Lipid Transfer Protein Allergy Research Articles

Group 2 innate lymphoid cells are key in lipid transfer protein allergy pathogenesis.

Immunopathology in food allergy is characterized by an uncontrolled type 2 immune response and specific-IgE production. Recent studies have determined that group 2 innate lymphoid cells (ILC2) participate in the food allergy pathogenic mechanism and their severity. Our objective was to investigate the role of ILC2 in peach-allergic patients due to non-specific lipid transfer protein (Pru p 3) sensitization. The immune response in peripheral blood mononuclear cells was characterized in lipid transfer protein-allergic patients and healthy controls. We have analyzed the Pru p 3 uptake on ILC2, the expression of costimulatory molecules, and their involvement on the T-cell proliferative response and cytokine production under different experimental conditions: cytokines involved in group 2 innate lymphoid cell activation (IL-33 and IL-25), Pru p 3 as main food allergen, and the combination of both components (IL-33/IL-25+Pru p 3) using cell sorting, EliSpot, flow cytometry, and confocal microscopy. Our results show that Pru p 3 allergen is taken up by group 2 innate lymphoid cells, regulating their costimulatory molecule expression (CD83 and HLA-DR) depending on the presence of Pru p 3 and its combination with IL-33/IL-25. The Pru p 3-stimulated ILC2 induced specific GATA3+Th2 proliferation and cytokine (IL-4, IL-5, and IL-13) production in lipid transfer protein-allergic patients in a cell contact-dependent manner with no changes in Tbet+Th1- and FOXP3+Treg cell differentiation. The results indicate that in lipid transfer protein-allergic patients, the responsible allergen, Pru p 3, interacts with group 2 innate lymphoid cells, promoting a Th2 cell response. Our results might be of interest in vivo, as they show a role of group 2 innate lymphoid cells as antigen-presenting cells, contributing to the development of food allergy. Consequently, group 2 innate lymphoid cells may be considered as potential therapeutic targets.

Clinical management of plant food allergy in patients sensitized to lipid transfer proteins is heterogeneous: identifying the gaps.

Patients sensitized to lipid transfer protein (LTP) present a wide clinical variability. The lack of practical diagnostic and therapeutic guidelines complicate their management. The aim of the study was to describe the clinical approach of Spanish allergists to this pathology using a survey designed by PICO method and subsequent Delphi approach validation. Designed survey was answered by 224 allergists (75% women; 57.1% with >20 years of professional experience). Homogeneity regarding clinical practice on the main points of LTP allergy diagnosis was observed, except for patients with suspected NSAID hypersensitivity (44.6% frequently include LTP skin testing). Oral food challenges were not frequently performed (63.6% occasionally to never), and they were generally (75.5%) used to confirm tolerance. It was common to recommend fruit skins avoidance (77.2%) and maintaining consumption of foods to which patients are sensitised but tolerant (99.1%). There was heterogeneity on other dietary indications, modifications due to co-factors, or traces avoidance. Peach sublingual immunotherapy (SLIT) was considered very/quite effective by 55.9% of allergists. The majority (79.5%) consider SLIT indicated in <25% of LTP allergic patients, based on severity (95.2%), frequency of reactions (99.4%), allergy to multiple food families (97.4%), and the quality of life/nutrition impairment (91.5%). There was different practice on SLIT prescription based on co-factor involvement. These data suggest that there is a need to increase evidence to reduce the clinical practice heterogeneity in the management of LTP allergy.

Sensitization to nsLTP: A Retrospective Study in An Italian Pediatric Population over the Last Decade.

Food allergy is common in the Mediterranean, especially concerning lipid transfer proteins (LTPs) allergy. LTPs are widespread plant food allergens in fruits, vegetables, nuts, pollen, and latex. Also, LTPs are prevalent food allergens in the Mediterranean area. They can sensitize via the gastrointestinal tract and cause a wide range of conditions: from mild reactions, such as oral allergy syndrome, to severe reactions, such as anaphylaxis. LTP allergy in the adult population is well described in the literature, concerning both the prevalence and clinical characteristics. However, there is poor knowledge about its prevalence and clinical manifestation in children living in the Mediterranean. This study, including 800 children aged from 1 to 18 years, investigated the prevalence of 8 different molecules of nonspecific LTP over time in an Italian pediatric population visited over the last 11 years. About 52% of the test population was sensitized to at least one LTP molecule. For all the LTPs analyzed, sensitization increased over time. In particular, using the years 2010 through 2020 as a comparison, the major increases were observed for the LTPs of the English walnut Jug r 3, the peanut Ara h 9, and the plane tree Pla a 3 (about 50%); the increase of the LTP of the Hazelnut Cor a 8 was about 36%, and that of the LTP of the artemisia Art v 3 was approximately 30%. The latest evidence in the literature indicates an increase in food allergy prevalence in the general population, including children. Therefore, the present survey represents an interesting perspective about the pediatric population of the Mediterranean area, exploring the trend of LTP allergy.

Lipid transfer protein allergy and anaphylaxis in children

Lipid transfer protein (LTP) is a pan-allergen widely distributed in plants, including Rosaceae family fruits, non-Rosaceae family fruits (such as Vitaceae, Solanaceae and Oleaceae), tree nuts, legumes, vegetables, cereals, seeds and latex1. Food allergy (FA) to LTP is an IgE-mediated allergy with increasing incidence in children2. Studies from Spain report that LTP allergy explains 5% of cases of pediatric FA and that up to 26% of children with a history of reactions to vegetables/fruits are LTP sensitized2, which can develop through direct gastrointestinal, cutaneous or respiratory exposure to LTP2, with current evidence arguing against a primary pollen sensitization3.

Lipid transfer protein allergy: characterization and comparison to birch-related food allergy.

Lipid transfer proteins (LTP) are a frequent elicitor of anaphylaxis to plant-derived food allergens in southern Europe. 15 German patients with LTP allergy were compared to 17 patients with birch-related food allergy (BRFA) using a detailed anamnesis, serology, skin tests, and the FAQLQ-AF quality of life questionnaire. While patients with BRFA mainly reacted to tree nuts, and pome and stone fruits, LTP allergic individuals reported vegetables, berry fruits, cereals, and seeds as common additional elicitors. Anaphylaxis was associated with cofactors in 73% of LTP allergic patients compared to only 6% in BRFA (P&lt;0.001). Symptoms occurred delayed by more than one hour in 40% and were triggered by raw and cooked foodstuffs in 86% of LTP allergic patients, compared to only 6% and 41% of BRFA patients, respectively. A peach prick test was positive in all LTP allergic patients, but only in 15% of BRFA patients (P&lt;0.001). Although patients with LTP allergy reported severe anaphylaxis more frequently, quality of life did not differ between groups. Anaphylaxis to plant-derived foodstuffs warrants assessment by IgE detection to Pru p 3 and skin tests with peach extract, particularly if cofactors and intolerance to heated foodstuffs are related.

Anaphylaxis across Europe: are pollen food syndrome and lipid transfer protein allergy so far apart?

Traditionally pollen-food syndrome (PFS) is considered to be a mild cross-reacting food allergy affecting only Northern Europe, with lipid transfer protein (LTP) allergy being more severe and mainly occurring in Southern Europe. This review seeks to update the reader on both types of plant food allergy and to determine whether the stereotypical presentations of these plant food allergies remain the same, with a particular focus on reaction severity. Recent findings suggest that both these types of plant food allergy occur in children and adults. Although it is true that PFS allergy is more prevalent in Northern Europe and LTP allergy is more well known in Southern Europe, these conditions are not hidebound by geography, and the increasing spread and allergenicity of pollen due to global warming continues to change their presentation. Both conditions have a spectrum of symptom severity, with PFS sometimes presenting with more severe symptoms, including anaphylaxis and LTP allergy with milder reactions. It is important to consider that in many parts of Europe, reactions to plant foods, especially fruits or vegetables, could be mediated either by pollen cross-reactivity or primary sensitization to LTP allergens. All those presenting with symptoms to plant foods will benefit from a detailed clinical history and appropriate tests so that an accurate diagnosis can be made, and correct management implemented.

Why lipid transfer protein allergy is not a pollen-food syndrome: novel data and literature review.

Background.Based on the cross-reactivity between pollen lipid transfer proteins (LTPs) and the peach LTP, Pru p 3, it has been suggested that the pollen might initiate the LTP sensitization process. Objective. To establish whether LTP allergy can be considered as a pollen-food syndrome. Methods. The literature was reviewed and new data of component-resolved diagnosis from Italy obtained by both ISAC immunoassay and ImmunoCAP on large populations of LTP hypersensitive patients were provided and analyzed. Results. Among Pru p 3 reactors, patients positive for Art v 3 and Pla a 3 largely exceeded those sensitized to the respective major pollen allergens, Art v 1 and Pla a 1/Pla a 2. Pru p 3 reactivity remained stable around 80-90% at all ages, whereas Art v 3 and Ole e 7 recognition was missing in younger patients. Pru p 3 IgE exceeded IgE specific for pollen LTP at all ages. Inhibition studies carried out on LTP reactors showed that commercial extracts of mugwort and plane pollen were unable to inhibit significantly Pru p 3 IgE reactivity. In follow-up studies, baseline Pru p 3 IgE levels exceeded Art v 3 IgE levels in 84% of those sensitized to both allergens, and all patients positive to only one LTP allergen at baseline were sensitized to Pru p 3. Further, most of the patients who did not show any LTP reactivity at baseline became exclusive Pru p 3 reactors. On ImmunoCAP singleplex Pru p 3 IgE levels exceeded Art v 3 IgE levels in 89% of cases (p less than 0.0001). Most literature data were in keeping with these new observations. Conclusions. The evidence for LTP syndrome being a pollen-food syndrome is presently very thin. Our data do not rule out the possible sensitization to the protein, via the airways or the skin.

Low Levels Matter: Clinical Relevance of Low Pru p 3 sIgE in Patients With Peach Allergy

Many clinical lab settings still use 0.35 KUA/L as the cut-off for serum specific-IgE (sIgE) immunoassays, while the detection limit is 0.1 KUA/L. The clinical relevance of -low-level sIgE (0.1–0.35 KUA/L) remains controversial. Pru p 3 sIgE is considered to be the main routine tool for assessing lipid transfer protein (LTP) sensitization. We aimed to evaluate the clinical relevance of Pru p 3 sIgE low levels in a population diagnosed with LTP allergy. Adults diagnosed with LTP allergy and Pru p 3 sIgE ≥ 0.1 KUA/L between 2012 and 2019 were included. Clinical data were reviewed. nPru p 3 basophil activation test (BAT) was performed and basophil reactivity (BR) and sensitivity (BS) correlated with the peach allergy symptoms. Pru p 3 sIgE from 496 subjects was recorded, 114 (23.0%) between 0.1 and 0.34 KUA/L (grLOW), the rest ≥ 0.35 KUA/L (grB). A total of 44.7% in grLOW and 59.9% in grB were allergic. Urticaria was more frequent in grLOW. In grLOW, Pru p 3 sIgE was higher in patients with local compared with systemic symptoms. In grB, Pru p 3 sIgE was higher in allergic patients. Pru p 3/Total IgE ratios were higher in allergic vs. tolerant in both groups. In BAT, BR was similar in both groups. In grLOW, it was higher on allergic compared with tolerant (p = 0.0286), and on those having systemic vs. local symptoms (p = 0.0286). BS showed no significant difference between groups. Patients with low levels represent a non-negligible fraction and around 45% are peach allergic. BAT showed functional sIgE in them. Pru p 3 sensitizations should be carefully evaluated even when sIgE levels are low.

Lipid transfer protein allergy: A review of current controversies.

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 analyse 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.

Pru p 3 Sublingual Immunotherapy in Patients with Lipid Transfer Protein Syndrome: Is It Worth?

Background: Lipid transfer proteins (LTPs) syndrome is an important cause of multiple plant food allergy in the Mediterranean area. The effectiveness of sublingual immunotherapy (SLIT) with the LTP Pru p 3 extract has been little investigated in the real-world setting. This study aimed to investigate the outcome of Pru p 3 SLIT in real-life patients with LTP syndrome with/without concurrent reactions to peanut and/or nuts. Methods: This was a prospective real-life study including all patients diagnosed with LTP allergy and treated with Pru p 3 SLIT between 2011 and 2018 in a tertiary hospital in Spain. Patients underwent open oral food challenge (OFC) tests for unpeeled peach and nuts/peanuts 1 year after the treatment started to assess food tolerance. A control group of patients diagnosed with LTP allergy who refused treatment with immunotherapy were included. Severity of symptoms and diet avoidance was recorded in both groups. Results: Twenty-nine patients with a median age of 24.7 years (range 5.5–43.1) were included: 100% were allergic to fruit; 72%, to peanut and/or nuts; 19 had a history of severe systemic reactions. Seven patients discontinued therapy; 3 (10%), due to adverse events. One year after SLIT start, 16 (73%) patients had negative OFC to peach; 95%, after 2 years; 69% had negative OFC to nuts/peanuts. The control group included 13 patients: 53.8% experienced reactions with new foods; severity of symptoms increased significantly (p < 0.001), and diet restrictions were maintained in this group. Conclusions: SLIT with Pru p 3 shows a good safety profile, and avoid dietary restrictions in patients with LTP syndrome treated in the real-life setting.

Hydrogen/deuterium exchange memory NMR reveals structural epitopes involved in IgE cross-reactivity of allergenic lipid transfer proteins

Identification of antibody-binding epitopes is crucial to understand immunological mechanisms. It is of particular interest for allergenic proteins with high cross-reactivity as observed in the lipid transfer protein (LTP) syndrome, which is characterized by severe allergic reactions. Art v 3, a pollen LTP from mugwort, is frequently involved in this cross-reactivity, but no antibody-binding epitopes have been determined so far. To reveal human IgE-binding regions of Art v 3, we produced three murine high-affinity mAbs, which showed 70-90% coverage of the allergenic epitopes from mugwort pollen-allergic patients. As reliable methods to determine structural epitopes with tightly interacting intact antibodies under native conditions are lacking, we developed a straightforward NMR approach termed hydrogen/deuterium exchange memory (HDXMEM). It relies on the slow exchange between the invisible antigen-mAb complex and the free 15N-labeled antigen whose 1H-15N correlations are detected. Due to a memory effect, changes of NH protection during antibody binding are measured. Differences in H/D exchange rates and analyses of mAb reactivity to homologous LTPs revealed three structural epitopes: two partially cross-reactive regions around α-helices 2 and 4 as well as a novel Art v 3-specific epitope at the C terminus. Protein variants with exchanged epitope residues confirmed the antibody-binding sites and revealed strongly reduced IgE reactivity. Using the novel HDXMEM for NMR epitope mapping allowed identification of the first structural epitopes of an allergenic pollen LTP. This knowledge enables improved cross-reactivity prediction for patients suffering from LTP allergy and facilitates design of therapeutics.

Sensitisation to lipid transfer proteins in pollen - allergic adults with food allergy.

IntroductionFood allergy affects 6–17% of Europeans and in 60% of the cases it is accompanied by inhalation allergy. This is due to two phenomena, namely co-sensitisation and cross-reactivity, which are caused by panallergens, such as lipid transfer proteins (LTP). These proteins are classified as defence proteins PR-14 and are responsible for protecting the plant from bacterial and fungal infections. Clinically, LTP allergy manifests with severe anaphylactic reactions or milder reactions, such as oral allergy syndrome.AimTo assess the incidence of specific IgE to components belonging to LTP based on molecular testing.Material and methodsThe study was conducted at the Department of Allergy, Clinical Immunology and Internal Diseases in Bydgoszcz, Poland. A total of 50 subjects participated in the study. Each subject had their asIgE levels determined with ImmunoCap ISAC.Results and ConclusionsAntigen-specific IgE antibodies to LTP components were identified in 24% of the subjects. In subjects with LTP allergy, adverse skin reactions were the most common after consumption of sensitising foods. Peach was the most common food allergen triggering these reactions. The Artemisia vulgaris component Art v 3 was the precursor of LTP allergy in our study population: the highest incidence and the highest mean levels of asIgE were demonstrated for this component.

Performance of basophil activation test and specific IgG4 as diagnostic tools in nonspecific lipid transfer protein allergy: Antwerp‐Barcelona comparison

Recent studies show that nsLTP sensitization is not limited to the Mediterranean basin and can present diverse clinical phenotypes. It remains challenging to predict clinical outcome when specific IgE antibodies (sIgE) to nsLTPs are present. This study compares both clinical and in vitro allergy characteristics but also diagnostic performance of a basophil activation test (BAT) and sIgG4 in nsLTP-sensitized patients from Antwerp (ANT, Belgium) and Barcelona (BCN, Spain). Adult subjects with positive sIgE rPru p 3 and/or rMal d 3≥0.10kUA /L (n=182) and healthy controls (n=37) were included. NsLTP-sensitized individuals were stratified according to clinical symptoms with peach/apple, respectively. BAT rPru p 3 and rMal d 3 were performed and sIgG4 antibodies to both components quantified. In BCN, only ratios of sIgG4/sIgE rMal d 3 and BAT rMal d 3 (0.001µg/mL) can identify clinically relevant Mal d 3 sensitization (sensitivity of 60%-63% and a specificity of 75%-67%, respectively). In ANT, only the sIgE/total IgE rPru p 3 ratio shows added value (sensitivity 60% and specificity 83%). Finally, it appears that symptomatic patients in BCN are more sensitive to lower allergen concentrations compared to ANT. In addition, it was shown that ANT patients were more often sensitized to pollen and that specific pollen sources differed between regions. NsLTP-related allergy profiles and diagnostic performance differ significantly between regions and are component-specific, which makes extrapolation of data difficult to do. In addition, it seems that basophil sensitivity might show geographical differences. Additional research is needed to confirm these findings.

Non-specific lipid transfer protein allergy in United Kingdom

Non-specific lipid transfer protein allergy in United Kingdom

Lipid Transfer Protein allergy in the United Kingdom: Characterization and comparison with a matched Italian cohort.

BackgroundAlthough 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.MethodThe 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.ResultsNone 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.ConclusionNative 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.

Food Allergies Caused by Allergenic Lipid Transfer Proteins: What Is behind the Geographic Restriction?

To critically examine evidence suggesting that food allergy induced by lipid transfer proteins (LTPs) follows a geographic pattern. LTP syndrome remains most common in the Mediterranean basin, with a clear gradient seen in prevalence of LTP sensitization between northern and southern Europe. We hypothesize that high levels of birch pollen seem to protect against LTP allergy, as these higher levels correlate with a lower prevalence of LTP hypersensitivity. Nevertheless, LTP food allergy cases still appear in areas having a high environmental level of birch pollen. Food allergy caused by LTP may be related to (1) primary sensitization to a food LTP allergen in the absence of pollinosis, (2) primary sensitization to LTP from a pollen source, and (3) co-sensitization to LTP from pollen and food.

The clinical relevance of lipid transfer protein.

Despite a huge number of studies, many aspects of the lipid transfer protein (LTP) syndrome, the most frequent primary food allergy in Mediterranean countries, remain unclear. Its peculiar geographical distribution, along with the extreme variability of its clinical expression, makes this type of food allergy something unique in the panorama of IgE-mediated food-induced allergic reactions. This review article tried to summarize the current knowledge about the most important aspects of LTP sensitization and allergy, along with the importance of positive and negative co-factors in the clinical expression of the syndrome as well as the issues regarding the cross-reactivity between LTPs present in botanically related and unrelated foods. Further, the possible absence of the protein from some plant foods is discussed.

SUN-PP272: Vitamin Status in Patients Subjected to Severe Dietary Restrictions Due to Lipid Transfer Protein Allergy

SUN-PP272: Vitamin Status in Patients Subjected to Severe Dietary Restrictions Due to Lipid Transfer Protein Allergy

Role of Art v 3 in pollinosis of patients allergic to Pru p 3

Food allergy caused by lipid transfer protein (LTP) from peach (Pru p 3) is frequently associated with sensitization to mugwort LTP (Art v 3). Although in vitro cross-reactivity is already well known, it has yet to be elucidated whether a pollen LTP can induce rhinitis. The aim of this study was to investigate whether mugwort LTP could elicit respiratory symptoms and whether a primary food LTP allergy could lead to a respiratory allergy. Patients with confirmed Pru p 3 allergy and control subjects were selected. Immediate responses to nasal allergen provocation tests (NAPTs) with Art v 3, Pru p 3, and mugwort were assessed by using the visual analog scale score, total nasal symptom score, and acoustic rhinometry. Tryptase and cysteinyl leukotriene (cysLT) levels were measured in nasal lavage fluid. Immunoblotting, ELISAs, and ELISA inhibition assays were also performed. Fifteen patients and 9 control subjects were selected. NAPT results with Art v 3 and Pru p 3 showed significant changes in acoustic rhinometry, visual analog scale scores, total nasal symptom scores, and cysLT levels (P < .001). Tryptase levels were only increased in NAPTs with Pru p 3. NAPTs with mugwort were used in those patients who were only sensitized to Art v 3, with similar results (P < .05). No significant changes were detected in control subjects. The results demonstrated that a pollen LTP can elicit rhinitis in sensitized patients. Findings also suggest that a primary sensitization to Pru p 3 can lead to a respiratory allergy through cross-reactivity.

Anaphylaxis to plant-foods and pollen allergens in patients with lipid transfer protein syndrome

Nonspecific lipid transfer protein (LTP) is the main cause of primary food allergy in adults living in the Mediterranean area. The way allergic patients get sensitized to this protein is all but established, and the clinical expression of sensitization is extremely variable, ranging from long-lasting symptomless sensitization to severe anaphylaxis. Such variability is seemingly due to the presence/absence of a number of cofactors. The possibility that LTP sensitization occurs via the inhalation of LTP-containing pollen particles seems unlikely; in contrast, peach particles containing the protein seem able to sensitize both via the airways and the skin. Cosensitization to pollen allergens as well as to labile plant food allergens makes LTP allergy syndrome less severe. In some LTP sensitized subjects clinical food allergy occurs only in the presence of cofactors such as exercise, NSAIDs, or chronic urticaria. Lipid transfer protein allergy syndrome shows some peculiarities that are unique in the primary food allergy panorama: geographical distribution, frequent asymptomatic sensitization, frequent need for cofactors, and reduced severity when pollen allergy is present. Future studies will have to address these points as the results may have favorable effects on other, more severe, types of food allergy.