Defining the window of opportunity and target populations to prevent peanut allergy.
Background: Peanut allergy affects 1% to 2% of European children. Early introduction of peanut into the diet reduces allergy in high-risk infants. Objective: We aimed to determine the optimal target populations and timing of introduction of peanut products to prevent peanut allergy in the general population. Methods: Data from the Enquiring About Tolerance (EAT; n = 1303; normal risk; 3-year follow-up; ISRCTN14254740) and Learning Early About Peanut Allergy study (LEAP; n = 640; high risk; 5-year follow-up; NCT00329784) randomized controlled trials plus the Peanut Allergy Sensitization (PAS; n = 194; low and very high risk; 5-year follow-up) observational study were used to model the intervention in a general population. Peanut allergy was defined by blinded peanut challenge or diagnostic skin prick test result. Results: Targeting only the highest-risk infants with severe eczema reduced the population disease burden by only 4.6%. Greatest reductions in peanut allergy were seen when the intervention was targeted only to the larger but lower-risk groups. A 77% reduction in peanut allergy was estimated when peanut was introduced to the diet of all infants, at 4 months with eczema, and at 6 months without eczema. The estimated reduction in peanut allergy diminished with every month of delayed introduction. If introduction was delayed to 12 months, peanut allergy was only reduced by 33%. Conclusions: The preventive benefit of early introduction of peanut products into the diet decreases as age at introduction increases. In countries where peanut allergy is a public health concern, health care professionals should help parents introduce peanut products into their infants’ diet at 4 to 6 months of life. https://doi.org/10.1016/j.jaci.2022.09.042
Expression, purification, characterization, and patient IgE reactivity of new macadamia nut iso-allergen.
Structural and functional information about food allergens is essential for understanding the allergenicity of food proteins. All allergens belong to a small number of protein families. Various allergens from different families have been successfully produced recombinantly in E. coli for their characterization and applications in allergy diagnosis and treatment. However, recombinant hexameric 11S seed storage protein has not been reported, although numerous 11S legumins are known to be food allergens, including the recently identified macadamia nut allergen Mac i 2. Here we report the production of a macadamia nut legumin by expressing it in E. coli with a substrate site of HRV 3C protease and cleaving the purified protein with HRV 3C protease. The protease divided the protein into two chains and left a native terminus for the C-terminal chain, resulting in a recombinant hexameric 11S allergen for the first time after the residues upstream to the cleavage site flipped out of the way of the trimer-trimer interaction. The 11S allergens are known to have multiple isoforms in many species. The present study removed an obstacle in obtaining homogeneous allergens needed for studying allergens and mitigating allergenicity. Immunoreactivity of the protein with serum IgE confirmed it to be a new isoform of Mac i 2. https://doi.org/10.1016/j.pep.2022.106211
Non-thermal processing of cashews: irradiation reduces allergenicity by altering the structure of Ana o 3.
Traditional thermal processing of cashews not only results in nutrient loss and harmful by-products, but also does not significantly reduce allergenicity. Irradiation could be an important non-thermal processing method to reduce cashew allergens' allergenicity and retain their nutritional properties. This study aimed to evaluate the effects of gamma irradiation processing on the structure and potential allergenicity of Ana o 3. The Ana o 3 solutions were gamma-irradiated at 0, 1, 3, 5, and 10 kGy. The structure change was monitored by Tricine-SDS-PAGE, circular dichroism spectroscopy, and fluorescence spectroscopy. The potential allergenicity was tested by immunoblotting, indirect competitive ELISA, and the human basophil KU812 degranulation assay using serum from cashew allergy patients. The results of CD spectroscopy showed that the content of α-helices decreased from 46.8% to 30.9% after 3 to 10 kGy, while the content of random coils increased from 23.7% to 33.3%. Meanwhile, a large number of hydrophobic regions were exposed, resulting in an increase in the hydrophobic surface of the protein. In terms of allergenicity, the IC50 values obtained by the competitive inhibition ELISA after irradiation increased from 0.628 to 4.054 μg mL-1, indicating that irradiation reduced the IgE binding capacity of Ana o 3, which was consistent with the results of western blotting. In addition, the basophil degranulation analysis showed that the release of IL-6, TNF-α, and histamine was decreased. It was shown that the potential allergenicity of the irradiated Ana o 3 was remarkably decreased since irradiation could mask or destroy the allergen epitopes, providing a new approach to reduce the allergenicity of cashew products. https://doi.org/10.1039/d2fo03057h
Structure and IgE Cross-Reactivity among Cashew, Pistachio, Walnut, and Peanut Vicilin-Buried Peptides.
Peanut and tree-nut allergies are frequently comorbid for reasons not completely understood. Vicilin-buried peptides (VBPs) are an emerging family of food allergens whose conserved structural fold could mediate peanut/tree-nut co-allergy. Peptide microarrays were used to identify immunoglobulin E (IgE) epitopes from the N-terminus of the vicilin allergens Ara h 1, Ana o 1, Jug r 2, and Pis v 3 using serum from three patient diagnosis groups: monoallergic to either peanuts or cashew/pistachio, or dual allergic. IgE binding peptides were highly prevalent in the VBP domains AH1.1, AO1.1, JR2.1, and PV3.1, but not in AO1.2, JR2.2, JR2.3, and PV3.2 nor the unstructured regions. The IgE profiles did not correlate with diagnosis group. The structure of the VBPs from cashew and pistachio was solved using solution-NMR. Comparisons of structural features suggest that the VBP scaffold from peanuts and tree-nuts can support cross-reactivity. This may help understand comorbidity and cross-reactivity despite a distant evolutionary origin. https://doi.org/10.1021/acs.jafc.2c07061
Real-World Safety Analysis of Preschool Tree Nut Oral Immunotherapy.
Background: Our group previously described preschool peanut oral immunotherapy (P-OIT) in a real-world multi-center setting, suggesting this therapy is safe for the vast majority of preschoolers. Objectives: We examined the safety and tolerability of tree nut (TN)-OIT in preschoolers in the real-world. Methods: As part of a Canada-wide quality improvement project, TN-OIT (cashew/pistachio, walnut/pecan, hazelnut, almond, macadamia nut) was administered to preschool-aged children who had (1) skin prick test ≥ 3mm or specific IgE level ≥ 0.35kU/L and convincing objective IgE-mediated reaction or (2) no ingestion history and specific IgE level ≥ 5kU/L. Patients built-up every two to four weeks to a maintenance dose of 300mg TN protein. Symptoms were recorded and classified using a modified World Allergy Organization Subcutaneous Immunotherapy Reaction Grading System (1 mildest, 5 fatal). Results: Of 92 patients who started TN-OIT from 2018-2021, 79 (85.9%) underwent single-food TN-OIT and 13 (14.1%) underwent multi-food TN-OIT to two (10.8%) or three (3.3%) TNs. Eighty-nine (96.7%) patients reached maintenance, and 4 dropped out (4.3%). Sixty-five (70.7%) patients experienced reactions during build-up: 35 (38.0%) grade 1, 30 (32.6%) grade 2 reactions, no grade 3 or 4 reactions, and 2 (2.17%) received epinephrine. Conclusions: Preschool TN-OIT in a real-world, multicenter setting appears safe and tolerable, with results comparable to our previously reported P-OIT findings. https://doi.org/10.1016/j.jaip.2023.01.031
Incorporating genetics in identifying peanut allergy risk and tailoring allergen immunotherapy: A perspective on the genetic findings from the LEAP trial.
Examining the genetics of peanut allergy (PA) in the context of clinical trial interventions and outcomes provides an opportunity to not only understand gene-environment interactions for PA risk but to also understand the benefit of allergen immunotherapy. A consistent theme in the genetics of food allergy is that in keeping with the dual allergen exposure hypothesis, barrier- and immune-related genes are most commonly implicated in food allergy and tolerance. With a focus on PA, we review how genetic risk factors across 3 genes (FLG, MALT1, and HLA-DQA1) have helped delineate distinct allergic characteristics and outcomes in the context of environmental interventions in the Learning Early about Peanut Allergy (LEAP) study and other clinical trials. We specifically consider and present a framework for genetic risk prediction for the development of PA and discuss how genetics, age, and oral consumption intertwine to predict PA outcome. Although there is some promise in this proposed framework, a better understanding of the mechanistic pathways by which PA develops and persists is needed to develop targeted therapeutics for established disease. Only by understanding the mechanisms by which PA develops, persists, and resolves can we identify adjuvants to oral immunotherapy to make older children and adults immunologically similar to their younger, more malleable counterparts and thus more likely to achieve long-term tolerance. https://doi.org/10.1016/j.jaci.2022.12.819
Allergenicity of peanut allergens and its dependence on the structure.
Food allergies are a global food safety problem. Peanut allergies are common due, in part, to their popular utilization in the food industry. Peanut allergy is typically an immunoglobulin E-mediated reaction, and peanuts contain 17 allergens belonging to different families in peanut. In this review, we first introduce the mechanisms and management of peanut allergy, followed by the basic structures of associated allergens. Subsequently, we summarize methods of epitope localization for peanut allergens. These methods can be instrumental in speeding up the discovery of allergenicity-dependent structures. Many attempts have been made to decrease the allergenicity of peanuts. The structures of hypoallergens, which are manufactured during processing, were analyzed to strengthen the desensitization process and allergen immunotherapy. The identification of conformational epitopes is the bottleneck in both peanut and food allergies. Further, the identification and modification of such epitopes will lead to improved strategies for managing and preventing peanut allergy. Combining traditional wet chemistry research with structure simulation studies will help in the epitopes' localization. https://doi.org/10.1111/1541-4337.13101
Factors associated with home epinephrine-treated reactions during peanut and tree-nut oral immunotherapy.
Background: Home reactions requiring epinephrine administration, a marker of their severity, restrict the widespread use of oral immunotherapy (OIT), but their risk factors are largely not known. Objective: To identify risk factors for such reactions during OIT to most allergenic foods. Methods: All patients who began OIT for peanut, tree nuts, sesame, or egg allergy at the Shamir Medical Center between April 2010 and January 2020 were enrolled. The patients were instructed to use their epinephrine autoinjectors during reactions consisting of severe abdominal pain, significant shortness of breath, or lethargy, or whenever in uncertainty of reaction severity. Patients with and without home epinephrine-treated reactions (HETRs) were compared. Results: A total of 757 OIT treatments for peanut (n = 346), tree nuts (n = 221; walnut n = 147, cashew n = 57, hazelnut n = 16, almond n = 1), sesame (n = 115), and egg (n = 75) allergies were administered to 644 patients. Eighty-three (10.9%) patients experienced HETRs. The highest rate of HETRs was experienced during walnut (20.4%) or hazelnut (25%) OIT, followed by peanut (9.8%), sesame (6.1%), egg (6.7%), and cashew (5.3%) OIT. Risk factors for HETRs included a reaction treated in an emergency department (ER) (P = .005) before starting OIT and a reaction treated with epinephrine during in-clinic induction (P < .001). Significantly fewer patients with (73.6%) than without (88.3%) HETRs achieved full desensitization (P = .001), but only a few patients with HETRs (8.4%) failed treatment. Conclusion: Previous reaction severity is the main predictor for HETRs during OIT. These reactions are more frequent during walnut and hazelnut OIT than during OIT for other foods studied. Most patients experiencing HETRs achieved desensitization. https://doi.org/10.1016/j.anai.2022.12.001
Narcolepsy-Like Sleepiness: A Symptom of Immediate-Type Reactions in Food-Allergic Children.
Background: It has been reported that sometimes children fall asleep and can barely be woken up during allergic reactions on food ingestion. Nevertheless, to date, there is scarce data on narcolepsy-like sleepiness as a symptom of allergic reactions. Objective: To investigate the frequency of narcolepsy-like sleepiness during oral food challenges and characterize this symptom regarding comorbidities, eliciting allergens, and severity of reactions. Methods: Children with immediate-type allergic reactions during oral food challenges (89% were double-blind, placebo-controlled) have been analyzed in this study. Narcolepsy-like sleepiness was defined as a somnolent condition during which patients could barely be woken up again, occurring within 2 hours of food intake and which was not due to drug side effects. Logistic generalized estimating equations were used to explore the effect of age, severity of reactions, and eliciting allergens on the occurrence of narcolepsy-like sleepiness. Results: In 106 (12.5%) of all 848 food-allergic children, narcolepsy-like sleepiness was observed during oral food challenges. Children with eczema had a higher risk of developing narcolepsy-like sleepiness (P = .006). Narcolepsy-like sleepiness occurred most often due to an allergic reaction to hazelnut (P = .009) or other tree nuts (P = .003). Moderate to severe reactions occurred more often than mild reactions (P = .026; odds ratio, 1.521; 95% CI, 1.051-2.202) in children with narcolepsy-like sleepiness. Conclusions: We were able to show for the first time that narcolepsy-like sleepiness is a frequently occurring clinical manifestation of immediate-type allergic reactions on food ingestion in childhood. Further research is needed to unravel the underlying mechanisms to gain a deeper insight into this underestimated symptom. https://doi.org/10.1016/j.jaip.2022.11.038
Food-specific immunoglobulin A does not correlate with natural tolerance to peanut or egg allergens.
ImmunoglobulinA (IgA) is the predominant antibody isotype in the gut, where it regulates commensal flora and neutralizes toxins and pathogens. The function of food-specific IgA in the gut is unknown but is presumed to protect from food allergy. Specifically, it has been hypothesized that food-specific IgA binds ingested allergens and promotes tolerance by immune exclusion; however, the evidence to support this hypothesis is indirect and mixed. Although it is known that healthy adults have peanut-specific IgA in the gut, it is unclear whether children also have gut peanut-specific IgA. We found in a cohort of non–food-allergic infants (n = 112) that there is detectable stool peanut-specific IgA that is similar to adult quantities of gut peanut-specific IgA. To investigate whether this peanut-specific IgA is associated with peanut tolerance, we examined a separate cohort of atopic children (n = 441) and found that gut peanut-specific IgA does not predict protection from development of future peanut allergy in infants nor does it correlate with concurrent oral tolerance of peanut in older children. We observed higher plasma peanut-specific IgA in those with peanut allergy. Similarly, egg white–specific IgA was detectable in infant stools and did not predict egg tolerance or outgrowth of egg allergy. Bead-based epitope assay analysis of gut peanut-specific IgA revealed similar epitope specificity between children with peanut allergy and those without; however, gut peanut-specific IgA and plasma peanut-specific IgE had different epitope specificities. These findings call into question the presumed protective role of food-specific IgA in food allergy. https://doi.org/10.1126/scitranslmed.abq0599