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The article discusses the assessment of IgE and basophil activity in blood samples from nonhuman primates, specifically cynomolgus monkeys, in the context of developing new drugs to combat allergies. The study compares IgE biology between humans and cynomolgus monkeys, finding similarities in key residues and binding affinities for FcεRI. The research suggests that cynomolgus monkeys could serve as a relevant model for testing novel anti-IgE therapies, with potential applications in drug development and clinical trials. [Extracted from the article]

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

The impact of human IgE glycosylation on structure, function and disease mechanisms is not fully elucidated, and heterogeneity in different studies renders drawing conclusions challenging. Previous reviews discussed IgE glycosylation focusing on specific topics such as health versus disease, FcεR binding or impact on function. We present the first systematic review of human IgE glycosylation conducted utilizing the PRISMA guidelines. We sought to define the current consensus concerning the roles of glycosylation on structure, biology and disease. Despite diverse analytical methodologies, source, expression systems and the sparsity of data on IgE antibodies from non‐allergic individuals, collectively evidence suggests differential glycosylation profiles, particularly in allergic diseases compared with healthy states, and indicates functional impact, and contributions to IgE‐mediated hypersensitivities and atopic diseases. Beyond allergic diseases, dysregulated terminal glycan structures, including sialic acid, may regulate IgE metabolism. Glycan sites such as N394 may contribute to stabilizing IgE structure, with alterations in these glycans likely influencing both structure and IgE‐FcεR interactions. This systematic review therefore highlights critical IgE glycosylation attributes in health and disease that may be exploitable for therapeutic intervention, and the need for novel analytics to explore pertinent research avenues. [ABSTRACT FROM AUTHOR]

Background: While B‐cells have historically been implicated in allergy development, a growing body of evidence supports their role in atopic dermatitis (AD). B‐cell differentiation across ages in AD, and its relation to disease severity scores, has not been well defined. Objective: To compare the frequency of B‐cell subsets in blood of 0–5, 6–11, 12–17, and ≥18 years old patients with AD versus age‐matched controls. Methods: Flow cytometry was used to measure B‐cell subset frequencies in the blood of 27 infants, 17 children, 11 adolescents, and 31 adults with moderate‐to‐severe AD and age‐matched controls. IgD/CD27 and CD24/CD38 core gating systems and an 11‐color flow cytometry panel were used to determine frequencies of circulating B‐cell subsets. Serum total and allergen‐specific IgE (sIgEs) levels were measured using ImmunoCAP®. Results: Adolescents with AD had lower frequencies of major B‐cells subsets (p <.03). CD23 expression increased with age and was higher in AD compared to controls across all age groups (p <.04). In AD patients, multiple positive correlations were observed between IL‐17‐producing T‐cells and B‐cell subsets, most significantly non‐switched memory (NSM) B‐cells (r =.41, p =.0005). AD severity positively correlated with a list of B‐cell subsets (p <.05). IL‐9 levels gradually increased during childhood, reaching a peak in adolescence, paralleling allergen sensitization, particularly in severe AD. Principal component analysis of the aggregated environmental sIgE data showed that while controls across all ages tightly clustered together, adolescents with AD demonstrated distinct clustering patterns relative to controls. Conclusions: Multiple correlations between B‐cells and T‐cells, as well as disease severity measures, suggest a complex interplay of immune pathways in AD. Unique B‐cell signature during adolescence, with concurrent allergen sensitization and IL‐9 surge, point to a potentially wider window of opportunity to implement interventions that may prevent the progression of the atopic march. [ABSTRACT FROM AUTHOR]

The European Academy of Allergy and Clinical Immunology (EAACI) has released updated clinical guidelines for the diagnosis and management of IgE-mediated food allergy. The guidelines provide evidence-based recommendations for clinicians treating patients with suspected food allergies. The guidelines emphasize the importance of a detailed clinical history, including dietary history, in reaching an accurate diagnosis. They also outline various diagnostic tests, such as skin prick tests and specific IgE tests, and recommend oral food challenges when necessary. The guidelines also address management strategies, including dietary advice, treatment plans for allergic reactions, and the potential use of immunomodulatory treatments. [Extracted from the article]

Background Objective Methods Results Conclusions Trial Registration Number In Europe, Omalizumab (anti‐IgE) is indicated for the treatment of moderate to severe asthma, but not for IgE‐mediated food allergy (FA).We assessed the impact of Omalizumab on efficacy, safety, and quality of life (FA‐QoL) in patients with moderate to severe asthma and who have a history of anaphylaxis to peanut, tree nuts, fish, egg, milk, and/or wheat.Food‐allergic children (6–18 years) with moderate to severe asthma underwent oral food challenges (OFCs) to establish the threshold of reaction to the culprit food(s) at baseline (T0) and at 4‐month intervals (T1, T2, and T3) during their first year of treatment with Omalizumab. We recorded the number and severity of food‐allergic reactions, Asthma Control Test (ACT) scores, FA‐QoL, and total IgE levels.In 65 patients allergic to 107 foods, the No Observed Adverse Events Level (NOAEL) at T1 increased: 243‐ and 488‐fold for fresh and baked milk, respectively; 172‐ and 134‐fold for raw and baked egg; 245‐fold for hazelnut; 55‐fold for peanut; 31‐fold for wheat; and 10‐fold for fish. Full tolerance was achieved in 66.4% of OFCs at T1, 58.3% at T2, and 75% at T3. Ninety‐five foods were liberalized in the diet of 55 patients; the remaining 12 were introduced by 10 patients at least in traces. Throughout the study, 40 out of 65 were able to get a free diet. ACT increased from 17 (Q1‐Q3: 15–17) to 23.6 (Q1‐Q3: 23–25). The FA‐QoL score in children ≤12 years decreased from 4.63 ± 0.74 to 2.02 ± 1.13, and in adolescents from 4.68 ± 0.92 to 1.90 ± 1.50.During Omalizumab therapy, a safe reintroduction of allergenic foods is feasible.ClinicalTrials.gov, NCT06316414. [ABSTRACT FROM AUTHOR]

Background: Limited information is available on the use of omalizumab (OMA) updosing since its introduction as a second‐line therapy in chronic spontaneous urticaria (CSU) in 2014. Practical guidelines from health authorities are lacking, and the specific characteristics of patients requiring higher doses remain unknown. Our objectives were to characterize the patterns of OMA updosing (defined as changes in dose and/or injection intervals), to identify the predictive factors associated with updosing, and to improve CSU management. Methods: We conducted a prospective, multicentric, real‐life observational study, including patients diagnosed with CSU and starting OMA. The data were collected at 0, 3, 6, and 9 months. The primary endpoint was the frequency of OMA updosing at 3 months. The secondary endpoints included an analysis of updosed patients' profile, and an assessment of OMA efficacy and safety. Results: We included 153 patients. Twenty percent of patients were updosed at 3 months, and 27% in total during the 9‐month follow‐up. Practitioners mainly chose to increase the frequency of injections (66%). At baseline, the updosed patients were more likely to have more severe CSU (UCT < 4, p < 0.030), a lower lymphocyte count (<2000/mm3, p = 0.037), and low IgE levels (<70 UI/mL, p = 0.024). The side effects of OMA were not more frequent after updosing. Conclusion: One in five patient underwent updosing within just 3 months. OMA updosing is frequent in particular in cases of severe disease and low IgE blood levels. [ABSTRACT FROM AUTHOR]

Type I hypersensitivity, also known as classical allergy, is mediated via allergen‐specific IgE antibodies bound to type I FcR (FcεRI) on the surface of mast cells and basophils upon cross‐linking by allergens. This IgE‐mediated cellular activation may be blocked by allergen‐specific IgG through multiple mechanisms, including direct neutralization of the allergen or engagement of the inhibitory receptor FcγRIIb which blocks IgE signal transduction. In addition, co‐engagement of FcεRI and FcγRIIb by IgE‐IgG‐allergen immune complexes causes down regulation of receptor‐bound IgE, resulting in desensitization of the cells. Both, activation of FcεRI by allergen‐specific IgE and engagement of FcγRIIb by allergen‐specific IgG are driven by allergen‐binding. Here we delineate the distinct roles of antibody affinity versus avidity in driving these processes and discuss the role of IgG subclasses in inhibiting basophil and mast cell activation. [ABSTRACT FROM AUTHOR]

Background Methods Results Conclusions Noninvasive biomarkers for diagnosing and monitoring eosinophilic esophagitis (EoE) are currently lacking. This study evaluates 20 biomarkers in serum and saliva, aiming to assess their diagnostic potential in pediatric EoE patients and healthy individuals.Blood and saliva from children undergoing upper endoscopy were analyzed for biomarkers, including absolute eosinophil count (AEC), eosinophil‐derived neurotoxin (EDN), total and specific IgG4‐antibodies (sIgG4), specific IgE‐antibodies (sIgE) and 15‐hydroxyeicosatetraenoic acid (15(S)‐HETE). Some patients participated twice, forming a longitudinal cohort. The ability to use the biomarkers to predict the EoE diagnosis was evaluated.Analysis from 105 children divided into active EoE, remission, and healthy, revealed elevated levels of serum biomarkers (AEC, EDN, 15(S)‐HETE, sIgG4, and sIgE) in active EoE compared to healthy individuals. A combination of biomarkers (AEC, EDN, sIgE to egg white and wheat) and symptoms showed an AUC of 0.92 in distinguishing between the three groups. We further showed that optimal cutoff values for these biomarkers could discriminate between active EoE and healthy with a sensitivity of 88% and a specificity of 100% in distinguishing EoE (active and in remission) from healthy. Longitudinally, levels of EDN, sIgG4 to Bos d 4, Bos d 5, Bos d 8, gliadin, and birch, and sIgE to milk decreased in patients progressing from active EoE to remission (p <.05).This study identified novel biomarkers associated with EoE and proposes a panel, together with symptoms, for effective discrimination between active EoE, EoE in remission, and healthy individuals. The findings may contribute to a less invasive diagnostic method and may be a potential surveillance tool for pediatric EoE patients. [ABSTRACT FROM AUTHOR]

Background: Anti‐IgE immunotherapy with monoclonal antibodies represents a breakthrough in treatment of severe allergic diseases. However, drawbacks such as short half‐life and high price are not negligible. Our objective is to develop an anti‐IgE vaccine based on virus‐like particles (VLPs) which can induce long‐lasting neutralizing IgG anti‐IgE antibodies reducing allergic responses without causing intrinsic mast cell activation due to IgE cross‐linking. Methods: The vaccines were made by chemically coupling three synthetic mouse IgE‐Fc fragments to plant‐derived immunologically optimized CuMVTT VLPs. The immunogenicity of the vaccines was tested by immunizing naive or allergic mice either with the coupled vaccines or the VLP control followed by systemic or local allergen challenge. Results: Mice immunized with the vaccines exhibited high titers of anti‐IgE antibodies in the sera and high levels of anti‐IgE secreting plasma cells in lymphoid organs. Moreover, free IgE in serum were reduced by the induced anti‐IgE antibodies; therefore, less IgE was bound to FcεRI on the surface of basophils. In line with these reduced IgE levels on effector cells after vaccination, immunized mice were protected from challenge with allergens. Importantly, despite presence of anti‐IgE antibodies, no signs of acute or chronic allergic response were seen in immunized allergic mice. Conclusion: The generated vaccines can effectively induce anti‐IgE antibodies that did not cause allergic responses in sensitized mice but were able to decrease the level of free and cell bound IgE and protected sensitized animals from allergic responses upon allergen challenge. [ABSTRACT FROM AUTHOR]

Background: There are no studies of longitudinal immunoglobulin measurements in a population‐based cohort alongside challenge‐confirmed peanut allergy outcomes. Little is known about biomarkers for identifying naturally resolving peanut allergy during childhood. Objectives: To measure longitudinal trends in whole peanut and component Ara h 2 sIgE and sIgG4 in the first 10 years of life, in a population cohort of children with challenge‐confirmed peanut allergy, and to determine whether peanut‐specific immunoglobulin levels or trends are associated with peanut allergy persistence or resolution by 10 years of age. Methods: One‐year‐old infants with challenge‐confirmed peanut allergy (n = 156) from the HealthNuts study (n = 5276) were prospectively followed at ages 4, 6, and 10 years with questionnaires, skin prick tests, oral food challenges, and plasma total‐IgE, sIgE and sIgG4 to peanut and Ara h 2. Results: Peanut allergy resolved in 33.9% (95% CI = 25.3%, 43.3%) of children by 10 years old with most resolving (97.4%, 95% CI = 86.5%, 99.9%) by 6 years old. Decreasing Ara h 2 sIgE (p =.01) and increasing peanut sIgG4 (p <.001), Ara h 2 sIgG4 (p =.01), peanut sIgG4/sIgE (p <.001) and Ara h 2 sIgG4/sIgE (p <.001) from 1 to 10 years of age were associated with peanut allergy resolution. Peanut sIgE measured at 1 year old had the greatest prognostic value (AUC = 0.75 [95% CI = 0.66, 0.82]); however, no single threshold produced both high sensitivity and specificity. Conclusion: One third of infant peanut allergy resolved by 10 years of age. Decreasing sIgE and sIgG4 to peanut and Ara h 2 over time were associated with natural resolution of peanut allergy. However, biomarker levels at diagnosis were not strongly associated with the natural history of peanut allergy. [ABSTRACT FROM AUTHOR]

Background Methods Results Conclusions The pathological mechanism of the gastrointestinal forms of food allergies is less understood in comparison to other clinical phenotypes, such as asthma and anaphylaxis Importantly, high‐IgE levels are a poor prognostic factor in gastrointestinal allergies.This study investigated how high‐IgE levels influence the development of intestinal inflammation and the metabolome in allergic enteritis (AE), using IgE knock‐in (IgEki) mice expressing high levels of IgE. In addition, correlation of the altered metabolome with gut microbiome was analysed.Ovalbumin‐sensitized and egg‐white diet‐fed (OVA/EW) BALB/c WT mice developed moderate AE, whereas OVA/EW IgEki mice induced more aggravated intestinal inflammation with enhanced eosinophil accumulation. Untargeted metabolomics detected the increased levels of N‐tau‐methylhistamine and 2,3‐butanediol, and reduced levels of butyric acid in faeces and/or sera of OVA/EW IgEki mice, which was accompanied with reduced Clostridium and increased Lactobacillus at the genus level. Non‐sensitized and egg‐white diet‐fed (NC/EW) WT mice did not exhibit any signs of AE, whereas NC/EW IgEki mice developed marginal degrees of AE. Compared to NC/EW WT mice, enhanced levels of lysophospholipids, sphinganine and sphingosine were detected in serum and faecal samples of NC/EW IgEki mice. In addition, several associations of altered metabolome with gut microbiome—for example Akkermansia with lysophosphatidylserine—were detected.Our results suggest that high‐IgE levels alter intestinal and systemic levels of endogenous and microbiota‐associated metabolites in experimental AE. This study contributes to deepening the knowledge of molecular mechanisms for the development of AE and provides clues to advance diagnostic and therapeutic strategies of allergic diseases. [ABSTRACT FROM AUTHOR]

The recent recognition of a syndrome of tick‐acquired mammalian meat allergy has transformed the previously held view that mammalian meat is an uncommon allergen. The syndrome, mediated by IgE antibodies against the oligosaccharide galactose‐alpha‐1,3‐galactose (alpha‐gal), can also involve reactions to visceral organs, dairy, gelatin and other products, including medications sourced from non‐primate mammals. Thus, fittingly, this allergic disorder is now called the alpha‐gal syndrome (AGS). The syndrome is strikingly regional, reflecting the important role of tick bites in sensitization, and is more common in demographic groups at risk of tick exposure. Reactions in AGS are delayed, often by 2–6 h after ingestion of mammalian meat. In addition to classic allergic symptomatology such as urticaria and anaphylaxis, AGS is increasingly recognized as a cause of isolated gastrointestinal morbidity and alpha‐gal sensitization has also been linked with cardiovascular disease. The unusual link with tick bites may be explained by the fact that allergic cells and mediators are mobilized to the site of tick bites and play a role in resistance against ticks and tick‐borne infections. IgE directed to alpha‐gal is likely an incidental consequence of what is otherwise an adaptive immune strategy for host defense against endo‐ and ectoparasites, including ticks. [ABSTRACT FROM AUTHOR]

Epidemiological studies have explored the relationship between allergic diseases and cancer risk or prognosis in AllergoOncology. Some studies suggest an inverse association, but uncertainties remain, including in IgE‐mediated diseases and glioma. Allergic disease stems from a Th2‐biased immune response to allergens in predisposed atopic individuals. Allergic disorders vary in phenotype, genotype and endotype, affecting their pathophysiology. Beyond clinical manifestation and commonly used clinical markers, there is ongoing research to identify novel biomarkers for allergy diagnosis, monitoring, severity assessment and treatment. Gliomas, the most common and diverse brain tumours, have in parallel undergone changes in classification over time, with specific molecular biomarkers defining glioma subtypes. Gliomas exhibit a complex tumour‐immune interphase and distinct immune microenvironment features. Immunotherapy and targeted therapy hold promise for primary brain tumour treatment, but require more specific and effective approaches. Animal studies indicate allergic airway inflammation may delay glioma progression. This collaborative European Academy of Allergy and Clinical Immunology (EAACI) and European Association of Neuro‐Oncology (EANO) Position Paper summarizes recent advances and emerging biomarkers for refined allergy and adult‐type diffuse glioma classification to inform future epidemiological and clinical studies. Future research is needed to enhance our understanding of immune–glioma interactions to ultimately improve patient prognosis and survival. [ABSTRACT FROM AUTHOR]

Background: Pollen allergy poses a significant health and economic burden in Europe. Disease patterns are relatively homogeneous within Central and Northern European countries. However, no study broadly assessed the features of seasonal allergic rhinitis (SAR) across different Southern European countries with a standardized approach. Objective: To describe sensitization profiles and clinical phenotypes of pollen allergic patients in nine Southern European cities with a uniform methodological approach. Methods: Within the @IT.2020 multicenter observational study, pediatric and adult patients suffering from SAR were recruited in nine urban study centers located in seven countries. Clinical questionnaires, skin prick tests (SPT) and specific IgE (sIgE) tests with a customized multiplex assay (Euroimmun Labordiagnostika, Lübeck, Germany) were performed. Results: Three hundred forty‐eight children (mean age 13.1 years, SD: 2.4 years) and 467 adults (mean age 35.7 years SD: 10.0 years) with a predominantly moderate to severe, persistent phenotype of SAR were recruited. Grass pollen major allergenic molecules (Phl p 1 and/or Phl p 5) ranged among the top three sensitizers in all study centers. Sensitization profiles were very heterogeneous, considering that patients in Rome were highly poly‐sensitized (sIgE to 3.8 major allergenic molecules per patient), while mono‐sensitization was prominent and heterogeneous in other cities, such as Marseille (sIgE to Cup a 1: n = 55/80, 68.8%) and Messina (sIgE to Par j 2: n = 47/82, 57.3%). Co‐sensitization to perennial allergens, as well as allergic comorbidities also broadly varied between study centers. Conclusions: In Southern European countries, pollen allergy is heterogeneous in terms of sensitization profiles and clinical manifestations. Despite the complexity, a unique molecular, multiplex, and customized in‐vitro IgE test detected relevant sensitization in all study centers. Nevertheless, this geographical diversity in pollen allergic patients imposes localized clinical guidelines and study protocols for clinical trials of SAR in this climatically complex region. [ABSTRACT FROM AUTHOR]

Background: Allergic rhinitis (AR) is one of the most common chronic diseases worldwide. There are limited prospective long‐term data regarding persistency and remission of AR. The objective of this study was to investigate the natural course of pollen‐induced AR (pollen‐AR) over 20 years, from childhood into early adulthood. Methods: Data from 1137 subjects in the Barn/Children Allergi/Allergy Milieu Stockholm Epidemiologic birth cohort (BAMSE) with a completed questionnaire regarding symptoms, asthma, treatment with allergen immunotherapy (AIT) and results of allergen‐specific IgE for inhalant allergens at 4, 8, 16 and 24 years were analyzed. Pollen‐AR was defined as sneezing, runny, itchy or blocked nose; and itchy or watery eyes when exposed to birch and/or grass pollen in combination with allergen‐specific IgE ≥0.35kUA/L to birch and/or grass. Results: Approximately 75% of children with pollen‐AR at 4 or 8 years had persistent disease up to 24 years, and 30% developed asthma. The probability of persistency was high already at low levels of pollen‐specific IgE. The highest rate of remission from pollen‐AR was seen between 16 and 24 years (21.5%); however, the majority remained sensitized. This period was also when pollen‐specific IgE‐levels stopped increasing and the average estimated annual incidence of pollen‐AR decreased from 1.5% to 0.8% per year. Conclusion: Children with pollen‐AR are at high risk of persistent disease for at least 20 years. Childhood up to adolescence seems to be the most dynamic period of AR progression. Our findings underline the close cross‐sectional and longitudinal relationship between sensitization, AR and asthma. [ABSTRACT FROM AUTHOR]

This article provides an update on the diagnosis, pathogenesis, and treatment of chronic spontaneous urticaria (CSU). CSU is a form of chronic urticaria characterized by the presence of urticarial lesions most days of the week and no identifiable cause. The article presents an algorithm for the diagnosis of CSU and discusses its association with autoimmunity. The recommended treatments for CSU include high-dose antihistamines, omalizumab, and cyclosporine. Other potential treatments are also being studied. The article emphasizes the importance of properly conducted clinical trials and highlights medications that are not recommended due to low success rates or inadequate study design. [Extracted from the article]

A study published in the journal Allergy explores the relationship between IgE-mediated allergies and Alzheimer's disease (AD). The study found that patients with clinical symptoms of IgE-mediated allergy had a higher risk of developing AD compared to those without allergies. The researchers detected AD biomarkers in the cerebrospinal fluid of patients with allergies, suggesting a potential link between allergic inflammation and neuroinflammation. However, the study's findings were limited by the small sample size, and further research is needed to fully understand the role of allergic inflammation in AD development. [Extracted from the article]

The existence of long‐lived IgE antibody‐secreting cells (ASC) is contentious, with the maintenance of sensitization by the continuous differentiation of short‐lived IgE+ ASC a possibility. Here, we review the epidemiological profile of IgE production, and give an overview of recent discoveries made on the mechanisms regulating IgE production from mouse models. Together, these data suggest that for most individuals, in most IgE‐associated diseases, IgE+ ASC are largely short‐lived cells. A subpopulation of IgE+ ASC in humans is likely to survive for tens of months, although due to autonomous IgE B cell receptor (BCR) signaling and antigen‐driven IgE+ ASC apoptosis, in general IgE+ ASC probably do not persist for the decades that other ASC are inferred to do. We also report on recently identified memory B cell transcriptional subtypes that are the likely source of IgE in ongoing responses, highlighting the probable importance of IL‐4Rα in their regulation. We suggest the field should look at dupilumab and other drugs that prohibit IgE+ ASC production as being effective treatments for IgE‐mediated aspects of disease in most individuals. [ABSTRACT FROM AUTHOR]

Background: Allergic bronchopulmonary aspergillosis (ABPA) develops in the presence or absence of asthma, either atopic or nonatopic. We have tried to explore the essential components in the pathogenesis of the disease, which are either consistent and variable according to the presence and type of asthma. Methods: Non‐cystic fibrosis ABPA cases satisfying Asano's criteria were extracted from a prospective registry of ABPA and related diseases in Japan between 2013 and 2023. According to the type of preceding asthma, ABPA was classified into three groups: ABPA sans asthma (no preceding asthma), ABPA with atopic asthma, and ABPA with nonatopic asthma. Exploratory and confirmatory factor analyses were performed to identify the components that determined the clinical characteristics of ABPA. Results: Among 106 cases of ABPA, 25 patients (24%) had ABPA sans asthma, whereas 57 (54%) and 24 (23%) had ABPA with atopic and nonatopic asthma, respectively. Factor analysis identified three components: allergic, eosinophilic, and fungal. Patients with atopic asthma showed the highest scores for the allergic component (p <.001), defined by total and allergen‐specific IgE titers and lung opacities, and the lowest scores for the fungal component defined by the presence of specific precipitin/IgG or positive culture for A. fumigatus. Eosinophilic components, including peripheral blood eosinophil counts and presence of mucus plugs/high attenuation mucus in the bronchi, were consistent among the three groups. Conclusion: The eosinophilic component of ABPA is considered as the cardinal feature of ABPA regardless of the presence of preceding asthma or atopic predisposition. [ABSTRACT FROM AUTHOR]

Background: Epicutaneous immunotherapy with investigational Viaskin™ Peanut 250 μg (DBV712) has demonstrated statistically superior desensitization versus placebo in peanut‐allergic children in clinical trials. It is unclear whether serologic biomarkers predict response. Methods: Serum‐specific IgG4 and IgE (whole peanut and components) from subjects enrolled in the phase 3 Efficacy and Safety of Viaskin Peanut in Children With IgE‐Mediated Peanut Allergy study were examined by exploratory univariate and multivariate analyses to determine trajectories and predictors of treatment response, based upon peanut protein eliciting dose (ED) at Month (M) 12 double‐blind placebo‐controlled food challenge. Results: Among Viaskin Peanut‐treated subjects, peanut sIgG4 significantly increased from baseline through M12 and peanut sIgE peaked at M3 and fell below baseline by M12, with sIgG4 and sIgE peanut components mirroring these trajectories. Placebo subjects had no significant changes. By univariate analysis, M12 peanut sIgG4/sIgE was higher in treatment responders (p < 0.001) and had highest area under the curve (AUC) for predicting ED ≥300 mg and ≥1000 mg (AUC 69.5% and 69.9%, respectively). M12 peanut sIgG4/sIgE >20.1 predicted M12 ED ≥300 mg (80% positive predictive value). The best performing component was Ara h 1 sIgE <15.7 kUA/L (AUC 66.5%). A multivariate model combining Ara h 1 and peanut sIgG4/sIgE had an AUC of 68.2% (ED ≥300 mg) and 67.8% (ED ≥1000 mg). Conclusions: Peanut sIgG4 rise most clearly differentiated Viaskin Peanut versus placebo subjects. sIgG4/sIgE ratios >20.1 and the combination of Ara h 1 and peanut sIgG4/sIgE had moderate ability to predict treatment response and could potentially be useful for clinical monitoring. Additional data are needed to confirm these relationships. [ABSTRACT FROM AUTHOR]

Background: Allergic diseases are triggered by signaling through the high‐affinity IgE receptor, FcεRI. In both mast cells (MCs) and basophils, FcεRI is a tetrameric receptor complex comprising a ligand‐binding α subunit (FcεRIα), a tetraspan β subunit (FcεRIβ, MS4A2) responsible for trafficking and signal amplification, and a signal transducing dimer of single transmembrane γ subunits (FcεRIγ). However, FcεRI also exists as presumed trimeric complexes that lack FcεRIβ and are expressed on several cell types outside the MC and basophil lineages. Despite known differences between humans and mice in the presence of the trimeric FcεRI complex, questions remain as to how it traffics and whether it signals in the absence of FcεRIβ. We have previously reported that targeting FcεRIβ with exon‐skipping oligonucleotides eliminates IgE‐mediated degranulation in mouse MCs, but equivalent targeting in human MCs was not effective at reducing degranulation. Results: Here, we report that the FcεRIβ‐like protein MS4A6A exists in human MCs and compensates for FcεRIβ in FcεRI trafficking and signaling. Human MS4A6A promotes surface expression of FcεRI complexes and facilitates degranulation. MS4A6A and FcεRIβ are encoded by highly related genes within the MS4A gene family that cluster within the human gene loci 11q12‐q13, a region linked to allergy and asthma susceptibility. Conclusions: Our data suggest the presence of either FcεRIβ or MS4A6A is sufficient for degranulation, indicating that MS4A6A could be an elusive FcεRIβ‐like protein in human MCs that performs compensatory functions in allergic disease. [ABSTRACT FROM AUTHOR]

Background: Ligelizumab is an anti‐IgE monoclonal antibody binding IgE with higher affinity than omalizumab that is under clinical investigation for several IgE‐mediated diseases. We previously showed that omalizumab removes IgE bound to FcεRI on plasmacytoid dendritic cells (pDCs) and restores their ability to produce IFN‐α and regulatory T cells (Tregs). The aim of this work is to investigate the capacity of ligelizumab to regulate functional properties of pDCs in comparison with omalizumab. Methods: pDCs were isolated from atopic donors and IgE was detached from FcεRI on pDCs with designed ankyrin repeat protein (DARPin) bi53‐79. pDCs were resensitized with IgE alone or in the presence of ligelizumab or omalizumab prior to IgE‐FcεRI crosslinking and Toll‐like receptor 9 (TLR9) stimulation. Flow cytometry, ELISA, coculture experiments and intranuclear staining were performed to determine cytokine production and Treg generation. An antigen‐specific model of resensitization and IgE‐crosslinking was also performed. Results: The levels of serum total free IgE show a non‐linear positive correlation with the frequency of IgE+ pDCs displaying IgE bound to FcεRI within the 43 individual donors included in the study. Ligelizumab displays stronger capacity than omalizumab to block the binding of free IgE to FcεRI on human pDCs, resulting in a greater restoration of TLR9‐L‐induced IFN‐α production. Ligelizumab also restores the ability of pDCs to generate FOXP3+ Tregs as previously reported for omalizumab. Conclusions: The uncovered novel molecular mechanisms of ligelizumab to regulate functional properties of pDCs from atopic donors might have important clinical implications for anti‐IgE treatments in different IgE‐mediated diseases. [ABSTRACT FROM AUTHOR]

Background: The mechanisms driving alopecia areata (AA) are still unclear, hindering development of targeted therapeutics. Specific Th2 targeting with dupilumab in AA provides a unique opportunity to dissect its pathogenesis and explore the role of Th2 pathway. Methods: We evaluated changes in scalp biomarkers in AA patients (with and without concomitant atopy) randomized to weekly dupilumab or placebo for 24 weeks, followed by open‐label dupilumab for 24 weeks. Changes in biomarker levels were measured at weeks 12, 24, and 48 and were also correlated with clinical hair regrowth. Results: At week 24, preceding clinical hair regrowth outcomes, only dupilumab‐treated patients presented significant suppression of cellular infiltrates, and multiple Th2‐related, markers (CCL13/MCP‐4, CCL18/PARC, CCL26/eotaxin‐3, CCL24/Eotaxin‐2), coupled with significant upregulation in the hair keratins. Th1‐related suppression was evident later (week 48) when all patients received open‐label dupilumab. Results were more pronounced in atopic AA patients, that showed 48% and 97% improvements in the lesional AA scalp profile at weeks 24 and 48, respectively, while 2% worsening was seen in the placebo arm at week 24. Moreover, placebo‐treated patients presented 54% worsening in hair keratins when compared with baseline at week 24. At week 24, increases in hair keratins showed significant correlations only with decreases in Th2‐related markers. Conclusions: Scalp biomarkers provide evidence of dupilumab efficacy in AA, detected even prior to clinical response, with exclusive correlations between early suppression of Th2 markers and increased hair keratins. These findings strengthen previous reports suggesting a possible role for Th2 cytokines as AA drivers. [ABSTRACT FROM AUTHOR]

Keywords: allergy; IgE; hypersensitivity; longevity; memory B cells EN allergy IgE hypersensitivity longevity memory B cells 2805 2807 3 10/04/23 20231001 NES 231001 Abbreviations B5 B5 viral envelope protein smallpox ICAM1 Intercellular adhesion molecule 1 IgE Immunoglobulin E IL4Ra Interleukin 4 receptor alpha LFA-1 Lymphocyte function-associated antigen 1 MBCs Memory B cells Siglec Sialic acid-binding immunoglobulin-type lectin Th2 T helper 2 The immunological memory allows fast responding to pathogens that previously invaded the immune system. The memory of pathogenic IgE is contained within CD23+ IgG1+ memory B cells poised to switch to IgE in food allergy. bioRxiv. B-cell proliferation is induced when the antigen presented by the B cell is recognized by the T-cell receptor. [Extracted from the article]

Background: Atopic diseases are characterized by IgE antibody responses that are dependent on cognate CD4 T cell help and T cell‐produced IL‐4 and IL‐13. Current models of IgE cell differentiation point to the role of IgG memory B cells as precursors of pathogenic IgE plasma cells. The goal of this work was to identify intrinsic features of memory B cells that are associated with IgE production in atopic diseases. Methods: Peripheral blood B lymphocytes were collected from individuals with physician diagnosed asthma or atopic dermatitis (AD) and from non‐atopic individuals. These samples were analyzed by spectral flow cytometry, single cell RNA sequencing (scRNAseq), and in vitro activation assays. Results: We identified a novel population of IgG memory B cells characterized by the expression of IL‐4/IL‐13 regulated genes FCER2/CD23, IL4R, IL13RA1, and IGHE, denoting a history of differentiation during type 2 immune responses. CD23+IL4R+IgG+ memory B cells had increased occurrence in individuals with atopic disease. Importantly, the frequency of CD23+IL4R+IgG+ memory B cells correlated with levels of circulating IgE. Consistently, in vitro stimulated B cells from atopic individuals generated more IgE+ cells than B cells from non‐atopic subjects. Conclusions: These findings suggest that CD23+IL4R+ IgG+ memory B cells transcribing IGHE are potential precursors of IgE plasma cells and are linked to pathogenic IgE production. [ABSTRACT FROM AUTHOR]

Chronic spontaneous urticaria (CSU) is a debilitating skin disease characterized by intensely itchy wheals, angioedema, or both. Symptoms recur spontaneously, on a near‐daily basis, over >6 weeks; many patients experience flare‐ups over several years and, consequently, reduced quality of life. Differences between the inflammatory profiles of the skin of CSU patients (wheals and nonlesional sites) and healthy controls indicate that key drivers such as mast cells, eosinophils, and basophils interact, release vasoactive mediators, and prime the skin, leaving patients predisposed to symptoms. Many cytokines and chemokines involved in these inflammatory networks and their corresponding intracellular signaling cascades have been identified. These insights informed the development of therapies such as omalizumab, dupilumab, and Bruton's tyrosine kinase (BTK) inhibitors, marking a renewed focus on pathogenesis in CSU clinical research. Despite progress, current therapies provide symptomatic control but do not appear to redress the inflammatory balance in the skin permanently. A deeper understanding of CSU pathogenesis will permit a more targeted approach to developing novel treatments with curative intent. Here, we review what is known about the pathogenesis of CSU and consider how this can be used to identify rational targets to improve patient care further. [ABSTRACT FROM AUTHOR]

Background: IgE‐epitope profiling can accurately diagnose clinical peanut allergy. Objective: We sought to determine whether sequential (linear) epitope‐specific IgE (ses‐IgE) profiling can provide probabilities of tolerating discrete doses of peanut protein in allergic subjects undergoing double‐blind, placebo‐controlled food challenges utilizing PRACTALL dosing. Methods: Sixty four ses‐IgE antibodies were quantified in blood samples using a bead‐based epitope assay. A pair of ses‐IgEs that predicts Cumulative Tolerated Dose (CTD) was determined using regression in 75 subjects from the discovery cohort. This epitope‐based predictor was validated on 331 subjects from five independent cohorts (ages 4–25 years). Subjects were grouped based on their predicted values and probabilities of reactions at each CTD threshold were calculated. Results: In discovery, an algorithm using two ses‐IgE antibodies was correlated with CTDs (rho = 0.61, p <.05); this correlation was 0.51 (p <.05) in validation. Using the ses‐IgE‐based predictor, subjects were assigned into "high," "moderate," or "low" dose‐reactivity groups. On average, subjects in the "high" group were four times more likely to tolerate a specific dose, compared with the "low" group. For example, predicted probabilities of tolerating 4, 14, 44, and 144 or 444 mg in the "low" group were 92%, 77%, 53%, 29%, and 10% compared with 98%, 95%, 94%, 88%, and 73% in the "high" group. Conclusions: Accurate predictions of food challenge thresholds are complex due to factors including limited responder sample sizes at each dose and variations in study‐specific challenge protocols. Despite these limitations, an epitope‐based predictor was able to accurately identify CTDs and may provide a useful surrogate for peanut challenges. [ABSTRACT FROM AUTHOR]

Keywords: allergens; anaphylaxis; IgE; insect venom; nanobodies EN allergens anaphylaxis IgE insect venom nanobodies 2859 2862 4 09/02/22 20220901 NES 220901 For the canonical antibody isotypes, antigen recognition is driven by the variable regions of both heavy and light chains. Nanobody-based human antibody formats act as IgE surrogate in hymenoptera venom allergy Nanobody-based human IgEs (nb-IgEs) were then generated by fusion of obtained allergen-specific nanobodies to the Fc domains of human IgE. [Extracted from the article]

Background: The involvement of allergen‐specific (s)IgE in local allergic rhinitis (LAR) has been debated. Here, we investigate the effect of nasal allergen challenge with Dermatophagoides pteronyssinus (NAC‐DP) in mucosal and peripheral B‐cell subpopulations in LAR patients. Methods: Nine LAR, 5 allergic rhinitis (AR), and 5 non‐atopic healthy control (HC) individuals were subjected to a 3‐day NAC‐DP protocol, and nasal biopsies and blood samples were collected before and after provocation. Nasal biopsies were used for immunohistochemistry and gene expression studies, whereas the frequency of lymphocyte subsets and basophil activation test (BAT) were analyzed in blood samples by flow cytometry. sIgG was measured in sera. Results: NAC‐DP induced an increase in IgE+CD38+ plasmablasts in the nasal mucosa of LAR patients, but not in AR or HC individuals. Markers of sequential recombination to IgE (εCSR) (from IgG) were observed in 33% of LAR, 20% of AR, and 0% of HC subjects. NAC‐DP increased the proportion of peripheral CD19+CD20+CD38+ plasmablasts in AR and LAR patients, but not in HC. Expression of the mucosal homing receptor CXCR3 in peripheral CD19+CD20+CD38+ plasmablasts from LAR, AR, and HC individuals was 7%, 5%, and 0.5%, respectively. In vitro DP stimulation increased proliferating CD19+CD20+CD38+ plasmablasts in LAR and AR patients, but not in HC. Serum DP‐sIgG was higher in LAR and AR patients as compared to HC. BAT was positive in 33%, 100%, and 0% of LAR, AR, and HC subjects, respectively. Conclusion: These results suggest that allergen exposure induces the sequential εCSR of IgG+CD19+CD20+CD38+ plasmablasts in the nasal mucosa of LAR patients. [ABSTRACT FROM AUTHOR]

Cannabis is the most widely used recreational drug in the world. Cannabis sativa and Cannabis indica have been selectively bred to develop their psychoactive properties. The increasing use in many countries has been accelerated by the COVID‐19 pandemic. Cannabis can provoke both type 1 and type 4 allergic reactions. Officially recognized allergens include a pathogenesis‐related class 10 allergen, profilin, and a nonspecific lipid transfer protein. Other allergens may also be relevant, and recognition of allergens may vary between countries and continents. Cannabis also has the potential to provoke allergic cross‐reactions to plant foods. Since cannabis is an illegal substance in many countries, research has been hampered, leading to challenges in diagnosis since no commercial extracts are available for testing. Even in countries such as Canada, where cannabis is legalized, diagnosis may rely solely on the purchase of cannabis for prick‐to‐prick skin tests. Management consists of avoidance, with legal issues hindering the development of other treatments such as immunotherapy. Education of healthcare professionals is similarly lacking. This review aimed to summarize the current status of cannabis allergy and proposes recommendations for the future management of this global issue. [ABSTRACT FROM AUTHOR]

Background: Ligelizumab, a next‐generation, humanized anti‐immunoglobulin E (IgE) monoclonal antibody is in development as a treatment for patients with chronic spontaneous urticaria, whose symptoms are inadequately controlled with standard‐of‐care therapy. Objective: To evaluate the long‐term safety and re‐treatment efficacy of ligelizumab 240 mg in patients who completed the core study and extension study. Methods: This open‐label, single‐arm, long‐term Phase 2b extension study was designed to assess patients who were previously administered various doses of ligelizumab, omalizumab or placebo in the Phase 2b, dose‐finding core study and who presented with active disease after Week 32. In the extension study, patients received ligelizumab 240 mg subcutaneously every 4 weeks, for 52 weeks and were monitored post‐treatment for 48 weeks. Results: Overall, ligelizumab was well‐tolerated with no newly identified safety signals. A total of 95.4% (226/237) screened patients received ligelizumab 240 mg in the extension study; 84.1% (190/226) of patients experienced at least one treatment‐emergent adverse event. Most reported events were mild (41.6%) or moderate (35.8%) and mostly unrelated to the study treatment. At Week 12, 46.5% of patients had a complete response increasing to 53.1% after 52 weeks. Following 52 weeks of extension study treatment, 75.8% (95% confidence interval, 69.9, 81.3) of patients had cumulative complete responses. The median time to relapse in complete responders was 38 weeks. Conclusion: The long‐term safety profile of ligelizumab 240 mg in patients with chronic spontaneous urticaria was consistent with the core study and re‐treatment efficacy was shown. Trial Registration: ClinicalTrials.gov Identifier: NCT02477332 and NCT02649218. [ABSTRACT FROM AUTHOR]

Furthermore, this hand book gives an overview on the basic mechanisms of test formats and the biology of allergen molecules and the application of allergen tests for exposure. Allergen, allergy, basophil, IgE, mast cell Keywords: allergen; allergy; basophil; IgE; mast cell EN allergen allergy basophil IgE mast cell 1139 1141 3 05/03/23 20230501 NES 230501 The need to improve the care of allergic patients and to provide up-to-date education of healthcare professionals and researchers about Molecular Allergology led to the idea of compiling existing knowledge on allergen molecules based on initial concepts proposed by Adriano Mari. [Extracted from the article]

The anti-Fc RI antibody MAR-1 depletes basophils and cross-reacts with myeloid cells through its Fc portion In humans, the high-affinity IgE receptor Fc RI is expressed as a tetramer in mast cells (MCs) and basophils, and as a trimer in additional myeloid cell populations, including monocytes, macrophages, dendritic cells (DCs), and Langerhans cells.1 In mice, the expression profile of Fc RI is more debatable. Keywords: anaphylaxis; basophil; IgE; mast cells EN anaphylaxis basophil IgE mast cells 1903 1906 4 05/31/22 20220601 NES 220601 ACKNOWLEDGMENT We are grateful to the staff of the flow cytometry core facility of INSERM UMR1291 (Infinity, Toulouse) for technical assistance, and the animal facility staff of INSERM US006 (CREFRE, Toulouse). [Extracted from the article]

Immunoglobulin E is the latest discovered of immunoglobulin family and has been long associated with anaphylaxis and worm expulsion. Immunoglobulin E, along with mast cells, basophils, and eosinophils, is also a hallmark of type 2 immunity which is dysregulated in numerous diseases such as asthma, rhinitis, atopic dermatitis, and eosinophilic esophagitis in addition to anaphylaxis as aforementioned. However, recent advances have shed light on IgE regulation and memory explaining the low level of free IgE, the scarcity of IgE plasma cells that are mainly short live and the absence of IgE memory B cells in homeostatic conditions. Furthermore, IgE was implicated in inflammatory conditions beyond allergic disorders where IgE‐mediated facilitated antigen presentation can enhance cellular and humoral response against autoantigens in systemic lupus or chronic urticaria leading to more severe disease and even against neoantigen facilitating tumor cell lysis. At last, IgE was unexpectedly associated with allograft rejection or atheromatous cardiovascular diseases where precise mechanisms remain to be deciphered. The purpose of this review is to summarize these recent advances in IgE regulation, biology, and physiopathology beyond allergic diseases opening whole new fields of IgE biology to explore. [ABSTRACT FROM AUTHOR]

Background: Oral immunotherapy (OIT) is frequently discontinued due to adverse events (AEs) and current data suggests that lowering OIT doses can minimize severity and frequency of AEs. However, the minimum daily dose that can enable desensitization and induce immune responses in multi‐food OIT (mOIT) is unknown. Methods: Participants aged 2–25 years with multi‐food allergies were pretreated with fixed‐dose omalizumab (150 mg, 3 doses, every 4 weeks), and randomized 1:1 to receive mOIT to a total maintenance dose of either 300 or 1200 mg total protein, (total dose includes at least two and up to a max of five allergens) and then transitioned to real‐food protein equivalents after 18 weeks of treatment. The primary endpoint was the proportion of subjects with increases in IgG4/IgE ratio of at least 2 allergens by ≥25% from baseline after 18 weeks of therapy. The primary efficacy and safety analyses were done in the intention‐to‐treat population. Results: Sixty participants were enrolled across two sites. Seventy percent of participants in both arms showed changes in sIgG4/sIgE ratio in at least 2 allergens with no difference between the treatment groups (OR [95% CI] = 1.00 [0.29, 3.49]). Overall, there were no differences in AEs between the 300 and 1200 mg groups (19% vs. 17%, p =.69), respectively. Conclusions: Our data suggest that plasma marker changes are induced early, even at a total protein dose of 300 mg inclusive of multiple allergens when mOIT is combined with fixed‐dose omalizumab. Identification of optimal mOIT dosing with adjunct omalizumab is needed for the long‐term success of OIT. Trial Registration: ClinicalTrials.gov (NCT03181009). [ABSTRACT FROM AUTHOR]

Background: Recent studies showed that a single injection of human monoclonal allergen‐specific IgG antibodies significantly reduced allergic symptoms in birch pollen‐allergic patients. Since the production of full monoclonal antibodies in sufficient amounts is laborious and expensive, we sought to investigate if smaller recombinant allergen‐specific antibody fragments, that is, nanobodies, have similar protective potential. For this purpose, nanobodies specific for Bet v 1, the major birch pollen allergen, were generated to evaluate their efficacy to inhibit IgE‐mediated responses. Methods: A cDNA‐VHH library was constructed from a camel immunized with Bet v 1 and screened for Bet v 1 binders encoding sequences by phage display. Selected nanobodies were expressed, purified, and analyzed in regards of epitope‐specificity and affinity to Bet v 1. Furthermore, cross‐reactivity to Bet v 1‐homologues from alder, hazel and apple, and their usefulness to inhibit IgE binding and allergen‐induced basophil activation were investigated. Results: We isolated three nanobodies that recognize Bet v 1 with high affinity and cross‐react with Aln g 1 (alder) and Cor a 1 (hazel). Their epitopes were mapped to the alpha‐helix at the C‐terminus of Bet v 1. All nanobodies inhibited allergic patients' polyclonal IgE binding to Bet v 1, Aln g 1, and Cor a 1 and partially suppressed Bet v 1‐induced basophil activation. Conclusion: We identified high‐affinity Bet v 1‐specific nanobodies that recognize an important IgE epitope and reduce allergen‐induced basophil activation revealing the first proof that allergen‐specific nanobodies are useful tools for future treatment of pollen allergy. [ABSTRACT FROM AUTHOR]

Background: Component‐resolved diagnostics (CRD) help predict hazelnut allergy (HA) in children, but are of unknown diagnostic value in adults. This study aimed to evaluate the diagnostic accuracy of IgE to hazelnut extract and components in adults. Methods: A Dutch population of consecutively presenting adults suspected of HA, who underwent a double‐blind placebo‐controlled food challenge, were included. Serum IgE to hazelnut extract and Cor a 1, 8, 9, and 14 was measured on ImmunoCAP. Diagnostic accuracy was assessed by area under the curve (AUC) analysis. Results: Of 89 patients undergoing challenge, 46 had challenge‐confirmed HA: 17 based on objective and 29 based on subjective symptoms. At commonly applied cutoffs 0.1 and 0.35 kUA/L, high sensitivity was observed for IgE to hazelnut extract and Cor a 1 (range 85–91%), and high specificity for IgE to Cor a 8, 9 and 14 (range 77–95%). However, the AUCs for hazelnut extract and components were too low for accurate prediction of HA (range 0.50–0.56). Combining hazelnut extract and component IgE measurements did not significantly improve accuracy. Higher IgE levels to Cor a 9 and 14 were tentatively associated with HA with objective symptoms, but the corresponding AUCs still only reached 0.68 and 0.63, respectively. Conclusions: Although hazelnut allergic adults are generally sensitized to hazelnut extract and Cor a 1, and hazelnut tolerant adults are usually not sensitized to Cor a 8, 9, or 14, challenge testing is still needed to accurately discriminate between presence and absence of HA in adults from a birch‐endemic country. [ABSTRACT FROM AUTHOR]

Background: The shrimp Litopenaeus vannamei is an important source of food allergens but its allergenic repertoire is poorly characterized. Cross‐reactivity between crustacean and mites has been reported, with tropomyosin, the most relevant allergen involved. The aim of this study was to investigate the structural and immunological properties of a recombinant Fatty Acid Binding Protein (FABP) family from L. vannamei (LvFABP). Methods: ELISA, skin prick test (SPT) and basophil activation assays were performed to determine IgE reactivity and allergenic activity of LvFABP. LC‐MS/MS and Circular Dichroism experiments were done for structural analysis. B‐cell epitope mapping with overlapping peptides, and cross‐inhibition studies using human sera were done to identify antigenic regions and cross‐reactivity. Results: The recombinant LvFABP bound serum IgE from 27% of 36 shrimp allergic patients and showed allergenic activity when tested for basophil activation and SPT in a selected number of them. CD‐spectroscopy of LvFABP revealed that the protein is folded with a secondary structure composed of mainly β‐strands and a smaller fraction of α helices. This is consistent with molecular modelling results, which exhibit a typical β barrel fold with two α‐helices and ten β‐strands. Epitope mapping identified two IgE‐binding antigenic regions and inhibition assays found high cross‐reactivity between LvFABP and Blo t 13, mediated by the antigenic region involving amino acids 54 to 72. Conclusions: Our results show that LvFABP is a shrimp allergen that cross reacts with the house dust mite allergen Blo t 13 and has allergenic activity, which suggest that it could be clinically relevant in case of shellfish allergy. This new allergen, named Lit v 13, will also help to understand basic mechanisms of sensitization to shrimp. [ABSTRACT FROM AUTHOR]

Background: Immunoglobulin E (IgE) sensitization is associated with asthma and allergic diseases. Gestational age influences early immune system development, thereby potentially affecting the process of tolerance induction to allergens. Objective: To study IgE sensitization to common allergens by gestational age from childhood up to early adulthood. Methods: Population‐based birth cohort, data from the Swedish BAMSE study were used. Allergen‐specific IgE antibodies to a mix of common food (fx5) and inhalant (Phadiatop) allergens were analysed at 4, 8, 16 and 24 years. Sensitization was defined as allergen‐specific IgE ≥0.35 kUA/L to fx5 and/or Phadiatop at each time point. Using logistic regression and generalized estimated equations, adjusted odds ratios (aORs) for sensitization in relation to gestational age were calculated. Replication was sought within the Swedish twin study STOPPA. Results: In BAMSE, 3522 participants were screened for IgE antibodies during follow‐up; of these, 197 (5.6%) were born preterm (<37 gestational weeks) and 330 (9.4%) post‐term (≥42 weeks). Preterm birth reduced the risk of sensitization to common food and/or inhalant allergens up to early adulthood by 29% (overall aOR = 0.71; 95% CI: 0.52–0.98), and to food allergens specifically by 40% (overall aOR = 0.60; 95% CI: 0.38–0.93). No relation was found between post‐term birth and IgE sensitization at any time point. Replication analyses in STOPPA (N = 675) showed similar risk estimates for sensitization to food and/or inhalant allergens (aOR = 0.72; 95% CI: 0.42–1.21), which resulted in a combined meta‐analysis aOR = 0.71 (95% CI: 0.54–0.94). Conclusions: Our study suggests an inverse association between preterm birth and long‐term IgE sensitization. [ABSTRACT FROM AUTHOR]

Background: Treatments for alopecia areata (AA) patients with extensive scalp hair loss are limited, and recent evidence supports a role for type 2 T‐cell (Th2)‐immune response in AA. Dupilumab, a monoclonal antibody inhibiting Th2 signaling, approved for type 2 diseases including atopic dermatitis, was evaluated in AA patients. Methods: Alopecia areata patients with and without concomitant atopic dermatitis were randomized 2:1 to receive weekly subcutaneous dupilumab (300 mg) or placebo for 24 weeks, followed by another 24‐week dupilumab open‐label phase. The primary outcome was change from baseline in the Severity of Alopecia Tool (SALT) score at week 24; secondary outcomes included a range of measures of hair regrowth. Results: Forty and 20 patients were assigned to the dupilumab and placebo arms, respectively. At week 24, disease worsening was documented in the placebo arm, with a least‐squares mean change in the SALT score of −6.5 (95% confidence‐interval [CI], −10.4 to −2.6), versus a change of 2.2 (95% CI, −0.6 to 4.94) in the dupilumab arm (p <.05). After 48 weeks of dupilumab treatment, 32.5%, 22.5% and 15% of patients achieved SALT30/SALT50/SALT75 improvement, respectively, while in patients with baseline IgE ≥ 200 IU/ml response rates increased to 53.8%, 46.2%, and 38.5%, respectively. Moreover, baseline IgE predicts treatment response with 83% accuracy. No new safety signals were detected. Conclusions: This hypothesis‐driven trial is the first to indicate the possible pathogenic role of the Th2 axis and Th2 targeting in AA patients. Patient selection based on baseline serum IgE levels may improve treatment results (Clinicaltrials.gov number, NCT03359356). [ABSTRACT FROM AUTHOR]

Background: Epicutaneous sensitization is an important route for the production of IgE, and skin inflammation‐induced IgE has recently been reported having features of natural antibody. Atopic dermatitis (AD) and psoriasis have differentially increased level of serum IgE; however, the production mechanism of IgE in these inflammatory skin diseases remains unknown. Objective: To explore the origin of IgE in AD and psoriasis by analyzing the B cell receptor repertoire. Methods: mRNA was prepared from peripheral blood mononuclear cells of AD and psoriasis patients that had elevated serum levels of IgE, and immunoglobulin heavy chain (IGH) repertoires were sequenced after reverse transcription. Clonal lineages of B cells containing members expressing IgE were identified, and somatic hypermutations in IGH inherited from common ancestors within the clonal lineage were used to infer the relationships between B cells. Results: The proportions of IGHE from AD and psoriasis were higher than that of normal control, which were positively correlated with the levels of serum total IgE. The somatic hypermutation value of IGHE variable region was lower than that of IGHG and IGHA, but higher than IGHM and IGHD, indicating a mixed natural and adaptive origins of IgE; and psoriasis demonstrated lower level of hypermutation than AD. The Shannon indexes of CDR3 in IGHE of AD and psoriasis were higher than that of normal control, also supporting the natural origin. The VH usage of IgE was weakly biased in AD and psoriasis patients with high level of house dust mite‐specific IgE. Comparison of the number of shared mutations in multi‐isotype lineages containing IgE showed that isotype‐switching from IgG‐expressing B cells might be the major source of IgE in AD and psoriasis. Conclusion: IgE has heterogeneous origin in AD and psoriasis, and skin inflammation may contribute to the increased production of natural IgE. [ABSTRACT FROM AUTHOR]

Background: In contrast to their clearly defined roles in allergic diseases, the physiologic functions of Immunoglobulin E antibodies (IgEs) and mast cells (MCs) remain enigmatic. Recent research supports the toxin hypothesis, showing that MCs and IgE‐related type 2 immune responses can enhance host defense against certain noxious substances, including honeybee venom (BV). However, the mechanisms by which MCs can interfere with BV toxicity are unknown. In this study, we assessed the role of IgE and certain MC products in MC‐mediated BV detoxification. Methods: We applied in vitro and in vivo fluorescence microscopyimaging, and flow cytometry, fibroblast‐based toxicity assays and mass spectrometry to investigate IgE‐mediated detoxification of BV cytotoxicity by mouse and human MCs in vitro. Pharmacologic strategies to interfere with MC‐derived heparin and proteases helped to define the importance of specific detoxification mechanisms. Results: Venom‐specific IgE increased the degranulation and cytokine responses of MCs to BV in vitro. Passive serum sensitization enhanced MC degranulation in vivo. IgE‐activated mouse or human MCs exhibited enhanced potential for detoxifying BV by both proteolytic degradation and heparin‐related interference with toxicity. Mediators released by IgE‐activated human MCs efficiently degraded multiple BV toxins. Conclusions: Our results both reveal that IgE sensitization enhances the MC's ability to detoxify BV and also assign efficient toxin‐neutralizing activity to MC‐derived heparin and proteases. Our study thus highlights the potential importance of IgE, MCs, and particular MC products in defense against BV. [ABSTRACT FROM AUTHOR]

Background: Longitudinal studies assessing the association of profiles of allergen‐specific IgE (sIgE) sensitization to a large range of allergen molecules and respiratory health are rare. We aimed to assess trajectories of molecular sIgE sensitization profiles from childhood to adulthood and their associations with respiratory health. Methods: IgE reactivity to microarrayed allergen molecules were measured in childhood (EGEA1) and 12 years later in adult life (EGEA2) among 291 EGEA participants (152 with asthma). At each time point, sIgE sensitization profiles were identified by latent class analysis (LCA) by considering IgE‐reactivity to the 38 most prevalent respiratory allergens. The LCA‐defined profiles were then studied in association with respiratory health. Results: At baseline, the mean (min‐max) age of the population was 11 (4.5–16) years. The LCA identified four sIgE sensitization profiles which were very similar at both time points (% at EGEA1 and EGEA2); A: "no/few allergen(s)" (48%, 39%), B: "pollen/animal allergens" (18%, 21%), C: "most prevalent house dust mite allergens" (22%, 27%) and D: "many allergens" (12%, 13%). Overall, 73% of the participants remained in the same profile from childhood to adulthood. The profiles were associated with asthma and rhinitis phenotypes. Participants of profiles C and D had lower FEV1% and FEF25‐75% as compared to profile A. Similar patterns of associations were observed for participants with asthma. There was no association with change in lung function. Conclusion: Using high‐resolution sIgE longitudinal data, the LCA identified four molecular sensitization profiles, mainly stable from childhood to adulthood, that were associated with respiratory health. [ABSTRACT FROM AUTHOR]

ABPA, asthma, COPD, IgE, allergy diagnosis In case of sensitisation to I Af i and a high level of total IgE, several diagnoses must be considered: sensitisation to I Af i without allergy, bronchopulmonary disease (e.g. asthma or COPD) with allergy to I Af i , or true ABPA. Keywords: ABPA; allergy diagnosis; asthma; COPD; IgE EN ABPA allergy diagnosis asthma COPD IgE 327 330 4 12/31/21 20220101 NES 220101 Allergic bronchopulmonary aspergillosis (ABPA) is a lung disease involving hypersensitivity to I Aspergillus fumigatus i ( I Af i ) antigens caused by repeated inhalation of spores in susceptible hosts. [Extracted from the article]

Background: There are no studies of longitudinal immunoglobulin measurements in a population-based cohort alongside challenge-confirmed peanut allergy outcomes. Little is known about biomarkers for identifying naturally resolving peanut allergy during childhood., Objectives: To measure longitudinal trends in whole peanut and component Ara h 2 sIgE and sIgG 4 in the first 10 years of life, in a population cohort of children with challenge-confirmed peanut allergy, and to determine whether peanut-specific immunoglobulin levels or trends are associated with peanut allergy persistence or resolution by 10 years of age., Methods: One-year-old infants with challenge-confirmed peanut allergy (n = 156) from the HealthNuts study (n = 5276) were prospectively followed at ages 4, 6, and 10 years with questionnaires, skin prick tests, oral food challenges, and plasma total-IgE, sIgE and sIgG 4 to peanut and Ara h 2., Results: Peanut allergy resolved in 33.9% (95% CI = 25.3%, 43.3%) of children by 10 years old with most resolving (97.4%, 95% CI = 86.5%, 99.9%) by 6 years old. Decreasing Ara h 2 sIgE (p = .01) and increasing peanut sIgG 4 (p < .001), Ara h 2 sIgG 4 (p = .01), peanut sIgG 4 /sIgE (p < .001) and Ara h 2 sIgG 4 /sIgE (p < .001) from 1 to 10 years of age were associated with peanut allergy resolution. Peanut sIgE measured at 1 year old had the greatest prognostic value (AUC = 0.75 [95% CI = 0.66, 0.82]); however, no single threshold produced both high sensitivity and specificity., Conclusion: One third of infant peanut allergy resolved by 10 years of age. Decreasing sIgE and sIgG 4 to peanut and Ara h 2 over time were associated with natural resolution of peanut allergy. However, biomarker levels at diagnosis were not strongly associated with the natural history of peanut allergy., (© 2024 European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Background: Accurate diagnosis of peanut allergy is a significant clinical challenge. Here, a novel diagnostic blood test using the peanut bead‐based epitope assay ("peanut BBEA") was developed utilizing the LEAP cohort and then validated using two independent cohorts. Methods: The development of the peanut BBEA diagnostic test followed the National Academy of Medicine's established guidelines with discovery performed on 133 subjects from the non‐interventional arm of the LEAP trial and an independent validation performed on 82 subjects from the CoFAR2 and 84 subjects from the POISED study. All samples were analyzed using the peanut BBEA methodology, which measures levels of IgE to two Ara h 2 sequential (linear) epitopes and compares their combination to a threshold pre‐specified in the model development phase. When a patient has an inconclusive outcome by skin prick testing (or sIgE), IgE antibody levels to this combination of two epitopes can distinguish whether the patient is "Allergic" or "Not Allergic." Diagnoses of peanut allergy in all subjects were confirmed by double‐blind placebo‐controlled food challenge and subjects' ages were 7–55 years. Results: In the validation using CoFAR2 and POISED cohorts, the peanut BBEA diagnostic test correctly diagnosed 93% of the subjects, with a sensitivity of 92%, specificity of 94%, a positive predictive value of 91%, and negative predictive value of 95%. Conclusions: In validation of the peanut BBEA diagnostic test, the overall accuracy was found to be superior to existing diagnostic tests for peanut allergy including skin prick testing, peanut sIgE, and peanut component sIgE testing. [ABSTRACT FROM AUTHOR]

Immunoglobulin E (IgE)‐mediated allergy is the most common hypersensitivity disease affecting more than 30% of the population. Exposure to even minute quantities of allergens can lead to the production of IgE antibodies in atopic individuals. This is termed allergic sensitization, which occurs mainly in early childhood. Allergen‐specific IgE then binds to the high (FcεRI) and low‐affinity receptors (FcεRII, also called CD23) for IgE on effector cells and antigen‐presenting cells. Subsequent and repeated allergen exposure increases allergen‐specific IgE levels and, by receptor cross‐linking, triggers immediate release of inflammatory mediators from mast cells and basophils whereas IgE‐facilitated allergen presentation perpetuates T cell–mediated allergic inflammation. Due to engagement of receptors which are highly selective for IgE, even tiny amounts of allergens can induce massive inflammation. Naturally occurring allergen‐specific IgG and IgA antibodies usually recognize different epitopes on allergens compared with IgE and do not efficiently interfere with allergen‐induced inflammation. However, IgG and IgA antibodies to these important IgE epitopes can be induced by allergen‐specific immunotherapy or by passive immunization. These will lead to competition with IgE for binding with the allergen and prevent allergic responses. Similarly, anti‐IgE treatment does the same by preventing IgE from binding to its receptor on mast cells and basophils. Here, we review the complex interplay of allergen‐specific IgE, IgG and IgA and the corresponding cell receptors in allergic diseases and its relevance for diagnosis, treatment and prevention of allergy. [ABSTRACT FROM AUTHOR]

Background: Multifood oral immunotherapy (mOIT) with adjunctive anti‐IgE (omalizumab, XOLAIR®) treatment affords safe, effective, and rapid desensitization to multiple foods, although the specific immune mechanisms mediating this desensitization remain to be fully elucidated. Methods: Participants in our phase 2 mOIT trial (NCT02643862) received omalizumab from baseline to week 16 and mOIT from week 8 to week 36. We compared the immune profile of PBMCs and plasma taken at baseline, week 8, and week 36 using high‐dimensional mass cytometry, component‐resolved diagnostics, the indirect basophil activation test, and Luminex. Results: We found (i) decreased frequency of IL‐4+ peanut‐reactive CD4+ T cells and a marked downregulation of GPR15 expression and CXCR3 frequency among γδ and CD8+ T‐cell subsets at week 8 during the initial, omalizumab‐alone induction phase; (ii) significant upregulation of the skin‐homing receptor CCR4 in peanut‐reactive CD4+ T and Th2 effector memory (EM) cells and of cutaneous lymphocyte‐associated antigen (CLA) in peanut‐reactive CD8+ T and CD8+ EM cells; (iii) downregulation of CD86 expression among antigen‐presenting cell subsets; and (iv) reduction in pro‐inflammatory cytokines, notably IL‐17, at week 36 post‐OIT. We also observed significant attenuation of the Th2 phenotype post‐OIT, defined by downregulation of IL‐4 peanut‐reactive T cells and OX40 in Th2EM cells, increased allergen component‐specific IgG4/IgE ratio, and decreased allergen‐driven activation of indirectly sensitized basophils. Conclusions: This exploratory study provides novel comprehensive insight into the immune underpinnings of desensitization through omalizumab‐facilitated mOIT. Moreover, this study provides encouraging results to support the complex immune changes that can be induced by OIT. [ABSTRACT FROM AUTHOR]

Background: More knowledge about sensitization patterns in early infancy, including impact of molecular allergology, is needed to help predict future allergy development more accurately. Objective: We aimed to determine the prevalence and patterns of allergic sensitization at 3 months of age, and explore possible associated factors. Methods: From the Scandinavian antenatally recruited PreventADALL mother–child cohort, we included 1110 3‐month infants with available serum. Sensitization was defined as s‐IgE of ≥0.1 kUA/L by Phadiatop Infant® (ThermoFisher Scientific) including birch, cat, grass, dog, milk, egg, peanut and wheat. Further ImmunoCAP analyses to ovomucoid, casein, Ara h 1‐3, omega‐5‐gliadin were performed in food extract s‐IgE‐positive children. Maternal sensitization was defined as s‐IgE ≥ 0.35 kUA/L to Phadiatop® (inhalant allergen mix) and/or Fx5 (food allergen mix) at 18‐week pregnancy. Results: Overall 79 (7.3%) infants had specific sensitization, many with low s‐IgE‐levels (IQR 0.16–0.81 kUA/L), with 78 being sensitized to food extract allergens; 41 to egg, 27 to milk, 10 to peanut, and 25 to wheat. A total of 62/78 were further analysed, 18 (29%) had s‐IgE to ovomucoid, casein, Ara h 1‐3 and/or omega‐5‐gliadin. Eight infants (0.7%) were sensitized to inhalant allergens. Maternal sensitization to food allergens was associated with infant sensitization, odds ratio 3.64 (95% CI 1.53–8.68). Conclusion: Already at 3 months of age, 7% were sensitized to food, mostly without detectable s‐IgE to food allergen molecules, and <1% to inhalant allergens. Maternal food sensitization was associated with infants' sensitization. [ABSTRACT FROM AUTHOR]