BACKGROUND:Hazelnut and walnut allergy may cause severe reactions, but the clinical relevance of individual seed storage proteins, including recently available vicilins, remains incompletely defined. METHODS:We performed an observational analysis of a consecutive tertiary-care cohort of 114 patients with tree nut allergy, including 70 with walnut allergy and 44 with hazelnut allergy. Clinical severity was classified as mild, moderate, or severe. Specific IgE to selected hazelnut and walnut components was assessed by ImmunoCAP. We evaluated sensitisation frequencies, severity-stratified molecular profiles, and the diagnostic contribution of newly available vicilins in a singleplex format, vicilin co-sensitisation patterns by network and heatmap analyses, ROC performance for severe reactions, and parsimonious multivariable logistic regression models adjusted for age and sex. RESULTS:Severe reactions were more frequent in hazelnut than in walnut allergy (43.2% vs. 24.3%). Cor a 14, Cor a 9, and Cor a 16 showed the clearest severity-related gradients in hazelnut allergy, and Jug r 1 and Jug r 2 in walnut allergy. Co-sensitisation was strongest between the type 2 vicilins Cor a 16 and Jug r 2. Cor a 16 showed the highest AUC among hazelnut components (0.72), with overlapping performance for Cor a 14 and Cor a 9, whereas Jug r 1 performed best among walnut components (AUC 0.89). After adjustment for age and sex, severe reactions remained associated with Cor a 14, Jug r 1, and Jug r 2. CONCLUSIONS:In this tertiary-care cohort, individual seed storage proteins differed in their associations with reaction severity. Cor a 14 and Jug r 1 showed the strongest adjusted associations, while type 2 vicilins dominated co-sensitisation patterns. Overall, these findings support the clinical value of molecule-resolved diagnostics and suggest that integrating multiple vicilin components may improve molecular stratification of tree nut allergy, although external validation is required.

BACKGROUND:Cereal allergy comprises a heterogeneous spectrum of sensitization patterns directed toward water-soluble and gluten-derived proteins. The role of molecular cross-reactivity with homologous allergens from other cereals remains only partially understood. OBJECTIVE:To investigate IgE reactivity to major wheat allergens (Tri a 14, Tri a 19, Tri a 30) and their homologs across cereals and pseudocereals, integrating bioinformatic, epidemiological, and clinical data. METHODS:Sequence homology was assessed using BLAST analysis across cereal and pseudocereal proteomes. IgE reactivity was evaluated in 17,510 patients using two multiplex platforms (ImmunoCAP ISAC and ALEX2). Clinical data were available for 7201 individuals. RESULTS:Tri a 14 displayed high sequence identity with multiple cereal nsLTPs, including a hitherto undefined maize-derived protein (72%), suggesting broad cross-reactivity, whereas Zea m 14 showed higher identity with Pru p 3 than with Tri a 14. Homologs of Tri a 30 and Tri a 19 were found in spelt and durum wheat. Sensitization to wheat allergens was rare (3.9%); Tri a 14 was the most frequent (64%), followed by Tri a 30 (23%) and Tri a 19 (18%). The limited cases of Tri a 14 or Tri a 19 were specifically associated with severe reactions and WDEIA. Limited co-sensitization indicated distinct IgE pathways to soluble and gluten-related proteins. CONCLUSIONS:IgE profiling revealed distinct cross-reactivity patterns across cereals. Tri a 14 frequently co-sensitized with nsLTPs from both gluten-containing and gluten-free cereals, while Tri a 19 was exclusive to gluten-containing species. These findings support the need to expand molecular diagnostic panels to enhance clinical accuracy and guide dietary recommendations.

Background: Hymenoptera venom allergy is a major cause of life-threatening anaphylaxis. Molecular diagnostics have improved the characterisation of sensitisation patterns, although the clinical role of cross-reactive allergens such as DPPIV and hyaluronidases remains unclear. Objective: To define IgE sensitisation to venom components, examine associations with clinical phenotypes, and assess the immunological impact of venom immunotherapy (VIT) in an Italian cohort. Methods: In this monocentric study, 378 patients with documented Hymenoptera adverse reactions underwent extract-based and component-resolved diagnostics. A prospective subset (n = 113) was followed during VIT. Commercial venom extracts were characterised by inhibition assays. Results: Systemic reactions occurred in 36% of patients, predominantly males, while large local reactions were more common in females. Sensitisation to Vespula spp. (52%) and Polistes dominula (48%) exceeded Apis mellifera (26%). Api m 1/3/10 and Ves v 5/Pol d 5 were the most relevant allergens. Multivariate analysis identified IgE to Api m 1, Api m 3, Ves v 1, and Ves v 5 as independent predictors of systemic reactions. Mixed-effect models revealed a progressive decline of species-specific IgE during VIT, with an earlier progressive reduction of Ves v 1 and Ves v 5 and a delayed decrease of Api m 1, while IgE to panallergens remained stable. Conclusion: Molecular diagnostics refine risk stratification and monitoring of VIT. Species-specific allergens provide reliable clinical markers, whereas panallergens help distinguish true double sensitisation from cross-reactivity. VIT induces a progressive but differential reduction in specific IgE and confers protection, supporting precision allergy care.

BACKGROUND:Pollen defensins such as Art v 1 (mugwort) and Amb a 4 (ragweed) are pivotal allergens in pollen-food syndromes, but their clinical role in Southern Europe is poorly defined. OBJECTIVE:To characterize sensitization to defensins and related allergens in Italy and its association with clinical phenotypes. METHODS:Between 2021 and 2025, 7176 patients underwent molecular testing in three Italian centers. Sensitization to the pollen defensins Art v 1 and Amb a 4 was evaluated, together with celery allergens representing different protein families: the PR-10 Api g 1, the nsLTPs Api g 2, Api g 6, and the defensin Api g 7 (tested in a subset). Panallergens were also assessed. RESULTS:Defensin sensitization occurred in 272 patients (3.8%). Art v 1 mono-sensitization (64.7%) was largely confined to respiratory disease. Dual Art v 1-Amb a 4 sensitization (30.5%) identified a distinct subgroup at high risk of food reactions (OR = 6.9; p < 0.0001). Amb a 4 sensitization followed a clear northward gradient. Among 90 patients tested for Api g 7, 82.7% were positive, all co-sensitized to Art v 1, and one-third also to Amb a 4. IgE inhibition confirmed Art v 1 as the primary sensitizer driving defensin cross-reactivity. In contrast, Api g 2 nsLTP sensitization was strongly associated with severe systemic reactions. CONCLUSIONS:Defensin sensitization in Italy reveals distinct molecular and geographic signatures. Isolated Art v 1 sensitization dominates and marks respiratory allergy, while co-sensitization to Amb a 4-often associated with Api g 7 co-recognition-defines patients at high risk for systemic food reactions.

BACKGROUND:Thaumatin-like proteins (TLPs) are conserved plant pathogenesis-related proteins with IgE-binding capacity, but their clinical relevance remains poorly defined. Unlike well-characterized panallergens, TLPs are underrepresented in diagnostic panels, and their role in food allergy is largely unexplored. OBJECTIVE:To assess the prevalence, quantitative IgE levels, co-sensitization patterns, and clinical significance of IgE reactivity to two TLPs-Act d 2 (kiwi) and Mal d 2 (apple)-in a large Italian allergic cohort. METHODS:We conducted a cross-sectional study of 7176 consecutive patients referred to Italian tertiary allergy centers. Specific IgE to TLPs and other plant allergens was measured using ALEX2. Clinical outcomes were evaluated, and associations with IgE levels and co-sensitizations were examined using multivariate models. ROC analyses were applied to evaluate the discriminatory ability of Act d 2 IgE for clinical severity. RESULTS:TLP sensitization occurred in 137 patients (1.9%), predominantly to Act d 2. Isolated TLP sensitization was rare (n = 20) and associated with low IgE levels (mean 0.61 ± 0.98 kUA/L) and minimal symptoms. Co-sensitized patients (n = 117) had higher and more variable IgE levels (mean 1.41 ± 3.49 kUA/L) and experienced more clinically relevant reactions, including oral allergy syndrome and food-dependent exercise-induced anaphylaxis. ROC analyses indicated limited discriminatory power of Act d 2 IgE for predicting reaction severity (AUC 0.51-0.61). Multivariate adjustment confirmed no independent association between TLP-specific IgE and moderate or severe symptoms. CONCLUSIONS:TLP sensitization is uncommon and generally clinically silent when isolated. Co-sensitization with other panallergens appears to drive allergic manifestations. Quantitative TLP-specific IgE alone provides limited predictive value, emphasizing the importance of integrating molecular diagnostics with clinical phenotyping in precision allergy management.

BACKGROUND:The role of autoimmune IgE responses in atopic dermatitis (AD) is highly debated. While IgE targeting self-proteins has been extensively studied, IgE responses induced by human-homologous exogenous molecular allergens (HEMAs) remains less understood. AIM:To investigate whether IgE antibody responses to HEMAs are associated with AD, its severity, and response to dupilumab. METHODS:We enrolled 3325 participants with a history of allergic diseases, including 577 (17.3%) diagnosed with AD. Serum IgE antibodies against 183 exogenous allergenic molecules were measured using the IgE microarray (Allergy Explorer-ALEX-2®, MADX, Vienna). Based on international classification criteria, participants were stratified by AD severity and clinical phenotypes. For each patient, we developed an 'IgE molecular-mimicry index' (IgE-MMI), calculated from IgE reactivity to a panel of five HEMA protein families: arginine kinase, enolase (ENO), cyclophilin (CYP), lipocalin, and MnSOD. Logistic regression was employed to assess the association between IgE to HEMAs or IgE-MMI and AD, its severity, and response to dupilumab. RESULTS:IgE sensitization to most HEMAs (32/48, 67%), but only to a small fraction of non-HEMAs (3/135, 2.2%), was significantly more common in patients with severe AD compared to other patient groups. The IgE-MMI was positive in 295/2748 (10.7%) of allergic patients without AD, and in 58/283 (20%), 52/134 (39%), and 86/160 (54%) of patients with remitting, moderate, or severe AD, respectively. It was strongly associated with specific phenotypes, such as flexural dermatitis (OR 8.4, 95% CI: 6.3-11.2), head and neck dermatitis (OR: 16.5, 95% CI: 7.4-37.2), and generalized eczema (OR: 8.6, 95% CI: 4.9-15.6). Poor response to dupilumab was associated with IgE antibodies to ENO (OR: 22.7, 95% CI: 1.7-302.9), but inversely associated with IgE antibodies to MnSOD (OR: 0.1, 95% CI: 0.02-0.8) and NPC-2 from dust mites (OR: 0.1, 95% CI: 0.01-0.9). CONCLUSION:IgE microarrays are useful for broadly assessing IgE to HEMAs in allergic patients. IgE reactivity to HEMAs and a positive IgE-MMI may serve as valuable biomarkers for severe AD, its clinical phenotypes, and the response to dupilumab.

Summary:Background. Lipid transfer proteins (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), Food-Dependent Exercise-Induced Anaphylaxis (FDEIA) in 10.8% of patients (p = 0.001), and Food-dependent NSAID-induced hypersensitivity (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.

Introduction: Shellfish allergy is an important cause of food allergies worldwide. Both in vivo and in vitro diagnostics failure nowadays is caused by the poor quality of the extracts associated with the scarce availability of allergenic molecules in the market. It is known that not all patients with shellfish allergies experience adverse reactions to mollusks. It is still unclear how to detect and diagnose these patients correctly. Aim: To investigate the features of shrimp-allergic patients either reactive or tolerant to mollusks, with the currently available diagnostic methods. Methods: Nineteen centers, scattered throughout Italy, participated in the real-life study, enrolling patients allergic to shrimp with or without associated reactions to mollusks. Patients underwent skin tests using commercial extracts or fresh raw and cooked shrimp and mollusks, and IgE reactivity to currently available allergenic extracts and molecules was measured in vitro. Results: Two hundred and forty-seven individuals with a self reported adverse reactions to shrimp participated in the study; of these 47.8% reported an adverse reaction to mollusks ingestion (cephalopod and/or bivalve). Neither of the tests used, in vivo nor in vitro, was able to detect all selected patients. Accordingly, a great heterogeneity of results was observed: in vivo and in vitro tests agreed in 52% and 62% of cases. Skin tests were able to identify the mollusk reactors (p < 0.001), also using fresh cooked or raw food (p < 0.001). The reactivity profile of mollusk reactors was dominated by Pen m 1, over Pen m 2 and Pen m 4 compared to tolerant subjects, but 33% of patients were not detected by any of the available molecules. Overall, a higher frequency of IgE rectivity to shrimp was recorded in northern Italy, while mollusk reactivity was more frequent in the center-south. Conclusion: The current diagnostic methods are inadequate to predict the cross-reactivity between crustaceans and mollusks. The detection of mollusks hypersensitivity should still rely on skin tests with fresh material. The exclusion of mollusks from shrimp allergic patients' diets should occur when clinical history, available diagnostic instruments, and/or tolerance tests support such a decision.

The coronavirus disease (COVID-19), during its course, may involve several organs, including the skin with a petechial skin rash, urticaria and erythematous rash, or varicella-like eruption, representing an additional effect of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, as commonly observed in other viral diseases. Considering that symptomatic patients with COVID-19 generally undergo multidrug treatments, the occurrence of a possible adverse drug reaction presenting with cutaneous manifestations should be contemplated. Pleomorphic skin eruptions occurred in a 59-year-old Caucasian woman, affected by a stable form of chronic lymphocytic leukemia, and symptomatic SARS-CoV-2 infection, treated with a combination of hydroxychloroquine sulfate, darunavir, ritonavir, sarilumb, omeprazole, ceftriaxone, high-flow oxygen therapy devices, filgrastim (Zarzio®) as a single injection, and enoxaparin. The patient stopped all treatment but oxygen and enoxaparin were continued and the patient received a high-dose Desametasone with complete remission of dermatological impairment in 10 days. It is very important to differentially diagnose COVID-19 disease-related cutaneous manifestations, where is justified to continue the multidrug antiviral treatment, from those caused by an adverse drug reaction, where it would be necessary to identify the possible culprit drug and to start appropriate antiallergic treatment.

BACKGROUND: Severe Covid-19 is associated with a cytokine storm leading to the hyper-expression of cytokines such as IFN-gamma, TNF-alpha, and IL-6, which may be responsible for most severe symptoms and signs of the disease. The immune response of the atopic patient is mostly Th2-oriented, associated with the expression of cytokines such as IL-4, IL-5, and IL-13, and atopic patients express fewer ACE-2 receptors than non-atopic individuals do. We assessed whether atopic status may protect from the most severe consequences of Covid-19. METHODS: Atopic status along with co-factors such as diabetes, hypertension, coronary heart disease, and thrombosis was investigated in severe Covid-19 patients admitted to different Italian hospitals. Patients were classified as having a mild, severe, or very severe disease based on the need of respiratory assistance; severity was plotted against the different co-factors and underwent multivariate analysis. RESULTS: 531 adults aged 25 - 100 years were studied; 57 (11.7%) were atopic. Atopic status showed a significant association with a milder disease irrespective of all other co-factors considered (p <0.001); the protective effect of atopy was detectable throughout all age groups (p< 0.001). CONCLUSIONS: Atopic status appears to protect from the most severe consequences of Covid-19.

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.

Mosquito bite is usually followed by a local reaction, but severe or systemic reaction may, in rare cases, occur. Allergic reactions to Aedes communis (Ac) may be underestimated due to the lack of reliable diagnostic tools. In this multicenter study, 205 individuals reporting large local reactions to Ac were enrolled and studied for cutaneous or IgE reactivity to Ac, Blattella germanica, Penaeus monodon, and Dermatophagoides pteronyssinus. Extract and molecular IgE reactivity to bees, wasps, hornets, and yellow jacket venoms were also studied in 119 patients with a clinical history of adverse reaction to Hymenoptera. Immunoblot (IB) analysis and immunoCAP IgE inhibition experiments were carried out in selected sera. Ac sensitization was recorded in 96 (46.8%) patients on SPT. Strict relationship between Ac and D. pteronyssinus, B. germanica, P. monodon, or Apis mellifera reactivity on SPT was observed. Ac IgE recognition was seen in 60/131 (45.8%) patients, 49 (81.6%) of them SPT positive, and 5/14 IB reactors. Ac IgE sensitization was associated with Tabanus spp, A. mellifera, Vespula vulgaris, and Polistes dominula reactivity. A strict relationship between Ac IgE reactivity and Api m 1, Api m 2, Api m 3, Api m 5, and Api m 10 was recorded. IgE reactivity to AC was inhibited in 9/15 cases after serum absorption with the A. mellifera extract. Both SPT and IgE Ac reactivity is observed in about half of patients with a history of large local reactions to mosquito bites. The significant relationship between Ac sensitization and either extract or single bee venom components is suggestive of a “bee-mosquito syndrome” occurrence.

Summary:The families of seed storage proteins, together with profilins, oil-bodies-associated oleosins, and pathogenesis-related (PR) proteins like PR-10 (Bet v 1-like), PR-12 (defensins) and PR-14 (non-specific lipid transfer protein), are the main causes of IgE sensitization to tree nuts, legumes and seeds. All these allergens, with the exclusion of profilins and of PR-10, are heat-stable and possibly responsible for fatal or almost fatal adverse reactions to such foods. In this short review, we will discuss the relationship and amino acid identities among some of the seed storage homologue molecules identified to date from tree nuts, seeds and legumes.

Background. The development of recombinant technology supported the allergy diagnostic work-up in the daily clinical practice, representing a useful tool for epidemiological studies. Methods. An atlas of the IgE sensitization profiles found throughout Italy was prepared from a nationwide, multicenter, cross-sectional study. Results. 6052 unselected consecutive individuals, belonging to North-West [NW], North-East [NE], Centre [C], South [S], and Islands subset [Is] were evaluated by means of the ImmunoCAP ISAC test. The top-ranked sensitizations found were Cup a 1 in [C] (58.1%) and [S] (53.6%), Phl p 1 in the North (from 46.1% to 49%), and Cyn d 1 in [Is] (44.2%). High frequency of house dust mite group 2 molecules sensitization was found in [C] (36.9%) and [S] Italy (40.8%), whilst low level of reactivity was recorded in [NW] (20%). Pellitory hypersensitivity was mainly found in [C], [S], and [Is], whilst ragweed Amb a 1 sensitivity was particularly found in [NW] Italy. IgE recognition of PR-10, profilin, and nsLTP was mutually exclusive in 69.1% of cases, PR-10 reactivity mostly occurring in [NE], profilin in [NW], and nsLTP molecules recognition mainly recorded in [C] and [S]. Conclusions. Divergent IgE sensitization patterns were found along Italy, possibly linked to the distinct geographical locations, indicating multiplex system IgE analysis as a reliable approach for epidemiological evaluation even in small geographical areas.

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Background: The order Fagales represents an important cause of tree-pollen allergy in northern countries. We investigated the IgE recognition profiles, mutual relationships, and association with clinical symptoms of a panel of allergens belonging to the PR-10 family, the main proteins responsible for Fagales allergy (Act d 8, Aln g 1, Api g 1, Ara h 8, Bet v 1, Cor a 1.0101, Cor a 1.0401, Gly m 4, Mal d 1, and Pru p 1). Methods: A total of 526 PR-10-reactive subjects living in central and southern Italy were studied by ImmunoCAP-ISAC-112 microarray analysis. Results: Overall, Bet v 1 reactivity was the most commonly (74%) observed among PR-10 proteins, but Cor a 1.0101 was the most prevalent in participants aged <6 years, and between 15 and 65 years. Overall, 26% of the PR-10-reactive persons were Bet v 1 negative, whilst 93.6% of the PR-10 polyreactive individuals were Bet v 1 positive. Among the 10 PR-10s evaluated, 100 combinations were recorded. The strongest association was observed between molecules with the highest sequence identities (Bet v 1 and Cor a 1.0101, Cor a 1.0401 or Aln g 1; Mal d 1 and Pru p 1). Bet v 1-, Cor a 1.0101-, and Aln g 1-specific IgE recognition was associated with respiratory symptoms, whilst Ara h 8, Cor a 1.0401, Gly m 4, Mal d 1, and Pru p 1 were selectively linked to an oral allergic syndrome. Conclusions: Testing IgE reactivity to a panel of PR-10s in a birch-free area discloses peculiar relationships between clinical phenotypes and sensitization profiles, allowing the identification of novel cluster patterns.

Nine hundred and thirty-nine rPla a 1, nPla a 2, and rPla a 3 ImmunoCAP ISAC reactors were studied. nPla a 2pos MUXF3pos but Pla a 1/2neg subjects were excluded from the study because they were cross-reactive carbohydrate determinant reactors. Among the 764 remaining participants, 71.9% were Pla a 3pos , 54.1% Pla a 2pos , and 10.9% Pla a 1pos . Among Pla a 3 reactors, 89.6% were Pru p 3pos and 86.8% Jug 3pos , 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. Cosensitization to Pla a 2 and Pla a 3 was associated with a lower past incidence of severe food-induced reactions.

Allergy to olive pollen (Olea europaea) is caused in most cases by Ole e 1, but other allergens, for example, profilin (Ole e 2), polcalcin (Ole e 3 and Ole e 8), glucanase (Ole e 4 and Ole e 9), and lipid transfer protein (LTP) (Ole e 7)1Tejera M.L. Villalba M. Batanero E. Rodriguez R. Identification, isolation, and characterization of Ole e 7, a new allergen of olive tree pollen.J Allergy Clin Immunol. 1999; 104: 797-802Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar, 2Ledesma A. Rodriguez R. Villalba M. Olive-pollen profilin: molecular and immunologic properties.Allergy. 1998; 53: 520-526Crossref PubMed Google Scholar may also be involved (World Health Organization/International Union of Immunological Societies database: www.allergen.org) (see Table E1 in this article's Online Repository at www.jacionline.org). Genuine molecules such as Ole e 1, Ole e 7, and Ole e 9 and panallergens such as profilin (Bet v 2.0101, Hev b 8.0204, Mer a 1.0101, and Phl p 12.0101) or polcalcin (Bet v 4.0101 and Phl p 7.0101)3Hiller R. Laffer S. Harwanegg C. Huber M. Schmidt W.M. Twardosz A. et al.Microarrayed allergen molecules: diagnostic gatekeepers for allergy treatment.FASEB J. 2002; 16: 414-416Crossref PubMed Scopus (399) Google Scholar can nowadays be detected by ImmunoCAP-ISAC. Nine hundred ninety-five consecutive Italian outpatient subjects of the Allergy Unit of IDI-IRCCS, Rome, with positive results on skin prick test with olive tree pollen extract (Stallergenes S.A., Antony, France) were studied between May 2013 and December 2014, after approval by the IDI-IRCCS Ethical Committee as well as written informed consent from the participants. At baseline, using a standardized questionnaire and before allergen testing, all patients were grouped into 4 overlapping categories: (1) asthma, allergic rhinitis, allergic conjunctivitis (“Respiratory symptoms” [RS]); (2) atopic dermatitis (AD); (3) localized oral mucosal symptoms (“Oral allergic syndrome” [OAS]); and (4) symptoms suggestive of systemic reactions to food, including urticaria, angioedema, and anaphylaxis according to Sampson et al4Sampson H.A. Munoz-Furlong A. Campbell R.L. Adkinson N.F. Bock S.A. Branum A. et al.Second symposium on the definition and management of anaphylaxis: summary report—Second National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network symposium.J Allergy Clin Immunol. 2006; 117: 391-397Abstract Full Text Full Text PDF PubMed Scopus (1648) Google Scholar (“Severe Reactions” [SR]). Sera were collected during the first visit, and IgE reactivity was analyzed using the 112 ImmunoCAP-ISAC platform (ThermoFisher Scientific, Uppsala, Sweden). A genuine sensitization to olive tree pollen molecules was observed in 839 of the 995 subjects (84.3%, 435 females and 404 males; mean age, 27.5 ± 16.2 years; range, 3-76 years). The remaining 156 (15.7%) reacted to profilin (n = 117, 75%), polcalcin (n = 33, 2.1%), or both (n = 6, 3.8%) and were excluded from the study. No differences in the prevalence of IgE recognition were noted between male and female patients, but males were younger (24 ± 15 years vs 30 ± 15 years; P < .01). The demographic characteristics and the distribution among clinical categories are summarized in Table I.Table IClinical and molecular characteristics of participantsCharacteristicN (%)Age (y)Female (age)Male (age)All patients83927 ± 16435 (30 ± 15)404 (24 ± 15)N (%)Age (y)Female (%)Male (%)Ole e 1708 (84.4)27 ± 16360 (50.8)348 (49.2)Ole e 7180 (21.5)27 ± 1390 (50)90 (50)Ole e 985 (10.1)24 ± 1435 (41.2)50 (58.8)1. RS674 (80.3)28 ± 16354 (52.5)320 (47.5)2. AD189 (22.5)23 ± 1499 (52.4)90 (47.6)3. OAS327 (39)27 ± 15168 (51.4)159 (48.6)4. SR365 (43.5)28 ± 16186 (51)179 (49) Open table in a new tab Ole e 1 reactivity was detected in 84.4% of the patients, followed by Ole e 7 (21.5%), a higher prevalence than in another Mediterranean population,5Barber D. De la Torre F. Feo F. Florido F. Guardia P. Moreno C. et al.Understanding patient sensitization profiles in complex pollen areas: a molecular epidemiological study.Allergy. 2008; 63: 1550-1558Crossref PubMed Scopus (187) Google Scholar and Ole e 9 (10.1%). Ole e 9 reactivity was higher among males than among females (12.4% vs 8.0%; P = .038). Ole e 7 IgE reactivity was significantly less frequent in children younger than 15 years (12.6% vs 24.1%; P < .001). The association between reactivity to olive tree molecules and the self-reported clinical profiles at baseline is shown in Fig 1. Ole e 1 reactivity was associated with RS (81.6%; P < .03), but inversely related to the occurrence of local symptoms or systemic reactions to food (36.9% for OAS, P < .005, and 39% for SR, P < .001). In contrast, Ole e 7 reactors showed a clinical history suggestive of both local (52.2%; P < .001) and/or systemic reactions to food (60.6%; P < .001), and a lower prevalence of RS (P < .03). Accordingly, a slight inverse relationship was observed between Ole e 1 and Ole e 7 IgE recognition (P < .001; ρ = −0.218) (see Fig E1 in this article's Online Repository at www.jacionline.org). Multiple logistic regression analysis, considering all the molecules studied as a whole, including also age and sex, showed a significant relationship between Ole e 7 reactivity and a history of OAS (P < .01; adjusted odds ratio [aOR], 1.730; 95% CI, 1.156-2.590) or SR (P = 0.03; aOR, 1.586; 95% CI, 1.060-2.371). Ole e 1 reactivity remained inversely associated with SR even after multiple adjustment (P < .001; aOR, 0.393; 95% CI, 0.241-0.639). Ole e 9–positive subjects presented a positive association with AD (49.4% vs 19.5% among Ole e 9–negative subjects; P < .001) and a lower rate of RS (P < .001). Multiple regression also confirmed the finding that Ole e 9 reactivity identifies a subset of patients with a history of AD (P < .001; aOR, 4.189; 95% CI, 2.540-6.919) and a lower risk of RS (P < .001; aOR, 0.319; 95% CI, 0.193-0.527). On the basis of these observations, Ole e 7 and Ole e 9 seem to be markers of sensitization to other panallergens, rather than specific olive pollen molecules. In effect, it has been suggested that Ole e 7 or Ole e 9 reactors might show a lower tolerance to immunotherapy at the recommended doses.5Barber D. De la Torre F. Feo F. Florido F. Guardia P. Moreno C. et al.Understanding patient sensitization profiles in complex pollen areas: a molecular epidemiological study.Allergy. 2008; 63: 1550-1558Crossref PubMed Scopus (187) Google Scholar Unlike mugwort and plane tree LTPs (Art v 3 and Pla a 3, respectively), which show approximately 50% sequence identity with the peach LTP Pru p 3,6Scala E. Till S.J. Asero R. Abeni D. Guerra E.C. Pirrotta L. et al.Lipid transfer protein sensitization: reactivity profiles and clinical risk assessment in an Italian cohort.Allergy. 2015; 70: 933-943Crossref PubMed Scopus (91) Google Scholar Ole e 7 shares less than 20% of amino acid sequence with Pru p 3, and therefore seems to be neither structurally nor immunologically related to food LTPs.7Tordesillas L. Sirvent S. Diaz-Perales A. Villalba M. Cuesta-Herranz J. Rodriguez R. et al.Plant lipid transfer protein allergens: no cross-reactivity between those from foods and olive and parietaria pollen.Int Arch Allergy Immunol. 2011; 156: 291-296Crossref PubMed Scopus (48) Google Scholar However, our study demonstrates that Ole e 7 reactivity is in strict relationship with adverse reactions to plant-derived food (mainly peach, walnut, and peanut), thus suggesting an intriguing involvement of Ole e 7 in the LTP panallergen family, despite the lack of structural homology.7Tordesillas L. Sirvent S. Diaz-Perales A. Villalba M. Cuesta-Herranz J. Rodriguez R. et al.Plant lipid transfer protein allergens: no cross-reactivity between those from foods and olive and parietaria pollen.Int Arch Allergy Immunol. 2011; 156: 291-296Crossref PubMed Scopus (48) Google Scholar Moreover, about 80% of Ole e 7 reactors were also positive to at least 1 of the plant food LTP tested on the microarray versus only 30% of Ole e 1 reactors. To our knowledge, the association between Ole e 9 reactivity and the higher prevalence of AD has never been described before. Ole e 9 contains 2 immunologically and structurally independent domains8Palomares O. Villalba M. Quiralte J. Polo F. Rodriguez R. 1,3-Beta-glucanases as candidates in latex-pollen-vegetable food cross-reactivity.Clin Exp Allergy. 2005; 35: 345-351Crossref PubMed Scopus (87) Google Scholar: the N-terminal domain has a 1,3-β-glucanase activity, thus belonging to the pathogenesis-related protein family-2, which is implicated in latex-pollen-vegetable food allergy syndrome.8Palomares O. Villalba M. Quiralte J. Polo F. Rodriguez R. 1,3-Beta-glucanases as candidates in latex-pollen-vegetable food cross-reactivity.Clin Exp Allergy. 2005; 35: 345-351Crossref PubMed Scopus (87) Google Scholar Accordingly, we observed a higher occurrence of latex reactivity among Ole e 9 reactors (15.3% vs 3.3% among nonreactors; P < .001; χ2 = 25.348; OR, 5.265; 95% CI, 2.582-10.737). Ole e 9 reactivity was never associated with a higher incidence of food reactions (OAS or SR). In conclusion, our study shows that distinct subsets can be recognized among olive tree reactors on the basis of molecular reactivity. Ole e 1 positivity identifies the specific olive tree pollen–allergic population with RS, possibly deserving specific immunotherapy, whereas Ole e 7 and Ole e 9 IgE recognition is associated with local or systemic reactions to food and AD, respectively. This suggests that testing for olive components may be useful for a better characterization of patients with atopy, as is the case for peanut components.9Klemans R.J. Broekman H.C. Knol E.F. Bruijnzeel-Koomen C.A. Otten H.G. Pasmans S.G. et al.Ara h 2 is the best predictor for peanut allergy in adults.J Allergy Clin Immunol Pract. 2013; 1: 632-638Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar It is likely, in the near future, that this concept could be extended to other allergens as well. We are grateful to Dr Marina Ruffelli, Dr Silvia Cadoni, and Miss Monica Bondi who performed the ISAC test. We thank Professor Moira Egan for the English revision of the manuscript. Table E1Olive tree pollen allergens identified to date according to the WHO/IUIS database (www.allergen.org)AllergenBiochemical nameBiological functionMWIgE prevalenceE1Ledesma A. Rodriguez R. Villalba M. Olive-pollen profilin: molecular and immunologic properties.Allergy. 1998; 53: 520-526Crossref PubMed Scopus (70) Google Scholar,E2Huecas S. Villalba M. Rodriguez R. Ole e 9, a major olive pollen allergen is a b-1,3-glucanase. Isolation, characterization, amino acid sequence and tissue specificity.J Biol Chem. 2001; 276: 27959-27966Crossref PubMed Scopus (92) Google ScholarOle e 1Common olive group 1Trypsin inhibitors16>70Ole e 2ProfilinActin-binding proteins15>40Ole e 3PolcalcinCalcium-binding proteins920Ole e 4∗Ole e 4 could be a proteolytic degradation product of Ole e 9 and not a genuine allergen.Glucanases3280Ole e 5Superoxide dismutaseSuperoxide Dismutases1635Ole e 6Cysteine-enriched allergenUnknown1015-55Ole e 7Putative nonspecific LTPLTPs9-1047Ole e 8Polcalcin-like protein (4 EF-hands)Calcium-binding proteins215Ole e 91,3-Beta glucanaseGlucanases4650Ole e 10X8 domain–containing proteinGlycosyl hydrolase1154Ole e 11Pectin methylesterasePectinesterases39.4EF, Calcium-binding motifs composed of 2 helixes (E and F) joined by a loop; IUIS, International Union of Immunological Societies; MF, molecular weight; WHO, World Health Organization.∗ Ole e 4 could be a proteolytic degradation product of Ole e 9 and not a genuine allergen. Open table in a new tab EF, Calcium-binding motifs composed of 2 helixes (E and F) joined by a loop; IUIS, International Union of Immunological Societies; MF, molecular weight; WHO, World Health Organization.