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Clinical severity of LTP syndrome is associated with an expanded IgE repertoire, FDEIA, FDHIH, and LTP mono reactivity
Abstract
Background. LTP allergy is often a challenge for clinicians. We evaluated a multiplex diagnostic approach with diverse cofactors to stratify LTP syndrome risk. Methods. Of the 1,831 participants screened with 'Allergy Explorer-ALEX-2', 426 had reactions to at least one LTP. Data was gathered and recorded via an electronic database. Results. Reactivity to peach Pru p 3 was found in 77% of individuals with LTP allergy. Higher levels of specific IgE and concurrent sensitization to more than 5 molecules (50% of all LTP-sensitised participants, 62% of symptomatic cases) were significantly associated with an increased risk of severe reactions (p = 0.001). Several cofactors, either alone or in combination, also influenced patients' clinical outcomes. Some cofactors increased the risk of severe reactions, such as mono reactivity to LTP in 44.6% of cases (p = 0.001), FDEIA in 10.8% of patients (p = 0.001), and FDNIH in 11.5% (p = 0.005). On the other hand, reactivity to PR10 (24.2%; p = 0.001), profilin hypersensitivity (10.3%; p = 0.001), and/or atopic dermatitis (16.7%; p = 0.001) had a mitigating effect on symptom severity. Conclusions. Clinical severity of LTP syndrome is associated with an expanded IgE repertoire in terms of the number of LTP components recognized and increased IgE levels in individual molecules. Ara h 9, Cor a 8, and Mal d 3 showed the strongest association with clinical severity. In addition, several cofactors may either exacerbate (FDEIA, FDHIH, and LTP monoreactivity) or ameliorate (atopic dermatitis and co-sensitization to profilin and/or PR10) individual patient outcomes. These factors may be utilized for the daily clinical management of LTP syndrome.
... There is little data regarding symptom severity in individuals with nsLTP allergy who are also sensitised to Bet v 1 or profilins, although one study found that despite concomitant sensitisation to birch pollen, the majority of individuals with LTP did report moderate to severe symptoms, when compared with those who had pollen food syndrome (PFS) [23]. Most recently, Scala and colleagues demonstrated that the recognition of increasing numbers of LTP components, especially those in peanut (Ara h 9), hazelnut (Cor a 8) and apple (Mal d 3), was associated with increased clinical severity [30]. ...
... It has been hypothesized that the concentration of LTPspecific IgE, particularly Pru p 3, might be associated with the severity of symptoms and the risk of an allergic reaction, although the supporting evidence remains contradictory [30,49,50,[53][54][55][56]. Elevated Pru p 3 sIgE levels have also been associated with an increased prevalence of allergies to peanuts, hazelnuts, and walnuts [28,55,57]. ...
... In a recent study on children sensitised to LTP, the most frequent sensitisations were to Pru p 3 (74%) and Cor a 8 (66%), with clinical reactivity being associated with a higher number of positive LTP [17]. It has been reported that sensitisation to more than five LTPs significantly correlates with a higher risk of severe allergic reactions [27,30], however this finding was not confirmed in a UK population [23]. In an Italian LTP allergic population, Ara h 9, Cor a 8, and Mal d 3 were most strongly associated with clinical symptom severity. ...
Purpose of Review
To provide an update on the diagnosis of non-specific Lipid Transfer Protein (nsLTP) allergy.
Recent Findings
More publications report the presence of nsLTP allergy in Northern European countries and nsLTP sensitisation in children. Individuals are more likely to have severe reactions if there is recognition of increasing numbers of LTP components. Diagnosis is problematic; not all those with nsLTP allergy will have a positive test to a peach extract containing Pru p 3, the peach nsLTP.
Summary
Sensitisation to nsLTP is being reported in more countries, including to the nsLTP in Cannabis Sativa in North America. Meals containing multiple nsLTP foods are more likely to be involved in co-factor reactions. Component-resolved diagnostics are superior to skin prick tests, to determine sensitisation to the individual nsLTP allergens causing symptoms and, in the future, the Basophil Activation test may best discriminate between sensitization and clinical allergy.
... This view is supported by in-vitro experiments showing that the pre-absorption of sera of LTP hypersensitive patients with peach LTP almost invariably completely inhibits IgE reactivity to other plant food sources (22). Pollen allergens such as Par j 1 and Par j 2 from Parietaria and Ole e 7 from olive tree do not cross-react with either nsLTP1 from plant foods or with each other (24), although they frequently score positive in peach-allergic patients (25)(26)(27). LTP2 proteins are cross-reactive with each other but have low sequence identity when compared to LTP1. The widespread presence of nsLTP in nature leads to a long list of foods linked to anaphylactic reactions (28). ...
... Furthermore, the clinical expression of nsLTP sensitization may sometimes require cofactors. Concurrent use of non-steroidal anti-inflammatory drugs (NSAIDs) alongside nsLTPcontaining foods can exacerbate adverse reactions (25,34). nsLTP is the primary cause of exercise-induced anaphylaxis triggered by food in Italy (31). ...
... Reactivity may also depend on the simultaneous presence or absence of different foods in the digestive tract (35). Conversely, cosensitization to PR10 and Profilin, or both, appears to play a protective role, resulting in a lower frequency of severe systemic reactions (25,36), despite an increased prevalence of first-degree oral allergy syndrome (27). Another protective factor is the presence of atopic dermatitis, where despite very high IgE levels and multiple LTP recognition, the frequency of severe reactions is significantly lower than observed in allergic patients without atopic eczema. ...
The primary cause of adult-onset food allergy in Mediterranean countries is IgE-mediated reactivity to non-specific Lipid Transfer Protein (nsLTP), with a prevalence of 9.5% in Italy. nsLTP is heat- and pepsin-stable due to its 3D structure, causing severe allergic reactions, even anaphylaxis. It's conserved across plants and a "panallergen" due to homologous forms in various vegetable foods. Found in Rosaceae fruits' skin, it's categorized into nsLTP1 (9 kDa) and nsLTP2 (7 kDa), representing 93% and 7% of the molecules described to date, respectively. Pru p 3 (nsLTP1) from peach is a primary sensitizer, binding more epitopes than other homologs. Cross-reactivity varies in sensitized patients, influenced by IgE levels. Clinical manifestations range from none to various symptoms. Managing patients sensitized to nsLTP without clinical allergy is a challenge. Sensitization hierarchy usually starts with peach, then expands through Prunoideae, Rosaceae, and other foods. Clinical symptoms don't always expand across LTPs. Patients can tolerate some nsLTP-containing foods and consuming them may maintain tolerance. The absence of guidelines led to the Associazione Allergologi Immunologi Italiani Territoriali e Ospedalieri (AAIITO) creating a consensus-based document. Strategies involve avoidance, self-injectable adrenaline, verification through in vivo and in vitro testing, considering cofactors, and peeling fruits. In localized reactions, abstinence is recommended if specific IgE is high. Concurrent pollinosis may complicates diagnosis, but may help management since symptoms are often less severe. Asymptomatic patients are advised to continue normal diets while considering cofactors and total IgE levels. Management strategies should be case-specific, based on expert Consensus Document.
... In particular, Pru p 3, the nsLTP from peach, is the primary sensitizer of LTP-mediated food allergies, involved in cross-reactive reactions with nsLTPs from apple, apricot, cherry, plum, raspberry, wheat, and others [84,106,107]. The common structural features of nsLTPs are the basis of their allergenic clinical crossreactivity that is usually referred to as LTP syndrome [105,108]. nsLTPs are ubiquitous vegetable proteins involved in lipid membrane biosynthesis and act as pathogenesisrelated proteins [109]. Together with the structurally closely related 2S-albumins and α-amylase/protease inhibitors, nsLTPs belong to the prolamin protein superfamily [109]. ...
... The structural homology of nsLTP largely depends on the taxonomic relationships between the sources of origin and botanically related molecules. The molecules with a higher identity will have a greater likelihood of IgE cross-reactivity than taxonomically distant molecules [108]. Interestingly, unlike other cross-reactive molecules (e.g., profilins and PR-10), proportions of structural identity greater than 60% are rarely recorded, indicating that nsLTPs are homologous molecules with a low structural identity [113]. ...
Food allergy (FA) has shown an increasing prevalence in the last decades, becoming a major public health problem. However, data on the prevalence of FA across the world are heterogeneous because they are influenced by several factors. Among IgE-mediated FA, an important role is played by FA related to plant-derived food which can result from the sensitization to a single protein (specific FA) or to homologous proteins present in different foods (cross-reactive FA) including non-specific lipid transfer proteins (nsLTPs), profilins, and pathogenesis-related class 10 (PR-10). In addition, the clinical presentation of FA is widely heterogeneous ranging from mild symptoms to severe reactions up to anaphylaxis, most frequently associated with nsLTP-related FA (LTP syndrome). Considering the potential life-threatening nature of nsLTP-related FA, the patient’s geographical setting should always be taken into account; thereby, it is highly recommended to build a personalized approach for managing FA across the world in the precision medicine era. For this reason, in this review, we aim to provide an overview of the prevalence of nsLTP-mediated allergies in the Mediterranean area and to point out the potential reasons for the different geographical significance of LTP-driven allergies with a particular focus on the allergenic properties of food allergens and their cross reactivity.
... 22 were more likely to experience severe allergic reactions. 15,23 Our study identified that aside from the ratio of Pru p 3:total IgE, other useful diagnostic markers included Ara h 9, Cor a 8, specific IgE to walnut, tomato and peach SPT. Also, statistically significant correlations were observed between Pru p 3 and Ara h 9, Cor a 8 and Jug r 3, underlining their usefulness as additional markers in the diagnostic workup. ...
Background
Sensitisation to Lipid Transfer Proteins (LTP), usually ascertained by undertaking a test to the peach LTP allergen Pru p 3, is common but does not always indicate LTP allergy. Improving the diagnostic process would ensure the correct diagnosis and management of this complex condition.
Objectives
To determine the diagnostic value of Pru p 3 and other LTP component allergens in UK adults.
Methods
A retrospective review was undertaken of adults referred to the Allergy Unit at the Royal Brompton & Harefield Hospitals (RBHT) London (UK), between 2012 and 2022 who were sensitised to Pru p 3. Those with a final diagnosis of LTP allergy were compared to those sensitized to Pru p 3 but not diagnosed with LTP allergy.
Results
Of 285 patients with a positive Pru p 3, 157 (55%) were diagnosed with LTP allergy. LTP allergic patients were more likely to have a higher level of Pru p 3, and a lower level of total IgE. The ratio of Pru p 3:total IgE was the most accurate diagnostic marker of LTP allergy, with a receiver operating characteristics AUC of 0.880. A diagnosis of LTP allergy was also significantly associated with sensitisation to the LTP in peanut (Ara h 9, p < 0.001), and hazelnut (Cor a 8, p < 0.001).
Conclusion
Sensitisation to Pru p 3 may not always indicate an LTP allergy. Our data suggests that the Pru p 3:total IgE ratio, and sensitisation to Ara h 9 and Cor a 8 can support the diagnosis of LTP allergy in individuals sensitised to Pru p 3.
... In a large study, anaphylactic reactions were particularly prevalent among patients sensitized to five or more nsLTPs [69]. A recent Italian study found that increased clinical severity was associated with the recognition of a greater number of LTP components, particularly nsLTP in peanuts (Ara h 9), hazelnuts (Cor a 8) and apples (Mal d 3) [72]. On the other hand, monosensitization to Pru p 3 is also linked to severe symptoms including anaphylaxis [73]. ...
Purpose of review
Adult food allergy, either unresolved from childhood, or new-onset in adult-life, is known to be increasingly prevalent. Although much of the reported anaphylaxis in adults is due to drug reactions, foods are becoming an increasingly important trigger, affecting adults of all ages, with a wide variation in food triggers which are often quite different to those reported in children.
Recent findings
Peanuts are well known to cause anaphylaxis in some adult populations, but other legumes such as soy may be more relevant in others. Reactions to natto, fermented soybeans, are currently mainly reported in Japan, but changing dietary practices and an increase in plant-based eating mean natto, other forms of soy and other legumes are increasingly linked to anaphylaxis in Western countries. Anaphylaxis to red meat, caused by sensitization to galactose-α-1,3-galactose and first reported in North America, is now a more world-wide concern. Co-factor induced anaphylaxis is increasingly associated with both wheat allergy and lipid transfer protein allergy.
Summary
More research is urgently needed to characterize adult food allergy, its triggers and symptom severity. Unusual food triggers and potential co-factors should be considered, so that anaphylaxis in adults can be correctly managed, not merely labelled as idiopathic.
Lipid Transfer Protein (LTP) allergy, traditionally more prevalent in adults from Southern Europe, is increasingly recognized in pediatric populations worldwide. This review explores the epidemiology, pathogenesis, clinical manifestations, diagnosis, and management of LTP allergy in children. LTP allergy can present with severe systemic symptoms both in children and adults; in children‐only studies, anaphylaxis is reported in up to half of the patients. Moreover, children often display polysensitization to multiple plant‐based foods. The prevalence of LTP allergy among children remains under‐researched, contributing to diagnostic and clinical practice variability. Key allergenic sources involved include peach (Pru p 3) and other Rosaceae fruits, as well as tree nuts, with cofactors such as physical activity frequently triggering or exacerbating reactions. Advancements in understanding natural tolerance and targeted therapies, along with expanding LTP immunotherapy, offer promising directions for improving the management of this challenging condition in pediatric patients.
Although the most prevalent plant food allergy in the United Kingdom (UK) is pollen food syndrome (PFS), there is increasing evidence that reactions to plant foods could also be due to sensitisation to Lipid Transfer Proteins (LTP). These proteins, highly resistant to heat and processing, are present in raw, cooked and processed plant foods and often provoke moderate to severe symptoms. LTP allergy is common in Mediterranean countries, but there is a lack of epidemiological data from Northern Europe, although small case series have been published characterising LTP allergy in both England and Scotland. To gather further information and aid the development of a clinical practice statement on LTP allergy, a survey was conducted by the British Society of Allergy and Clinical Immunology (BSACI). The results confirmed that LTP allergy is being diagnosed in both children and adults in all areas of the UK. The survey results, along with published UK data, confirm that tree nuts, peanuts, apples, stone fruits, tomatoes and processed foods, such as pizza or curry, are common food triggers. Anaphylactic reactions are not uncommon and are often facilitated by the presence of co‐factors such as exercise or alcohol. Unlike LTP allergy in Spain and Italy, UK individuals are also more likely to be sensitised to birch and grass pollen, but this does not appear to reduce the severity of the condition. Diagnosis can be complex; a positive test to individual LTP allergens can only be confirmatory of a diagnosis of LTP allergy when accompanied by a typical clinical history. Management can be difficult, and individualised advice is vital to avoid the exclusion of multiple foods and minimise the likelihood of co‐factors. Given the diverse range of foods, co‐factor involvement and highly idiosyncratic nature of LTP allergy, the need for adrenaline autoinjectors should always be considered.
Background
Lipid transfer proteins (LTP) are associated with a wide range of severity of allergic reactions. However, the risk factors associated with this severity are not fully understood.
Objectives
To describe the clinical characteristics of peach-allergic patients due to LTP sensitization and analyze the relationship between the severity of the reactions and patients’ sensitization profiles.
Methods
A retrospective study of peach-allergic patients was performed. Patients were classified into LTP-monoallergic (only peach allergy) or LTP-Syndrome (peach allergy and allergy to other plants-foods related with LTP). Symptoms with Rosaceae family and other related plant foods, skin prick tests (SPTs), and IgE values were recorded.
Results
Seventy-one patients were included, 46.5% suffering from anaphylaxis, 32.3% from urticaria angioedema, and 21.2% from oral allergy syndrome. Six had monoallergy to LTP and 65 LTP syndrome. Clinical severity showed no differences according to peach SPT wheal size or Pru p 3 IgE levels. We also found no differences between the components of LTP-containing foods analyzed, the number of LTPs recognized, and the severity of symptoms. However, anaphylaxis was more frequent in patients with concomitant allergies to ≥3 groups of plant foods.
Conclusions
LTP syndrome was the most common presentation in patients with Rosaceae food allergy. The severity of the reactions was not related to peach SPT wheal size or sIgE levels to Pru p 3, but concomitant allergies to ≥3 plant food groups could be a good marker of severity.
Non-specific lipid transfer proteins (nsLTPs) as the primary sensitizer in plant-food allergic patients used to be seen primarily in the Mediterranean area. However, more recently, increasing numbers of clinically relevant sensitizations are being observed in Northern Europe. We herein report an unusual case of a woman who developed an anaphylactic reaction during a meal including a variety of different foods ranging from fruits and nuts to oats, wheat, and salmon. Allergy diagnostics showed no Bet v 1 sensitization but an nsLTP-mediated food allergy. Despite the much more prominent birch food syndrome in Central and Northern Europe, LTPs should be considered disease-causing agents, especially for patients developing severe reactions after consuming LTP-containing foods.
Non-specific lipid transfer proteins (LTPs) are well studied allergens that can lead to severe reactions, but often cause oral allergy syndrome in the Mediterranean area and other European countries. However, studies focused on LTP reactivity in allergic individuals from the United States are lacking because they are not considered major allergens. The goal of this study is to determine if differences in immunoglobulin (Ig) E binding patterns to the peanut allergen Ara h 9 and two homologous LTPs (walnut Jug r 3 and peach Pru p 3) between the US and Spain contribute to differences observed in allergic reactivity. Synthetic overlapping 15-amino acid-long peptides offset by five amino acids from Ara h 9, Jug r 3, and Pru p 3 were synthesized, and the intact proteins were attached to microarray slides. Sera from 55 peanut-allergic individuals from the US were tested for IgE binding to the linear peptides and IgE binding to intact proteins using immunofluorescence. For comparison, sera from 17 peanut-allergic individuals from Spain were also tested. Similar IgE binding profiles for Ara h 9, Jug r 3, and Pru p 3 were identified between the US and Spain, with slight differences. Certain regions of the proteins, specifically helices 1 and 2 and the C-terminal coil, were recognized by the majority of the sera more often than other regions of the proteins. While serum IgE from peanut-allergic individuals in the US binds to peptides of Ara h 9 and its homologs, only IgE from the Spanish subjects bound to the intact LTPs. This study identifies Ara h 9, Jug r 3, and Pru p 3 linear epitopes that were previously unidentified using sera from peanut-allergic individuals from the US and Spain. Certain regions of the LTPs are recognized more often in US subjects, indicating that they represent conserved and possible cross-reactive regions. The location of the epitopes in 3D structure models of the LTPs may predict the location of potential conformational epitopes bound by a majority of the Spanish patient sera. These findings are potentially important for development of peptide or protein-targeting diagnostic and therapeutic tools for food allergy.
Background
Discovered and described 40 years ago, non‐specific lipid transfer proteins (nsLTP) are present in many plant species and play an important role protecting plants from stressors such as heat or drought. In the last 20 years, sensitization to nsLTP and consequent reactions to plant foods has become an increasing concern.
Aim
The aim of this paper is to review the evidence for the structure and function of nsLTP allergens, and cross‐reactivity, sensitization, and epidemiology of nsLTP allergy.
Materials and Methods
A Task Force, supported by the European Academy of Allergy & Clinical Immunology (EAACI), reviewed current evidence and provide a signpost for future research. The search terms for this paper were “Non‐specific Lipid Transfer Proteins”, “LTP syndrome”, “Pru p 3”, “plant food allergy”, “pollen‐food syndrome”.
Results
Most nsLTP allergens have a highly conserved structure stabilised by 4‐disulphide bridges. Studies on the peach nsLTP, Pru p 3, demonstrate that nsLTPs are very cross‐reactive, with the four major IgE epitopes of Pru p 3 being shared by nsLTP from other botanically related fruits. These nsLTP allergens are to varying degrees resistant to heat and digestion, and sensitization may occur through the oral, inhaled or cutaneous routes. In some populations, Pru p 3 is the primary and sole sensitizing allergen, but many are poly‐sensitised both to botanically un‐related nsLTP in foods, and non‐food sources of nsLTP such as Cannabis sativa, Platanus acerifolia, (plane tree), Ambrosia artemisiifolia (ragweed) and Artemisia vulgaris (mugwort). Initially, nsLTP sensitization appeared to be limited to Mediterranean countries, however more recent studies suggest clinically relevant sensitization occurs in North Atlantic regions and also countries in Northern Europe, with nsLTP sensitisation profiles being broadly similar.
Discussion
These robust allergens have the potential to sensitize and provoke symptoms to a large number of plant foods, including those which are raw, cooked or processed. It is unknown why some sensitized individuals develop clinical symptoms to foods whereas others do not, or indeed what other allergens besides Pru p 3 may be primary sensitising allergens. It is clear that these allergens are also relevant in non‐Mediterranean populations and there needs to be more recognition of this.
Conclusion
Non‐specific LTP allergens, present in a wide variety of plant foods and pollens, are structurally robust and so may be present in both raw and cooked foods. More studies are needed to understand routes of sensitization and the world‐wide prevalence of clinical symptoms associated with sensitization to these complex allergens.
Sensitization to one or more non‐specific lipid transfer proteins (nsLTPs), initially thought to exist mainly in southern Europe, is becoming accepted as a cause of allergic reactions to plant foods across Europe and beyond. The peach nsLTP allergen Pru p 3 is a dominant sensitizing allergen and peaches a common food trigger, although multiple foods can be involved. A frequent feature of reactions is the requirement for a cofactor (exercise, alcohol, non‐steroidal anti‐inflammatory drugs, Cannabis sativa) to be present for a food to elicit a reaction. The variability in the food and cofactor triggers makes it essential to include an allergy‐focused diet and clinical history in the diagnostic workup. Testing on suspected food triggers should also establish whether sensitization to nsLTP is present, using purified or recombinant nsLTP allergens such as Pru p 3. The avoidance of known trigger foods and advice on cofactors is currently the main management for this condition. Studies on immunotherapy are promising, but it is unknown whether such treatments will be useful in populations where Pru p 3 is not the primary sensitizing allergen. Future research should focus on the mechanisms of cofactors, improving diagnostic accuracy and establishing the efficacy of immunotherapy.
Purpose of Review
To provide an overview of the prevalence and clinical manifestation of non-specific lipid transfer proteins (LTP)-mediated allergies outside the Mediterranean area and to address potential reasons for the different geographical significance of LTP-driven allergies.
Recent Findings
LTPs are major allergens in the Mediterranean area, which frequently can elicit severe reactions. Pru p 3 the LTP from peach is reported as genuine allergen and is considered a prototypic marker for LTP-mediated allergies. However, both food and pollen LTP allergies exist outside the Mediterranean area, but with lower clinical significance, different immunogenicity, and less clarified role.
Summary
Evidence has been reported that in areas with high exposure to pollen, in particular to mugwort, pollen-derived LTPs can act as a primary sensitizer to trigger secondary food allergies. Co-sensitization to unrelated allergens might be causative for less severe reactions in response to LTPs. However, the reason for the geographical different sensitization patterns to LTPs remains unclear.
Background
Although pollen‐related food allergy occurs in all European populations, lipid transfer protein (LTP) allergy is considered to manifest mainly in Mediterranean countries. We aimed to characterize adults presenting with LTP allergy in a northern European country.
Method
The clinical history and sensitization patterns of subjects born and residing in the United Kingdom (UK), with a prior diagnosis of LTP allergy and sensitization to the peach LTP allergen Pru p 3, were compared to UK subjects with pollen food syndrome (PFS). The sensitization patterns were also evaluated against a matched cohort of Italian subjects diagnosed with LTP allergy.
Results
None of the 15 UK PFS subjects had a positive SPT to LTP‐enriched peach reagent, compared to 91% of the 35 UK LTP subjects. The UK LTP cohort were also more likely to have positive skin prick tests to cabbage, lettuce and mustard and sensitization to the LTP allergens in peach, walnut, mugwort and plane tree These sensitization patterns to individual allergens were not significantly different to those obtained from the Italian LTP subjects, with significant correlations between Pru p 3 and the LTP allergens in peanuts, walnuts, plane tree and mugwort in both groups.
Conclusion
Native UK subjects with LTP allergy are not dissimilar to those with LTP allergy in southern Europe. Testing to LTP‐enriched peach SPT reagent and/or LTP allergens in peach, walnut, mugwort and plane tree may enhance diagnostic accuracy.
Background:
Measurement of IgE antibody to peanut components can aid in the prediction of allergic responses the food.
Objective:
To investigate the association between patient demographics (age, location) and allergic sensitization to peanut components across the United States.
Methods:
Serum samples from 12,155 individuals with peanut extract specific IgE levels of 0.35 kUA/L or higher were analyzed for IgE antibodies to Ara h 1, 2, 3, 8, and 9 by ImmunoCAP.
Results:
Among this population of peanut sensitized individuals, 79.1% of children (<3 years old) were sensitized to one or more peanut storage proteins (Ara h 1, 2, and/or 3), in contrast to 64.2% of adolescents (12-15 years old) and 22.1% of adults (>20 years old). Although sensitization was more prevalent to Ara h 2 than to the other storage proteins, a sizable fraction of patients were sensitized to Ara h 1 and/or 3 but not to Ara h 2 (eg, 13% of children <3 years old). Moreover, 9.6% of children, 10.2% of adolescents, and 10.5% of adults were sensitized to Ara h 9, whereas 2.4% of children, 49.4% of adolescents, and 42.9% of adults produced IgE to Ara h 8 (pathogenesis-related protein 10). Sensitization to Ara h 8 alone was markedly higher in the Northeastern United States relative to other regions of the country.
Conclusion:
We conclude that sensitization to individual peanut components is highly dependent on age and geographic location. Given that a severe allergic reaction to peanut is unlikely in individuals with isolated sensitization to Ara h 8, a sizable fraction of patients, in particular adolescents and adults, may be at lower risk than anticipated based only on demonstration of sensitization to whole peanut extract.
The study of cross-reactivity in allergy is key to both understanding. the allergic response of many patients and providing them with a rational treatment In the present study, protein microarrays and a co-sensitization graph approach were used in conjunction with an allergen microarray immunoassay. This enabled us to include a wide number of proteins and a large number of patients, and to study sensitization profiles among members of the LTP family. Fourteen LTPs from the most frequent plant food-induced allergies in the geographical area studied were printed into a microarray specifically designed for this research. 212 patients with fruit allergy and 117 food-tolerant pollen allergic subjects were recruited from seven regions of Spain with different pollen profiles, and their sera were tested with allergen microarray. This approach has proven itself to be a good tool to study cross-reactivity between members of LTP family, and could become a useful strategy to analyze other families of allergens.
The roles played by different peach allergens with respect to symptom severity have not been completely ascertained. We have evaluated the diagnostic efficacy of peach recombinant allergens ImmunoCAP compared to peach in the identification of subjects at an increased risk for severe reactions to peaches.
148 peach-allergic patients were divided based on their symptom severity into 2 groups: mild oral allergy syndrome (OAS) and severe OAS. Anti-rPru p 1, 3 and 4 IgE levels were measured. Statistical analyses were carried out using parametric and non-parametric tests.
anti-rPru p 1 and anti-rPru p 4 IgE levels were significantly higher in patients with mild OAS than in patients with severe OAS (p = 0.0001); in contrast, anti-rPru p 3 IgE levels were significantly higher in patients with severe OAS than in patients with mild OAS (p < 0.00005). Moreover, we found that any unitary increase in anti-rPru p 1 IgE values corresponded to a 2.48% reduction in the odds of having severe OAS (p = 0.048), whereas any unitary increase in anti-rPru p 3 IgE values corresponded to a 9.02% increase in the probability of having severe OAS (p = 0.001). Unexpectedly, we found that patients positive to rPru p 3 as well as rPru p 1 and 4 demonstrated a significant reduction of the odds of developing severe symptoms than those positive to rPru p 3 alone. Anti-rPru p 3 IgE levels were a significantly better indicator than anti-peach IgE values (p = 0.016) of patients with the highest risk for severe OAS. A cutoff of 2.69 kUA/l for anti-rPru p 3 IgE values better discriminated peach-allergic patients at a higher risk for symptoms.
Italian patients with positive anti-rPru p 1, 4 and 3 IgE levels seemed less likely to experience the clinical effects of high anti-rPru p 3 IgE values.
Microarray experiments generate vast amounts of data. The functional context of differentially expressed genes can be assessed by querying the Gene Ontology (GO) database via GoMiner. Directed acyclic graph representations, which are used to depict GO categories enriched with differentially expressed genes, are difficult to interpret and, depending on the particular analysis, may not be well suited for formulating new hypotheses. Additional graphical methods are therefore needed to augment the GO graphical representation.
We present an alternative visualization approach, area-proportional Euler diagrams, showing set relationships with semi-quantitative size information in a single diagram to support biological hypothesis formulation. The cardinalities of sets and intersection sets are represented by area-proportional Euler diagrams and their corresponding graphical (circular or polygonal) intersection areas. Optimally proportional representations are obtained using swarm and evolutionary optimization algorithms.
VennMaster's area-proportional Euler diagrams effectively structure and visualize the results of a GO analysis by indicating to what extent flagged genes are shared by different categories. In addition to reducing the complexity of the output, the visualizations facilitate generation of novel hypotheses from the analysis of seemingly unrelated categories that share differentially expressed genes.
Background:
There are hypersensitivity reactions (HRs) to foods in which nonsteroidal anti-inflammatory drugs (NSAIDs) act as aggravating factors (NSAID-exacerbated food allergy, NEFA) or cofactors (NSAID-induced food allergy, NIFA), often misdiagnosed as HRs to NSAIDs. Urticarial/angioedematous and/or anaphylactic reactions to ≥ 2 chemically unrelated NSAIDs do not meet the current classification criteria. However, they may be considered as part of a cross-reactive type of acute HR, which is NSAID-induced urticaria/angioedema with/without respiratory and/or systemic symptoms of anaphylaxis (NIUAA).
Objective:
To evaluate patients reporting acute HRs to NSAIDs and classify them according to updated criteria.
Methods:
414 patients with suspected HRs to NSAIDs were studied prospectively. NEFA/NIFA was diagnosed in those who met all the following criteria: 1) mild reactions to (NEFA) or tolerance of (NIFA) the suspected foods without taking NSAIDs; 2) cutaneous and/or anaphylactic reactions to the combination foods + NSAIDs; 3) positive allergy tests to the suspected foods; 4) negative drug challenges (DCs) with the NSAIDs involved.
Results:
252 patients (60.9%) were diagnosed with NSAID hypersensitivity, 108 of whom had NIUAA. NSAID hypersensitivity was excluded in 162 patients (39.1%) who tolerated DCs with the suspected NSAIDs, 9 of whom were diagnosed with NEFA and 66 with NIFA. Pru p 3 was implicated in 67 of these 75 cases.
Conclusion:
NEFA/NIFA accounts for about 18% of patients reporting HRs to NSAIDs, with Pru p 3 as the main responsible food allergen. Therefore, patients with cutaneous and/or anaphylactic reactions to NSAIDs should be carefully questioned about all foods ingested within 4 hours before or after NSAID exposure, and targeted food allergy tests should be considered in the diagnostic workup of these patients. If testing is positive, DCs with the suspected NSAIDs should also be considered.
The lipid transfer protein (LTP) is a pan-allergen found across a wide range of pollens and plant-based foods. The LTPs are highly resistant to heat treatment and proteolytic digestion, and have a propensity to cause severe food allergy reactions. A significant possibility of cross-sensitisation exists among LTP-containing foods. This can lead to a syndrome of allergies to multiple LTP-containing foods, most commonly the Rosaceae fruits and nuts, termed the ‘LTP syndrome.ʼ To date, LTP syndrome has been described commonly in Mediterranean Spain and less frequently in other areas of the world. This case report describes the case of a South African patient in his forties presenting with multiple new-onset food allergies, consistent with LTP syndrome.
Sensitization to lipid transfer protein (LTP), the most frequent cause of food allergy in southern Europe still shows several controversial, but also intriguing aspects. Some of these include the degree of cross‐reactivity between LTPs from botanically distant sources, the definition of risk factors, the role of some cofactors, clinical outcomes, geographical differences and the identification of the primary sensitizer in different areas. This review article tries to analyze and comment on these aspects point by point suggesting some explanatory hypotheses with the final scope to stimulate critical thoughts and elicit the scientific discussion about this issue in the readership.
Background:
Atopic dermatitis (AD) represents a chronic skin disorder seriously affecting patients' QoL and is often associated with immunological imbalance, disorders of the skin barrier function and environmental factors.
Objective:
We extensively studied the proteomic IgE sensitization profile in a large AD Mediterranean cohort.
Methods:
A total of 588 individuals with moderate-severe (70.6%) or mild and/or history of (29.4%) AD were evaluated in comparison to 1285 unselected atopic controls (AC) with a history of adverse reactions to foods, allergic rhinitis and/or bronchial asthma by means of ImmunoCAP ISAC112 ® and Allergy Explorer-ALEX® microarray analysis.
Results:
The olive tree pollen β-1,3-glucanase rOle e 9 and the manganese superoxide dismutase from Aspergillus rAsp f 6 were the molecules most significantly associated with AD occurrence and allowed to discriminate among the moderate and severe forms of disease. An IgE hyper-reactivity to cypress, grasses, olive tree, house dust mites (including rDer p 11), and to all cross-reactive components except profilin and polcalcin was observed. About 60% of adults with severe AD were sensitized to nsLTPs. Cross-reactive carbohydrate determinants (CCDs) IgE was found in about one-third of AD participants. Hen eggs nGal d 1 IgE sensitization was more prevalent in the paediatric population, whilst rAsp f 6 and rOle e 9 reactivity was found particularly in older patients. Despite the status of widespread IgE sensitization to both environmental and food allergens, a reduced frequency of patient-reported severe reactions to food or of asthma was observed in AD patients compared to AC, particularly in case of concomitant Ole e 9 reactivity.
Conclusion and clinical relevance:
Testing IgE reactivity to a large panel of molecular components unveils important associations between IgE reactivity profiles and AD clinical presentation, highlights the allergens useful for a precise AD signature and allows the detection of interesting sensitisations patterns.
Nine hundred thirty-nine rPla a 1, nPla a 2 and rPla a 3 ImmunoCAP ISAC reactors were studied. nPla a 2(pos) MUXF3(pos) but Pla a 1/2(neg) subjects were excluded from the study because they were CCD reactors. Amongst the 764 remaining participants, 71.9% were Pla a 3(pos) , 54.1% Pla a 2(po) s and 10.9% Pla a 1(pos) . Among Pla a 3 reactors, 89.6% were Pru p 3(pos) and 86.8% Jug 3(pos) , but the strongest IgE recognition relationship was observed between Pla a 3 and Jug r 3. Distinctive clinical subsets could be documented among plane-tree allergic patients. Pla a 3 reactors had both local and systemic food-induced reactions, but lower past respiratory symptoms occurrence. Pla a 2 reactivity was associated with respiratory symptoms but inversely related to systemic reactions to food. Co-sensitization to Pla a 2 and Pla a 3 was associated with a lower past incidence of severe food-induced reactions. This article is protected by copyright. All rights reserved.
1. An active fraction which stimulates the exchange of phospholipids between microsomal fractions and mitochondria was isolated by gel filtration from potato tuber homogenates.
Non-specific lipid transfer proteins (nsLTPs) represent a major cause of systemic food allergic reactions in the Mediterranean area. This study investigate hierarchical patterns and cluster relationships of IgE sensitization to different nsLTPs, and the relationship to clinical allergy in a large Italian cohort.
568 nsLTPs positive subjects after IgE ImmunoCAP ISAC microarray analysis with Ara h 9, Art v 3, Cor a 8, Jug r 3, Pla a 3, Pru p 3 and Tri a 14 allergens, were studied. IgE inhibition experiments were carried out with mugwort and plane tree pollen extracts.
82% of nsLTP positive participants (94% if <6 years old) were Pru p 3(pos) and 71% were Jug r 3(pos) . Participants who reacted to >5 nsLTPs reported a higher incidence of food-induced systemic reactions. Only Art v 3 and Pla a 3 (mugwort and plane tree nsLTPs, respectively) were associated with respiratory symptoms, and a correlation was observed between sensitization to pollen and plant food nsLTPs, particularly between Pla a 3 and tree nut/peanut nsLTPs. Co-sensitization to Par j 2 and PR-10 or profilin pan-allergens was associated with a lower prior prevalence of severe food-induced reactions. In inhibition assays, plane and mugwort pollen extracts inhibited 50%-100% of IgE binding to food nsLTPs in microarrays.
Testing IgE reactivity to a panel of nsLTP allergens unveils important associations between nsLTP sensitization profiles and clinical presentation, and allows the identification of novel cluster patterns indicating likely cross-reactivities and highlighting potential allergens for nsLTP immunotherapy. This article is protected by copyright. All rights reserved.
This article is protected by copyright. All rights reserved.
Lipid transfer proteins (LTPs) are clinically relevant plant food panallergens and have been proposed as ideal tools to study true food allergy. Pru p 3, the major peach allergen in the Mediterranean area, is among the best-characterized allergenic members of the LTP family. Its diagnostic value for Rosaceae fruit allergy has been demonstrated both in vivo and in vitro.Objective
We sought to locate major IgE-binding epitopes of Pru p 3.MethodsA serum pool and individual sera from patients with peach allergy and positive skin prick test results to Pru p 3 were used. Three-dimensional modeling was achieved by using experimentally available structures of Pru p 3 homologues as templates. Theoretical prediction of potential IgE-binding regions was performed by selecting specific residues on the molecular surface displaying prominent electrostatic potential features. Point mutants of Pru p 3 were constructed by standard polymerase chain reaction procedures with the appropriate primers. Mutants were expressed in P pastoris by means of the pPIC 9 vector and purified from the corresponding supernatants by gel-filtration chromatography followed by RP-HPLC. IgE binding by Pru p 3 mutants was tested by immu-nodetection and quantified by ELISA and ELISA inhibition assays. Synthetic peptides (10 mer; 5 amino acids overlapping) covering the full Pru p 3 sequence were used to detect IgE epitopes by 125I–anti-IgE immunodetection.ResultsPru p 3 showed a 3-dimensional structure comprising 4 α-helixes and a nonstructured C-terminal coil (residues 73 to 91). Regions around amino acids in positions 23 to 36, 39 to 44, and 80 to 91, particularly residues R39, T40, and R44, K80 and K91, were predicted as potential antibody recognition sites according to their relevant surface and electrostatic properties. Point mutants K80A and K91A were found to have an IgE-binding capacity similar to that of recombinant Pru p 3, but the triple mutant R39A/T40A/R44A showed a substantial decrease (approximately 5 times) of IgE binding. IgE immu-nodetection of synthetic peptides led to the identification of Pru p 3 sequence regions 11 to 25, 31 to 45, and 71 to 80 as major IgE epitopes.Conclusions
Main IgE-binding regions of the Pru p 3 amino acid sequence were identified. The three major ones comprised the end of an α-helix and some residues of the following interhelix loop. These data can help to search for Pru p 3 hypoallergenic forms.
Allergy to fresh fruits and vegetables is mostly observed in subjects with pollinosis, especially from birch, because of cross-reacting allergens in vegetable foods and pollens. However, allergic reactions to fruits, specifically Rosaceae fruits, have been reported in subjects without pollinosis.
This study evaluated the pattern of IgE reactivity, identifying the allergen responsible in 2 groups of patients with oral allergy syndrome to peach with or without birch pollinosis.
The allergenic components of peach were detected by SDS-PAGE and immunoblotting. The major peach allergen was purified by HPLC with a cation-exchange column followed by gel filtration chromatography. Its IgE-binding capacity and its homology with the protein of the crude extract were demonstrated by immunoblotting inhibition techniques. To better characterize this allergen, periodic acid-Schiff stain and isoelectrofocusing were used. The amino acid sequencing was done with a gas-phase sequencer.
SDS-PAGE and immunoblotting of the 15 patients allergic to peach, 8 without and 7 with birch pollinosis, showed that they all recognized a protein with a molecular weight of 9 kd. This was the only allergen recognized by patients not sensitized to pollen, whereas the birch pollen-sensitive patients had IgE binding to other allergenic proteins at higher molecular weights. The purified 9-kd protein retained its IgE-binding capacity, was negative to periodic acid-Schiff stain, and had an isoelectric point value of greater than 9. A search in the Swiss Prot Bank showed this was a lipid transfer protein, belonging to a group of molecules involved in the defensive system of plants.
The major allergen of peach is a 9-kd protein belonging to the group of lipid transfer proteins. This is the only allergen recognized by patients allergic to peach but not sensitized to birch pollen.
One of the major challenges of molecular allergy is to predict the allergenic potential of a protein, particularly in novel foods. Two aspects have to be distinguished: immunogenicity and cross-reactivity. Immunogenicity reflects the potential of a protein to induce IgE antibodies, whereas cross-reactivity is the reactivity of (usually preexisting) IgE antibodies with the target protein. In addition to these two issues, the relation between IgE-binding potential and clinical symptoms is of interest. This is influenced by physical properties (eg, stability and size) and immunologic properties (affinity and epitope valence). Discussions on immunogenicity and cross-reactivity of allergens rely on the establishment of structural similarities and differences among allergens and between allergens and nonallergens. For comparisons between the 3-dimensional protein folds, the representation as 2-dimensional proximity plots provides a convenient visual aid. Analysis of approximately 40 allergenic proteins (or parts of these proteins), of which the protein folds are either known or can be predicted on the basis of homology, indicates that most of these can be classified into 4 structural families: (1) antiparallel beta-strands: the immunoglobulin-fold family (grass group 2, mite group 2), serine proteases (mite group 3, 6, and 9), and soybean-type trypsin inhibitor (Ole e 1, grass group 11); (2) antiparallel beta-sheets intimately associated with one or more alpha-helices: tree group 1, lipocalin, profilin, aspartate protease (cockroach group 2); (3) (alpha+beta) structures, in which the alpha- and beta-structural elements are not intimately associated: mite group 1, lysozyme/lactalbumin, vespid group 5; and (4) alpha-helical: nonspecific lipid transfer protein, seed 2S protein, insect hemoglobin, fish parvalbumin, pollen calmodulin, mellitin from bee venom, Fel d 1 chain 1, serum albumin. Allergens with parallel beta-strands (in combination with an alpha-helix linking the two strands, a motif commonly found in, for example, nucleotide-binding proteins) seem to be underrepresented. The conclusion is that allergens have no characteristic structural features other than that they need to be able to reach (and stimulate) immune cells and mast cells. Within this constraint, any antigen may be allergenic, particularly if it avoids activation of T(H)2-suppressive mechanisms (CD8 cells and T(H)1 cells).
Lipid transfer proteins : the most frequent sensitizer in Italian subjects with food-dependent exercise-induced anaphylaxis
- A Romano
- E Scala
- G Rumi
- F Gaeta
- C Caruso
- C Alonzi
Romano A, Scala E, Rumi G, Gaeta F, Caruso C, Alonzi C et al. Lipid transfer proteins : the most
frequent sensitizer in Italian subjects with food-dependent exercise-induced anaphylaxis
Clinical & Experimental Allergy. 2012;:1643-1653. DOI: 10.1111/all.14797
Relationship between peach lipid transfer protein specific IgE levels and hypersensitivity to non-Rosaceae vegetable foods in patients allergic to lipid transfer protein
- R Asero
- G Mistrello
- D Roncarolo
- S Amato
Asero R, Mistrello G, Roncarolo D, Amato S. Relationship between peach lipid transfer protein
specific IgE levels and hypersensitivity to non-Rosaceae vegetable foods in patients allergic
to lipid transfer protein. Ann Allergy, Asthma Immunol 2004;92:268-272. DOI:
10.1016/S1081-1206(10)61559-1