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Background: During the COVID‐19 pandemic, novel nanoparticle‐based mRNA vaccines were developed. A small number of individuals developed allergic reactions to these vaccines although the mechanisms remain undefined. Methods: To understand COVID‐19 vaccine‐mediated allergic reactions, we enrolled 19 participants who developed allergic events within 2 h of vaccination and 13 controls, nonreactors. Using standard hemolysis assays, we demonstrated that sera from allergic participants induced stronger complement activation compared to nonallergic subjects following ex vivo vaccine exposure. Results: Vaccine‐mediated complement activation correlated with anti‐polyethelyne glycol (PEG) IgG (but not IgM) levels while anti‐PEG IgE was undetectable in all subjects. Depletion of total IgG suppressed complement activation in select individuals. To investigate the effects of vaccine excipients on basophil function, we employed a validated indirect basophil activation test that stratified the allergic populations into high and low responders. Complement C3a and C5a receptor blockade in this system suppressed basophil response, providing strong evidence for complement involvement in vaccine‐mediated basophil activation. Single‐cell multiome analysis revealed differential expression of genes encoding the cytokine response and Toll‐like receptor (TLR) pathways within the monocyte compartment. Differential chromatin accessibility for IL‐13 and IL‐1B genes was found in allergic and nonallergic participants, suggesting that in vivo, epigenetic modulation of mononuclear phagocyte immunophenotypes determines their subsequent functional responsiveness, contributing to the overall physiologic manifestation of vaccine reactions. Conclusion: These findings provide insights into the mechanisms underlying allergic reactions to COVID‐19 mRNA vaccines, which may be used for future vaccine strategies in individuals with prior history of allergies or reactions and reduce vaccine hesitancy. [ABSTRACT FROM AUTHOR]

Background: Conventional basophil activation tests (BATs) measure basophil activation by the increased expression of CD63. Previously, fluorophore‐labeled avidin, a positively‐charged molecule, was found to bind to activated basophils, which tend to expose negatively charged granule constituents during degranulation. This study further compares avidin versus CD63 as basophil activation biomarkers in classifying peanut allergy. Methods: Seventy subjects with either a peanut allergy (N = 47), a food allergy other than peanut (N = 6), or no food allergy (N = 17) were evaluated. We conducted BATs in response to seven peanut extract (PE) concentrations (0.01–10,000 ng/mL) and four control conditions (no stimulant, anti‐IgE, fMLP (N‐formylmethionine‐leucyl‐phenylalanine), and anti‐FcεRI). We measured avidin binding and CD63 expression on basophils with flow cytometry. We evaluated logistic regression and XGBoost models for peanut allergy classification and feature identification. Results: Avidin binding was correlated with CD63 expression. Both markers discriminated between subjects with and without a peanut allergy. Although small by percentage, an avidin+/CD63− cell subset was found in all allergic subjects tested, indicating that the combination of avidin and CD63 could allow a more comprehensive identification of activated basophils. Indeed, we obtained the best classification accuracy (97.8% sensitivity, 96.7% specificity) by combining avidin and CD63 across seven PE doses. Similar accuracy was obtained by combining PE dose of 10,000 ng/mL for avidin and PE doses of 10 and 100 ng/mL for CD63. Conclusions: Avidin and CD63 are reliable BAT activation markers associated with degranulation. Their combination enhances the identification of activated basophils and improves the classification accuracy of peanut allergy. [ABSTRACT FROM AUTHOR]

Our data demonstrate that IgG-anaphylaxis can still occur in neutropenic mice and that neutrophil-targeting mAbs likely protect from anaphylaxis through their capacity to desensitize effector cells by engaging Fc Rs and inducing the release of PAF, rather than via neutrophil depletion I per se i . In humans, it is largely accepted that anaphylaxis relies predominately on IgE antibodies.[1] However, IgG might also contribute to anaphylaxis induced by infused drugs.[1] Several mouse models have been developed to identify key effector cells and mediators of anaphylaxis. [Extracted from the article]

However, our findings align with those showing changes in gene expression profiles of peripheral T cells in patients undergoing OIT,7 suggesting an important role of T cells in immune homeostasis in food allergy. Gastrointestinal T cells reveal differentially expressed transcripts and enriched pathways during peanut oral immunotherapy Oral immunotherapy (OIT) has been successful in desensitizing patients to offending food allergens,1 although the identification of tissue-resident T-cell subsets and cognate pathways leading to desensitization has been challenging. [Extracted from the article]

OVA/EW: OVA-sensitized and EW diet-fed mice, NC/EW: non-sensitized and EW diet-fed mice. OVA/EW: OVA-sensitized and EW diet-fed mice, NC/EW: non-sensitized, and EW diet-fed mice. Mast cells partly contribute to allergic enteritis development: Findings in two different mast cell-deficient mice. [Extracted from the article]

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: 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]

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]

Keywords: basic immunology; IgE; mast cell; stem cell factor; transcriptome EN basic immunology IgE mast cell stem cell factor transcriptome 2288 2291 4 07/02/21 20210701 NES 210701 Mouse mast cells (MCs) have been classified as connective tissue MCs (CTMCs) and mucosal MCs (MMCs).1 Mouse bone marrow-derived cultured MCs (BMCMCs) generated with IL-3 (IL-3-MCs) have been considered "immature", with partial maturation induced by changing to SCF (stem cell factor)-containing media (SCF-MCs).2 We investigated the molecular mechanisms of SCF-induced BMCMC maturation using transcriptome profiling. Because the human homolog of I Mrgprb2 i mediates SP-induced MC activation, upregulation of Mrgprb2 probably mediates SP-induced and compound 48/80-induced MC activation in SCF-MCs5 and also contributes to SP-induced PMC activation. Transcriptome programming of IL-3-dependent bone marrow-derived cultured mast cells by stem cell factor (SCF). [Extracted from the article]

In this pilot study, we sought to characterize the gut microbiome from a cohort of peanut-allergic patients who participated in our double-blind, randomized, placebo-controlled, phase 2 peanut OIT study and who successfully desensitized.5 We retrospectively investigated stool samples collected from seven participants who received peanut flour as OIT, sampled before and after 52 weeks of OIT (Table 1). Microbiome, food allergy, OIT, peanut allergy, clinical trial Manipulating the gut microbiota has been proposed as an adjunct to FA immunotherapy to enhance safety and efficacy.3 Oral immunotherapy (OIT) is widely studied in clinical trials, and the PALFORZIA (AR101) OIT regimen is the first FDA-approved treatment for peanut allergy.4 However, whether the gut microbial composition is altered during successful OIT in peanut-allergic patients is unknown. Keywords: microbiome; food allergy; OIT; peanut allergy; clinical trial EN microbiome food allergy OIT peanut allergy clinical trial 927 930 4 03/09/21 20210301 NES 210301 It has been estimated that around 10.8% of adults in the United States suffer from food allergy (FA), and 1.8% of adults are allergic to peanut.1 The striking generational increase of FA prevalence has been associated with changes in the environment, including the gut microbiota.2 The gut microbiota shapes the development of the host immune system, and the host immune system in return influences the microbial composition. [Extracted from the article]

Background: Short‐chain fatty acids (SCFAs) are fermented dietary components that regulate immune responses, promote colonic health, and suppress mast cell–mediated diseases. However, the effects of SCFAs on human mast cell function, including the underlying mechanisms, remain unclear. Here, we investigated the effects of the SCFAs (acetate, propionate, and butyrate) on mast cell–mediated pathology and human mast cell activation, including the molecular mechanisms involved. Method: Precision‐cut lung slices (PCLS) of allergen‐exposed guinea pigs were used to assess the effects of butyrate on allergic airway contraction. Human and mouse mast cells were co‐cultured with SCFAs and assessed for degranulation after IgE‐ or non–IgE‐mediated stimulation. The underlying mechanisms involved were investigated using knockout mice, small molecule inhibitors/agonists, and genomics assays. Results: Butyrate treatment inhibited allergen‐induced histamine release and airway contraction in guinea pig PCLS. Propionate and butyrate, but not acetate, inhibited IgE‐ and non–IgE‐mediated human or mouse mast cell degranulation in a concentration‐dependent manner. Notably, these effects were independent of the stimulation of SCFA receptors GPR41, GPR43, or PPAR, but instead were associated with inhibition of histone deacetylases. Transcriptome analyses revealed butyrate‐induced downregulation of the tyrosine kinases BTK, SYK, and LAT, critical transducers of FcεRI‐mediated signals that are essential for mast cell activation. Epigenome analyses indicated that butyrate redistributed global histone acetylation in human mast cells, including significantly decreased acetylation at the BTK, SYK, and LAT promoter regions. Conclusion: Known health benefits of SCFAs in allergic disease can, at least in part, be explained by epigenetic suppression of human mast cell activation. [ABSTRACT FROM AUTHOR]

Larry joined Dr. Abraham Osler's laboratory at JHU as a Ph.D. student in 1962. We are profoundly saddened by the passing of Dr. Lawrence M. Lichtenstein, a founder of modern Allergy and Clinical Immunology. Dr. Lichtenstein - known to all as "Larry" - graduated from the University of Chicago School of Medicine in 1960. [Extracted from the article]

To the Editor, Allergies to hen's egg and cow's milk are the most common allergies in infants and young children. GLO:1X5/01jun20:all14107-fig-0001.jpg PHOTO (COLOR): sIgE (A) and sIgG4 (B) levels to egg and 3 components (Gal d 1-3) in participants who were never egg-allergic, allergic to egg and subsequently successfully desensitized by OIT to egg, or outgrew their egg allergy. Egg allergen specific IgE diversity predicts resolution of egg allergy in the population cohort HealthNuts. [Extracted from the article]

Summary: Mast cells are hematopoietic cells that reside in virtually all vascularized tissues and that represent potential sources of a wide variety of biologically active secreted products, including diverse cytokines and growth factors. There is strong evidence for important non‐redundant roles of mast cells in many types of innate or adaptive immune responses, including making important contributions to immediate and chronic IgE‐associated allergic disorders and enhancing host resistance to certain venoms and parasites. However, mast cells have been proposed to influence many other biological processes, including responses to bacteria and virus, angiogenesis, wound healing, fibrosis, autoimmune and metabolic disorders, and cancer. The potential functions of mast cells in many of these settings is thought to reflect their ability to secrete, upon appropriate activation by a range of immune or non‐immune stimuli, a broad spectrum of cytokines (including many chemokines) and growth factors, with potential autocrine, paracrine, local, and systemic effects. In this review, we summarize the evidence indicating which cytokines and growth factors can be produced by various populations of rodent and human mast cells in response to particular immune or non‐immune stimuli, and comment on the proven or potential roles of such mast cell products in health and disease. [ABSTRACT FROM AUTHOR]

The article offers information on the 23rd Scientific Meeting of the Foundation Rene Touraine, an international foundation for dermatology, to be held in Paris, France on December 4, 2015.

Mast cells are widely distributed in tissues, particularly near surfaces exposed to the environment. Mast cells can be activated to secrete diverse mediators and cytokines by IgE and specific Ag and many other stimuli, including products derived from either pathogens or the host during innate immune responses. Although mast cells are best known for their role in IgE-associated allergic disorders, mast cells can also exacerbate models of autoimmunity, enhance the sensitization and/or effector phases of certain cutaneous contact hypersensitivity responses, and increase inflammation and mortality during some severe bacterial infections. In other settings, however, mast cells can limit inflammation and tissue injury: mast cells promote host resistance in certain models of bacterial or parasite infection, limit pathology during some acquired immune responses to environmental Ag, including examples of severe contact hypersensitivity, and have adjuvant-like properties that can enhance the development of protective immunity against pathogens. These and other findings suggest that mast cells occupy a critical niche at the interface of innate and acquired immunity, where, depending on circumstances that remain to be fully understood, mast cells may function to perturb or help to restore homeostasis (or both), with consequences that can either promote health or contribute to disease. [ABSTRACT FROM AUTHOR]

• Introduction • The ‘unit granule’ and evidence of granule–granule fusion • Evidence for two models of secretory granule formation, unit addition and random fusion • Formation of unit granules: progranule fusion, immature granule maturation and membrane conservation - Progranule fusion and immature granule maturation - Membrane conservation • Functional implications • Conclusions and future directions Morphometric evidence derived from studies of mast cells, pancreatic acinar cells and other cell types supports a model in which the post-Golgi processes that generate mature secretory granules can be resolved into three steps: (1) fusion of small, Golgi-derived progranules to produce immature secretory granules which have a highly constrained volume; (2) transformation of such immature granules into mature secretory granules, a process often associated with a reduction in the maturing granule’s volume, as well as changes in the appearance of its content and (3) fusion of secretory granules of the smallest size, termed ‘unit granules’, forming granules whose volumes are multiples of the unit granule’s volume. Mutations which perturb this process can cause significant pathology. For example, Chediak–Higashi syndrome / lysosomal trafficking regulator ( CHS)/( Lyst) mutations result in giant secretory granules in a number of cell types in human beings with the Chediak–Higashi syndrome and in ‘beige’ ( Lystbg/Lystbg) mice. Analysis of the secretory granules of mast cells and pancreatic acinar cells in Lyst-deficient beige mice suggests that beige mouse secretory granules retain the ability to fuse randomly with other secretory granules no matter what the size of the fusion partners. By contrast, in normal mice, the pattern of granule–granule fusion occurs exclusively by the addition of unit granules, either to each other or to larger granules. The normal pattern of fusion is termed unit addition and the fusion evident in cells with CHS/ Lyst mutations is called random addition. The proposed model of secretory granule formation has several implications. For example, in neurosecretory cells, the secretion of small amounts of cargo in granules constrained to a very narrow size increases the precision of the information conveyed by secretion. By contrast, in pancreatic acinar cells and mast cells, large granules composed of multiple unit granules permit the cells to store large amounts of material without requiring the amount of membrane necessary to package the same amount of cargo into small granules. In addition, the formation of mature secretory granules that are multimers of unit granules provides a mechanism for mixing in large granules the contents of unit granules which differ in their content of cargo. [ABSTRACT FROM AUTHOR]

Observations of increased numbers of mast cells at sites of chronic inflammation have been reported for over a hundred years. Light and electron microscopic evidence of mast cell activation at such sites, taken together with the known functions of the diverse mediators, cytokines, and growth factors that can be secreted by appropriately activated mast cells, have suggested a wide range of possible functions for mast cells in promoting (or suppressing) many features of chronic inflammation. Similarly, these and other lines of evidence have implicated mast cells in a variety of adaptive or pathological responses that are associated with persistent inflammation at the affected sites. Definitively characterizing the importance of mast cells in chronic inflammation in humans is difficult. However, mice that genetically lack mast cells, especially those which can undergo engraftment with wildtype or genetically altered mast cells, provide a means to investigate the importance of mast cells and specific mast cell functions or products in diverse models of chronic inflammation. Such work has confirmed that mast cells can significantly influence multiple features of chronic inflammatory responses, through diverse effects that can either promote or, perhaps more surprisingly, suppress aspects of these responses. [ABSTRACT FROM AUTHOR]

This article discusses the association between cytotoxic effector memory CD8+ T cells and sustained unresponsiveness (SU) after peanut oral immunotherapy (OIT). The study found that a higher frequency of effector memory CD8+ T cells was associated with a higher likelihood of achieving SU. The researchers also identified differentially expressed immune genes and observed that cytolytic molecules such as Granulysin (Gnly) and Granzyme B (GzB) may play a supportive role in the development of SU. However, the study acknowledges the need for further validation using larger cohorts. [Extracted from the article]

The roôle in cutaneous physiology and pathology has long been a subject of intense speculation and great clinical interest. In this brief review, which is focused primarily on murine systems, we outline certain important aspects of the biology of the mast cell, including their ability to produce a variety of cytokines, describe the development of a model system (the "mast cell knock-in mouse") for studying the roles of cutaneous mast cells in biological responses in vivo, and illustrate a few examples of how this approach has been used to investigate the contributions of mast cells and their cytokines to cutaneous inflammatory or immune responses. [ABSTRACT FROM AUTHOR]

The exponential growth of precision diagnostic tools, including omic technologies, molecular diagnostics, sophisticated genetic and epigenetic editing, imaging and nano-technologies and patient access to extensive health care, has resulted in vast amounts of unbiased data enabling in-depth disease characterization. New disease endotypes have been identified for various allergic diseases and triggered the gradual transition from a disease description focused on symptoms to identifying biomarkers and intricate pathogenetic and metabolic pathways. Consequently, the current disease taxonomy has to be revised for better categorization. This European Academy of Allergy and Clinical Immunology Position Paper responds to this challenge and provides a modern nomenclature for allergic diseases, which respects the earlier classifications back to the early 20th century. Hypersensitivity reactions originally described by Gell and Coombs have been extended into nine different types comprising antibody- (I-III), cell-mediated (IVa-c), tissue-driven mechanisms (V-VI) and direct response to chemicals (VII). Types I-III are linked to classical and newly described clinical conditions. Type IVa-c are specified and detailed according to the current understanding of T1, T2 and T3 responses. Types V-VI involve epithelial barrier defects and metabolic-induced immune dysregulation, while direct cellular and inflammatory responses to chemicals are covered in type VII. It is notable that several combinations of mixed types may appear in the clinical setting. The clinical relevance of the current approach for allergy practice will be conferred in another article that will follow this year, aiming at showing the relevance in clinical practice where various endotypes can overlap and evolve over the lifetime., (© 2023 European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Background: Peanut and tree nut allergies are the most important causes of anaphylaxis. Co-reactivity to more than one nut is frequent, and co-sensitization in the absence of clinical data is often obtained. Confirmatory oral food challenges (OFCs) are inconsistently performed., Objective: To investigate the utility of the basophil activation test (BAT) in diagnosing peanut and tree nut allergies., Methods: The Markers Of Nut Allergy Study (MONAS) prospectively enrolled patients aged 0.5-17 years with confirmed peanut and/or tree nut (almond, cashew, hazelnut, pistachio, walnut) allergy or sensitization from Canadian (n = 150) and Austrian (n = 50) tertiary pediatric centers. BAT using %CD63 + basophils (SSClow/CCR3pos) as outcome was performed with whole blood samples stimulated with allergen extracts of each nut (0.001-1000 ng/mL protein). BAT results were assessed against confirmed allergic status in a blinded fashion to develop a generalizable statistical model for comparison to extract and marker allergen-specific IgE., Results: A mixed effect model integrating BAT results for 10 and 100 ng/mL of peanut and individual tree nut extracts was optimal. The area under the ROC curve (AUROC) was 0.98 for peanut, 0.97 for cashew, 0.92 for hazelnut, 0.95 for pistachio, and 0.97 for walnut. The BAT outperformed sIgE testing for peanut or hazelnut and was comparable for walnut (AUROC 0.95, 0.94, 0.92) in a sub-analysis in sensitized patients undergoing OFC., Conclusions: Basophil activation test can predict allergic clinical status to peanut and tree nuts in multi-nut-sensitized children and may reduce the need for high-risk OFCs in patients., (© 2020 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.)