whereas others (Jamba, Gloster, Boskop) are tolerated without any symptoms or with moderate symptoms (63). 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 18 kDa allergen (63). The Mal d 1 content of Golden delicious apples was shown to rise considerably during maturation and storage (64). Golden delicious apples had the most 18 kDa allergen (compared with Macintosh, Red delicious, and Granny Smith). The 18 kDa allergen was found at levels in this order: Golden delicious > Boskoop > Jamba. This would explain the different results of skin prick test to allergens from different Apple extracts (65). Mal d 1 content ranged from 0.84 to 33.2 µg/g fresh weight in 39 selected cultivars (25). Other factors may influence the protein content or allergenicity of Apple. Apples in stores have been shown to have higher levels of allergens than freshly picked fruit. The amount of the 18 kDa allergen (Mal d 1) increased significantly when Apples were stored at 4 °C, but not under controlled exposure to oxygen and carbon dioxide (3).

Whether Apple cultivars containing low amounts of Mal d 1 are better tolerated by Apple-allergic patients was assessed: 3 different Apple cultivars induced wheals of similar size in most patients, but 2 cultivars induced significantly more-severe symptoms in 2/7 cases each, suggesting that allergy to Mal d 1 is characterised by significant inter-patient variability as well as marked inter-Apple and intra-Apple variability (20).

Further, different Mal d 1 isoforms can be present within a single cultivar (6). 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 of Birch tree pollen resulted in a drastic reduction of allergenicity of both the pollen and the food allergen, obviously having removed the cross-reactive epitope (6). Also, it was demonstrated that, although Mal d 1 did not induce basophil activation after gastrointestinal digestion, digested Mal d 1 (and Hazelnut Cor a 1.04) still activated Bet v 1-specific T cells, suggesting that gastrointestinal degradation of Bet v 1-related food allergens destroys their histamine-releasing, but not T cell-activating, property. This data emphasises that Birch pollen-related foods are relevant activators of pollen-specific T cells (66).

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 to 5 mg per 100 g fresh weight. A bite of Apple of approximately 10 g, which is able to elicit symptoms in Apple-allergic patients, represents 0.1-0.5 mg of the ingested major allergen (63).

Mal d 2, a thaumatin-like protein, shows high stability to proteolysis and heat treatment and remains intact after 2 hours each of gastric and subsequent duodenal digestion, retaining its full IgE-binding capacity. Mal d 2, although detected by an anti-TLP antibody in cloudy Apple juice, did not bind IgE of a serum pool of Apple-allergic patients. These findings suggest that Mal d 2 maintains its structure in the gastrointestinal tract, a feature essential for sensitising the mucosal immune system and provoking allergic reactions (32).

Mal d 3, a lipid transfer protein, was assessed in 53 Apple cultivars grown in Italy and 35 grown in The Netherlands, in order to determine whether levels of LTP varied among cultivars. Differences of around 100-fold in LTP levels existed between certain Apple cultivars. The authors suggested that whether the lowest observed levels of LTP warrant designation as hypo-allergenic required more extensive confirmation by oral challenges (44,67). Furthermore, LTP levels are greatly dependent on the position of the fruit growing on the tree, maturity, storage conditions, and cultivar. The highest LTP levels are found in mature, freshly picked fruits, whereas LTP levels decrease during storage (with the greatest decrease happening under controlled atmosphere conditions) (46,67). Most LTP concentrates in the pericarp (skin) of the fruit, whereas the pulp contains lower amounts of the allergen (45).

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 (68). 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 prick test and IgE antibody test should not be taken as the only guide for multi-species dietary restrictions but that, nevertheless, the potential for clinical allergy to other Rosaceae should not be neglected (69).

Early studies reported cross-reactivity between Birch pollen and a number of foods, e.g., Apple, Pear, Celery, Carrot and Potato (70). Subsequently, a number of allergens or panallergens have been identified, and this has shed light on the causes and patterns (71).

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 (72). 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 (73-79).

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 is the molecular basis for this phenomenon. No 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%) presented symptoms of allergy after eating Apples (80).

In a Japanese study of 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%) (81). Similar results were reported from a study in Hokkaido. In patients with Birch pollen allergy, the higher the serum IgE antibody level to Birch pollen were, the higher was the incidence of hypersensitivity to Apple pulp (82).

Laboratory evidence 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 shown by serological and cellular immunoassays (6,11,83-84). 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 a 55.6% identity on the nucleic acid level (12).

Clinical and laboratory evidence is supported by research demonstrating that patients who are Birch pollen- and Apple-allergic improve if desensitised to Birch pollen (85); and by research showing a marked reduction or a total disappearance of Apple-induced oral allergy syndrome after injection immunotherapy with Birch pollen extracts (86). These recent studies contradict an earlier study that reported a poorer response (85).

Allergy to Apple is commonly associated with Birch pollinosis because the 2 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 (39). 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 (87). 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 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 may represent 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 (9). Cross-inhibition assays have also demonstrated 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 (88).

In Mediterranean areas, oral allergy syndrome occurs without 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 (89).

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 (90).

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 have common epitopes with antigens in Apple, Carrot and Celery tuber (91). 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 (57,76). 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 (5).

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 (36, 38,41). Similarly, the LTP present in Peach and beer may cross-react with LTP from several other plant-derived foods (36,92).

Although cross-reactivity has been clearly established between Apple and Birch tree pollen, cross-reactivity may occur between Apple and other pollens as well. In a study of cross-allergenicity between Apple pulp and 5 pollen species (Birch, Japanese cedar, Orchard grass, Mugwort and Ragweed), investigated by RAST inhibition, it was demonstrated that Apple pulp extract effectively inhibited RASTs to all the pollens except Japanese Cedar pollen (93). Similarly, a study reported an association between grass pollen allergy and sensitisation to Tomato, Potato, Green pea, Peanut, Watermelon, Melon, Apple, Orange and Kiwi (94). This may be 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 plant foods and may therefore contribute to cross-reactivity in patients allergic to various pollens and plant food (95).

Some patients with grass allergy show polysensitisation against other pollens and plant-derived foods. In these patients, oral allergic syndrome (OAS) is frequently found. This is a result of cross-reactive Bet v 1- and Bet v 2-like allergens. The most common foods implicated are Hazelnut, Peanut, Kiwi, Apple and Walnut. IgE antibodies for Bet v 1 is associated more with nuts and legumes, while Bet v 2 is more often related to fresh fruit and vegetables (96).

Allergy to Apple has been associated with Kiwi-allergic individuals (97). Individuals with allergy to Grape or related products are often co-sensitised to Apple (98-99).

Sensitisation to profilin and/or bromelain-type cross-reacting carbohydrate determinants (CCD), caused by pollen (Timothy grass, Mugwort) or Hymenoptera venom allergens, can elicit positive IgE antibody tests against Natural rubber latex and Apple (100). These antibodies are most often of less clinical relevance.

Minor allergenic determinants cross-reactive with Apple and Birch pollen epitopes have also been isolated in the pollen of the Apple tree (101). Apple seed allergens have been reported to cross-react with Birch pollen allergen(s) (102).

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 (51,87,103-111). 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 (112). Individuals may be highly allergic to Apple, with symptoms being elicited even from kissing, resulting in local or regional, mild, moderate or severe symptoms, including angioedema, bronchospasm, acute respiratory distress and anaphylaxis (113-114).

In a Japanese study of sera of 4,797,158 patients collected in laboratories during 1994-1998, evaluation of IgE antibody values of greater than 0.70 kUA/l showed that among food allergens, Apple had the highest response (115). Similarly, in a food hypersensitivity study of Finnish university students, among 172 subjects, Apple was a frequent (29.1%) cause of symptoms (116). Approximately 2% of the Northern and Central European population is allergic to Apple (117). A study was conducted at 17 clinics in 15 European cities to describe the differences among some Northern countries regarding what foods, according to the patients, elicit hypersensitivity symptoms, and it was found that Apple was responsible in 45% of 1139 participants (111).

However, symptoms of Apple allergy may show a geographically skewed distribution. In Northern and Central Europe, where Birch trees predominate, symptoms tend to be mild, whereas in Southern Europe and the Mediterranean, symptoms are more likely to be severe. This is illustrated by a study that sought to investigate the primary sensitisers in Apple allergy across Europe, the individual allergens involved, and whether these differences determine the clinical presentation. Results from 389 patients with Apple allergy (case histories and positive skin prick test) showed that in the Netherlands, Austria, and Italy, Apple allergy was mild (>90% isolated oral symptoms) and related to Birch pollen allergy and sensitisation to Bet v 1 and its Apple homologue, Mal d 1. In Spain, Apple allergy was severe (>35% systemic reactions) and related to Peach allergy and sensitisation to Mal d 3 (lipid transfer protein) (22).

A study of an unselected Danish population of children and adults reported that 17% of pollen-sensitised adults were allergic to Apple (118). In an Indian study of 24 children aged 3 to 15 years with documented deterioration in control of their perennial asthma, the presence of  IgE antibodies to Apple was found in 21 (88%) (119).

“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 Apple (120). These became known as oral allergy syndrome, and Apple is the most frequently reported offending food in Birch pollen-sensitive patients with OAS (65,82,121-130). 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: for example, in 196 Birch pollen-hypersensitive patients with oral allergy syndrome caused by various vegetable foods, 195 patients had Apple and/or Hazelnut allergy (131).

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 (132). Because of symptoms of oral allergy syndrome, many individuals avoid eating fresh Apples. A study demonstrated that the allergens responsible vary between cultivars: out of 15 Apple-allergic individuals who underwent an open oral challenge with 3 different Apple cultivars – Santana, Golden Delicious, and Topaz – during the Birch pollen season, 8 of the participants (53%) developed no symptoms following challenge with Santana apple, than after challenge with the Topaz apple (1 participant) and Golden Delicious apple (1 participant) (117). Apple allergy confined to the gingival tissues was reported in a 48-year-old woman. Skin  reactivity and IgE antibodies detection with commercial extract of Apple were negative, whereas the oral challenge test resulted in blister and ulcer formation (133).

Among 1,129 adult patients with bronchial asthma and/or allergic rhinitis responding to a questionnaire regarding food sensitivity, 276 (24%) reported allergic symptoms on eating or handling various foods, of which Hazel nut, Apple and shellfish were the most often named (134).

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 did Golden delicious. RAST for Apple, Peach, and Hazelnut was positive in 53 (68.8%), 13 (16.9%), and 31 (40.3%) patients, respectively (65).

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 (51,135).

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 (93). Anaphylaxis may occur in association with other allergic manifestations such as contact urticaria (136). Anaphylaxis may be precipitated by Apple in association with exercise: this is food-dependant exercise-induced anaphylaxis (FDEIA) (137-143). Food-dependent exercise-induced anaphylaxis as a result of Apple has been described in a 14-year-old Japanese male who experienced repeated episodes of generalised urticaria and dyspnoea after ingesting Apple followed by exercise (143).

In a study of 99 children with atopic dermatitis, Hen’s 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 Hen’s egg (144).

Contact urticaria, although uncommon, can occur following contact with Apple (145).

Apple may present as a “hidden allergen” (146).

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 (147).

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 they should not be consumed in large quantities. In small quantities, hydrogen cyanide has been shown to stimulate respiration and improve digestion; it is also claimed (probably not accurately) to be of benefit in the treatment of cancer. 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 (148).

The acidity of Apple juice may result in bronchoconstriction in some individuals (149).

Auriculotemporal syndrome (Frey’s syndrome, gustatory flushing) has occurred within minutes of eating Apple (150).

Compiled by Dr Harris Steinman, harris@zingsolutions.com

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