Latin name: Malus domestica
Source material: rMal d 3 is a CCD-free recombinant protein.
Common names: Lipid transfer protein
ImmunoCAP allergen components:
rMal d 1 - f434
rMal d 3 – f435
Allergen: rMal d 3. (1, 2, 3, 4, 5) rMal d 3 is a CCD-free recombinant protein.
Biological function: Lipid transfer protein.
Mw: 9 kDa
Mal d 3, a lipid transfer protein, is a heat-stable allergen which retains its heat stability, and therefore its allergenicity even after cooking. (6)
Lipid transfer proteins are often associated with severe allergic reactions, (5) and may be major allergens in certain populations (e.g. Italian patients) as is the lipid transfer protein from peach. (5) Sensitisation to Mal d 3 is a risk factor for systemic reactions. (7)
Recombinant Mal d 3, similar to recombinant nut allergens, can be used to assess patient reactivity (in particular to a very stable apple allergen), to characterise IgE binding epitopes, and for studying the effect of mutations on IgE binding. (8)
Apple-allergic patients sensitised to Mal d 3 should avoid raw as well as cooked apple.
Apple-allergic patients sensitised to Mal d 3 may react to other LTP-containing foods, such as peach, walnut and other nuts, or grapes.
See Apple, f49
Mal d 3 is a lipid transfer protein (LTP). (1, 9, 10)
LTPs are panallergens that have ubiquitous distribution in tissues of many plant species, resulting in variable degrees of cross-reactivity; and in particularly relevant cross-reactivity in fruits and vegetables. (5)
According to their molecular masses, non-specific LTPs can be classified into the 9- to 10-kDa LTP1 and the 7-kDa LTP2 sub-families. LTPs localise mainly in epidermal plant tissues, and corresponding gene products are secreted and accumulate outside the cell walls of aerial organs (LTP1) or roots (LTP2). Due to their role in plant defence, LTPs have been classified as PR-14 protein members (the family of pathogenesis-related proteins). Although both LTP1 and LTP2 proteins can be found in plant seeds, thus far only LTP1 proteins have been characterised as allergens. (11)
Non-specific LTPs are important allergens in fruits, vegetables, nuts, pollen, and latex, although the predominant clinical reactivity is due to their presence in a range of foods. Despite their wide distribution throughout the plant kingdom, their clinical relevance is confined mostly to the Mediterranean area. IgE reactivity to LTPs is often associated with severe systemic symptoms. (11)
Allergenic LTP1s, commonly referred to as LTPs, are small molecules of approximately 9 to 10 kDa that demonstrate great stability and are very resistant to digestion and heat treatment. (12) Lipid transfer proteins were thought to facilitate the transport of phospholipids and galactolipids across membranes; some scientists consider that despite their name, a role in intracellular lipid transport is considered unlikely, based on their extracellular localisation. A number of other biological roles – including antimicrobial defence, signalling, and cell-wall loosening – have been proposed; but conclusive evidence is generally lacking, and these functions are not well correlated with in vitro activity or structure. (13)
Lipid transfer proteins are heat stable. (6) Only severe heat treatment results in a significant decrease in the allergenicity of Mal d 3, but glycation has a protective effect suggesting that the presence of sugars in fruits may contribute to the thermostability of the allergenic activity of LTP in heat-processed foods. (14)
Lipid transfer proteins (LTP) are highly conserved and widely distributed throughout the plant kingdom. They have been linked to severe and systemic symptoms and induce sensitisation by the oral route in fruit-allergic patients who do not have associated pollen allergy. LTP allergens possess a compact structure stabilised by four disulphide bridges that confer them a high stability to both thermal treatment and proteolytic digestion; the allergens probably reach the intestinal tract in an almost unmodified form.
They were originally identified as important allergens in the Rosaceae family (peach, apricot, plum, apple), but allergenic LTPs have now been identified in other fruits (Act c 10 from kiwi, Vit v 1 from grape, Cit s 3 from orange, Cit r 3 from mandarin, Cit l 3 from lemon, Mus a 3 from banana, Mor n 3 from blackberry, Pun g 3 from pomegranate), nuts (Jug r 3 from walnut, Cor a 8 from hazelnut, Cas s 8 from chestnut, Hel a 3 from sunflower seed), legumes (Ara h 9 from peanut, Len c 3 from lentil, Pha v 3 from haricot bean), other seeds (Sin a 3 from mustard), vegetables (Lyc e 3 from tomato, Lac s 1 from lettuce, Aspa o 1 from asparagus, Api g 2 from celery, All c 3 from onion, Dau c 3 from carrot, Pet c 3 from parsley, Cro s 3 from saffron, Bra o 3 from broccoli, Bra r 3 from turnip), and cereals (Hor v 14 from barley, Tri a 14 from wheat, Tri s 14 from spelt, Zea m 14 from corn, and Ory s 14 from rice), as well as pollens (Ole e 7, Par j 1 and 2, Par o 1, Art v 3, Amb a 6, Pla a 3) and latex (Hev b 12). CR has been observed with several of these allergens, although frequently with no clinical manifestations. (15)
In apple and peach, non-specific LTP levels are greatly dependent on maturity, storage conditions and cultivar. For apple, the highest LTP levels were found in mature, freshly-picked fruits, whereas LTP levels were shown to decrease during storage (with the greatest decrease under controlled atmosphere conditions). (10, 16)
Importantly, the lipid transfer proteins (LTP) essentially concentrate in the skin of fruits and vegetables, e.g. in Rosaceae fruits as cell-surface-exposed allergens. (17, 18) There are a few exceptions, which include plum and apricot. (19) LTP is found in peach peel in amounts approximately 7 times greater than in pulp; e.g. measured LTP contents were: yellow peach peel, 15.48; yellow peach pulp, 2.25; red peach peel, 14.67, and red peach pulp, 1.84. (20) It may be absent from chemically peeled fruit, and levels of LTP vary in different cultivars and at different stages of the ripening process, showing a progressive increment during ripening. (21) A study in Northern Europe was made to evaluate the hypothesis that peach may lose its allergenicity (and therefore its primary role as a sensitiser to LTP) as a consequence of processing preceding marketing. Peach surface fuzz reactivity in peach-allergic individuals was shown to be stronger than reactivity to peel. Pre-absorption of one serum with peach LTP caused an 87% reduction of IgE reactivity to peach fuzz extract. (22)
Whereas Mal d 1 and Mal d 2 are distributed throughout the apple pulp and peel, Mal d 3 is restricted to the peel. Mal d 1 content ranged from 0.84 to 33.17 [mu]g/g fresh weight in 39 selected cultivars. The study also demonstrated that different apple cultivars showed a markedly different expression of major allergens. (23) Further studies have confirmed that LTP levels vary 100-fold between apple cultivars, as demonstrated in a study of a wide range of apple cultivars (53 cultivars grown in Italy and 35 grown in the Netherlands). The authors considered that whether or not the lowest observed levels of LTP warrant designation as hypo-allergenic, confirmation by oral challenge is required. Importantly, Mal d 1 levels in the same cultivars demonstrated no correlation with Mal d 3 levels. (24) Similar findings were described in a study assessing 88 apple cultivars from Italy and the Netherlands. The same cultivars grown at two different locations demonstrated significant differences in LTP content, of up to a factor of 10. Allergenicity differences between cultivars were confirmed by in vivo assays. (16)
A number of factors influence the levels of Mal d 3. As apples mature, Mal d 3 levels increase, although the rate is dependent on cultivar and tree position. During storage, levels of Mal d 3 decreased in all cultivars, the rate of overall decrease being greatest under controlled atmosphere conditions. There was no correlation between Mal d 3 levels and total apple peel protein, indicating specific alterations in Mal d 3 expression. Thus, pre- and post-harvest treatments (i.e. storage) can modify the allergen load in apple peel, the highest levels being found in overly mature and in freshly harvested fruits. (10)
Lipid transfer protein allergy syndrome shows some peculiarities that are unique: geographical distribution, frequent asymptomatic sensitisation, frequent need for co-factors, and reduced severity when pollen allergy is present. (25)
Sensitisation follows a geographical distribution. Few studies have reported sensitisation to LTPs in Central and Northern Europe, and food allergies caused by LTPs have not been described as a major feature in the USA. The reasons for these differences are still unknown. Some researchers have debated the possibility that LTPs from certain pollens, which are less abundant in Central and Northern Europe, may act as primary sensitising allergens. (26)
Allergy to lipid transfer protein (LTP) is quite common in the Mediterranean countries, but virtually absent in northern Europe. (22, 27) Lipid transfer protein is usually associated with more severe systemic reactions than oral allergy syndrome. For example, peach LTP (Pru p 3) is a minor allergen in northern European countries but a major allergen in the south, affecting over 60% of patients allergic to peach in the Spanish population. (28) In peach-allergic patients who have experienced systemic reactions to peach, up to 100% may be sensitised to LPT. (29)
For example, in the Netherlands, Austria, and Italy, apple allergy is 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 is severe (>35% systemic reactions) and related to peach allergy and sensitisation to Mal d 3. (7)
Importantly, the clinical expression of sensitisation to LTP is extremely variable, ranging from symptomless sensitisation to severe anaphylaxis. Such variability is attributed to the presence or absence of a number of co-factors. (25)
As a number of pollens contain LTP, the possibility that LTP sensitisation occurs via the inhalation of LTP-containing pollen particles was considered, but seems unlikely; in contrast with peach particles containing the protein, which seem to be able to sensitise via both the airways and the skin. (25)
Co-sensitisation to pollen allergens as well as to labile plant food allergens makes LTP allergy syndrome less severe. In some LTP-sensitised subjects, clinical food allergy occurs only in the presence of co-factors such as exercise, NSAIDs, or chronic urticaria. (25)
LTPs from different allergen sources are generally IgE cross-reactive, due to high structural homology between these proteins. However, sensitisation profiles among allergic individuals are extremely heterogeneous, and individual cross-reactivity patterns may be restricted to a single LTP, or encompass many different LTPs. (11) Since this family of allergens is widely distributed in the plant kingdom and a high degree of IgE cross-reactivity exists among its members, it is common that patients allergic to LTP react to a wide variety of plant foods, including non-Rosaceae fruits, tree nuts, and vegetables. (30) However, a lack of correlation between sequence identity and clinical cross-reactivity has been noted. (26) Therefore IgE-binding cross-reactivity due to fruit lipid transfer protein has varying degrees of clinical relevance, and this cross-reactivity is not necessarily accompanied by a cross-allergenicity to the corresponding fruits. (31)
Although there is a high degree of cross-reactivity between LTP-containing foods, there are a number of factors that may reduce the degree of clinical effect:
a. LTP may vary greatly from one cultivar to another, e.g. Mal d 1.
b. LTP may be totally or partially heat-labile: patients with positive skin-prick test for an LTP food may tolerate the food after cooking – legumes are a typical example. (32) This was demonstrated in a study in which most patients were SPT-positive to pea, bean, and/or soya bean extracts; however, only two patients experienced symptoms after eating legumes. (32) Similarly, maize was frequently SPT-positive, but only four patients reported maize allergy, and all of them experienced their reactions after ingesting canned corn or salted maize snacks, whereas all tolerated ‘polenta’ (a long-boiled cornbread dish) without any problem. (32) The authors suggested that LTP is certainly pepsin-resistant and only partially heat-stable, but accepted that this was not in keeping with previous findings of other authors.
c. Distribution of the allergen within the offending food may play a role. LTP is found in the superficial layer (peel) rather than in the pulp of vegetables. Procedures such as peeling of carrots may cause the loss of the effect of LTP allergens. Authors have described how a patient experienced contact urticaria while preparing (scratching or grating) raw carrots, but tolerated their ingestion. (32)
These factors are illustrated by a report of a 7-year-old girl who developed abdominal pain with vomiting and anaphylactic reaction a few minutes after ingestion of cow’s milk and cereals containing barley malt. She was shown to be sensitised to the lipid transfer protein from barley. However, no IgE reactivity was detected to purified LTP from peach and apple. (33)
Potential cross-reactivity between Mal d 3 and 24 foods has been shown to vary according to the food, with significant cross-reactivity being demonstrated to peach (confirmed with purified rPru p 3), cherry and nectarine, and to a lesser extent to hazelnut and plum. (2)
Similarly, in a study aimed at finding new mustard allergens, 15 mustard-allergic patients with symptoms to peach were assessed. The majority suffered from systemic symptoms when eating mustard (13/15), as well as OAS. All patients had OAS on eating fresh peach, and 5/15 patients also suffered from systemic symptoms. Most of them also presented symptoms with other plant-derived foods, such as nuts (11/15), legumes (5/15), peanut (10/15), melon (12/15) and kiwi (9/15), but not commonly with apple. The LTP from mustard, Sin a 3, has a 65% identity with the amino acid sequence of Bra o 3 and the LTP from cabbage; and moderate identity (from 51 to 55%) with Pru p 3 (peach), Mal d 3, Pru av 3 (apricot), Fra a 3 (strawberry) and Cor a 8 (hazelnut). (34)
Evidence of the potential of cross-reactivity has been demonstrated between food LTP allergens, but not food LTP allergens and LTP allergens found in pollen, e.g., Ole e 7 in olive tree pollen and Par j 1 in Wall Pellitory pollen. (35)
The LTP from raspberry, Rub i 3, shows high sequence identity to proteins in Rosaceae species like Mal d 3 from apple, Pru av 3 from cherry and Pru p 1 and Pru p 3 from peach. (36) Partial cross-reactivity of the LTP from lettuce, Lac s 1, has been shown with Platanus pollen, but a more pronounced cross-reactivity has been demonstrated with the LTPs from a number of members of the Rosaceae family, including Mal d 3 from apple. (37, 38) Although the highest degree of sequence identity of Lac s 1 was found with Mal d 3, only one subject from the lettuce-allergic patient group reported apple allergy. (37) Therefore, the authors postulated a lack of correlation between sequence identity and clinical cross-reactivity. (26)
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 besides LTP.
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. (39, 40, 41, 42, 43, 44, 45) 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. (46) 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. (47, 48)
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%). (49) However, it is evident that sensitisation to Mal d 3 is a risk factor for systemic reactions. (7)
A study estimated the role of LTP in the 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. (50)
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 tests 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 investigation was needed to clarify if a single patient could 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 sIgE, but there was no correlation between apple 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 could not be analysed in this study. (51)
See Apple f49 for clinical information and further details on Apple allergy.
Compiled by Dr Harris Steinman,
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