Introduction
Non-specific lipid transfer proteins (LTPs) are ubiquitous in terrestrial plants and described as pan allergens in plant-derived food (Rosaceae fruits, vegetables), as well as in tree (plane and olive) and weed (pellitory, ragweed, and mugwort) pollen. Potentially, any antigen can elicit an allergic response, but only a limited number of allergens and restricted number of protein families cause the majority of allergic reactions. Although allergens seem to display an intrinsic TH2-inducing immunogenicity, geographical differences for the prevalence of specific allergies are well described, e.g., for peanut allergy (in the USA in comparison to Europe), the birch food syndrome (in Central/Northern Europe, but not in the Mediterranean area), or the LTP syndrome (in Southern Europe, but, e.g., not in Scandinavia). Differences in the allergic sensitization can be associated with a different level of exposure to the respective allergens, e.g., to inhalant allergens due to pollen endemic areas and, depending on the climate condition, to food allergens due to different dietary habits, food processing techniques applied, and the age of children when foods are introduced to the diet. It is tempting to speculate that other factors such as the genetic background of individuals, the life style including rural or urban housing, the co-incidence with microbial and parasite infections, potential concomitant respiratory and immune modifying diseases, or the sensitization profile will contribute to a different geographical significance of certain allergies.
Allergic reactions to non-specific lipid transfer proteins (LTPs) from plant pollen and food predominantly occur in the Mediterranean area and are rare in the Northern and Central Europe (reviewed in [
1]). In Southern Europe, sensitization to LTPs is dominated by peach Pru p 3: IgE responses to LTP are (almost) never seen without it, and IgE titers are usually the highest among those against LTPs. These observations are at the basis of the established consensus that peach is the primary sensitizer for Mediterranean LTP-driven allergy. Because of its high clinical significance, Pru p 3 is considered the prototypic marker for the LTP syndrome in this geographical area. To a lesser extent, LTP-mediated allergies also occur outside the Mediterranean, but the reasons for this geographic difference in the sensitization prevalence are still unknown.
The present review addresses differences between the established Mediterranean “cradle” of the LTP syndrome and other geographical locations, with particular attention on the clinical impact of co- and cross-sensitization patterns to pollen.
Prevalence of Food and Pollen LTP Sensitization Outside the Mediterranean Area
The first food allergen from the LTP family described was Pru p 3 (initially designated Pru p 1) from peach [
4,
5]. Up to now, numerous LTPs have been reported and characterized as food allergens, and respiratory LTP allergens have been found in tree and weed pollen as well as food (e.g., wheat LTP contributing to baker’s asthma), but also as contact allergens. However, almost all reports are from studies performed in Southern Europe countries of Southern European countries indicating the important clinical relevance of this allergen family in that area (reviewed in [
2]). In the Mediterranean basin, more than 90% of patients with reactions to plant-derived foods, especially fruits from the
Rosaceae family, are sensitized against the respective LTPs, and almost all peach allergic patients with severe systemic reactions show sensitization to Pru p 3 [
6], the clinically most important and best characterized food LTP. In line with this, reports on LTP-mediated allergies were initially limited exclusively to the Mediterranean area. In contrast, nowadays, there is an increasing awareness that sensitization to LTPs is not exclusively limited to Southern Europe (reviewed in [
7]). Meanwhile, sensitization to LTPs outside the Mediterranean area has been documented by several case reports and studies applying component-resolved diagnosis (CRD) (Table
1). However, the pathogenesis and clinical significance of LTP allergies for these patient populations is controversially discussed and not fully characterized.
Table 1
Epidemiology of LTP sensitization in the non-Mediterranean area (exemplary reports)
Pru p 3 | Peach | CN (Northern) | 96 | 23/24 | Peach allergy with mugwort allergy (history): all Artv3+ | CAP | |
Peach allergy without mugwort allergy (history): 6/15 Artv3+ and mugwort allergy without peach allergy (history): 12/31 Artv3+ |
ES (Northern) | 88–961 | 63–691/72 | Adults with plant food allergy (history, Prup3 SPT+, birch pollen and profilin neg.) | 1ISAC/CAP | |
AT | 77 | 10/13 | Plant food allergy (history of anaphylactic reaction or SPT+ > 8 mm) | ISAC or CAP | |
CN | 80 | 86/107 | Mugwort pollen-related food allergy (history): 69% Arah9+, 63% Cora8+ | CAP | |
Cor a 8 | Hazelnut | NL | 100 | 8/8 | Pediatric hazelnut allergies (spec. IgE, DBPCFC+) | CRD (RAST, IB) | |
6 | 1/18 | Pediatric hazelnut patients (spec. IgE, without objective symptoms upon DBPCFC) |
DK | 5 | 1/20 | Adult hazelnut allergies (DBPCFC+) | CRD (CAP) | |
CH | 15 | 3/20 |
NL | 8 | 3/40 | Pediatric hazelnut allergies (DBPCFC+) | CRD (CAP) | |
5 | 2/39 | Adult hazelnut allergies (15 DBPCFC+ & 24 history) |
NL | 12 | 5/42 | Hazelnut and/or apple allergies (history, HN and/or apple spec. IgE or SPT+), 9/42 Prup3+, 3/9 anaphylactic HN patients were Cora8+ | CAP | |
Central/Northern Europe | < 15 | < 51/343 | Hazelnut allergies (history, with & w/o DBPCFC), 343 from 8 EU cities (non-Mediterranean) | CRD (CAP) | |
CN | 63 | 59/107 | Mugwort pollen-related food allergy (history): 69% Arah9+, 80% Prup3+ | CAP | |
Ara h 9 | Peanut | US | 67 | 4/6 | Adult PN allergies (history, PN spec. IgE), 3/4 Arah9+ US patients were Prup3+ | CAP, IB2 | |
DE | 6 | 2/352 |
SE | 14 | 5/35 | Pediatric PN allergies (food challenge positive or history, PN spec. IgE) | CRD (CAP) | |
US | 8 | 2/30 |
JP | 153–584 | 43–154/26 | Pediatric PN allergic (OFC+), 3 > 0.35 kU/L, 4 > 0.1 kU/L, 3,4 not significant vs tolerant group | CRD (CAP) | |
SE | 165 | 45/25 | Pediatric PN allergies (DBPCFC+, PN spec. IgE or SPT+), 5not significant vs tolerant group | CRD | |
TW | 24 | 7/29 | Preschool children (history, preselected by PN spec. IgE ≥ 3.5 kU/L = CAP class 3) | CD (CAP) | |
UK | 20 | 38/192 | Pediatric PN allergies (history), subgroup (n = 2) Arah9+ but Prup3 negative | CRD (CAP) | |
TH | 26 | 5/19 | Pediatric/adolescent PN allergic (history or DBPCFC+, PN spec. IgE), 1 Arah9+/21 PN tolerance | CRD (CAP) | |
Europe | 24 | 14/59 | Children and adults (40 history or 28 DBPCFC+), 59 from 8 non-Mediterranean EU countries (Arah9+ in CH, NL, UK, CZ) | CRD (CAP) | |
CN | 83 | 15/18 | 38 Adult/adolescent PN sensitized patients: 18 symptomatic and 20 tolerant, 14 Arah9+/20 PN tolerant | CRD (CAP) | |
UK | 63 | 22/35 | Patients with pollen-food syndrome, preselected by LTP-allergy (Prup3+): 52% Cora8+, 86% Jugr3+, 83% Prup3+, 23% Tria14+, 60% Artv3+, 17% Olee7+, 66% Plaa3+ | ISAC | |
CN | 69 | 64/107 | Mugwort pollen-related food allergy (history): 80% Prup3+, 63% Cora8+ | CAP | |
Mal d 3 | Apple | NL | 1 | 1/99 | Adult apple allergy (history, apple SPT+) | CRD (RAST) | |
AT | 2 | 2/94 |
PL | 95 | 20/21 | Pediatrics with birch pollen and apple allergy (birch and apple spec. IgE), putative LTP in apple extracts by IB (data from individual sera not shown) | CAP, IB | |
DE | Case report | n = 1 | Adult with FDEIA to apple (history, apple spec. IgE) | CAP | |
Tri a 14 | Wheat | DE | 3 | 1/40 | Patients with baker’s asthma (history, wheat flour spec. IgE) | CAP | |
Act d 10 | Kiwi | IS | 3 | 1/29 | Children and adults (history), 266 from 9 non-Mediterranean EU countries | CRD (CAP) | |
Eastern Europe | 9 | 5/56 |
Western/Central Europe | 11 | 20/181 |
Api g 6 | Celery | AT | 38 | 12/32 | Celery allergies (celeriac spec. IgE and/or SPT+), no correlation od Apig6 with Apig2 or Artv3 | ELISA | |
Len c 3 | Lentil | AT | Case report | 2/3 | Adult lentil or legume allergy (history, lentil spec. IgE), all Prup3+ | CAP, IB | |
Pru av 3 | Cherry | DE | 3 | 3/101 | Adult cherry allergies (history, cherry spec. IgE) | EAST | |
CH | 4 | 1/24 | Adult cherry allergies (history, DBPCFC+, 23/24 cherry SPT+) | CRD (SPT) | |
DE & CH | 5 | 1/22 | Adult cherry allergies (DBPCFC+, 20 CH and 2 DE) | CRD (CAP) | |
12 | 12/99 | Adult (history, 97 CH & 2 DE) |
Vit v 1 | Grape | DE | Case report | n = 1 | Adult case history (spec. IgE and SPT+) | | |
Vac m 3 | Blueberry | DE | Case report | n = 1 | Adult, case history (spec. IgE and SPT+) | | |
Art v 3 | Mugwort | AT & CA | 89 | 8/9 | Mugwort (9) and/or ragweed (10) allergies (history, SPT+, spec. IgE), 10 AT and 9 CA | CRD (array, ELISA) | |
CN (Northern) | 100 | 24/24 | Mugwort allergies with peach allergy (history): 23/24 Prup3+ | CAP | |
39 | 12/31 | Mugwort allergy without peach allergy (history): 9/31 Prup3+, all 9 also Artv3+ |
CN | 53 | 127/240 | Mugwort allergy (history, spec. IgE) | CRD (CAP) | |
(Southwest) | 9 | 3/32 | In Yunnan |
(Northern) | 66 | 117/178 | In Shanxi (but 25%, 7/30 in Shandong with lower mugwort pollen load) |
CN | 73 | 108/148 | Mugwort allergies from Peking (with/without food allergy) (history, mugwort SPT+ and spec. IgE) | CAP | |
87 | 93/107 | Mugwort allergic with food allergy |
37 | 11/31 | Mugwort allergic without food allergy |
CN | 57 | 36/63 | Patient with autumn (incl. mugwort 94%) pollinosis (history, pollen SPT+ and spec. IgE) from Peking | CAP | |
79 | 26/33 | Patients with autumn pollinosis and food allergy (history, SPT+ and/or spec. IgE), 52% |
33 | 10/30 | Patients with autumn pollinosis w/o food allergy, 48% |
Can s 3 | Cannabis | BE | 72 | 18/25 | Cannabis allergies (history) with likely anaphylactic reactions (25/120), 92% of Cans3+ also LTP+ | CAP, BAT | |
Jug r 3 | Walnut | CH | 42 | 13/31 | Adolescent/adult walnut allergic patients (history or DBFCFC+ or OFC+) | CRD (CAP) | |
DE | 32 | 10/31 |
Amb a 6 | Ragweed | AT & CA | 30 | 3/10 | Mugwort (9) and/or ragweed (10) allergies (history, SPT+, spec. IgE), 10 AT and 9 CA | CRD (array, ELISA) | |
On the one hand, the importance of pollen and food LTP in the sensitization process outside the Mediterranean area has been demonstrated. The LTP syndrome in mugwort and/or peach allergics from Northern China can either be driven by the mugwort pollen LTP Art v 3 (see chapter 3) or Pru p 3 which was identified as major allergen in peach allergics tolerating mugwort [
8•]. Pru p 3 is suggested even as a marker allergen for LTP sensitization in the non-Mediterranean area [
9]. Furthermore, the prominent role of Pru p 3 is supported by a study showing sensitization to Pru p 3 in patients with allergy to raspberry and apricot from Austria [
10]. However, these patients were preselected by a history of severe allergic symptoms. Sensitization to cannabis LTP Can s 3 was reported in Belgium among cannabis allergic patients, and with a frequency of 72% reporting severe reactions [
42]. Remarkably, Can s 3 positive patients had high prevalence (92%) of sensitization to other LTP such as apple Mal d 3, hazelnut Cor a 8, walnut Jug r 3, wheat Tri a 14, and mugwort Art v 3 but also Pru p 3. In addition, Anantharachagan et al. reported eight patients with LTP-driven allergy in Northwestern England [
44]. Patients were sensitized to a broad panel of LTPs, at which 7/8 were reactive to Pru p 3 and 5/8 were reactive to Ara h 9. Data from these reports suggest that outside the Mediterranean area both Pru p 3 and Art v 3 can act as immuno-dominant LTP.
On the other hand, in the majority of studies from the non-Mediterranean area, sensitization to LTPs seems to be of limited importance, and LTPs were frequently classified as minor allergens. Case reports of allergic reaction to grape LTP Vit v 1 in a German wine maker [
37] and suspected allergy to Vit v 1 and apple LTP Mal d 3 in a 12-year-old female from Australia [
45] are available. In addition, other case reports suggested the association of a LTP sensitization and food-dependent exercise-induced anaphylaxis (FDEIA) in a patient from Poland after eating several, also LTP-containing, foods [
46] and demonstrated the presence of IgE to apple LTP in a German patient with food allergy to apple but without sensitization to Bet v 1-like proteins, storage proteins, or profilin [
29]. Of note, sensitization against LTPs can also cause occupational allergies outside the Mediterranean area [
30]. However, the reactivity to wheat LTP Tri a 14 was a less frequent trigger (2.5%) of baker’s asthma in Central Europe [
30] than in Southern Europe (60%) [
47]. In a retrospective explorative study, 15% of 305 adult patients visiting the outpatient clinic in Utrecht (the Netherlands) were sensitized to food LTPs, as measured by the ISAC112 microarray methodology. The majority of LTP-positive patients was co-sensitized to PR-10 allergens rather than to storage proteins, and only a minority of subjects was mono-sensitized to LTPs [
48]. An additional survey performed in Belgium ruled out a high percentage of more than 25% out of 718 patients with pollen and/or food allergy be sensitized to any of the tested LTPs [
49,
50]. Using a panel of four foods and two pollen LTPs, the study demonstrated IgE reactivity not to be correlated with a clinical phenotype due to frequent clinically insignificant sensitization. However, the authors did not provide an explanation for the high frequency of sensitization to LTP in this study cohort.
So far, several CRD studies contribute to the understanding of the role of LTPs outside the Mediterranean area. One of the first studies applying LTP in CRD was performed in cherry allergic patients from Spain and Switzerland [
35]. Ballmer-Weber et al. [
35] found that only 1 out of 24 double-blind placebo-controlled food challenge (DBPCFC)-positive Swiss cherry allergic patients was sensitized to cherry LTP Pru av. 3, which was classified as a major allergen in Spain (prevalence of 89%). A follow-up study with patients from Germany and Switzerland revealed that only 11% (13/121) of cherry allergics were sensitized to Pru av. 3 [
36]. Remarkably, all study subjects reported exclusively OAS, and only 1/11 patients tested was mono-sensitized to Pru av. 3. Similar results were obtained for Dutch and Austrian patients (
n = 193) selected by history of adverse reactions and positive SPT to apple at which sensitization to Mal d 3 was almost not observed (< 3%) [
27]. CRD of kiwi fruit allergy across Europe revealed a frequency of sensitization to kiwi LTP Act d 10 of 3–11% outside the Mediterranean area vs 22% in Southern Europe [
31]. An early study in a birch-endemic area in the Netherlands revealed that sensitization to purified hazelnut LTP Cor a 8 was associated with objective symptoms in all children with IgE to hazelnut LTP [
12]. Interestingly, 6/8 tested sera did not react to Pru p 3. Using the ISCAC microarray approach [
51], an age-dependent association of systemic reactions to hazelnut with sensitization to Cor a 8 was found in 12%, 17%, and 33% of pre-school, school-aged children, and adults from Belgium, respectively, but not in patients reporting OAS. Later studies did not confirm the suggested prominent role of Cor a 8 in systemic allergic reactions to hazelnut, suggesting that likely other inclusion criteria were applied or by false-positive results due to potential contamination of natural Cor a 8 by, e.g., seed storage proteins [
13,
14,
52]. A CRD study of hazelnut allergy across Europe in DBPFC-positive patients revealed a prevalence of sensitization to Cor a 8 of 5% (1/20) in Denmark and 15% (3/20) in Switzerland [
13], with only 1/4 of these Cor a 8-sensitized hazelnut allergic patients reporting severe reactions. In the control group consisting of birch pollen allergics with tolerance to hazelnut, no IgE binding to Cor a 8 was detected. Unfortunately, this study did not explore further individual sensitization patterns, such as to Pru p 3 or pollen LTPs. A Dutch study by Masthoff et al. [
14] reported no substantial difference of Cor a 8 sensitization rates of 5% and 8% in children and adults with objective symptoms to hazelnut, respectively. In addition, a so-called molecular map of hazelnut allergy across 12 European cities revealed Cor a 8 sensitization of minor importance in almost all cities by a frequency of less than 15% (except Madrid and Athens) [
16]. Similar results were obtained from the analysis of the sensitization pattern in hazelnut-positive individuals across the USA showing that approximately 10% were sensitized to Cor a 8 regardless of the age, and Cor a 8 sensitization was considered not a predictive marker for severe reactions [
53]. Cor a 8 was not a reliable diagnostic marker in hazelnut open food challenge (OFC)-positive children from Japan [
54]. Moreover, the low prevalence of sensitization to Pru p 3 in Japanese children was attributed to eating habits, since peaches are consumed without peel in Japan [
55]. Therefore, LTPs that preferentially accumulate in the peel are almost removed. In terms of the sensitization pattern to peanut, a previous study showed a heterogeneous reactivity to peanut LTP Ara h 9 in different populations investigated: IgE reactivity was found in 29/32 Spanish and 6/41 non-Mediterranean peanut allergics [
17]. Similar results were published by Vareda et al. [
18]: Ara h 9 sensitization was confirmed in 8% and 14% of peanut allergics in the USA and Sweden vs 60% in Spain. Of note, the highest percentage of mono-sensitization to Ara h 9 (but no IgE binding to other peanut allergens) was found in patients from Spain (18/50), which corresponded to systemic reactions in 16/18 patients. Later, IgE sensitization pattern in peanut allergy was investigated within the EuroPrevall study [
24]. Briefly, 68 peanut allergic subjects from 11 European countries, thereof 59 patients from 8 countries not belonging to the Mediterranean area, were enrolled. Approximately 20% (12/59) of these patients were sensitized to Ara h 9. Sensitization to Ara h 9 (and to Bet v 1-like protein Ara h 8), but not sensitization to storage proteins, was frequently associated with tolerance to peanuts. However, in contrast to Vereda et al. [
18], the authors [
24] further concluded that sensitization to Ara h 9 usually seems not to be acquired in childhood. Moreover, sensitization to Ara h 9 in 3/33 Swedish patients, all co-sensitized to Bet v 1, was not associated with severe clinical reactions [
56]. Recently, interesting data were provided by a Chinese CRD study reporting that the most common allergen in peanut-sensitized subjects is Ara h 9 (in 83% of 38 subjects), of which more than half (
n = 24) suffered from mugwort pollinosis and peach allergy [
25]. In 18/38 subjects, peanut sensitization was symptomatic, and 15/18 peanut allergic patients were reactive to Ara h 9, among whom 12 were Ara h 9 mono-sensitized. Of the 5 patients presenting severe reactions, 4 were mono-sensitized to Ara h 9 [
25]. CRD in walnut allergic patients from Spain, Switzerland, and Germany showed that a high rate of 32% and 42% of patients from Germany and Switzerland were sensitized to walnut LTP Jug r 3, respectively [
43•]. Based on all three patient groups, sensitization to Jug r 3 was not significantly associated with severe symptoms. Remarkably, in patients from Switzerland and Germany, reporting systemic reactions, the frequency of reactivity to Jug r 3 was moderate (15/32), but none of the patients was mono-sensitized to Jug r 3. Severe reactions were reported by patients sensitized to storage proteins, but were not associated with LTP or PR-10 allergens. In contrast, all patients from Spain with severe symptoms exhibited IgE to Jug r 3, and 5/8 patients were Jug r 3 mono-sensitized (considering six walnut allergens tested). Data further suggest that sensitization to LTPs outside the Mediterranean basin is accompanied by a broad reactivity to other allergens from the same source which in case of the storage proteins contribute to more severe reaction rather than LTP.
In summary, sensitization patterns to LTP in China and Central/Northern Europe do not resemble the Mediterranean serotype. The prevalence of LTP sensitization is not comparable, and lower in patients recruited outside the Mediterranean area (except China), defining them as minor allergens. Typically, patients are frequently poly-sensitized to broad spectrum of other allergens from the same allergenic source. In line with this, diagnosis of LTP sensitization using plant extracts is limited due to frequent concomitant pollen allergies, e.g., to birch pollen, and cross-reactive allergens thereof, but can be dissected by CRD. In general (except China), LTP reactivity seems to be of less clinical importance when patients are co-sensitized to other allergic proteins. It needs be taken into account that heterogeneous results in terms of the epidemiology of LTP-mediated allergies can be confounded by non-standardized diagnostic procedures or by different inclusion criteria of the studies. The explanation for the different geographical relevance of LTPs remains elusive since food and vegetables consumed in Central and Northern Europe express high levels of LTPs, and different dietary habits and food processing practices may not serve as solely explanation. In this context, a potentially different pollen environment with different exposure of LTP-containing pollen needs to be taken into consideration.
Conclusions
Although LTP-mediated allergies are common in the Mediterranean area, the number of reports on allergies caused by LTPs outside this area is continuously increasing and strengthens the awareness that the LTP syndrome is not restricted exclusively to Southern Europe. The reason probably is not an increasing incidence of LTP allergies rather than the utilization of purified allergens for CRD allowing to dissect sensitization to LTP from other allergens present in the same or potentially cross-reactive materials. However, the reason for the lower frequency of LTP-driven allergies in Central/Northern Europe still remains unclear, considering no obvious substantial differences in the genetic background and the nutritional behavior (processing and time point of introduction of LTP-containing food) in the population. It is tempting to speculate that the immune system of atopic individuals in Central/Northern Europe is employed with the response to a highly immunogenic pollen, which does not express substantial amounts of LTP (e.g., birch pollen), hampering a substantial immune response to LTPs. So far, geographical differences in the role of LTPs have not been attributed to potential differences in the B and T cell epitopes in both populations.
The clinical manifestation of LTP allergy outside the Mediterranean can be grouped in diverse phenotypes, which remain challenging to predict by presence of specific IgE. There is some evidence that co-sensitization to LTP-unrelated allergens, likewise in the birch-food syndrome, transforms into less severe LTP-mediated clinical reactivity, a phenomenon sometimes described as a “protective” effect by IgE directed against allergens other than LTPs.
The prevailing opinion is that Pru p 3 displays the strongest allergenicity among the LTP family and induces sensitization to other food LTPs. The role of LTPs in the Mediterranean area can be classified as follows: (1) Pru p 3 acts as a primary sensitizer in areas with low exposure of LTP-containing pollen but shows relevant IgE cross-reactivity with LTPs from pollen and food (very frequent), (2) both Pru p 3 and pollen-LTP can act as primary sensitizers in areas with high exposure of LTP-containing pollen (olive and plane tree and mugwort, ragweed, pellitory) and possess limited IgE cross-reactivity leading to a mixed phenotype (frequent), and (3) pollen LTP act as a primary sensitizer in areas with extremely high exposure to LTP-containing pollen and no IgE cross-reactivity with Pru p 3, e.g., in olive pollen LTP mono-sensitized patients (less frequent).
The role of LTPs in the outside the Mediterranean basin is suggested as follows: (1) Pru p 3 or other food LTPs can act as a primary sensitizer in areas with low exposure of LTP-containing pollen but with high abundance of non-LTP-containing allergic pollen (preferentially birch in Central/Northern Europe) and display a strong cross-reactivity with pollen and food LTPs and (2) pollen LTPs which are genuine allergens in areas with extremely high exposure to LTP-containing pollen (e.g., mugwort pollen in Northern China) leading to secondary LTP-mediated food allergies.
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