rJug r 3, Walnut

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Code: f442
Latin name: Juglans regia
Source material: rJug r 3 is a CCD-free recombinant protein.
Family: Juglandaceae
Common names: Lipid transfer protein

ImmunoCAP allergen components:

rJug r 1 - f441
rJug r 3 – f442

Allergen: Jug r 3. (1) rJug r 3 is a CCD-free recombinant protein.

Biological function: Lipid transfer protein.

Mw: 9 kDa

Clinical Utility

Jug r 3, a lipid transfer protein, a heat-stable allergen which retains its heat stability, and therefore its allergenicity, towards different thermal processing methods. (2)

IgE antibodies to Jug r 3 (LTP) indicate cross-reactivity with other LTP-containing foods, often originating from a primary peach allergy. (3, 4, 5)

Lipid transfer proteins are often associated with severe allergic reactions, (6) and in specific populations (e.g. Italian patients) may be a major allergen similar to that of the lipid transfer protein from peach. (3)

The presence of IgE antibodies to Jug r 3 indicates that local symptoms as well as systemic reactions can occur. (3, 5, 7)

Recombinant Jug r 3, like other recombinant nut allergens, can be used to assess patient reactivity (in particular to a very stable walnut allergen), characterise IgE binding epitopes, and study the effect of mutations on IgE binding. (8)

Walnut-allergic patients sensitised to Jug r 1 and/or Jug r 3 should avoid raw as well as roasted or heated walnuts. (9, 10)

Walnut-allergic patients sensitised to Jug r 3 may react to other LTP-containing foods, such as peach, other nuts, apple or grapes. (7)

A positive walnut f256 with negative Jug r 1 and Jug r 3 results may be explained by sensitisation to:

  • Other walnut storage proteins;
  • Cross-reactivity with pollen proteins like profilin or PR-10 proteins. Due to high degree of similarity markers like Bet v 2 (profilin) and Bet v 1 (PR-10) may be used;
  • CCD (cross-reacting carbohydrate determinants). 

Allergen Exposure

See Walnut, f256

Allergen description:

Jug r 3 is a lipid transfer protein (LTP). (1)

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. (4)

According to their molecular masses, nonspecific LTPs can be classified into the 9 kDa – 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. (7)

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. (7)

Allergenic LTP1s, commonly referred to as LTPs, are small molecules of approximately 9 kDa - 10 kDa that demonstrate great stability and are very resistant to digestion and heat treatment. (11) 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. (12)

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 sunfl ower 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. (13)

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. (14, 15) 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. (16) 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. (17) A study 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 in Northern Europe. 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. (18)

Lipid transfer protein allergy syndrome shows some peculiarities that are unique: geographical distribution, frequent asymptomatic sensitisation, frequent need for cofactors, and reduced severity when pollen allergy is present. (19)

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. (20)

Allergy to lipid transfer protein (LTP) is quite common in the Mediterranean countries, but virtually absent in Northern Europe. (18) 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. (21) In peach-allergic patients who have experienced systemic reactions to peach, up to 100% may be sensitised to LPT. (22)

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. (19)

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. (19)

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. (19)

Potential Cross-Reactivity

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 can be restricted to a single LTP or encompass many different LTPs. (7) Since this family of allergens is widely distributed in the plant kingdom and a high degree of IgE cross-reactivity exists among their 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. (23) However, a lack of correlation between sequence identity and clinical cross-reactivity has been noted. (20)

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. (24) This was demonstrated in a study in which most patients were SPT-positive to pea, bean, and/or soyabean extracts; however, only two patients experienced symptoms after eating legumes. (24) 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. (24) 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) raw carrots, but tolerated their ingestion. (24)

There have been a number of reports that have clarified cross-reactivity between walnut and other foods as a result of the presence of LTP.

In a walnut-allergic Italian population, of whom 78% were sensitised to LTP, IgE binding to walnut LTP was completely inhibited by peach LTP. LTP is a major allergen in the Italian population. (3)

Walnut and pecan nut are closely related botanically, and show extensive cross-reactivity.

Researchers have suggested that in view of the high prevalence and severity of the allergic reactions induced by LTP-hypersensitive patients, hazelnut, walnut, and peanut should be regarded as potentially hazardous for these patients. In a study of 20 LTP-monosensitive patients with a clinical history of allergic reactions following the ingestion of Rosaceae fruits (apple, pear, peach, cherry, apricot, plum, or almond), 80% reported clinical reactivity to nuts (hazelnut, walnut, pistachio). In 11 cases (55%) nuts caused systemic symptoms, with urticaria/angioedema in 9 cases and anaphylaxis in 2. Maize and beer were not tolerated by four (20%) and 2 (10%) respectively. Two patients experienced immediate gastroenteritis/rhinitis and oral allergy syndrome, respectively, after ingesting grapes. Cashew and pistachio induced an anaphylactic reaction in a single patient, but the authors point out that cashew nuts are rarely eaten in Italy. Only 2 patients had ever eaten pistachio; one who had, reacted. The authors concluded that these two nuts may be significant LTP-containing foods for adverse reactions. (24) The study confirmed the important role of LTP in cross-reactivity concluded in a previous study. (25)

Other studies have clarified to some degree the role of LTP in cross-reactivity. An in vitro and in vivo study was performed of 15 peach-allergic Italian adults monosensitised to LTP, in order to assess their allergy and hypersensitivity to apple, hazelnut, walnut, peanut, soybean, lentil, maize, celery, carrot, banana, melon, tomato, kiwi, buckwheat, and sunflower, poppy, mustard, and sesame seeds. The study showed that 8, 7, 10, 5, 3, 2, 1, 1, and 1 patients were allergic to apple, hazelnut, walnut, peanut, tomato, kiwi, melon, lentil, and maize, respectively. The authors concluded that the study confirmed that peach was the primary sensitiser to LTP; and that the level of IgE to peach LTP was the main factor associated with cross-reactivity (and clinical allergy) to non-Rosaceae foods; and that clinically irrelevant sensitisation was common in LTP-hypersensitive patients; and that positive in vivo and/or in vitro test results were of little help in detecting potential clinical reactors, (26) the latter finding supporting the conclusions of an earlier study. (27)

Of clinical relevance, individuals allergic to walnut may be cross-reactive with other foods or allergens as a result of the presence of other panallergens besides LTP.

Clinical Experience

Walnut is one of the most common causes of allergic reactions to tree nuts. (3, 10) The estimated prevalence of walnut allergy in the general population is up to 0.5%; and in food-allergic children, up to 4%. (3, 28) Walnut was most commonly reported to be allergenic by participants in the Food Allergy and Anaphylaxis Network (FAAN) Peanut and Tree Nut registry in the United States. A questionnaire of 5149 patients (mainly children) found that for allergic reactions to tree nuts, 34% of reactions were to walnut. (29)

Walnut allergy is potentially life-threatening, increasing in prevalence, and rarely outgrown. (3, 30, 31) Walnut allergy can appear early in life; symptoms can be elicited upon first known exposure, and the dose can be very low. (3, 30, 31)

Walnut can induce food-dependent anaphylaxis elicited by exercise or other co-factors, such as NSAID drugs or alcohol. (5, 32, 33)

Walnut-allergic patients have high risk of experiencing severe allergic reactions, (34, 35) attributable in particular to heat-labile allergens such as the 2S albumins and LTP. Although symptoms such as mild laryngeal irritation, urticaria and asthma have been reported, severe systemic symptoms including angioedema and anaphylaxis have been described. (36)

Recently, an Italian study conducted to explore the many unexpected cases of isolated serum positivity to nJug r 2 (vicilin) experienced at a centre evaluated the association of specific-IgE reactivity with clinical symptoms, and the relationship between serum IgE, nJug r 2 and cross-reactive carbohydrate determinants (CCDs). Sera from 320 consecutive allergic outpatients were evaluated utilising the ImmunoCAP ISAC, which included native walnut nJug r 1, nJug r 2 (vicilin) and nJug r 3 (lipid transfer protein). Thirty-seven (12%) of 320 sera tested were positive to nJug r 2. Among them, 3 (8%) and 8 (22%) were shown to have raised specific IgE for nJug r 1 and nJug r 3 respectively. Sera of 73% (27) showed isolated positivity for nJug r 2, and only those with raised serum IgE for nJug r 1 had symptoms referring to walnut allergy. Sixty-eight per cent of nJug r 2-positive sera were shown to have concomitant raised serum IgE for nMUXF3; and further evaluation suggested that isolated serum IgE reactivity to nJug r 2 is frequently related to reactivity to CCD epitopes, and therefore lacks clinical significance. (37)

A study in an Italian population of 46 patients – either with oral allergy syndrome confirmed by open oral challenge, or with systemic symptoms after ingestion of walnut – comparing the walnut IgE-binding profile in patients with or without pollen allergy, found the only major allergen recognised was a lipid transfer protein recognised by 36 patients (78%). Two other minor allergens of approximately 9 kDa, both belonging to the vicilin family, were recognised by 10 patients (22%). IgE binding to walnut LTP was completely inhibited by peach LTP. The authors pointed out that in the Italian population, the LTP is a major allergen. (3)

In a study evaluating recombinant (r) Jug r 1 and (r) Jug r 3, IgE antibody responses were assessed in walnut-sensitised subjects, and compared with natural (n) Jug r 1 and Jug r 3.[confirm changes] Sera from 66 walnut-sensitised subjects (26 from Spain and Italy (SEU) and 40 from North/Central Europe (NEU) and North America (NA)) were recruited. IgE binding to rJug r 1 and rJug r 3 correlated well with that of their purified natural counterparts. 61 subjects (92%) displayed IgE to rJug r 1 and/or rJug r 3. Of the remaining five subjects, four were sensitised to cross-reactive carbohydrate determinants (CCD). Seven subjects (11%) displayed IgE antibody binding to rJug r 1, but not to rJug r 3; 29 (44%) to rJug r 3, but not to rJug r 1; and 25 (38%) to both. Twenty-three of the 66 subjects (35%) displayed CCD-reactive IgE. In 53 of the 66 subjects (80%), the sum of IgE to rJug r 1, rJug r 3 and CCD corresponded to >90% of the IgE to walnut extract. Subjects from NEU and NA mainly showed IgE binding to Jug r 1 and CCD, while individuals from SEU displayed dominant sensitisation to Jug r 3. Significant correlation in IgE binding between Jug r 3 and Pru p 3 was observed. (38)

See Walnut f256 for clinical information and further details on Walnut allergy.

Compiled by Dr Harris Steinman,

harris@allergyadvisor.com

References

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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.