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Background: Although proteins derived from cats are an important contributor to indoor allergen exposure in relation to asthma, it has been known for at least twenty years that some children who live in a house with a cat can become clinically tolerant to these animals. In 2001, we reported that children exposed to high levels of cat allergens made high levels of IgG4 antibodies to the cat allergen Fel d 1, and we coined the term "a modified Th2 response". However, this phenomenon is still poorly understood., Methods: We studied serum antibodies among 616 individuals in the Viva unselected birth cohort recruited at their early teen visit (mean age 13.1 SD 0.8). IgE and IgG4 antibodies were measured by ImmunoCAP to inhaled allergens as well as the best characterised component allergens of cat, Fel d 1, Fel d 2, Fel d 4, and Fel d 7, and the dust mite allergens Der p 1, Der p 2, Der p 10, and Der p 23., Findings: The results confirm that young teens living in a home with a cat make high levels of IgG4 specific for cat allergens, and that those antibodies, and specifically those to Fel d 1 are negatively associated with asthma. By contrast, the IgG4 responses to Fel d 4 and Fel d 7 are significantly lower and have no significant association with asthma. Perhaps more surprisingly, a similar effect is seen in relation to dust-mite allergens. Although the allergen Der p 1 is a major part of the IgE response to mite allergens, this protein also induced high prevalence and levels of IgG4 antibodies and has a less strong relationship to asthma than IgE to Der p 2 or Der p 23. Indeed, values of specific IgE to Der p 1 >3.5 IU/mL were not significantly related to asthma (OR 1.5 CI 0.8-2.8, p = 0.3, Chi 2 test). The prevalence and levels of specific IgG4 to these less abundant allergens are significantly lower for Der p 2 and almost absent for Der p 23., Interpretation: High exposure to specific allergens in household dust can enhance production of both sIgE and sIgG4 antibodies, while allergens where abundance is significantly lower in dust can induce sIgE with limited or no sIgG4. The result is that the less abundant allergens, i.e., Fel d 4, Fel d 7, Der p 2, and Der p 23, may have a significantly higher relevance to asthma than expected because they induce less sIgG4., Funding: This work was funded by R01-AI20565 (TPM) and support for the IgE and IgG4 assays provided by Phadia/Thermo Fisher Kalamazoo, Michigan. Project Viva is also supported by NIH R01HD034568 and R24ES., Competing Interests: Declaration of interests The primary funding source for the experimental studies is the National Institute of Allergy and Infectious Diseases of the NIH and the specific grant is A1-20565-37 on which Dr. Platts-Mills is the principle investigator. Dr. Platts-Mills received funding to attend meetings from Phadia and Thermo Fisher, and was on the data safety monitoring board NIAID (2014–2023). In addition, we have had extensive support in the form of assay materials for IgE and IgG4 antibodies from Phadia/ThermoFisher, Upsala, Sweden. That support includes no restriction on the studies carried out and has no restrictions on publication. The main funding for the Project Viva cohort comes from NIH grants R01HD034568 and R24ES to Emily Oaken and Diane Gold. None of the authors have significant personal conflicts in relation to the findings of this article. However, Martin Chapman, PhD is owner of the company InBio and has stocks in InBio, he also receives a grant NIH NIAID R01AI077653-13. Jonas Lidholm, PhD is employed full-time by Phadia/ThermoFisher and has stocks in Thermo Fisher Scientific. Jeffrey Wilson receives material support from Thermo-Fisher Scientific for research assays unrelated to current work., (Copyright © 2025 The Authors. Published by Elsevier B.V. All rights reserved.) more...

Background: Data on oral immunotherapy (OIT) for hazelnut allergy is limited and its potential to cross-desensitize for other nuts is unknown., Objective: To study the efficacy and safety of hazelnut OIT in desensitizing to hazelnut and additional tree nuts., Methods: This was a prospective observational study of 30 hazelnut-allergic patients aged 4 years or older who underwent hazelnut OIT. Full desensitization (4,000 mg protein) rates were compared with those of 14 observational controls, and immunologic changes during OIT were measured. We determined cross-desensitization in cases of walnut and cashew co-allergy (n = 12). Inhibition of IgE binding to walnut by hazelnut was evaluated by ELISA in a separate set of dual walnut-hazelnut allergic patients., Results: The rate of full hazelnut desensitization following OIT was 96.7% (29 of 30 patients) compared with 14.3% (two of 14) in controls (odds ratio = 25.7; 95% CI, 3.7-178.7; P < .001). Five patients (16.7%) were treated with injectable epinephrine for home reactions. Hazelnut skin prick test and specific IgE to hazelnut and its main components, Cor a 9, 14 and 16, decreased whereas specific IgG 4 increased during OIT. A maintenance dose of 1,200 mg hazelnut protein was sufficient to maintain full desensitization. No cross-desensitization was noted in dual hazelnut-cashew allergic patients (n = 6). In dual hazelnut-walnut allergic patients, an increase in the walnut eliciting dose was observed in two of six patients (33.2%) (to 1,200 and 4,200 mg, respectively). Similarly, by cross-inhibition ELISA, hazelnut competed for IgE-binding to walnut in five of 25 (20%) hazelnut-walnut co-allergic patients (20%)., Conclusions: Hazelnut OIT is highly effective, with a safety profile similar to that of OIT to other nuts. Cross-desensitization to walnut and cashew is unlikely., (Copyright © 2025 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.) more...

Sensitization to cross-reactive allergens complicates identifying the culprit insect in Hymenoptera venom allergy via diagnostic tests. This study evaluates sensitization to hyaluronidases (Api m 2 from honey bee ( Apis mellifera ) venom, HBV; Pol d 2 from European paper wasp ( Polistes dominula ) venom, PDV; and Ves v 2.0101 and Ves v 2.0201 from yellow jacket ( Vespula vulgaris ) venom, YJV) and their cross-reactivity in allergic patients from Italy, Spain, and Germany using ImmunoCAPs, ELISA, and basophil activation tests. Sensitization rates were 45% for Api m 2 in HBV-allergic subjects, 25% for Pol d 2 in PDV-allergic individuals, and 20% and 10% for Ves v 2.0201 and Ves v 2.0101 in YJV-allergic patients, respectively. Patients primarily sensitized to Api m 2 showed minimal cross-reactivity to vespid hyaluronidases, whereas those primarily sensitized to Pol d 2 or Ves v 2.0201 exhibited IgE reactivity to Api m 2. Neither Pol d 2 nor Ves v 2.0201 triggered basophil activation. Cross-reactivity of Api m 2, Pol d 2, and Ves v 2.0201 depends on the primary sensitizing venom. Sensitization to Pol d 2 and Ves v 2.0201 remains below 25%, yet these patients may exhibit cross-reactivity to Api m 2. Conversely, HBV-allergic patients sensitized to Api m 2 show minimal reactivity to Pol d 2 or Ves v 2.0201. more...

Background: Celery root is known to cause severe allergic reactions in patients sensitized to mugwort pollen., Objective: We studied clinically well-characterized patients with celery allergy by IgE testing with a comprehensive panel of celery allergens to disentangle the molecular basis of what is known as the celery-mugwort syndrome., Methods: Patients with suspected food allergy to celery underwent a standardized interview. Main inclusion criteria were a positive food challenge with celery or an unambiguous case history of severe anaphylaxis. IgE to celery allergens (rApi g 1.01, rApi g 1.02, rApi g 2, rApi g 4, nApi g 5, rApi g 6, rApi g 7) and to mugwort allergens (rArt v 1, rArt v 3, rArt v 4) were determined. IgE levels ≥0.35 kU A /L were regarded positive., Results: Seventy-nine patients with allergy to celery were included. Thirty patients had mild oral or rhinoconjunctival symptoms, and 49 had systemic reactions. Sixty-eight percent had IgE to celery extract, 80% to birch pollen, and 77% to mugwort pollen. A combination of Api g 1.01, 1.02, 4, 5, and 7 increased the diagnostic sensitivity for celery allergy to 92%. The lipid transfer proteins Api g 2 and Api g 6 were not relevant in our celery-allergic population. IgE to Api g 7, detected in 52% of patients, correlated closely (r = 0.86) to Art v 1 from mugwort pollen. Eleven of 12 patients with monosensitization to Api g 7 were IgE negative to celery extract. The odds ratio for developing a severe anaphylactic reaction rather than only mild oral symptoms was about 6 times greater (odds ratio, 5.87; 95% confidence interval, 1.08-32.0; P = .0410) for Api g 7-sensitized versus -nonsensitized subjects., Conclusion: There is an urgent need for routine diagnostic tests to assess sensitization to Api g 7, not only to increase test sensitivity but also to identify patients at risk of a severe allergic reaction to celery., (Copyright © 2024 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.) more...

Background: Cyclophilins are ubiquitous panallergens whose epidemiologic, diagnostic, and clinical relevance is largely unknown and whose sensitization is rarely examined in routine allergy practice., Objective: We investigated the epidemiologic, diagnostic, and clinical relevance of cyclophilins in seasonal allergic rhinitis and its comorbidities., Methods: We examined a random sample of 253 (25%) of 1263 Italian children with seasonal allergic rhinitis from the Panallergens in Pediatrics (PAN-PED) cohort with characterized disease phenotypes. Nested studies of sensitization prevalence, correlation, and allergen extract inhibition were performed in patients sensitized to birch pollen extract but lacking IgE to Bet v 1/2/4 (74/1263) or with highest serum level of IgE to Bet v 1 (26/1263); and in patients with sensitization to various extracts (ragweed, mugwort, pellitory, Plantago, and plane tree), but not to their respective major allergenic molecule, profilins, and polcalcins. IgE to cyclophilin was detected with recombinant Bet v 7, and extract inhibition tests were performed with the same rBet v 7., Results: IgE to rBet v 7 was detected in 43 (17%) of 253 patients. It was associated with asthma (P < .028) and oral allergy syndrome (P < .017) in univariate but not multivariate analysis adjusted for IgE to profilins (Phl p 12), PR-10s (Bet v 1), and lipid transfer proteins (Pru p 3). IgE to rBet v 7 was also highly prevalent (47/74, 63%) among patients with unexplained sensitization to birch pollen extract. In patients with unexplained sensitization to ragweed, mugwort, pellitory, Plantago and plane tree pollen, the levels of IgE to those extracts correlated with the levels of IgE to rBet v 7, and they were also significantly inhibited by rBet v 7 (inhibition range 45%-74%)., Conclusions: IgE sensitization to cyclophilin is frequent in pollen-allergic patients living in temperate areas and can produce "false" positive outcomes in skin prick and IgE tests to pollen extracts. Molecular diagnostic guidelines should include this panallergen family., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.) more...

Background: Because of the high cross-sensitization among tree nuts, the NUT CRACKER (Nut Co-reactivity-Acquiring Knowledge for Elimination Recommendations) study proposed a diagnostic algorithm to minimize the number of required oral food challenges (OFCs)., Objective: To validate the algorithm for cashew and pistachio allergy and determine markers for allergic severity., Methods: Patients (n = 125) with a median age of 7.8 (interquartile range, 5.9-11.2) years with suspected tree nut allergy were evaluated prospectively with decision tree points on the basis of skin prick test (SPT), basophil activation test (BAT), and knowledge of the coincidence of allergies. Validation of allergic status was determined by OFC. Markers of clinical severity were evaluated using the combined original and prospective cohort (n = 187) in relationship to SPT, BAT, and Ana o 3-sIgE., Results: Reactivity to cashew in SPT, BAT, and Ana o 3-sIgE and the incidence of abdominal pain on challenge were significantly higher in dual-allergic cashew/pistachio patients (n = 82) versus single cashew allergic patients (n = 18) (P = .001). All 3 diagnostic tests showed significant inverse correlation with log 10 reaction doses for positive cashew OFC. The algorithm reduced overall the total number of OFCs by 72.0%, with a positive predictive value and negative predictive value of 93.0% and 99.0%, respectively. Cashew false-positives were observed primarily in hazelnut-allergic patients (P = .026). In this population, Ana o 3-specific IgE could diagnose cashew allergy with a sensitivity of more than 90% and a specificity of more than 95%., Conclusions: The NUT CRACKER diagnostic algorithm was validated and reduced the number of diagnostic OFCs required. Markers for severity phenotypes may guide oral immunotherapy protocols, improving the risk/benefit ratio for patients., (Copyright © 2024 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.) more...

Allergy is defined clinically, by symptoms on allergen exposure. A patient is considered sensitized when allergen-specific IgE (sIgE) antibody can be detected in serum or plasma or a skin test result is positive, even if no clinical reaction has been experienced. Sensitization should be regarded as a requisite and risk factor for allergy but is not synonymous with an allergy diagnosis. To provide a correct allergy diagnosis, test results regarding allergen-sIgE must always be considered in view of the patient's case history and clinical observations. Correct assessment of a patient's sensitization to specific allergens relies on the use of accurate and quantitative methods for detection of sIgE antibodies. The evolution of sIgE immunoassays toward higher analytical performance and the use of different cutoff levels in the interpretation of test results sometimes cause confusion. Earlier versions of sIgE assays offered a limit of quantitation of 0.35 kilounits of sIgE per liter (kU A /L), which also became an established cutoff level for a positive test result in the clinical use of the assays. Current sIgE assays are capable of reliably measuring sIgE levels as low as 0.1 kU A /L and can thereby demonstrate sensitization in cases in which previous assays could not. When the outcome of sIgE test results is evaluated, it is critically important to distinguish between the analytical data as such and their clinical interpretation. Even though sIgE may be present in the absence of symptoms of allergy, available information suggests that sIgE concentrations between 0.1 kU A /L and 0.35 kU A /L may be clinically relevant in some individuals, not least among children, although this should be further evaluated for various allergies. Moreover, it is becoming widely adopted that nondichotomous interpretation of sIgE levels may offer a diagnostic benefit compared with using a predefined cutoff level., (Copyright © 2023. Published by Elsevier Inc.) more...

Background: Pru p 3 and Pru p 7 have been implicated as risk factors for severe peach allergy. This study aimed to establish sensitization patterns to five peach components across Europe and in Japan, to explore their relation to pollen and foods and to predict symptom severity., Methods: In twelve European (EuroPrevall project) and one Japanese outpatient clinic, a standardized clinical evaluation was conducted in 1231 patients who reported symptoms to peach and/or were sensitized to peach. Specific IgE against Pru p 1, 2, 3, 4 and 7 and against Cup s 7 was measured in 474 of them. Univariable and multivariable Lasso regression was applied to identify combinations of parameters predicting severity., Results: Sensitization to Pru p 3 dominated in Southern Europe but was also quite common in Northern and Central Europe. Sensitization to Pru p 7 was low and variable in the European centers but very dominant in Japan. Severity could be predicted by a model combining age of onset of peach allergy, probable mugwort, Parietaria pollen and latex allergy, and sensitization to Japanese cedar pollen, Pru p 4 and Pru p 7 which resulted in an AUC of 0.73 (95% CI 0.73-0.74). Pru p 3 tended to be a risk factor in South Europe only., Conclusions: Pru p 7 was confirmed as a significant risk factor for severe peach allergy in Europe and Japan. Combining outcomes from clinical and demographic background with serology resulted in a model that could better predict severity than CRD alone., (© 2023 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.) more...

Competing Interests: Magnus Molin, Robert Movérare, Jonas Lidholm and Magnus P. Borres are employed by Thermo Fisher Scientific. Ida Waern, Andrei Malinovschi and Christer Janson have no conflicts of interest to declare. more...

Background: Oral immunotherapy (OIT) is a treatment option for patients with milk, egg, and peanut allergy, but data on the efficacy and safety of cashew OIT are limited., Methods: A cohort of 50 cashew-allergic patients aged ≥4 years, who were consecutively enrolled into cashew OIT (target dose 4000 mg protein) between 4/2016 and 12/2019. Fifteen cashew-allergic patients who continued cashew elimination served as observational controls. Co-allergy to pistachio and walnut was determined. Full desensitization rate and associated immunological changes in both groups were compared. Patients fully desensitized to cashew were instructed to consume a dose of 1200 mg cashew protein for 6 months and were then challenged to a full dose. Patients with co-allergy to pistachio or walnut were challenged to the respective nut., Results: Forty-four of 50 OIT-treated patients (88%) compared to 0% in controls tolerated a dose of 4000 mg cashew protein at the end of the study (odds ratio 8.3, 95% CI 3.9-17.7, p < 0.001). An additional three patients were desensitized to 1200 mg cashew protein, and three patients stopped treatment. Three patients (6%) were treated with injectable epinephrine for home reactions. Desensitized patients had decreased SPT, sIgE, basophil reactivity, and increased sIgG4, following treatment. Following cashew desensitization, all pistachio (n = 35) and four of eight walnut co-allergic patients were cross-desensitized to the respective nut. All (n = 44) patients consuming a low cashew dose for ≥6 months following desensitization passed a full-dose cashew OFC., Conclusions: Cashew OIT desensitizes most cashew-allergic patients and cross-desensitizes to pistachio. Safety is similar to OIT for other foods., (© 2022 European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.) more...

Background: The prevalence of sesame food allergy (SFA) is increasing worldwide with the potential of anaphylactic reactions upon exposure. Utility of specific component IgE testing as an alternative to the oral food challenge (OFC), the diagnostic standard, is being investigated., Methods: Patients (n = 42) with suspected SFA completed an open OFC to sesame. Diagnostic testing included serum levels of Ses i 1-specific IgE, skin prick test with high-protein extract, and basophil reactivity (% induced CD63 expression) for each patient. The diagnostic utility of these tests was evaluated at a 95% sensitivity, with the outcome measure being the number of OFCs required., Results: Twenty-seven patients (64%) were diagnosed with SFA. Ses i 1 IgE differed significantly between allergic and tolerant patients (p = .0001). ROC curve analysis for Ses i 1 IgE yielded an AUC of 0.88 ± 0.05. Levels of Ses i 1 IgE correlated to induced CD63+ expression on basophils (p = .0001). Ses i 1 IgE was not sufficiently robust as a single step for diagnosis. Used concurrently, BAT and Ses i 1 IgE yielded correct positive classifications for 25 of 27 sesame-allergic patients with two false positives (93% PPV). Both tests were negative in 5 non-allergic patients. Patients with divergent Ses i 1 IgE and BAT results required OFC (n = 10, 24% of patients). Alternatively, sequential use of BAT, ruling in SFA followed by Ses i 1 IgE diagnosing non-allergic patients, yielded a 89% PPV, with 19% requiring OFC., Conclusion: Ses i 1 IgE and BAT used together can decrease the need for OFC in most SFA patients. A prospective cohort trial is necessary to validate these results., (© 2021 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.) more...

Until recently, glycan epitopes have not been documented by the WHO/IUIS Allergen Nomenclature Sub-Committee. This was in part due to scarce or incomplete information on these oligosaccharides, but also due to the widely held opinion that IgE to these epitopes had little or no relevance to allergic symptoms. Most IgE-binding glycans recognized up to 2008 were considered to be "classical" cross-reactive carbohydrate determinants (CCD) that occur in insects, some helminths and throughout the plant kingdom. Since 2008, the prevailing opinion on lack of clinical relevance of IgE-binding glycans has been subject to a reevaluation. This was because IgE specific for the mammalian disaccharide galactose-alpha-1,3-galactose (alpha-gal) was identified as a cause of delayed anaphylaxis to mammalian meat in the United States, an observation that has been confirmed by allergists in many parts of the world. Several experimental studies have shown that oligosaccharides with one or more terminal alpha-gal epitopes can be attached as a hapten to many different mammalian proteins or lipids. The classical CCDs also behave like haptens since they can be expressed on proteins from multiple species. This is the explanation for extensive in vitro cross-reactivity related to CCDs. Because of these developments, the Allergen Nomenclature Sub-Committee recently decided to include glycans as potentially allergenic epitopes in an adjunct section of its website (www.allergen.org). In this article, the features of the main glycan groups known to be involved in IgE recognition are revisited, and their characteristic structural, functional, and clinical features are discussed., (© 2021 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.) more...

Background: Manifestation of respiratory allergy to American cockroach ( Periplaneta americana ) is prominent in the subtropical and tropical areas. However, co-existing perennial indoor inhalant allergies frequently compromise clinical diagnosis of cockroach allergy, and the analysis of sensitization pattern is limited by the lack of Periplaneta allergens widely available for component-resolved diagnostics (CRD). Objective: To evaluate a collection of previously described recombinant Periplaneta allergens for CRD in cockroach allergy. Methods: A panel of nine recombinant Periplanet a allergens (Per a 1-5, 7-10) was generated, purified, and subjected to physicochemical characterization by applying circular dichroism (CD) spectroscopy, dynamic light scattering (DLS), amino acid (AA) analysis, and mass spectrometry (MS). Patients ( n = 117) from India, Korea, Venezuela, and Iran, reporting perennial respiratory indoor allergies with IgE sensitization to cockroach ( P. americana and/or Blattella germanica ), were included. The sensitization profile was monitored by the experimental ImmunoCAP testing. Results: ImmunoCAP testing confirmed IgE sensitization to Periplaneta and/or Blattella extract in 98 of 117 patients ( r = 0.95). Five out of 117 patients were sensitized to only one of the two cockroach species. Within the whole study group, the prevalence of sensitization to individual allergens varied from 4% (Per a 2) to 50% (Per a 9), with the highest IgE values to Per a 9. Patients from four countries displayed different sensitization profiles at which Per a 3 and Per a 9 were identified as major allergens in India and Korea. Periplaneta -derived lipocalin and myosin light chain were characterized as new minor allergens, designated as Per a 4 and Per a 8. Periplaneta extract showed higher diagnostic sensitivity than all individual components combined, suggesting the existence of allergens yet to be discovered. Conclusion: Utilization of a panel of purified Periplaneta allergens revealed highly heterogeneous sensitization patterns and allowed the classification of lipocalin and myosin light chain from Periplaneta as new minor allergens., Competing Interests: JL was employed by company Thermo Fisher Scientific. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Wangorsch, Jamin, Eichhorn, Pablos, Sharma, Schweidler, Kastner, Wildner, Saloga, Führer, Reyna Orozco, Sherkat, Sadeghi, Teifoori, Park, Briza, Vieths, Ferreira, Arora, Lidholm, Gadermaier and Scheurer.) more...

Background: It is not well-understood why symptom severity varies between patients with peanut allergy (PA). Objective: To gain insight into the clinical profile of subjects with mild-to-moderate and severe PA, and investigate individual and collective predictive accuracy of clinical background and IgE to peanut extract and components for PA severity. Methods: Data on demographics, patient history and sensitization at extract and component level of 393 patients with probable PA (symptoms ≤ 2 h + IgE sensitization) from 12 EuroPrevall centers were analyzed. Univariable and penalized multivariable regression analyses were used to evaluate risk factors and biomarkers for severity. Results: Female sex, age at onset of PA, symptoms elicited by skin contact with peanut, family atopy, atopic dermatitis, house dust mite and latex allergy were independently associated with severe PA; birch pollen allergy with mild-to-moderate PA. The cross-validated AUC of all clinical background determinants combined (0.74) was significantly larger than the AUC of tests for sensitization to extract (0.63) or peanut components (0.54-0.64). Although larger skin prick test wheal size, and higher IgE to peanut extract, Ara h 1 and Ara h 2/6, were associated with severe PA, and higher IgE to Ara h 8 with mild-to-moderate PA, addition of these measurements of sensitization to the clinical background model did not significantly improve the AUC. Conclusions: Models combining clinical characteristics and IgE sensitization patterns can help establish the risk of severe reactions for peanut allergic patients, but clinical background determinants are most valuable for predicting severity of probable PA in an individual patient., Competing Interests: Outside of submitted work: MF-R reported grants and personal fees from Aimmune Therapeutics and Diater, personal fees from DBV, Allergy Therapeutics, GSK, HAL Allergy, Novartis, ThermoFisher Scientific, and SPRIM. BB-W reported personal fees from ThermoFisher Scientific. FB reported personal fees from Aimmune; grants from Stallergènes Greer, Chiesi, Mundipharma, Novartis, and Regeneron; and board membership for DVB, Stallergènes Greer, Novartis, ALK, Mundipharma, Boehringer, AstraZeneca, Medapharma, and Boston Scientific. JL was an employee of ThermoFisher Scientific. NP reported personal fees from Novartis, Nutricia, HAL Allergy BV, Menarine/Faes Farma, Sanofi, Mylan/Meda, Biomay, AstraZeneca, GSK, MSD, ASIT Biotech, Boehringer Ingelheim; and grants from Gerolymatos International SA, and Capricare. SV reported personal fees from Ärzteverband Deutscher Allergologen, Swiss Society for Allergy and Immunology, Schattauer Allergologie Handbuch, Elsevier Nahrungsmittelallergien und Intoleranzen, Karger Food Allergy: Molecular Basis and Clinical Practice, and Pharmacon. EM reported grants from Reacta Biotech; and was shareholder of Reacta Biotech Ltd. RR reported personal fees from HAL Allergy BV, Citeq BV, Angany Inc., and ThermoFisher Scientific. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Datema, Lyons, Fernández-Rivas, Ballmer-Weber, Knulst, Asero, Barreales, Belohlavkova, de Blay, Clausen, Dubakiene, Fernández-Perez, Fritsche, Gislason, Hoffmann-Sommergruber, Jedrzejczak-Czechowicz, Jongejan, Kowalski, Kralimarkova, Lidholm, Papadopoulos, Popov, Prado, Purohit, Reig, Seneviratne, Sinaniotis, Vassilopoulou, Versteeg, Vieths, Welsing, Mills, Le, Zwinderman and van Ree.) more...

Evidence has suggested that major peanut allergen Ara h 1 activates dendritic cells (DCs) via interaction with DC-SIGN (dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin), a C-type lectin receptor, and contributes to development of peanut allergy. Since macrophages, as well as DCs, play a crucial role in innate immunity, we investigated whether natural Ara h 1 (nAra h 1) activates two different subsets of macrophages, human monocyte derived macrophage type 1 (hMDM1: pro-inflammatory model) and type 2 (hMDM2: anti-inflammatory model). hMDM1 and hMDM2 predominantly produced pro-inflammatory cytokines (IL-6 and TNF-α) and an anti-inflammatory cytokine (IL-10) in response to nAra h 1, respectively. hMDM2 took up nAra h 1 and expressed DC-SIGN at higher levels than hMDM1. However, small interfering RNA knockdown of DC-SIGN did not suppress nAra h 1 uptake and nAra h 1-mediated cytokine production in hMDM2. Inhibitors of scavenger receptor class A type I (SR-AI) suppressed the response of hMDM2, but not of hMDM1, suggesting that SR-AI is a major receptor in hMDM2 for nAra h 1 recognition and internalization. nAra h 1 appears to exert stimulatory capacity on DC and macrophages via different receptors. This study advances our understanding how a major peanut allergen interacts with innate immunity. more...

Background and Objectives: Peach gibberellin-regulated protein (peamaclein) has recently emerged as a relevant food allergen in cypress pollen-hypersensitive patients. Objective: We investigated monosensitization to peamaclein among Italian cypress pollen-allergic patients., Material and Methods: A total of 835 cypress pollen-hypersensitive patients from 28 Italian allergy centers underwent a thorough work-up to determine food-allergic reactions and performed skin prick testing with a commercial peach extract containing peamaclein. IgE to rPru p 3 was measured in peach reactors, and those with negative results were enrolled as potentially monosensitized to peamaclein. IgE reactivity to rPru p 7 was evaluated using immunoblot and an experimental ImmunoCAP with rPru p 7., Results: Skin prick tests were positive to peach in 163 patients (19.5%); however, 127 (77.9%) were excluded because they reacted to Pru p 3. Twenty-four patients (14.7%) corresponding to 2.8% of the entire study population) were considered potentially monosensitized to peamaclein. No geographic preference was observed. Seventeen of the 24 patients (70.8%) had a history of food allergy, mainly to peach (n=15). Additional offending foods included other Rosaceae, citrus fruits, fig, melon, tree nuts, and kiwi. On peach immunoblot, only 3 of 18 putative peamaclein-allergic patients reacted to a band at about 7 kDa; an additional 4 patients reacted at about 50-60 kDa. Ten of 18 patients (56%) had a positive result for Pru p 7 on ImmunoCAP., Conclusion: Allergy and sensitization to peamaclein seem rare in Italy. Most patients react to peach, although other Rosaceae fruits and several citrus fruits may also be offending foods. Peach and cypress pollen probably also share cross-reacting allergens other than peamaclein. more...

Background: Walnut allergy is common across the globe, but data on the involvement of individual walnut components are scarce., Objectives: To identify geographical differences in walnut component sensitization across Europe, explore cosensitization and cross-reactivity, and assess associations of clinical and serological determinants with severity of walnut allergy., Methods: As part of the EuroPrevall outpatient surveys in 12 European cities, standardized clinical evaluation was conducted in 531 individuals reporting symptoms to walnut, with sensitization to all known walnut components assessed in 202 subjects. Multivariable Lasso regression was applied to investigate predictors for walnut allergy severity., Results: Birch-pollen-related walnut sensitization (Jug r 5) dominated in Northern and Central Europe and lipid transfer protein sensitization (Jug r 3) in Southern Europe. Profilin sensitization (Jug r 7) was prominent throughout Europe. Sensitization to storage proteins (Jug r 1, 2, 4, and 6) was detected in up to 10% of subjects. The walnut components that showed strong correlations with pollen and other foods differed between centers. The combination of determinants best predicting walnut allergy severity were symptoms upon skin contact with walnut, atopic dermatitis (ever), family history of atopic disease, mugwort pollen allergy, sensitization to cat or dog, positive skin prick test result to walnut, and IgE to Jug r 1, 5, 7, or carbohydrate determinants (area under the curve = 0.81; 95% CI, 0.73-0.89)., Conclusions: Walnut-allergic subjects across Europe show clear geographical differences in walnut component sensitization and cosensitization patterns. A predictive model combining results from component-based serology testing with results from extract-based testing and information on clinical background allows for good discrimination between mild to moderate and severe walnut allergy., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.) more...

Background: Severe allergy to fruits mediated by a 7 kDa allergen belonging to the gibberellin-regulated protein (GRP) family is known to be associated with Cupressaceae pollinosis., Objective: To identify and characterize Cupressaceae pollen allergens involved in GRP-related fruit allergy., Methods: Pru p 7-related proteins from pollen of Cupressus sempervirens, Juniperus ashei and Cryptomeria japonica were identified using a rabbit anti-Pru p 7 antiserum, purified chromatographically and sequenced by mass spectrometry and bioinformatic comparisons. The C sempervirens protein was produced as a recombinant allergen in Pichia pastoris. IgE antibody binding to pollen GRP proteins was analysed in a peach allergic (n = 54) and a cypress pollen allergic (n = 88) patient population from southern France using ImmunoCAP., Results: In each of the three Cupressaceae species studied, a 7 kDa pollen protein related to Pru p 7 was identified and found to comprise an amino acid sequence of 63 residues in length, 92%-98% identical to each other and 67%-68% identical to Pru p 7. The C sempervirens, J ashei and C japonica GRP allergens have been officially recognized by the WHO/IUIS Allergen Nomenclature Sub-Committee and named Cup s 7, Jun a 7 and Cry j 7, respectively. Recombinant Cup s 7 showed IgE antibody binding capacity comparable to that of the purified natural allergen. Among 51 peach allergic subjects sensitized to Pru p 7, substantially higher levels of IgE to Cup s 7 than to Pru p 7 were found. Further, the pollen protein was able to completely outcompete IgE binding to Pru p 7, while the reverse competition effect was modest, consistent with primary sensitization by the pollen allergen., Conclusion and Clinical Relevance: Pru p 7-related pollen allergens from three Cupressaceae species have been characterized and may become useful for the identification of pollinosis patients at risk of developing severe fruit allergy., (© 2020 John Wiley & Sons Ltd.) more...

Background: Sensitization to peanuts and hazelnuts is common among young asthmatics and can be primary or a result of cross-reactivity. Sensitization as a result of cross-reactivity to birch pollen is typically associated to tolerance or mild and local symptoms upon intake of peanut or hazelnut., Aim: The aim of this study was to investigate relationships between IgE antibody responses against peanut and hazelnut components, airway and systemic inflammation markers, lung function parameters and reported food hypersensitivity in a cohort of asthmatic children and young adults., Methods: A population of 408 asthmatic individuals aged 10-35 years were investigated. Information on hypersensitivity symptoms upon intake of peanut or hazelnut were recorded in a standardized questionnaire. Fraction of exhaled nitric oxide (FeNO), blood eosinophil count (B-Eos), spirometry, methacholine challenge outcome and IgE antibodies to peanut and hazelnut allergens were measured by standard clinical and laboratory methods., Results: Subjects sensitized to any of the peanut (Ara h 1, 2 or 3) or hazelnut (Cor a 9 or 14) storage proteins were significantly younger (17.6 vs 21.2 years), had higher levels of FeNO (23.2 vs 16.7 ppb) and B-Eos (340 vs 170 cells/mcl) than those displaying only pollen-related cross-reactive sensitization. Levels of FeNO correlated with levels of IgE to storage proteins in children, but not in adults. Levels of B-Eos correlated with levels of IgE to all allergen components investigated in children, but only to levels of IgE to storage proteins in adults. Anaphylaxis and skin reactions upon intake of peanuts or hazelnuts were more often reported among subjects sensitized to the respective storage proteins than among those with only pollen-related cross-reactive sensitization. As compared to peanut, hazelnut was more often reported to cause gastrointestinal symptoms and less often oral cavity symptoms., Conclusions: Sensitization to peanut and hazelnut storage proteins was associated with higher levels of inflammation markers and food hypersensitivity symptoms in this population of subjects with asthma., Competing Interests: Competing interestsJL, CJP and MPB are employed by ThermoFisher Scientific, Uppsala, Sweden. All other authors declare that they have no competing interests., (© The Author(s) 2020.) more...

Background: Small, basic peanut proteins are often poorly extracted in pH-neutral buffers that are optimal for the extraction of peanut storage proteins such as Ara h 1. As a result, such proteins are easily missed as potential allergens., Objective: To analyse the allergenic composition of the basic peanut protein (BPP) fraction., Methods: A peanut extract prepared at pH 4 was fractionated by physicochemical procedures. Chemical analysis was performed by SDS-PAGE and mass spectrometry. Because immunoblotting was found to be inefficient for most of these small basic proteins, IgE-binding activity was measured by coupling the fractions to CNBr-activated Sepharose, followed by incubation with sera from 55 Dutch peanut-allergic children and 125 I-labelled anti-IgE., Results: Most IgE reactivity of the BPP fraction was due to the 5-7 kDa amino-terminal fragment of Ara h 1. This finding was confirmed by the use of the fragment in recombinant form, to which 25/55 of the sera was IgE-positive., Conclusion: The amino-terminal fragment of Ara h 1, a member of a family of small anti-microbial proteins, is an allergen independent of the carboxy-terminal fragment of Ara h 1., (© 2019 John Wiley & Sons Ltd.) more...

Background: Diagnostic methods for distinguishing walnut-allergic patients from walnut-sensitized but walnut-tolerant individuals are limited. Furthermore, characteristics of single walnut versus dual walnut-pecan allergy are lacking., Objective: To provide clinical and molecular characteristics of walnut- and pecan-allergic patients., Methods: A prospective cohort study of 76 walnut-sensitized patients was performed. Walnut skin prick test and serum measurements of specific IgE to walnut and its components were performed. Patients were challenged to walnut and pecan unless they regularly consumed walnut and pecan., Results: Of the 76 patients studied, 61 were diagnosed as walnut-allergic and 15 as walnut-tolerant. IgE levels greater than or equal to 0.35 kU A /L to Jug r 1 or 4 provided the best diagnostic method for identifying walnut-allergic patients (accuracy, 0.93). Of the 61 walnut-allergic patients, 49 were pecan-allergic whereas 12 were pecan-tolerant. None of the walnut-tolerant patients was allergic to pecan. Dual allergic patients had significantly lower walnut reaction dose (median, 100 mg vs 1230 mg; P < .001). IgE levels greater than or equal to 0.35 kU A /L to Jug r 4, low-molecular-weight vicilins, or high-molecular-weight vicilins best segregated dual walnut-pecan-allergic patients from single walnut-allergic patients. Inhibition studies demonstrated that walnut pretreatment completely blocked IgE binding to pecan, whereas in some patients, pecan incubation only partially blocked IgE binding to walnut., Conclusions: Walnut components are helpful in diagnosing walnut allergy and in identifying patients with pecan coallergy. Competitive ELISA indicates that pecan comprises a subset of the allergenic determinants of walnut., (Copyright © 2019 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.) more...

Background: The presence of sesame in Western diet is increasing, making its avoidance by sesame-allergic patients more challenging., Objective: To report the efficacy and safety of sesame oral immunotherapy (OIT)., Methods: Sixty patients aged 4 years or older, diagnosed as sesame-allergic on the basis of a positive oral food challenge, were consecutively enrolled into OIT between November 2014 and November 2017. Fifteen patients with sesame allergy, based on a positive oral food challenge or a recent immediate reaction, and a positive skin prick test result or specific IgE, continued sesame elimination and served as observational controls. Immunologic parameters were measured in a subset (OIT, n = 16; controls, n = 11) at the start and end of the study. Fully desensitized patients continued daily consumption of 1200 mg sesame protein and challenged with 4000 mg after more than 6 months., Results: Fifty-three OIT-treated patients (88.4%) were fully desensitized to sesame, compared with 0% of controls. Four additional patients (total 57 of 60 = 95%) were desensitized to more than 1000 mg protein. Reactions occurred in 4.7% of hospital doses and 1.9% of home doses. Epinephrine-treated reactions occurred in 16.7% of patients for hospital and 8.3% for home doses. Significant decreases in rSes i 1 IgE (P = .007) and basophil reactivity (P = .001) and increases in sesame and rSes i 1 IgG 4 (P = .001) occurred in OIT-treated patients but not in controls. Forty-seven patients desensitized to 4000 mg were evaluated more than 6 months after reaching maintenance. Only mild reactions were reported during maintenance, and all passed the 4000-mg challenge., Conclusions: Sesame-OIT is an effective alternative to sesame avoidance in allergic patients. The potential for adverse events necessitates its performance in specialized centers., (Copyright © 2019 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.) more...

Background: The safety and efficacy of oral immunotherapy for tree nut allergy has not been demonstrated to date, and its effectiveness is complicated by the high prevalence of co-allergies to several nuts. This study aimed to investigate the use of walnut oral immunotherapy in the desensitisation of walnut and additional tree nuts in patients who are co-allergic to several nuts., Methods: In a single-centre, prospective cohort study (the Nut Co-Reactivity ACquiring Knowledge for Elimination Recommendations study) at the Institute of Allergy, Immunology, and Paediatric Pulmonology at the Yitzhak Shamir Medical Centre, we recruited patients aged 4 years or older who were allergic to walnut, with or without co-allergy to pecan, hazelnut, and cashew. The diagnosis of each food allergy was based on a positive skin prick test or specific serum IgE (≥0·35 kU A /L) to the corresponding nut together with a positive oral food challenge, unless an immediate (within 2 h of exposure) reaction in the past year had been documented. Patients with uncontrolled asthma or a medical contraindication to receive adrenaline were excluded. Patients were assigned to walnut oral immunotherapy or the control group (observation and strict dietary exclusion) on the basis of the order of presentation to the clinic. Oral immunotherapy began with a 4-day dose-escalation phase to establish the single highest tolerated dose, which was consumed daily at home for 24 days; subsequent monthly dose escalations were repeated until 4000 mg walnut protein was achieved. Patients who were desensitised to walnut continued to consume 1200 mg walnut protein daily for 6 months as maintenance. The primary outcome was walnut desensitisation (passing an oral food challenge with 4000 mg of walnut protein) at the end of the study, analysed by intention to treat. In patients who were co-allergic to pecan, hazelnut, and cashew, the proportion who achieved cross-desensitisation to these nuts in addition to walnut desensitisation was examined., Findings: 73 patients with a walnut allergy were enrolled between May 15, 2016, and Jan 14, 2018. 49 (89%) of 55 patients in the oral immunotherapy group were desensitised to walnut compared with none of 18 patients in the control group (odds ratio 9·2, 95% CI 4·3-19·5; p<0·0001). Following walnut desensitisation, all patients who were co-allergic to pecan (n=46) were also desensitised to pecan. Additionally, 18 (60%) of 30 patients who were co-allergic to hazelnut or cashew, and 14 (93%) of 15 patients who were co-allergic to hazelnut alone, were either fully desensitised or responded to treatment. 47 (85%) of 55 patients had an adverse reaction (mostly grade 1 or 2) during up-dosing in the clinic; eight patients required intramuscular epinephrine in response to a dose at home. Of 45 patients who had follow-up data for the maintenance phase, all maintained walnut desensitisation and one patient required epinephrine during this period., Interpretation: Walnut oral immunotherapy can induce desensitisation to walnut as well as cross-desensitisation to pecan and hazelnut in patients who have tree nut co-allergies, with a reasonable safety profile. A low daily dose of the allergen maintains desensitisation., Funding: None., (Copyright © 2019 Elsevier Ltd. All rights reserved.) more...

Background: Walnut is an important elicitor of food allergy in children and adults with a high rate of severe reactions. Multicenter studies using a common clinical protocol and a comprehensive allergen are lacking., Objective: To investigate potential correlations between molecular sensitization patterns and clinical characteristics of walnut-allergic patients., Methods: A total of 91 walnut-allergic subjects and 24 tolerant controls from Switzerland, Germany, and Spain were included. Walnut allergy was established by food challenge in all but anaphylactic subjects. Specific IgE (sIgE) to walnut extract, rJug r 1 (2S albumin), rJug r 3 (nonspecific lipid transfer protein 1), nJug r 4 (11S globulin), rJug r 5 (PR-10 protein), 2 vicilin fractions, profiling, and cross-reactive carbohydrate determinant was determined by ImmunoCAP. A threshold of 0.10 kU A /L was used for positivity., Results: Sensitivity of sIgE to walnut extract was 87% and increased to 96% for the sum of all walnut components. sIgE to walnut extract and all walnut components, except rJug r 5, was significantly higher in patients younger than 14 years at inclusion. Stratification by age at onset of walnut allergy led to similar results. All patients younger than 14 years had severe reactions, whereas 38% of patients 14 years or older were mild reactors. Severe reactors (n = 70) had higher sIgE levels than did mild reactors (n = 21) to walnut extract (P < .0001), rJug r 1 (P < .0001), nJug r 4 (P = .0003), and both vicilin fractions (P < .0001), but not to Jug r 3 and Jug r 5., Conclusions: Sensitization to walnut storage proteins is acquired in childhood and correlates with severe reactions. sIgE levels to storage proteins Jug r 1 and Jug r 4 and vicilin fractions, but not to nonspecific lipid transfer protein and PR-10 proteins, correlate with systemic reactions to walnut., (Copyright © 2019 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.) more...

Background: Peach is a common elicitor of food allergic reactions. Peach-induced immediate reactions may occur as benign pollen-food syndromes, usually due to birch pollen-related PR-10 cross-reactivity in temperate climates, and as potentially severe primary food allergies, predominantly related to nsLTP Pru p 3 in Mediterranean regions. The newly described peach allergen Pru p 7 has gained recent attention as a potential peach allergy severity marker. Sensitization to Pru p 7 and its allergenic homologues of the gibberellin-regulated protein family occurs in areas with high Cupressaceae tree pollen exposure., Objective: We sought to investigate the distribution, clinical characteristics and molecular associations of Pru p 7 sensitization among subjects with suspected peach allergy in different regions of France., Methods: Subjects with suspected peach allergy (n = 316) were included. Diagnostic work-up was performed according to current guidelines, including open food challenge when required. IgE antibody measurements and competition experiments were performed using the ImmunoCAP assay platform., Results: Sensitization to Pru p 7 was present in 171 (54%) of all subjects in the study and in 123 of 198 (62%) diagnosed as peach allergic, more than half of whom were sensitized to no other peach allergen. Frequency and magnitude of Pru p 7 sensitization were associated with the presence of peach allergy, the clinical severity of peach-induced allergic reactions and the level of cypress pollen exposure. Cypress pollen extract completely outcompeted IgE binding to Pru p 7. Pru p 7 was extremely potent in basophil activation tests., Conclusion and Clinical Relevance: A subtype of Cupressaceae pollinosis, characterized by Pru p 7 sensitization, can be an underlying cause of severe peach allergy., (© 2019 John Wiley & Sons Ltd.) more...

Background: Measurement of IgE antibody to hazelnut components can aid in the prediction of allergic responses to the food., Objective: To investigate the association between patient demographics (age, location) and patterns of allergic sensitization to hazelnut components across the United States and to investigate the degree of correlation between hazelnut sensitization with sensitization to other tree nuts, peanuts, and their components., Methods: Serum samples from 10,503 individuals with hazelnut extract specific IgE (sIgE) levels of 0.35 kU A /L or higher were analyzed for IgE antibodies to Cor a 1, 8, 9, and 14 by ImmunoCAP. A subset of these patients were analyzed for IgE antibodies to peanut, walnut, and cashew nut IgE along with associated components., Results: Among hazelnut sensitized individuals, children (<3 years old) were predominantly sensitized to Cor a 9 and Cor a 14. Conversely, Cor a 1 sIgE sensitization was much higher in adults than children, especially in the Northeastern United States. Cor a 8 sensitization was relatively constant (near 10%) across all ages. Cosensitization of hazelnut with other tree nuts and peanuts was related to correlation of IgE concentrations of individual component families., Conclusion: We conclude that sensitization to individual hazelnut components is highly dependent on age and/or geographic location. Component correlations suggest that cosensitization to hazelnut and walnut may be caused by their pathogenesis-related protein 10 allergens, nonspecific lipid transfer proteins, or seed storage proteins, whereas hazelnut and peanut cosensitization is more often caused by cross-reactivity of pathogenesis-related protein 10 (Cor a 1 and Ara h 8) and nonspecific lipid transfer proteins (Cor a 8 and Ara h 9)., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.) more...

Background: Common wheat (Triticum aestivum) and durum wheat (T. turgidum) are both involved in Baker's asthma (BA) and food allergy (FA) including wheat-dependent exercise-induced asthma (WDEIA). However, allergens in durum wheat have not been described, and the over-expression of T. turgidum non-specific lipid-transfer protein (nsLTPs) is considered to increase resistance to phytopathogens., Objective: To identify and assess the allergenicity of nsLTP from T. turgidum., Methods: Recombinant T. turgidum nsLTP Tri tu 14 was generated and tested for structural integrity (circular dichroism-spectroscopy) and purity (SDS-PAGE). Thirty-two wheat allergic patients were enrolled: 20 Spanish patients (BA) with positive bronchial challenge to wheat flour, and 12 Italian patients (wheat FA/WDEIA) with positive double-blind placebo-controlled food challenge/open food challenge (OFC) to pasta. IgE values to wheat, Tri tu 14, Tri a 14 (T. aestivum) and Pru p 3 (P. persica) were determined by ImmunoCAP testing. Allergenic potency (in vitro mediator release) and IgE cross-reactivity were investigated., Results: Tri tu 14 was found to share 49% and 52% amino acid identity with Tri a 14 and Pru p 3, respectively. Among 25 Tri a 14 CAP positive sera, 23 (92%) were reactive to wheat extract, 22 (88%) to Tri tu 14 and 20 (80%) to Pru p 3. The correlation between Tri a 14 and Tri tu 14 specific IgE levels was r = 0.97 (BA) and r = 0.93 (FA/WDEIA), respectively. FA/WDEIA patients showed higher specific IgE values to Tri tu 14 and Pru p 3 than BA patients. Tri tu 14 displayed allergenic activity by mediator release from effector cells and IgE cross-reactivity with Pru p 3. The degree of IgE cross-reactivity between the two wheat nsLTPs varied between individual patients., Conclusions and Clinical Relevance: Sensitization to Tri tu 14 likely appears to be more important in wheat FA/WDEIA than in BA. Over-expression of Tri tu 14 in wheat would represent a risk for patients with nsLTP-mediated FA., (© 2018 John Wiley & Sons Ltd.) more...

Background: Cat allergy is a major trigger of asthma world-wide. Molecular patterns of cat sensitization vary between individuals, but their relationship to inflammation in asthmatics has not been extensively studied., Objective: To investigate the prevalence and levels of IgE antibodies against different cat allergen components and their relationship to type-2 inflammation and total IgE among young asthmatic subjects sensitized to furry animals., Methods: Patients with asthma (age 10-35 years; n = 266) and IgE sensitization to cat, dog or horse extract (ImmunoCAP), were analysed for IgE to the cat allergen components Fel d 1 (secretoglobin), Fel d 2 (serum albumin), Fel d 4 and Fel d 7 (lipocalins). Independent associations between IgE-antibody concentrations, and fraction of exhaled nitric oxide (FeNO), blood eosinophil (B-Eos) count, and total IgE were analysed by multiple linear regression after adjustment for possible confounders., Results: The level of IgE against Fel d 2 was independently related to FeNO (P = .012) and total IgE (P < .001), and IgE against Fel d 4 associated with Β-Eos count (P = .009) and total IgE (P < .001). IgE antibodies against Fel d 1 or cat extract did not independently relate to these inflammatory markers (P = .23-.51)., Conclusions: Levels of IgE to lipocalin (Fel d 4) and serum albumin (Fel d 2), but not to secretoglobin (Fel d 1) or cat extract, were independently associated with type-2 biomarkers and total IgE in young asthmatics., Clinical Relevance: We suggest that measurement of IgE to minor cat allergen components may be useful when investigating asthma morbidity in cat allergic subjects., (© 2018 John Wiley & Sons Ltd.) more...

A systematic nomenclature for allergens originated in the early 1980s, when few protein allergens had been described. A group of scientists led by Dr. David G. Marsh developed a nomenclature based on the Linnaean taxonomy, and further established the World Health Organization/International Union of Immunological Societies (WHO/IUIS) Allergen Nomenclature Sub-Committee in 1986. Its stated aim was to standardize the names given to the antigens (allergens) that caused IgE-mediated allergies in humans. The Sub-Committee first published a revised list of allergen names in 1986, which continued to grow with rare publications until 1994. Between 1994 and 2007 the database was a text table online, then converted to a more readily updated website. The allergen list became the Allergen Nomenclature database (www.allergen.org), which currently includes approximately 880 proteins from a wide variety of sources. The Sub-Committee includes experts on clinical and molecular allergology. They review submissions of allergen candidates, using evidence-based criteria developed by the Sub-Committee. The review process assesses the biochemical analysis and the proof of allergenicity submitted, and aims to assign allergen names prior to publication. The Sub-Committee maintains and revises the database, and addresses continuous challenges as new "omics" technologies provide increasing data about potential new allergens. Most journals publishing information on new allergens require an official allergen name, which involves submission of confidential data to the WHO/IUIS Allergen Nomenclature Sub-Committee, sufficient to demonstrate binding of IgE from allergic subjects to the purified protein., (Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.) more...

Background: Allergen-specific IgG 4 (sIgG 4 ) antibodies are often associated with tolerance, but sIgG 4 antibodies to causally relevant foods have been reported recently in adults with eosinophilic esophagitis (EoE). Prevalence and levels of food sIgG 4 are not well established in the general pediatric population., Objective: We sought to investigate serum food sIgG 4 with component diagnostics in children with EoE and children from an unselected birth cohort and to explore the effects of sex, age, and milk consumption on sIgG 4 levels., Methods: Sera from 71 pediatric patients with EoE and 210 early adolescent children from an unselected birth cohort (Project Viva) were assayed for sIgG 4 and specific IgE (sIgE) to major cow's milk (CM) proteins (α-lactalbumin, β-lactoglobulin, and caseins) and to wheat, soy, egg, and peanut proteins., Results: In the EoE cohort high-titer sIgG 4 (≥10 μg/mL) to CM proteins was more common than in control sera and achieved odds ratios for EoE ranging from 5.5 to 8.4. sIgE levels to CM proteins were mostly 4 IU/mL or less in patients with EoE, such that sIgG 4 /sIgE ratios were often 10,000 or greater. When adjusted for age and milk consumption, high-titer sIgG 4 to CM proteins was strongly associated with EoE, with an odds ratio of greater than 20 to all 3 CM proteins in boys., Conclusions: sIgG 4 to CM proteins are common and high titer in children with EoE. Although it is not clear that this response is pathogenic, sIgG 4 levels imply that these antibodies are an important feature of the local immune response that gives rise to EoE., (Copyright © 2018 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.) more...

Background: Component-resolved diagnosis (CRD) has revealed significant associations between IgE against individual allergens and severity of hazelnut allergy. Less attention has been given to combining them with clinical factors in predicting severity., Aim: To analyze associations between severity and sensitization patterns, patient characteristics and clinical history, and to develop models to improve predictive accuracy., Methods: Patients reporting hazelnut allergy (n = 423) from 12 European cities were tested for IgE against individual hazelnut allergens. Symptoms (reported and during Double-blind placebo-controlled food challenge [DBPCFC]) were categorized in mild, moderate, and severe. Multiple regression models to predict severity were generated from clinical factors and sensitization patterns (CRD- and extract-based). Odds ratios (ORs) and areas under receiver-operating characteristic (ROC) curves (AUCs) were used to evaluate their predictive value., Results: Cor a 9 and 14 were positively (OR 10.5 and 10.1, respectively), and Cor a 1 negatively (OR 0.14) associated with severe symptoms during DBPCFC, with AUCs of 0.70-073. Combining Cor a 1 and 9 improved this to 0.76. A model using a combination of atopic dermatitis (risk), pollen allergy (protection), IgE against Cor a 14 (risk) and walnut (risk) increased the AUC to 0.91. At 92% sensitivity, the specificity was 76.3%, and the positive and negative predictive values 62.2% and 95.7%, respectively. For reported symptoms, associations and generated models proved to be almost identical but weaker., Conclusion: A model combining CRD with clinical background and extract-based serology is superior to CRD alone in assessing the risk of severe reactions to hazelnut, particular in ruling out severe reactions., (© 2017 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.) more...

Background: Thirty percent of children with food allergies have multiple simultaneous allergies; however, the features of these multiple allergies are not well characterized serologically or clinically., Objective: We comprehensively evaluated 60 multifood-allergic patients by measuring serum IgE to key allergen components, evaluating clinical histories and medication use, performing skin tests, and conducting double-blind, placebo-controlled food challenges (DBPCFCs)., Methods: Sixty participants with multiple food allergies were characterized by clinical history, DBPCFCs, total IgE, specific IgE, and component-resolved diagnostics (IgE and IgG4) data. The food allergens tested were almond, egg, milk, sesame, peanut, pecan, walnut, hazelnut, cashew, pistachio, soy, and wheat., Results: Our data demonstrate that of the reactions observed during a graded DBPCFC, gastrointestinal reactions occurred more often in boys than in girls, as well as in individuals with high levels of IgE to 2S albumins from cashew, walnut, and hazelnut. Certain food allergies often occurred concomitantly in individuals (ie, cashew/pistachio and walnut/pecan/hazelnut). IgE testing to components further corroborated serological relationships between and among these clustered food allergies., Conclusions: Associations of certain food allergies were shown by DBPCFC outcomes as well as by correlations in IgE reactivity to structurally related food allergen components. Each of these criteria independently demonstrated a significant association between allergies to cashew and pistachio, as well as among allergies to walnut, pecan, and hazelnut., (Copyright © 2017 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.) more...

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., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.) more...

Knowledge of the susceptibility of proteins to endolysosomal proteases provides valuable information on immunogenicity. Though Ole e 1-like proteins are considered relevant allergens, little is known about their immunogenic properties and T cell epitopes. Thus, six representative molecules, i.e., Ole e 1, Fra e 1, Sal k 5, Che a 1, Phl p 11 and Pla l 1, were investigated. Endolysosomal degradation and peptide generation were simulated using microsomal fractions of JAWS II dendritic cells. Kinetics and peptide patterns were evaluated by gel electrophoresis and mass spectrometry. In silico MHC (major histocompatibility complex) class II binding prediction was performed with ProPred. Cleavage sites were assigned to the primary and secondary structure, and in silico docking experiments between the protease cathepsin S and Ole e 1 were performed. Different kinetics during endolysosomal degradation were observed while similar peptide profiles especially at the C-termini were detected. Typically, the identified peptide clusters comprised the previously-reported T cell epitopes of Ole e 1, consistent with an in silico analysis of the T cell epitopes. The results emphasize the importance of the fold on allergen processing, as also reflected by conserved cleavage sites located within the large flexible loop. In silico docking and mass spectrometry results suggest that one of the first Ole e 1 cleavages might occur at positions 107-108. Our results provided kinetic and structural information on endolysosomal processing of Ole e 1-like proteins., Competing Interests: The authors declare no conflict of interest. more...