Origins and clonal convergence of gastrointestinal IgE+ B cells in human peanut allergy.
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ABSTRACT:
SUBMITTER: Hoh RA
PROVIDER: S-EPMC7691169 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Rationale: Oral immunotherapy (OIT) is an emerging treatment for food allergy. While desensitization is achieved in most subjects, many experience gastrointestinal symptoms and few develop eosinophilic gastrointestinal disease. It is unclear whether these subjects have subclinical gastrointestinal eosinophilia (GE) at baseline. We aimed to evaluate the presence of GE in subjects with food allergy before peanut OIT. Methods: We performed baseline esophagogastroduodenoscopies on 21 adults before undergoing peanut OIT. Subjects completed a detailed gastrointestinal symptom questionnaire. Endoscopic findings were assessed using the Eosinophilic Esophagitis (EoE) Endoscopic Reference Score (EREFS) and biopsies were obtained from the esophagus, gastric antrum, and duodenum. Esophageal biopsies were evaluated using the EoE Histologic Scoring System. Immunohistochemical staining for eosinophil peroxidase (EPX) was also performed. Hematoxylin and eosin and EPX stains of each biopsy were assessed for eosinophil density and EPX/mm2 was quantified using automated image analysis. Results: All subjects were asymptomatic. Pre-existing esophageal eosinophilia (>5 eosinophils per high-power field [eos/hpf]) was present in five participants (24%), three (14%) of whom had >15 eos/hpf associated with mild endoscopic findings (edema, linear furrowing, or rings; median EREFS = 0, IQR 0-0.25). Some subjects also demonstrated basal cell hyperplasia, dilated intercellular spaces, and lamina propria fibrosis. Increased eosinophils were noted in the gastric antrum (>12 eos/hpf) or duodenum (>26 eos/hpf) in 9 subjects (43%). EPX/mm2 correlated strongly with eosinophil counts (r = 0.71, p < 0.0001). Conclusions: Pre-existing GE is common in adults with IgE-mediated peanut allergy. Eosinophilic inflammation (EI) in these subjects may be accompanied by mild endoscopic and histologic findings. Longitudinal data collection during OIT is ongoing.
| S-EPMC6261984 | biostudies-literature
Project description:BackgroundPeanut allergy is characterized by the development of IgE against peanut antigen.ObjectiveWe sought to evaluate the evolution of epitope-specific (es)IgE and esIgG4 in a prospective cohort of high-risk infants to determine whether antibody profiles can predict peanut allergy after age 4 years.MethodsThe end point was allergy status at age 4+ years; samples from 293 children were collected at age 3 to 15 months and 2 to 3 and 4+ years. Levels of specific (s)IgE and sIgG4 to peanut and component proteins, and 50 esIgE and esIgG4 were quantified. Changes were analyzed with mixed-effects models. Machine learning algorithms were developed to identify a combination of antigen- and epitope-specific antibodies that using 3- to 15-month or 2- to 3-year samples can predict allergy status at age 4+ years.ResultsAt age 4+ years, 38% of children were Tolerant or 14% had Possible, 8% Convincing, 24% Serologic, and 16% Confirmed allergy. At age 3 to 15 months, esIgE profiles were similar among groups, whereas marked increases were evident at age 2 and 4+ years only in Confirmed and Serologic groups. In contrast, peanut sIgE level was significantly lower in the Tolerant group at age 3 to 15 months, increased in Confirmed and Serologic groups but decreased in Convincing and Possibly Allergic groups over time. An algorithm combining esIgEs with peanut sIgE outperformed different clinically relevant IgE cutoffs, predicting allergy status on an "unseen" set of patients with area under the curves of 0.84 at age 3 to 15 months and 0.87 at age 2 to 3 years.ConclusionsEarly epitope-specific plus peanut-specific IgE is predictive of allergy status at age 4+ years.
| S-EPMC8095129 | biostudies-literature
Project description:There are no available clinical tests that can accurately predict peanut allergy (PA) and/or anaphylaxis. This study is aimed at evaluating whether the component-resolved diagnostic (CRD) IgE and IgG4 tests can (i) distinguish PA from asymptomatic peanut sensitization (PS) and (ii) differentiate anaphylactic from nonanaphylactic PA.This study included 20 nonatopic controls, 58 asymptomatically peanut-sensitized children, 55 nonanaphylactic, and 53 anaphylactic PA cases from the Chicago Food Allergy Study. IgE and IgG4 to 103 allergens were measured using the ImmunoCAP ISAC technology and were compared among each group of children. The random forest test was applied to estimate each allergen's ability to predict PA and/or peanut anaphylaxis.Peanut allergy cases (with or without anaphylaxis) had significantly higher IgE reactivity to Ara h 1-3 (peanut allergens) and Gly m 5-6 (soy allergens) than asymptomatically sensitized children (P < 0.00001). Similar but more modest relationships were found for IgG4 to Ara h 2 (P < 0.01). IgE to Ara h 2 was the major contributor to accurate discrimination between PA and asymptomatic sensitization. With an optimal cutoff point of 0.65 ISU-E, it conferred 99.1% sensitivity, 98.3% specificity, and a 1.2% misclassification rate in the prediction of PA, which represented a higher discriminative accuracy than IgE to whole peanut extract (P = 0.008). However, none of the IgE and/or IgG4 tests could significantly differentiate peanut anaphylaxis from nonanaphylactic PA.IgE to Ara h 2 can efficiently differentiate clinical PA from asymptomatic PS, which may represent a major step forward in the diagnosis of PA.
| S-EPMC3499645 | biostudies-literature
Project description:Severity of peanut allergies is linked to allergen-specific immunoglobulin E (IgE) antibodies in blood, but diagnostics from assays using glycoprotein allergen mixtures may be inaccurate. Measuring IgEs specific to individual peptide and carbohydrate epitopes of allergenic proteins is promising. We report here the first immunoarray for IgEs utilizing both peptide and carbohydrate epitopes. A surface plasmon resonance imaging (SPRi) microarray was equipped with peptide and ?-xylosyl glycoside (BXG) epitopes from major peanut allergen glycoprotein Arachis hypogaea h2 (Ara-h2). A monoclonal anti-IgE antibody was included as positive control. IgEs were precaptured onto magnetic beads loaded with polyclonal anti-IgE antibodies to enhance sensitivity and minimize non-specific binding. As little as 0.1 attomole (0.5 pg mL(-1)) IgE was detected from dilute serum in 45 min. IgEs binding to Ara-h2 peptide and BXG were quantified in 10 ?L of patient serum and correlated with standard ImmunoCAP values.
| S-EPMC4205568 | biostudies-literature
Project description:Background10% of US residents have food allergies, including 2% with peanut allergy. Mast cell mediators released during the allergy effector phase drive allergic reactions. Therefore, targeting sensitized mast cells may prevent food allergy symptoms.ObjectiveWe used novel, human, allergen-specific, IgE monoclonal antibodies (mAbs) created using human hybridoma techniques to design an in vitro system to evaluate potential therapeutics targeting sensitized effector cells.MethodsTwo human IgE mAbs specific for peanut, generated through human hybridoma techniques, were used to sensitize rat basophilic leukemia (RBL) SX-38 cells expressing the human IgE receptor (FcϵRI). Beta-hexosaminidase release (a marker of degranulation), cytokine production, and phosphorylation of signal transduction proteins downstream of FcϵRI were measured after stimulation with peanut. Degranulation was also measured after engaging inhibitory receptors CD300a and Siglec-8.ResultsPeanut-specific human IgE mAbs bound FcϵRI, triggering degranulation after stimulation with peanut in RBL SX-38 cells. Sensitized RBL SX-38 cells stimulated with peanut increased levels of phosphorylated SYK and ERK, signal transduction proteins downstream of FcϵRI. Engaging inhibitory cell surface receptors CD300a or Siglec-8 blunted peanut-specific activation.ConclusionAllergen-specific human IgE mAbs, expressed from human hybridomas and specific for a clinically relevant food allergen, passively sensitize allergy effector cells central to the in vitro models of the effector phase of food allergy. Peanut reproducibly activates and induces degranulation of RBL SX-38 cells sensitized with peanut-specific human IgE mAbs. This system provides a unique screening tool to assess the efficacy of therapeutics that target allergy effector cells and inhibit food allergen-induced effector cell activation.
| S-EPMC9556733 | biostudies-literature
Project description:BackgroundThe rising prevalence of food allergy reported in the United States, UK, and Australia may be attributable to the rise in peanut allergy prevalence. The food allergy prevalence in other parts of the world such as Asia is, however, less well documented.ObjectiveThis study aimed to evaluate the prevalence of cow's milk, egg, and peanut allergies in a general population of Singaporean children below 30 months of age.MethodsA total of 4,115 children from the general population who attended well-baby visits between 2011 and 2015 completed standardized questionnaires to elicit a convincing history of food allergy to estimate the population prevalence of food allergies.ResultsThe prevalence of a convincing history of cow's milk allergy was 0.51% (95% confidence interval [CI], 0.3-0.7), hen's egg allergy 1.43% (95% CI, 1.1-1.8), and peanut allergy 0.27% (95% CI, 0.12-0.42). Of the 15 of 59 children with a convincing history of hen's egg allergy who consented, 12 (80%) had corroborative positive skin prick tests.ConclusionThe prevalence of food allergy, in particular peanut allergy, in children below 2 years of age is lower in this South East Asian population than reported in Western cohorts. Further research should focus on deciphering differential risk factors for food allergy across different geographical locations.
| S-EPMC9353200 | biostudies-literature
Project description:IgE-mediated peanut allergic is common, often serious, and usually lifelong. Not all individuals who produce peanut-specific IgE will react upon consumption of peanut and can eat the food without adverse reactions, known as sensitized tolerance. Here, we employ high-dimensional mass cytometry to define the circulating immune cell signatures associated with sensitized tolerance and clinical allergy to peanut in the first year of life. Key features of clinical peanut allergic are increased frequency of activated B cells (CD19hiHLADRhi), overproduction of TNFα and increased frequency of peanut-specific memory CD4 T cells. Infants with sensitized tolerance display reduced frequency but hyper-responsive naive CD4 T cells and an increased frequency of plasmacytoid dendritic cells. This work demonstrates the utility and power of high-dimensional mass cytometry analysis to interrogate the cellular interactions that are associated with allergic sensitization and clinical food allergy in the first year of life.
| S-EPMC7046671 | biostudies-literature
Project description:Peanut allergy is an IgE-mediated, persisting immune disorder that is of major concern worldwide. Currently, no routine immunotherapy is available to treat this often severe and sometimes fatal food allergy. Traditional subcutaneous allergen immunotherapy with crude peanut extracts has proven not feasible due to the high risk of severe systemic side effects. The allergen-specific approaches under preclinical and clinical investigation comprise subcutaneous, oral, sublingual and epicutaneous immunotherapy with whole-peanut extracts as well as applications of hypoallergenic peanut allergens or T cell epitope peptides. Allergen-nonspecific approaches include monoclonal anti-IgE antibodies, TCM herbal formulations and Toll-like receptor 9-based immunotherapy. The potential of genetically engineered plants with reduced allergen levels is being explored as well as the beneficial influence of lactic acid bacteria and soybean isoflavones on peanut allergen-induced symptoms. Although the underlying mechanisms still need to be elucidated, several of these strategies hold great promise. It can be estimated that individual strategies or a combination thereof will result in a successful immunotherapy regime for peanut-allergic individuals within the next decade.
| S-EPMC5548240 | biostudies-other
Project description:Food allergy is a collective term for several immune-mediated responses to food. IgE-mediated food allergy is the best-known subtype. The patients present with a marked diversity of clinical profiles including symptomatic manifestations, threshold reactivity and reaction kinetics. In-vitro predictors of these clinical phenotypes are evasive and considered as knowledge gaps in food allergy diagnosis and risk management. Peanut allergy is a relevant disease model where pioneer discoveries were made in diagnosis, immunotherapy and prevention. This review provides an overview on the immune basis for phenotype variations in peanut-allergic individuals, in the light of future patient stratification along emerging omic-areas. Beyond specific IgE-signatures and basophil reactivity profiles with established correlation to clinical outcome, allergenomics, mass spectrometric resolution of peripheral allergen tracing, might be a fundamental approach to understand disease pathophysiology underlying biomarker discovery. Deep immune phenotyping is thought to reveal differential cell responses but also, gene expression and gene methylation profiles (eg, peanut severity genes) are promising areas for biomarker research. Finally, the study of microbiome-host interactions with a focus on the immune system modulation might hold the key to understand tissue-specific responses and symptoms. The immune mechanism underlying acute food-allergic events remains elusive until today. Deciphering this immunological response shall enable to identify novel biomarker for stratification of patients into reaction endotypes. The availability of powerful multi-omics technologies, together with integrated data analysis, network-based approaches and unbiased machine learning holds out the prospect of providing clinically useful biomarkers or biomarker signatures being predictive for reaction phenotypes.
| S-EPMC7876438 | biostudies-literature
Project description:B cells expressing IgE contribute to immunity against parasites and venoms and are the source of antigen specificity in allergic patients, yet the developmental pathways producing these B cells in human subjects remain a subject of debate. Much of our knowledge of IgE lineage development derives from model studies in mice rather than from human subjects.We evaluate models for isotype switching to IgE in human subjects using immunoglobulin heavy chain (IGH) mutational lineage data.We analyzed IGH repertoires in 9 allergic and 24 healthy adults using high-throughput DNA sequencing of 15,843,270 IGH rearrangements to identify clonal lineages of B cells containing members expressing IgE. Somatic mutations in IGH inherited from common ancestors within the clonal lineage are used to infer the relationships between B cells.Data from 613,641 multi-isotype B-cell clonal lineages, of which 592 include an IgE member, are consistent with indirect switching to IgE from IgG- or IgA-expressing lineage members in human subjects. We also find that these inferred isotype switching frequencies are similar in healthy and allergic subjects.We found evidence that secondary isotype switching of mutated IgG1-expressing B cells is the primary source of IgE in human subjects, with lesser contributions from precursors expressing other switched isotypes and rarely IgM or IgD, suggesting that IgE is derived from previously antigen-experienced B cells rather than naive B cells that typically express low-affinity unmutated antibodies. These data provide a basis from which to evaluate allergen-specific human antibody repertoires in healthy and diseased subjects.
| S-EPMC4747810 | biostudies-literature