rMal d 1, Apple

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Code: f434
Latin name: Malus domestica
Source material: rMal d 1 is a CCD-free recombinant protein.
Family: Rosaceae
Common names: Bet v 1-like protein

ImmunoCAP allergen components:

rMal d 1 – f434
rMal d 3 – f435

Allergen: rMal d 1 (1, 2, 3, 4, 5, 6, 7, 8, 9) is a CCD-free recombinant protein.

Biological function: A ribonuclease.

Mw: 17-18 kDa

Clinical Utility

Mal d 1, a ribonuclease and a Bet v 1-related protein, is a heat-labile allergen.

Recombinant Mal d 1 can be used to assess patient reactivity, characterise IgE binding epitopes, and study the effect of mutations on IgE binding.

Apple-allergic patients sensitised to Mal d 1 should avoid raw apple but may tolerate cooked apple if sensitisation to Mal d 3 is absent.

Apple-allergic patients sensitised to Mal d 1 may display cross-reactivity with pollen or food containing Bet v 1-like allergens, e.g. common silver birch tree, celery, carrot, etc.

Allergen Exposure

See Apple, f49

Allergen description:

Mal d 1 is a ribonuclease and a Bet v 1 homologue (Bet v 1-like allergen). (10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28)

Bet v 1 homologues are a ubiquitous group of genes in flowering plants encoding a class of highly conserved defence-related proteins. (29) Some of these proteins are induced under stress conditions as part of the plant defence mechanism. Other homologues are developmentally regulated and their expression varies in different plant organs. Defence-related proteins, also known as pathogenesis-related (PR) proteins, have been characterised into different PR groups, e.g. PR-10. Bet v 1 homologues are PR-10 proteins, are encoded by multigene families, have a weight of about 17 kDa and are found in the cytosol. (30)

Bet v 1 is a major birch tree pollen and Bet v 1 and homologous proteins represent major cross-reactive allergens for more than 95% of tree pollen-, fruit-, and vegetable-allergic individuals. (31) A number of Bet v 1-related food allergens have been cloned and characterised: Mal d 1 from apple, Pru av 1 from cherry, Pru ar 1 from apricot, Pur c 1 from pear, Api g 1 from celery, and Dau c 1 from carrot.

PR-10 proteins are thought to be involved in plant defence because their genes are usually induced upon the attack of various pathogens, by environmental stresses (abiotic stress), or developmentally regulated. However, PR-10 proteins display several additional functions, including a role in developmental processes and enzymatic activities in secondary metabolism. (32)

PR-10 proteins are expressed in high concentrations in reproductive tissues such as pollen, seeds and fruits. Bet v 1 homologues are primarily localised to the pulp of the fruit, in contrast to lipid transfer proteins (LTP) which are localised to the peel. The biological function of these proteins is unclear. Some studies, e.g. related to Mal d 1, suggest ribonuclease activity. (33)

In the birch-rich areas of northern and central Europe almost all birch-pollen-allergic patients are sensitised to Bet v 1, and most of them have Bet v 1-IgE antibodies as the only specificity. In southern Europe, where birch trees are uncommon or absent, a positive test to birch pollen often reflects sensitisation to Bet v 1 homologues in other trees closely related to birch (e.g. alder, hazel, hornbeam, beech and chestnut) or sensitisation to other pollen allergens such as profilins (Bet v 2 homologues) in grass and weed (e.g. mugwort and Parietaria).

The Bet v 1 homologous proteins in the Rosaceae family, including Mal d 1, are very sensitive to heat and proteases. Therefore, allergic reactions to Rosaceae fruits in Bet v 1 homologous food allergy are mainly triggered by fresh fruits and primarily restricted to the mouth (OAS), since Bet v 1 will be destroyed in the stomach. OAS may also occur due to LTP, and allergic reactions from Bet v 1-homologous foods may occasionally be more severe. However, the Bet v 1-homologous proteins in hazelnut, celery and peanut/soybean have been shown in some studies to be more heat stable than fruits from the Rosaceae family, and may explain why those plant foods sometimes trigger more serious systemic reactions in Bet v 1-related food allergy. (34)

Potential Cross-Reactivity

Cross-reactivity between apple and other foods, plants and pollens may occur as a result of the presence of one or more panallergens in apple, e.g. lipid transfer protein (Mal d 3), a thaumatin-like protein (Mal d 2), profilin (Mal d 4), or a Bet v 1 homologue (Mal d 1). (35)

Mal d 1 and the major birch pollen allergen, Bet v 1, are members of the PR-10 family. Cross-reactivity between Mal d 1 and Bet v 1 results in symptoms of food allergy – often oral allergy syndrome (OAS), in birch-tree-pollen-allergic individuals with allergic rhinitis, and individuals allergic to other trees containing closely related Bet v 1 homologous allergens – on ingestion of apple. (36, 37, 38, 39 ) Other closely-related, Bet v 1 cross-reactive allergens have been found in the pollen of other trees from the order Fagales, such as hazel, alder, and chestnut. (40) Many birch-pollen-allergic patients display allergic reactions to various fruits and vegetables as a result of IgE cross-reactivity between Bet v 1 and homologous allergens in plant foods, e.g. in members of certain plant families: Rosaceae (apple, pear, stone fruits), Apiaceae (celery, carrot), and Fabaceae (soybean, peanut). (36, 41)

The major cause of cross-reactivity between birch and apple is biochemical and immunological similarity between the major allergens Bet v 1 and Mal d 1. (16, 42) More than 95% of birch-pollen-allergic patients show IgE reactivity to Bet v 1, and more than 60% are exclusively sensitised to Bet v 1 in birch pollen. (43)

Bet v 1 homologues have been identified in (among others) apple (Mal d 1), hazelnut (Cor a 1), almond (Pru du 1), apricot (Pru ar 1), cherry (Pru av 1), peach (Pru p 1), pear (Pyr c 1), raspberry (Rub i 1), strawberry (Fra a 1), Carrot (Dau c 1), celery (Api g 1), parsley (Pet c 1), mung bean (Vig r 1), peanut (Ara h 8), soybean (Gly m 4), asparagus (Aspa o 17kD), bell pepper (Cap a 17 kD), potato (STH-2/STH-21), mango (Man i 14 kD), melon (musk) (Cuc m 3).

Studies illustrate this relationship.

In a study evaluating the effect on Bet v 1-induced T cell proliferation, of 14 patients with allergic rhinitis and monosensitised to birch, 4 also experienced symptoms of OAS to apple. (44)

Significantly, the risk of cross-reactivity between Mal d 1 and other Bet v 1-homologues depends on the degree of amino acid sequence identity between the allergens. (45) For example, amino acid sequence of Rub i 1 from raspberry has been shown to have the highest level of identity with the allergens Pru av 1.02 (cherry) (identity 79.0%) and Fra a 1 (strawberry) (identity 77.0%) followed by Pru p 1 (peach), Mal d 1 (apple), Pyr c 1 (pear) and Pru ar 1 (apricot). (46) Alternatively, Fra a 1 from strawberry is homologous to the major birch pollen allergen Bet v 1, and has been shown to have a 54-61 and 77-78% sequence identity with Bet v 1 and Mal d 1 respectively. (47, 48)

Of clinical relevance, individuals allergic to apple may be cross-reactive with other foods or allergens as a result of the presence of other panallergens, e.g. a lipid transfer protein (Mal d 3).

Clinical Experience

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. (49, 50, 51, 52, 53, 54, 55, 56) Itching, tingling and other mild reactions on the oropharyngeal mucosa are the most common complaints after eating raw apple; angioedema, urticaria and shock are less common. Other symptoms may include rhinoconjunctivitis, asthma, laryngeal oedema, abdominal effects, pruritis and hand dermatitis. (57) 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. (58, 59)

Apple contains a number of allergens, and patients are heterogeneously sensitised to one or more of these allergens. For example, a study to determine the pattern of recognition of individual major and minor allergens among subjects with a positive in vitro diagnosis for apple reported the following sensitisation frequencies: nMal d1 (87%), rMal d2 (57%), nMal d3 (31%), nMal d4 (29%). (60)

Food allergy to the PR-10 protein Mal d 1 in apple occurs commonly; and clinically, often presents with oral allergy syndrome (OAS) and non-anaphylactic symptoms. However, it has been suggested that in certain situations, e.g. when drinks containing PR-10 proteins are rapidly consumed, for example after sporting activities, large concentrations of allergen can result in anaphylaxis as described for soya milk and in a patient ingesting an apple drink with 60% fruit concentration. (61)

A study estimated the role of LTP in diagnosis of apple allergy in 21 children allergic to birch pollen. Six patients' sera were hypersensitive to birch pollen and apple proteins. Almost all sera recognised specifically the main allergen of apple peel Mal d 3 with molecular weight <10kDa (LTP). Positive oral challenge to apple was found in 52.4% of investigated children. Children allergic to Mal d 1 presented different clinical symptoms. (62)

Mal d 1 and Mal d 3 were also evaluated in skin-prick tests where skin-prick test responses to apple cultivars were evaluated in patients with apple allergy: 19 patients underwent prick-to-prick skin-prick test with eleven commercial and non-commercial apple cultivars, and evaluation of specific IgE to apple and recombinant apple allergens Mal d 1 and Mal d 3. The results showed that different reactions might be evoked in a single patient by different apple cultivars and also separately for the peel and the pulp of a single cultivar. The authors suggested that further investigations were needed to clarify whether a single patient can be allergic only to well-defined apple cultivars, and which allergy tests are necessary to ascertain this. Apple serum-specific IgE showed a correlation with Mal d 3 serum-specific IgE, whereas there was no correlation between apple serum-specific IgE (sIgE) and Mal d 1 sIgE. A few patients, despite having had an allergic reaction to apple ingestion, had negative sIgE to both Mal d 1 and Mal d 3. The authors suggested that in these cases, different allergens were probably involved (possibly Mal d 2 and Mal d 4), but they were not assessed in the study. (8)

See Apple f49 for clinical information and further details on Apple allergy.


Compiled by Dr Harris Steinman,



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