Allergy (and clinical immunology)

In this study, researchers identified significant practice variations in management & diagnosis of FPIAP among pediatric gastroenterologists and immunologists.

Alpha-gal Syndrome (AGS) is a unique allergy to non-primate mammalian meat (and derived-products) that is associated with tick bites and is due to a specific IgE antibody to the oligosaccharide gal...

Abstract Background A few studies have investigated the antecedents and outcomes of infants who demonstrate IgE sensitization to foods that they clinically tolerate. Improved understanding of this ...

Abstract IgE mediated food allergy remains a significant and growing problem across the globe. Of the various treatment modalities, oral immunotherapy (OIT) and epicutaneous immunotherapy (EPIT) ha...

Via Krishan Maggon

Meeting Summary Asthma is one of the most common chronic diseases, with ≤25% of patients experiencing uncontrolled disease.1Patients with uncontrolled, moderate-to-severe asthma are at increased risk of recurrent exacerbations, accelerated decline in lung function, fixed airway obstruction, and have increased utilisation of health care resources.2,3Furthermore, reduced lung function, as assessed by measures such as forced expiratory volume in 1 second (FEV1), is a strong independent predictor of exacerbations, progressive decline in lung function, and all-cause pulmonary and cardiovascular mortality in patients with asthma.2 Achieving asthma control in these patients is therefore critical. The recognition of distinct inflammatory phenotypes within this population has been instrumental in addressing this need. In these patients, there is robust evidence of the pathogenic role of Th2 cytokines, such as IL-4 and IL-13, in the eosinophilic and allergic inflammatory processes.4This in turn has driven the development of targeted biological therapies, particularly selective targeted monoclonal antibodies such as dupilumab which inhibit the biological effects of both IL-4 and IL-13.5 This article reviews four posters displayed at the European Respiratory Society (ERS) International Congress 2019 that presented results demonstrating the efficacy and safety of dupilumab, an anti-IL-4 receptor human monoclonal antibody, compared to placebo for the treatment of uncontrolled, moderate-to-severe asthma, as measured by a range of outcomes. Background Atypical production of several Th2 cytokines, including IL-4, IL-5, and IL-13, play a central pathogenic role in multiple atopic conditions.6-9Specifically, IL-4 and IL-13 are associated with the pathogenesis of certain types of asthma, including allergic and nonallergic forms.5,6,9-12 IL-4 and IL-13 were historically thought to mediate identical signalling pathways because they share receptor complexes; however, IL-4 and IL-13 elicit distinct allergic hallmarks.IL‑4 is the central mediator of Th2 cell differentiation, isotype class switching (especially to IgE), B cell growth, and eosinophil (EoS) recruitment.12-14IL‑13 has roles in goblet cell hyperplasia induction and smooth muscle contractility.9,15Therefore, IL-4 and IL-13 activate multiple cell types and induce various mediators involved in inflammation, contributing to airflow limitation and increasing the risk of severe exacerbations.11-15Little is currently known regarding the roles of IL-4/IL-13 in IgE and non-IgE-mediated inflammatory pathways, or the effect of inhibiting IL-4/IL-13 in these pathways in asthma. Dupilumab, a fully human anti-IL-4Rαmonoclonal antibody, inhibits signalling of both IL-4 and IL-13 by specifically binding to the IL-4Rαsubunit shared by both receptor complexes.5,10-12This effect is associated with the marked suppression of biomarkers of Type 2 inflammation including total serum IgE, thymus and activation regulated chemokine, eotaxin-3, and fractional exhaled nitric oxide (FeNO).13 Liberty Asthma QUEST Trial The Liberty Asthma QUEST16was a Phase III, randomised, placebo-controlled, parallel-group trial in 1,902 patients with persistent asthma, receiving continuous inhaled corticosteroids (ICS), plus up to two additional controller medications.17Patients with uncontrolled, moderate-to-severe asthma (based on the Global Initiative for Asthma [GINA] 2015 guidelines),18with a history of one or more exacerbations in the previous year and without a minimum requirement for baseline blood EoS count or any other Type 2 biomarkers (FeNO or serum total lgE),19were randomised in a 2:2:1:1 ratio to receive 52 weeks of add-on therapy with subcutaneously administered dupilumab 200 mg or 300 mg every 2 weeks, or matched placebo.5 The co-primary efficacy endpoints included an annualised rate of severe exacerbation events during the 52-week treatmentperiod and absolute change from baseline in pre-bronchodilator (BD) FEV1at Week 12. A secondary endpoint was the percentage change from baseline to Week 12 in pre-BD FEV1.19 This study showed that add-on dupilumab significantly reduced severe asthma exacerbations; improved lung function, asthma control, and quality-of-life measures; and was generally well-tolerated.13 Moreover, treatment effects were greater in patients with elevated Type 2 biomarkers at baseline (blood EoS and FeNO).17,19   Dupilumab Effect on Lung Function in Patients with Uncontrolled, Moderate-to-Severe Asthma with an Allergic Phenotype Professor Mario Castro This post hoc subset analysis of the Liberty Asthma QUEST trial assessed the effect of dupilumab on lung function parameters in patients with uncontrolled, moderate-to-severe asthma with and without evidence of allergic asthma. In this study, allergic asthma was defined as total serum IgE ≥30.00 IU/mL and ≥1.00 perennial aeroallergen-specific IgE ≥0.35 kU/L. The study assessments included the change from baseline in pre-BD FEV1(L), post-BD FEV1(L), pre-BD forced expiratory flow at 25–75% of pulmonary volume (FEF25–75%, L/s), and pre-BD FEV1/forced vital capacity (FVC) ratio (%) during the 52-week treatment period in patients receiving dupilumab 200 mg every 2 weeks, 300 mg every 2 weeks, or matched placebos stratified by evidence of allergic asthma.20 Of the patients, 57% had allergic asthma (n=1,083) with a mean age of 44.40 years, 58.40% were female, and the mean number of severe exacerbations was 1.96. In the nonallergic asthma group, the mean age was 52.70 years, 70.40% were female, and the mean number of severe exacerbations was 2.32.20 This post hoc analysis showed that dupilumab improved pre and post-BD FEV1, pre-BD FEF25-75% (L/s), and FEV1/FVC ratio (%) at Weeks 12 and 52 in patients with uncontrolled, moderate-to-severe asthma with and without evidence of allergic asthma. Dupilumab 200 mg and 300 mg every 2 weeks versus placebo also improved lung function parameters at Week 12 (change from baseline least squares [LS] mean difference pre-BD FEV1:0.13/0.16 L; post-BD FEV1:0.13/0.11 L; FEF25–75%: 0.14/0.22 L/s; FVC: 0.15/0.11 L; FEV1/FVC ratio: 0.56/2.78%; all p<0.05 except dupilumab 200mg, FEV1/FVC ratio [p=0.35]). Sustained or better improvements were observed at Week 52 (all p<0.05).20 The incidence of treatment-emergent adverse events (TEAE) was similar across treatment groups and the most common TEAE reported were viral upper respiratory tract infections (18.2% versus 19.6%), injection-site erythema (13.8% versus 5.5%), upper respiratory tract infection (11.6% versus 13.6%), and bronchitis (11.4% versus 14.0%) in dupilumab versus placebo, respectively.20 Prof Castro concluded that in addition to reducing severe asthma exacerbations and biomarkers of Type 2 inflammation, including total serum IgE,21dupilumab therapy demonstrated rapid and sustained improvement in lung function in uncontrolled, moderate-to-severe asthma patients, with or without evidence of allergic asthma, during the 52-week treatment period. Dupilumab improved both large (pre and post-BD FEV1) and small (pre-BD FEF25-75%)airway function, as well as airway obstruction (pre-BD FEV1 /FVC). The magnitude of improvement was consistent between patients with and without evidence of allergic inflammation and the maximum effect was achieved by Week 12 and sustained to Week 52.20These results are supported by a previous post hoc analysis, in which similar results were observed in QUEST patients with and without evidence of allergic asthma.21 Dupilumab Efficacy in Patients with Uncontrolled, Moderate-to-Severe Asthma by Immunoglobulin E Levels at Baseline Doctor Warner W. Carr This post hoc analysis assessed the effect of dupilumab on severe exacerbations and FEV1, as well as the impact on overall asthma control in patients with uncontrolled, moderate-to-severe asthma as defined by baseline IgE levels. The aim was to investigate whether there was a differential effect on these efficacy measures defined by baseline IgE levels. The study assessments included the annualised rate of severe exacerbations, LS mean change from baseline in pre-BD FEV1(L), and LS mean change from baseline in the 5-item Asthma Control Questionnaire (ACQ-5) score during the 52-week treatment period.22 Patients with uncontrolled, moderate-to-severe asthma were characterised at baseline by IgE level (381 patients had an IgE level <100; 782 patients had ≥100 to <500; 419 patients had ≥500; 313 patients had ≥700; and 212 patients had ≥1,000 IU/mL Figure 1. Baseline demographics and disease characteristics were generally similar across IgE groups.22 Dupilumab 200 mg and 300 mg every 2 weeks versus placebo significantly reduced severe exacerbations in all baseline IgE groups (-38.9 to -67.9%; all p<0.05) and significantly improved pre-BD FEV1at Weeks 24 and 52 in all baseline IgE groups (LS mean difference: 0.11–0.31 L; all p<0.05), except for 300 mg in IgE <100 IU/mL and ≥1,000 IU/mL groups (Figure 2).22 In the overall safety population, the incidence of TEAE was similar across treatment groups. Conjunctivitis was observed in 2.3% versus 3.3% of patients receiving dupilumab versus placebo, respectively.22 Dr Carr concluded that in general, baseline demographics and disease characteristics were balanced between treatment groups across the patient subgroups by total serum IgE levels at baseline. Dupilumab reduced severe asthma exacerbation rates and improved FEV1and asthma control in patients with moderate-to-severe asthma in all IgE subgroups. For exacerbations, these effects reached statistical significance for both dupilumab 200 mg and 300 mg every 2 weeks groups in all IgE subgroups. For FEV1and asthma control, these effects reached statistical significance for patients receiving dupilumab 200 mg every 2 weeks in all IgE subgroups; but for where dupilumab was prescribed 300 mg every 2 weeks dose, not all IgE subgroups reached statistical significance. In conclusion, regardless of atopic status as categorised by baseline IgE levels, dupilumab can reduce severe exacerbations and improve FEV1.22 Dupilumab Efficacy in Type 2 Inflammatory Asthma: Liberty Asthma QUEST Study (Poster OA3807) Professor Ian D. Pavord The new GINA report for difficult-to-treat and severe asthma proposes baseline blood Eos ≥150 cells/µL and/or baseline FeNO ≥20 parts per billion (ppb) as cut-offs to define Type 2 inflammatory asthma.23 This post hoc analysis assessed dupilumab efficacy in patient subgroups defined by the GINA proposed markers for Type 2 asthma, namely in patients with baseline Eos ≥150 cells/µL, FeNO ≥20 ppb, and in other quadrant subgroups. The endpoints assessed included annualised rate of severe exacerbations during the 52-week treatment period and change from baseline in pre-BD FEV1(L) at Week 12.24 Baseline disease characteristics were generally comparable across the subgroups. The mean age was 47.20 years, 59.00% were female, the mean percent predicted pre-BD FEV1was 58.55, the mean exacerbations in the past year was 2.22, and the mean ACQ-5 score was 2.76.24 In patients with baseline Eos ≥150 cells/µL and FeNO ≥20 ppb (n=922), dupilumab 200 mg and 300 mg every 2 weeks versus placebo significantly reduced severe exacerbations by 66% and 63% respectively, and improved FEV1 by 0.26 L and 0.22 L, respectively (all p<0.0001). Similar results were observed at Week 52 and dupilumab efficacy was not significant in the other patient subgroups.24 Overall, the most frequently reported AE in the dupilumab versus placebo group was injection-site reactions.24 Prof Pavord concluded that dupilumab significantly reduced severe exacerbations and improved FEV1in patients with Type 2 inflammatory asthma. Moreover, the effect of dupilumab treatment in reducing exacerbations and improving FEV1was greatest in patients with elevation of both baseline blood EoS count (≥150 cells/µL) and FeNO (≥20 ppb).24 Dupilumab Efficacy in Asthma Patients with FEV160–80% Predicted on Medium-Dose Inhaled Corticosteroids : LIBERTY ASTHMA QUEST Study Professor Alberto Papi This post hoc analysis aimed to assess dupilumab efficacy in patients with moderate asthma defined as asthma with baseline pre-BD FEV160–80% predicted (60–90% in adolescents <18 years), on medium-dose ICS (implying milder asthma than other QUEST patients), and one or more additional controller therapy, without a minimum requirement for baseline blood Eos count or FeNO. The co-primary endpoints were the annualised severe asthma exacerbation rates during the 52-week treatment period and the change from baseline in pre-BD FEV1at Week 12, analysed using negative binomial models and mixed-effects models with repeated measures, respectively. Study assessments included the annualised severe exacerbation rates, LS mean change from baseline in pre-BD FEV1(L), and LS mean change from baseline in the ACQ-5 score during the 52-week treatment period. The medium ICS dose was fluticasone propionate at a total daily dose of 250–500 μg or an equipotent equivalent.25 Twenty-seven percent (517/1,902) of patients had pre-BD FEV160–80% predicted and were on medium-dose ICS at baseline. The mean age was 43.50 years, 61.90% were female, the mean percent predicted pre-BD FEV1was 69.49, the mean exacerbations in the past year was 1.82, and the mean ACQ-5 score was 2.56.25 In these patients, dupilumab 200 mg and 300 mg every 2 weeks versus placebo reduced annualised severe exacerbation rates by 44% and 51%, respectively (p=0.06; p=0.01; Figure 3. Dupilumab 200 mg and 300 mg every 2 weeks versus placebo also improved FEV1at Week 12 with a LS mean difference of 0.11 L/ 0.09 L, respectively (p=0.01/p=0.05).25 Overall, the most frequent adverse event reported in the dupilumab 200 mg and 300 mg groups versus placebo groups were injection-site reactions (15%/18% versus 5%/10%).25 Conclusion Prof Papi concluded that dupilumab demonstrated meaningful reductions in severe exacerbations and significantly improved pre-BD FEV1in the studied patient population. The magnitude of these effects was comparable to those previously seen in the LIBERTY ASTHMA QUEST patients with severe asthma. Numerical improvements in ACQ-5 were observed at all time points, with the trend comparable to results observed in the overall QUEST population and, furthermore, dupilumab was generally well-tolerated.25 Dupilumab is approved in the European Union (EU) for patients >12 years as an add-on maintenance treatment for severe asthma with Type 2 inflammation. This is characterised by raised blood EoS and/or raised FeNO; inadequately controlled with high dose ICS and another medicinal product for maintenance treatment; and in certain patients with asthma, chronic rhinosinusitis with nasal polyps, or atopic dermatitis in a number of countries.17,26-33These four posters presented at the ERS International Congress 2019 demonstrate that dupilumab treatment is relatively well-tolerated and could significantly improve FEV1, symptoms, asthma control, quality of life, and reduce severe exacerbation risk in patients with uncontrolled asthma. This therapy offers an important new option for respiratory clinicians to manage their patients with uncontrolled asthma.

Patient history, clinical evaluation, and specific IgE tests are valuable tools in diagnosing food allergies.

KEY POINTS The structure of mite Der p 2 in complex with murine IgG mAb 7A1 was determined. Human IgE construct identified from phage-display library overlaps with mAb 7A1. Epitope mutagenesis analysis contributes to designing hypoallergens for therapy. Abstract Der p 2 is one of the most important allergens from the house dust mite Dermatophagoides pteronyssinus. Identification of human IgE Ab binding epitopes can be used for rational design of allergens with reduced IgE reactivity for therapy. Antigenic analysis of Der p 2 was performed by site-directed mutagenesis based on the x-ray crystal structure of the allergen in complex with a Fab from the murine IgG mAb 7A1 that binds an epitope overlapping with human IgE binding sites. Conformational changes upon Ab binding were confirmed by nuclear magnetic resonance using a 7A1–single-chain variable fragment. In addition, a human IgE Ab construct that interferes with mAb 7A1 binding was isolated from a combinatorial phage-display library constructed from a mite-allergic patient and expressed as two recombinant forms (single-chain Fab in Pichia pastoris and Fab in Escherichia coli). These two IgE Ab constructs and the mAb 7A1 failed to recognize two Der p 2 epitope double mutants designed to abolish the allergen–Ab interaction while preserving the fold necessary to bind Abs at other sites of the allergen surface. A 10–100-fold reduction in binding of IgE from allergic subjects to the mutants additionally showed that the residues mutated were involved in IgE Ab binding. In summary, mutagenesis of a Der p 2 epitope defined by x-ray crystallography revealed an IgE Ab binding site that will be considered for the design of hypoallergens for immunotherapy. This article is featured in In This Issue, p.2353 Footnotes This work was supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health (NIH) under Award R01AI077653 (to principal investigators A.P., M.D.C., and M.C.; and to J.A.W. and M.O.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. This research was also supported in part by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (Project Z01-ES102906 to R.E.L.), and by the Swedish Research Council (Grants 521-2011-3282 and 2016-01720) (to M.O.). This work was partially supported by an Advanced Support for Innovative Research Excellence III grant from the Office of the Vice President of Research at the University of South Carolina. The models presented in this article have been submitted to the Protein Data Bank (http://www.rcsb.org/structure/6OY4) under accession number 6OY4. The online version of this article contains supplemental material. Abbreviations used in this article: 7A1scFv mAb 7A1 single-chain variable fragment Der p 2.0103–7A1Fab Der p 2 in complex with Fab from mAb 7A1 H CDR2 CDR2 from H chain H CDR3 CDR3 from H chain HMQC heteronuclear multiple-quantum coherence IgE-scFv human anti–Der p 2 IgE single-chain variable fragment Ab construct L CDR3 CDR3 from L chain NMR nuclear magnetic resonance PDB Protein Data Bank scFab single-chain Fab scFv single-chain variable fragment SPR surface plasmon resonance. Received May 22, 2019. Accepted August 15, 2019. Copyright © 2019 by The American Association of Immunologists, Inc.

Via Krishan Maggon

All shrimp oral challenge test (OCT)-positive patients were positive for IgE against Der p 10.The level of anti-Der p 10 IgE >1.2 kUA/mL had the best diagnostic performance (sensitivity 100%, specificity 65%) Conclusion: Anti-Der p 10 IgE is useful for predicting shrimp allergy diagnosis and cou ...

Abstract Background Atopic diseases are an increasing problem that involve both immediate hypersensitivity reactions mediated by IgE and unique cellular inflammation. Many forms of specific immunot...

Our study suggests that the mast cell activation test can be used to diagnose IgE/FcεRI-dependent immediate drug hypersensitivity reactions.It also shows potential to assess the clinical relevance of drug-specific IgE antibodies in their ability to elicit mast cell degranulation, and therefore disc...

Morning Session  Morning Chair: Dr Tom Marrs 09:00 Welcome and Introduction Dr Tom Marrs Consultant in Paediatric Allergy St Thomas' Hospital, London 09:10 Remote managment of eczema and urticaria in primary care  Dr Alya Abdul-Wahab Consultant Dermatologist St George's Hospital, London 09:50 How to fix common gastro-intestinal symptoms in children Dr Rakesh Vora Paediatric Gastroenterology Consultant St Thomas' Hospital, London 10:35 << BREAK >>   11:00 How to manage IgE and non-IgE food allergies Dr Tom Marrs Consultant in Paediatric Allergy St Thomas' Hospital, London 11:40 How to recomment avoidance of egg and nuts  Rebecca Brocklehurst Paediatric Allergy Dietitian St Thomas' Hospital, London 12:20 << LUNCH >>  Afternoon Session Afternoon Chair: Dr Rosy Wells 13:00 Preventing food allergy: what to tell parents Dr Michael Perkin Consultant Allergist and Reader in Clinical Epidemiology St George's Hospital, London 13:30 Priorities to Tell Families Living With Food Allergy Professor Adam Fox   Professor in Paediatric Allergy St Thomas' Hospital, London 14:00 QUICK FIRE: Adrenaline auto-injector guide IN PRACTICE: Spare pens in schools Alia Boardman Clinical Nurse Specialst in Paediatric Allergy St George's Hospital, London 14:30 << BREAK >>  15:00 Managing Long-Term Asthma in a Virtual World  Dr Richard Iles Paediatric Respirology Consultant St Thomas' Hospital, London 15:40 How to recognise and treat allergic rhinitis Dr Anne Chsitopher Consultant Paediatrician and Allergist St George's Hospital, London 16:10  New inhalers and nasal sprays Katherine Knight Clinical Nurse Specialist in Paediatric Allergy St Thomas' Hospital, London  16:40 Webinar feedback and Close of meeting

Approximately one-third of the world’s population suffers from allergies1. Exposure to allergens crosslinks immunoglobulin E (IgE) antibodies that are bound to mast cells and basophils, triggering the release of inflammatory mediators, including histamine2. Although IgE is absolutely required for allergies, it is not understood why total and allergen-specific IgE concentrations do not reproducibly correlate with allergic disease3–5. It is well-established that glycosylation of IgG dictates its effector function and has disease-specific patterns. However, whether IgE glycans differ in disease states or affect biological activity is completely unknown6. Here we perform an unbiased examination of glycosylation patterns of total IgE from individuals with a peanut allergy and from non-atopic individuals without allergies. Our analysis reveals an increase in sialic acid content on total IgE from individuals with a peanut allergy compared with non-atopic individuals. Removal of sialic acid from IgE attenuates effector-cell degranulation and anaphylaxis in several functional models of allergic disease. Therapeutic interventions—including removing sialic acid from cell-bound IgE with a neuraminidase enzyme targeted towards the IgE receptor FcεRI, and administering asialylated IgE—markedly reduce anaphylaxis. Together, these results establish IgE glycosylation, and specifically sialylation, as an important regulator of allergic disease. A specific type of glycosylation—sialylation—is more common on immunoglobulin E from individuals with a peanut allergys than from non-atopic people, suggesting that it has a role in regulating anaphylaxis.

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Some people produce immunoglobulin E (IgE) antibodies to proteins in common foods. As a result, these foods can trigger severe allergic inflammation (anaphylaxis). There are several structurally and functionally distinct antibody isotypes (IgM, IgD, IgG, IgA, and IgE), and which isotype binds to a target molecule (antigen) influences what happens next. For example, IgG that binds peanut proteins is harmless, but IgE bound to the same proteins can induce anaphylaxis and death. Therefore, how, where, and why allergen-reactive IgE is made are decades-old questions. Hoh et al. (1) found that gut tissue is a likely place for IgE development in peanut-allergic individuals. In addition, despite vast sequence possibilities, they found that many individuals share similar peanut-reactive IgE DNA sequences. This suggests that IgE antibodies in different individuals recognize peanut proteins in a similar manner, which could inform strategies for pharmacological interventions. Antibodies are produced by cells of the B lymphocyte lineage and consist of four Ig polypeptide chains—two identical heavy (H) chains and two identical light (L) chains—and each chain has a variable (V) region and a constant (C) region. The V region forms the surface that physically binds to antigens such as peanut proteins. The C region of IgH (CH) dictates antibody function largely by triggering processes that lead to neutralization, elimination, or induction of inflammation. Assembly of multiple IGH gene segments through the process of V(D)J recombination results in enormous sequence diversity, particularly in the exon encoding the V region, which comprises much of the antigen binding surface. Next to the V exon are a variety of C-region exons arranged in tandem (e.g., Cµ, Cγ, Cε, and Cα), which define the different antibody isotypes (2). Newly assembled Ig is produced as IgM. However, during an immune response, the same V region of IgH (VH) can be expressed in the context of another C-region isotype through a process called class switch recombination (CSR). This positions an alternative CH region next to the VH exon by permanent excision of the intervening DNA and associated CH-encoding exons. The position of CH exons relative to each other thus determines which IgH isotypes are available for secondary switch events. For example, an IgM-expressing B cell can switch to IgG1, and then that same IgG1+ B cell can switch to IgE because Cε is 3′ (downstream) to Cγ1 in the IGH locus. However, IgE-expressing B cells cannot switch to IgG1 (or any other isotype whose CH is positioned 5′ to Cε). Somatic hypermutation (SHM) further diversifies V regions by introducing mutations that can enhance affinity to antigen (3). The V(D)J recombination–, CSR-, and SHM-mediated processing of IGH enable phylogenetic mapping of how B-lineage cells and the antibodies they produce are related to one another. To gain insights into the origins of IgE production and the relationships between antibody-producing cells, Hoh et al. sequenced the IGH genes from B-lineage plasma cells in upper digestive tract tissues of 19 peanut-allergic individuals and compared them with those of nonallergic controls. They found more IgE-expressing cells in gut tissue in food-allergic individuals, confirming previous findings (4). Multiple clonally related VH-encoding sequences in IgE antibodies were also shared with other IgH isotypes. These findings suggest that B cells undergo CSR to IgE in the gut tissue as opposed to undergoing CSR to IgE elsewhere before migrating to the gut. This is different to the case of bone marrow, which is a major destination for antibody-producing cells after CSR elsewhere. This raises an important question: What features of the gut environment favor CSR to IgE? Moreover, because the bone marrow is a major location of antibody production, including IgE in allergic disease (5), the degree to which gut-derived versus bone marrow–derived IgE affects clinical disease, prognosis, and treatment approaches remains to be determined (see the figure). Hoh et al. identified antibody sequences that are reactive to the peanut protein Ara h 2 (Arachis hypogaea allergen 2) and found groups of similar sequences among multiple individuals. Similar sequences were also found in analyses of IgE+ B cells from peripheral blood in individuals with peanut allergy (6), further validating the concept of convergent IgE development to peanut proteins. Nonallergic individuals also had Ara h 2–reactive sequences, but only in non-IgE isotypes such as IgM, IgG, and IgA. These findings highlight how antibodies that induce a food-allergic response are generated. The production of antibodies that bind peanut proteins does not seem to be the problem per se; instead, the switching of that antibody to the IgE isotype appears to be key. This is consistent with observations that humans make IgG to a variety of dietary proteins without correlation to food allergy (7). In addition, it is possible that IgG to food antigens may be protective from food allergy by either blocking IgE binding or otherwise interfering with IgE function (8, 9). Perhaps an intervention that discourages gut IgE CSR could prevent food allergy. The convergence of IgE sequences in multiple peanut-allergic individuals suggests that immune recognition may occur through antibody binding to a few finite regions on key proteins. In this regard, drugs that block IgE binding to these regions holds promise as a therapy in allergic disease. There is proof of principle: Two therapeutic monoclonal IgG antibodies against a cat allergen inhibited IgE binding, and treatment with the combination of these two antibodies alone was sufficient to reduce allergic symptoms in 34 cat-allergic individuals in a clinical trial (10). Blocking IgE to peanut antigens may be similarly efficacious. Although seemingly innocuous, food allergens may influence the gut environment to generate conditions that induce CSR to IgE. In this regard, allergenic foods may have properties that induce allergic inflammation, as has been proposed (11, 12). Understanding the influences of the gut microbiota, age of exposure, and environment on the regulation of allergic responses to food (13, 14) promises to provide clues to elucidating how IgE CSR is regulated. http://www.sciencemag.org/about/science-licenses-journal-article-reuse This is an article distributed under the terms of the Science Journals Default License. References and Notes ↵ R. A. Hoh et al., Sci. Immunol. 5, eaay4209 (2020). ↵ P. Tong, D. R. Wesemann, Curr. Top. Microbiol. Immunol. 388, 21 (2015).OpenUrl ↵ L. Mesin, J. Ersching, G. D. Victora, Immunity 45, 471 (2016).OpenUrlPubMed ↵ C. Caffarelli, E. Romanini, P. Caruana, M. E. Street, G. De' Angelis, Pediatr. Res. 44, 485 (1998).OpenUrlPubMed ↵ S. Asrat et al., Sci. Immunol. 5, eaav8402 (2020). ↵ D. Croote, S. Darmanis, K. C. Nadeau, S. R. Quake, Science 362, 1306 (2018). ↵ J. Gocki, Z. Bartuzi, Postepy Dermatol. Alergol. 33, 253 (2016).OpenUrl ↵ O. T. Burton et al., J. Allergy Clin. Immunol. 134, 1310 (2014).OpenUrlCrossRef ↵ O. T. Burton, J. M. Tamayo, A. J. Stranks, K. J. Koleoglou, H. C. Oettgen, J. Allergy Clin. Immunol. 141, 189 (2018).OpenUrl ↵ J. M. Orengo et al., Nat. Commun. 9, 1421 (2018).OpenUrlCrossRef ↵ M. Profet, Q. Rev. Biol. 66, 23 (1991). ↵ N. W. Palm, R. K. Rosenstein, R. Medzhitov, Nature 484, 465 (2012). ↵ O. I. Iweala, C. R. Nagler, Annu. Rev. Immunol. 37, 377 (2019).OpenUrl ↵ D. R. Wesemann, C. R. Nagler, Immunity 44, 728 (2016).OpenUrl Acknowledgments: D.R.W. is supported by the NIH (AI121394, AI139538, and AI137940), the Burroughs Wellcome Fund, and an anonymous donor. C.R.N. is supported by the NIH (AI106302, AI134923, and AI146099) and the Sunshine Charitable Foundation. C.R.N. is president and co-founder of ClostraBio, Inc.

The immunological mechanism underlying Immunoglobuline E (IgE)-mediated cow&rsquo;s milk allergy has been subject to investigations for many years. Identification of the key immune cells (mast cells, B cells) and molecules (IgE) in the allergic process has led to the understanding that avoidance...

Peanut allergy is one of the most common and severe food allergies, affecting about
2% of school-aged children in the United Kingdom and United States. Current management of peanut allergy consists of strict allergen avoidance and carrying emergency medication to treat acute allergic reactions...

Via Krishan Maggon