Allergy

Diets and environments are critical determinants for food allergy development. Harnessing unprecedented epidemiological and nutritional data, we examined the overall dietary environments for common food allergens and their intrinsic nutrient composition. We found that food and macronutrient supplies minimally impacted food allergy prevalence, but higher protein and glycine in food allergens correlated with less allergies. These findings offer new directions in food allergy research and management.

TGF-{beta}1 is known to have a pro-inflammatory impact by inducing Th9 cells, while it also induces anti-inflammatory Treg cells (Tregs). In the context of allergic airway inflammation (AAI) its dual role can be of critical importance in influencing the outcome of the disease. Here we demonstrate that TGF-{beta} acts in AAI by driving effector T cells into Th9 cells, while Tregs differentiate independently. Induction of experimental AAI and airway hyperreactivity in a mouse model with inducible genetic ablation of the TGF{beta}-receptor 2 (TGFBR2) on CD4+T cells significantly reduced the disease phenotype. Further, it blocked the induction of Th9 cell frequencies, but increased Treg cells. To translate these findings into a human clinically relevant context, Th9 and Treg cells were quantified both locally in induced sputum and systemically in blood of allergic rhinitis and asthma patients with or without allergen-specific immunotherapy (AIT). Natural allergen exposure induced local and systemic Th2, Th9 cell and reduced Tregs, while therapeutic allergen exposure by AIT suppressed Th2 and Th9 cell frequencies along with TGF-{beta} and IL-9 secretion. Altogether, these findings support that neutralization of TGF-{beta} represents a viable therapeutic option in allergy and asthma, not posing the risk of immune dysregulation by impacting Tregs.

The COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has had a profound global impact, resulting in millions of cases and deaths. As COVID-19 continues to circulate, the interplay between COVID-19 and other chronic diseases, particularly asthma, remains an important public health concern. Asthma, a heterogeneous disease affecting over 300 million people globally, is characterized by airway inflammation and hyper-reactivity. Asthma exacerbations are often triggered by respiratory infections, leading to an increased risk of pulmonary complications. Given that the COVID-19 pandemic has spurred significant debate on its relationship with asthma, understanding how different asthma phenotypes, particularly allergic versus non-allergic asthma, affect COVID-19 risk is critical. Using Mendelian randomization (MR), this study investigates the genetic determinants of asthma subtypes in relation to COVID-19 susceptibility and severity. Our findings reveal a complex relationship, with non-allergic asthma associated with increased COVID-19 risk, while allergic asthma, particularly when co-occurring with allergic rhinitis, correlates with reduced COVID-19 risk. Although COVID-19 and allergic asthma are independent clinical manifestations, the above results indicate the trade-off between allergic asthma and COVID-19 risk, implying a shared origin of allergic disease and allergic immune defense. As such, I proposed an alternative perspective for allergic diseases: the ability to mount an allergic immune defense can be protective in the face of infectious diseases such as COVID-19; however, when excessive and misguided to allergens, the allergic immune defense can result in allergic disease. Thus, the dramatic rise of allergic diseases during the past few decades might be caused by the survival advantage of allergic immune defenses, which increases the adaptation of the host to lethal infections and thus is favored in the evolutionary process of natural selection. HighlightsCOVID-19 pandemic complicates disease progression and management in the asthmatic population. COVID-19 risk increases with non-allergic asthma but decreases with allergic asthma. The trade-off between allergic asthma and COVID-19 risk implies a shared origin of allergic disease and allergic immune defense.

Background Growing evidence suggests that the gut microbiome influences nasal and ocular allergic inflammation through gut-mucosal immune interactions. Yet, its association with Allergic rhinitis (AR) and allergic eye symptoms (AES) remains incompletely understood in large population-based cohorts. Objective To examine associations between the gut microbiome and self-reported AR and AES in Finnish adults. Methods Shallow metagenomic sequencing was performed on stool samples from a population-based cohort (FINRISK02; n = 7,231). Microbial taxonomic and functional profiles were compared between individuals with AR (n = 1,950), AES (n = 1,554), combined allergies (AR and/or AES; n = 2,305), and controls without reported symptoms (n = 3,175). Results Allergic groups exhibited lower microbial richness and phylogenetic diversity than controls. Shared microbial and functional signatures were observed across AR and AES, consistent with their high co-occurrence (N = 1,199). Compared with controls, allergic groups showed enrichment of 17 bacterial species, predominantly from the Clostridia class, including taxa previously associated with asthma, chronic obstructive pulmonary disease, and atopic dermatitis. Allergic individuals also exhibited enrichment of pathways related to mucosal carbohydrate processing, shikimate metabolism, histidine turnover, and broader amino acid metabolism. Concurrent enrichment of histidine biosynthesis and degradation suggested altered microbial histidine metabolism. Conclusions Adult allergic symptoms are associated with gut microbiome taxonomic and functional alterations linked to mucosal barrier function and immune-related metabolism, supporting a shared gut-mucosal immune axis across allergic phenotypes.

IntroductionAn enzyme-linked immunosorbent assay (ELISA) system capable of profiling IgE-recognising epitopes in patients with cows milk allergy (CMA) was established previously. This assay can reveal qualitative differences and imbalances between IgE- and IgG4-recognising epitopes as well as quantify IgE specific to the mixture of 14 epitopes (14 epitopes-ALL) that correlate with the value obtained using the ImmunoCAP sIgE(milk) test. To apply this system clinically, we determined the cutoff range of IgE contents detected by the 14 epitopes-ALL, and identified pathogenic IgE-epitopes and tolerance-related IgG4-epitopes by comparing the profiles of both IgE and IgG4. MethodsSerum samples from 38 patients with CMA and 34 non-CMA volunteers were assessed to determine their IgE levels towards 14 epitopes using our ELISA system. Epitope profiles of the samples were analysed individually. Using clinical data on oral immunotherapy status and allowed milk intake assessed by the oral food challenge test, the IgE and IgG4 profiles were compared to extract pathogenic, non-pathogenic, and tolerance-related epitope candidates. ResultsThe cutoff range of IgE was 1.5-4.5 ng/mL with an area under the curve of 89% in receiver operating characteristic analysis. Serum samples of ImmunoCAP class 3 and lower classes were divided into upper and lower proportions by this cutoff range, which can be useful for predicting risk of eliciting symptoms by allergenic food exposure. Extraction of candidate pathogenic and non-pathogenic epitopes showed that pathogenic epitopes formed a cluster in hydrophobic regions of caseins and appeared to be near each other on the molten globule of micelles. ConclusionsThe 14 epitopes of cows milk allergens are useful for determining the allergen-specific IgE concentration in patients with CMA. The IgE vs. IgG4 profile identified pathogenic, non-pathogenic, and tolerance-related epitopes. This profiling analysis may explain why oral immunotherapy is effective in some individuals but not others. Key MessagesO_LIIgE antibodies recognising 14 cows milk allergen epitopes correlate with IgE values detected using ImmunoCAP. C_LIO_LIThis test can accurately assess risk of symptoms in patients with class 3 ImmunoCAP sIgE. C_LIO_LIEpitope-based quantitative/qualitative analyses of antibodies are reliable for assessing allergic symptoms and oral immunotherapy effects. C_LI

IntroductionWhile reliable, quantitative in vitro testing for sensitivity to aeroallergens has been available for decades, if and how asthma severity markers might be predictably expressed in clusters matched for comparable multiple sensitizations is unknown. ObjectiveOur aim is to use machine learning techniques to explore how allergic poly-sensitization (APS) clusters may serve as precision markers in adult urban patients with moderate to severe asthma. MethodsWe constructed a database of sensitizations to the 25 aeroallergens in the Zone 1 Northeastern US ImmunoCAP(R) assay. We used the Scikit-Learn(R) machine learning library to perform model-based clustering to identify APS clusters. Clusters were compared for differences in common clinical markers of asthma. ResultsThe database consisted of 509 patients. Unbiased mixture modeling identified ten clusters of increasing APS of varying size (n = 1 to 339) characterized by significant increases in mean serum immunoglobulin E (p<.001), peripheral blood eosinophil count (p<.001), and DLCO (p=.02). There was a significant decline in mean age at presentation (p<.001), FEV1/FVC (p=.01), and FEF25-75 (p=.002), but not FEV1 (p=.29), nor RV/TLC (p=.14) with increasing APS by simple linear regression. Finally, we identified two divergent paths for the poly-atopic march, one driven by perennial and the other by seasonal allergens. ConclusionWe conducted a pilot study for a novel machine learning understanding and approach to the classification of APS and potential influences if included in asthma cluster analyses. The methods used here can be easily applied to other geographic regions with different allergens

Innate mononuclear phagocytic system (MPS) cells preserve mucosal immune homeostasis. Here, we investigated their role at nasal mucosa following challenge with house dust mite. We combined single cell proteome and transcriptome profiling on immune cells from nasal biopsy cells of allergic rhinitis and non-allergic subjects, before and after repeated nasal allergen challenge. Nasal biopsies of patients showed infiltrating inflammatory HLA-DRhi CD14+ monocytes and CD16+ monocytes, and transcriptional changes in resident CD1C+ CD1A+ conventional dendritic cells (cDC)2 following challenge. Importantly, although clinically silent, non-allergic individuals displayed a distinct innate MPS response to allergen challenge: predominant infiltration of myeloid-derived suppressor cells (HLA-DRlow CD14+ monocytes), as well as cDC2 clusters expressing increased inhibitory/tolerogenic transcripts. Therefore, we identified not only clusters involved in airway inflammation but also a non-inflammatory, homeostatic blueprint of innate MPS responses to allergens in non-allergic individuals. Future therapies should target innate MPS for treatment of inflammatory airway diseases. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=112 SRC="FIGDIR/small/20189886v2_ufig1.gif" ALT="Figure 1"> View larger version (39K): org.highwire.dtl.DTLVardef@e6e970org.highwire.dtl.DTLVardef@1e7e8bdorg.highwire.dtl.DTLVardef@60d55forg.highwire.dtl.DTLVardef@1587d4d_HPS_FORMAT_FIGEXP M_FIG C_FIG

Asthma is a chronic inflammatory disease associated with increased Staphylococcus aureus airway colonization. However, the causal relationship is unknown. S. aureus secretes several virulence factors that promote allergic sensitization. These include the serine protease-like protein (Spl) B, a secreted protease that elicits a type 2-biased immune response in humans. We studied the allergenic properties of SplB in a mouse model of chronic allergic airway inflammation (AAI). We induced AAI by repeated intratracheal inoculations of recombinant SplB in C57BL/6J mice, wild-type, Rag2 ko, IL-33 ko, and PAR2 ko. We also exposed wild-type mice to an enzymatically inactive mutant of SplB. Airway inflammation was assessed by flow cytometry and airway hyperreactivity measurements. The specific antibody response was characterized by ELISA. We observed severe eosinophil inflammation in the airways and lungs of SplB-sensitized mice, as well as airway hypersensitivity and high SplB-specific serum IgE titers. Remarkably, SplB induced this asthma phenotype without the need for adjuvants. Characterization of the pathomechanisms revealed that the proteolytic activity of SplB and a functional adaptive immune system were essential for the development of murine asthma. The soluble protease sensor IL-33 was necessary for eosinophil tissue invasion, whereas the membrane-bound protease sensor PAR2 was dispensable. Based on these results, we propose a new mechanism to explain the relationship between S. aureus colonization and asthma: S. aureus itself can cause allergic airway inflammation via its potent allergen SplB.

Airborne fungi are potent inducers of respiratory disease and cause the debilitating conditions severe asthma with fungal sensitisation (SAFS) and allergic bronchopulmonary aspergillosis (ABPA). However, the immune cell types and the inflammatory airway environment that defines SAFS and ABPA patients is not extensively characterised. To address this, we recruited SAFS and ABPA patients, asthmatics without evidence of fungal sensitisation and healthy controls (n= 20 individuals per group). Immune cells were isolated from collected sputum and peripheral blood samples and immunophenotyping was performed via flow cytometry. By applying a machine learning approach to our dataset, we identify a critical association between CD4+ T cells, type 2 conventional dendritic cells, eosinophils, proinflammatory factors and severe respiratory disease. These complex immune signatures should be investigated further to improve the diagnostics and treatment of SAFS and ABPA. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=46 SRC="FIGDIR/small/25327430v1_ufig1.gif" ALT="Figure 1"> View larger version (13K): org.highwire.dtl.DTLVardef@88968aorg.highwire.dtl.DTLVardef@153488eorg.highwire.dtl.DTLVardef@c06c8borg.highwire.dtl.DTLVardef@1163ae3_HPS_FORMAT_FIGEXP M_FIG C_FIG

Atopic dermatitis (AD) is a chronic inflammatory skin disease that often precedes the development of food allergy, asthma, and allergic rhinitis. The prevailing paradigm holds that a reduced frequency and function of natural killer (NK) cell contributes to AD pathogenesis, yet the underlying mechanisms and contributions of NK cells to allergic comorbidities remain ill-defined. Herein, analysis of circulating NK cells in a longitudinal early life cohort of children with AD revealed a progressive accumulation of NK cells with low expression of the activating receptor NKG2D, which was linked to more severe AD and sensitivity to allergens. This was most notable in children co-sensitized to food and aero allergens, a risk factor for development of asthma. Individual-level longitudinal analysis in a subset of children revealed co-incident reduction of NKG2D on NK cells with acquired or persistent sensitization, and this was associated with impaired skin barrier function assessed by transepidermal water loss. Low expression of NKG2D on NK cells was paradoxically associated with depressed cytolytic function but exaggerated release of the proinflammatory cytokine TNF-. These observations provide important insights into a potential mechanism underlying the development of allergic co-morbidity in early life in children with AD which involves altered NK-cell functional responses, and define an endotype of severe AD.

Peanut allergy represents a major food-allergy burden, raising concerns about food processing and novel dietary products. Current diagnostics assess primarily allergic endpoints rather than immune mechanisms initiating and maintaining type 2 inflammation, particularly DC2-mediated Th2 polarization. Here, an in vitro autologous monocyte-derived dendritic cell (moDC)-T cell and B cell assay has been established to study immunomodulatory effects induced by unprocessed (P-D) and processed (P-DH (heated) or P-DHG (heated and glycated)) peanut proteins and emerging foods (protein concentrates or whole biomass), related to ex vivo DC2-T cell reactions. CD14+ monocytes, CD4+ T cells and CD19+ B cells were isolated from six peanut-allergic patients PBMCs. MoDCs generated with IL4/GM-CSF were exposed (48h) to type 2 polarizing cytokine (DC2) mix, or DC2 mix combined with the food samples. Next, DC2s were co-cultured with T cells (5d), followed by B cells incubation with DC2/T cell supernatant and food samples (10d). Supernatants and cells were analyzed for Th1/Th2/Th-regulatory (Treg) cells, IgE and IgG profiles. DC2 induced a strong Th2 phenotype and activity, P-D DC2 further enhanced IL13 secretion and %Tregs. P-DH DC2 favored Th2, whereas P-DHG DC2 increased IFN{gamma}, with neither increasing %Treg. All increased CD40L+CD25+ memory Th2 cells. Wheat, whey and seaweed biomass had little effect, whereas algae DC2 showed distinct immunomodulatory, adjuvant-like activity. In conclusion, this autologous in vitro assay captures peanut-specific and generic Th2 responses and reactivity to food samples, supporting its use as additional tool to assess type 2-driving potential and allergenicity of emerging foods and processing methods in peanut-allergic patients. Clinical trial registrationThe current in vitro study was conducted in accordance with the Declaration of Helsinki and approved by the Medical Ethics Review Committee (METC) of the Erasmus MC (NL79534.078.21 MEC-2021-0905) and registrated at International Clinical Trials Registry Platform (NL-OMON51765). Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=124 SRC="FIGDIR/small/705773v1_ufig1.gif" ALT="Figure 1"> View larger version (39K): org.highwire.dtl.DTLVardef@1f42191org.highwire.dtl.DTLVardef@c7e4baorg.highwire.dtl.DTLVardef@1798547org.highwire.dtl.DTLVardef@11d0d96_HPS_FORMAT_FIGEXP M_FIG C_FIG Immune cell illustrations were adapted (1, 2) with permission; permission conveyed through Copyright Clearance Center, Inc. Capsule summaryThe autologous moDC-T cell-B cell in vitro assay may be used to assess whether processing methods or new foods might have intrinsic capacity to affect type 2 inflammation in peanut-allergic patients.

Atopic dermatitis (AD) commonly precedes food allergy and asthma in the atopic march. Epicutaneous (EC) sensitization in mice with ovalbumin (OVA) results in allergic skin inflammation that mimics AD and promotes food anaphylaxis or asthma following a gastric or intranasal challenge with OVA, respectively. Using our mouse model of EC sensitization with OVA we evaluate whether anti-IL-4R blocking antibody improve allergic skin inflammation and impact the atopic march. IL-4R blockade at the end of EC sensitization decreased allergic skin inflammation in OVA-sensitized mice, evidenced by significantly decreased eosinophil infiltration, decrease production of IL-4, IL-13 by OVA- restimulated splenocytes and reduced serum levels OVA-specific IgE. However, late IL- 4R blockade did not affect food anaphylaxis or airway inflammation in EC sensitized mice following an oral or intranasal challenge with OVA. IL-4R blockade at the beginning of EC sensitization not only impact allergic skin inflammation and systemic response to the antigen, but also decreased food anaphylaxis or airway inflammation following OVA challenge. These results suggest that the blockade of sensitization through the skin by IL-4R blockade could impact the atopic march.

Peanut allergy reaction severity correlates with increased intestinal epithelial cell (IEC) barrier permeability. CC027/GeniUnc mice develop peanut allergy by intragastric administration of peanut proteins without adjuvant. We report that peanut-allergic CC027/GeniUnc mice showed increased IEC barrier permeability and systemic peanut allergen Ara h 2 after challenge. Jejunal epithelial cell transcriptomics showed effects of peanut allergy on IEC proliferation, survival, and metabolism, and revealed IEC-predominant angiopoietin like-4 (Angptl4) as a unique feature of CC027/GeniUnc peanut allergy. CC027/GeniUnc mice and peanut-allergic pediatric patients demonstrated significantly higher serum Angptl4 and ANGPTL4 compared to control C3H/HeJ mice and non-peanut-allergic but atopic patients, respectively, highlighting its potential as a biomarker of peanut allergy.

Type 2 inflammatory diseases (T2IDs) such as atopic dermatitis (AD), asthma, food allergy, eosinophilic esophagitis (EoE), chronic sinusitis (CS), and others, are immune-mediated conditions that frequently co-occur across organ systems and contribute to substantial disease burden. While the atopic march has long served as a conceptual model for T2ID progression, it remains unclear whether this linear sequence captures the broader comorbidity structure of T2IDs. In this study, we systematically analyzed comorbidity patterns across nine T2IDs using two complementary methodological approaches: Large-scale real-world data (RWD) from over 129 million electronic health records and genome-wide genetic correlation, including data from three novel (asthma, chronic sinusitis and allergic rhinitis) metanalyses of genome-wide association studies. Retrospective matched cohort analyses revealed a highly interconnected disease network in which CS emerged as a central driver of downstream comorbidities, increasing the risk of multiple other T2IDs across diverse patient populations. AD, food allergy, and vasomotor and allergic rhinitis also showed strong cross-disease effects. Subgroup analyses uncovered notable age-, sex-, and race-specific disparities. Genetic correlation analyses supported shared heritability among many disease pairs and integration with RWD allowed to infer directionality. While some disease pairs showed discordant findings between genetic correlation and RWD, most associations aligned across both methodologies. Together, our results highlight that T2ID progression extends beyond the atopic march and is shaped by a complex and heterogeneous network of interactions. This work provides a data-driven framework to guide risk stratification, inform early preventive strategies, and prioritize upstream disease targets within the type 2 inflammatory spectrum.

Ethnicity seems to be a risk factor for asthma and its exacerbation, but no general consensus has been reached so far. Ethnic diversity and differences have long been overlooked and most studies in these regards are observational, lacking in-depth mechanistic insights. Harnessing comprehensive transcriptomic data at organ system and single cell levels, we comparatively analyzed the signalling landscapes of African American/Black (AA) and other ethnicities. In healthy individuals, most AA PBMC subsets exhibited elevated IL2-STAT5 signals, which is critically implicated in asthma pathogenesis. This extended to various compartments (bronchial and airway epithelium, circulating CD4+ T cells and blood) in asthma, where AA upregulated IL2-STAT5 pathway relative to other ethnicities. Mechanistically, the increased IL2-STAT5 signalling correlated with enhanced T cell migration and recruitment. Together, they might contribute to the greater predisposition towards asthma exacerbation in AA. This first-of-its-kind study sheds some in-depth insights into the biology of ethnic differences in asthma. Our findings, if further validated, will be valuable for future asthma research and clinical practice like therapeutic development and treatment guidance, highlighting the need for ethnicity diversity and inclusions in these areas.

Monocytes are critical regulators of allergic inflammation, whose functions are modified by IgE-driven processes. Monocytes are heterogeneous; comprised of multiple subsets which implies differential functions. In allergic inflammation, this heterogeneity is likely influenced by IgE-mediated effects. We sought to identify phenotypically distinct monocyte subsets related to allergic disease and then further delineate functional differences in cytokine release and antiviral responses. Using high dimensional spectral flow cytometry, we identified monocyte surface phenotypes directly related to surface levels of the high affinity IgE receptor (Fc{epsilon}RI) and surface-bound IgE. Fc{epsilon}RI+IgE+ monocytes, or FIMs, correlated with allergic disease and the level of atopy (i.e. serum IgE levels) of individual subjects. The FIM population also had differential surface expression of other molecules of monocyte maturation, which closely resembled a type 2 conventional dendritic cell (cDC2) phenotype. Functionally, FIMs had enhanced antiviral responses and IgE-driven IL-10 cytokine release. Finally, we showed that FIMs could be identified at higher levels in lung tissue from individuals with asthma. This study supports that atopic disease drives differential monocyte phenotypes, with the FIM population, specifically, as a more mature cell population closely related to dendritic cells with enhanced antiviral responses. The presence of monocytes in lung tissue during lethal asthma exacerbation further supports a role in regulating tissue inflammatory responses in allergic airway disease.

BackgroundHazelnut allergy is a major cause of food-induced anaphylaxis yet remains poorly defined at the molecular level. ObjectiveWe aimed to identify molecular differences between individuals with primary hazelnut allergy and nonallergic controls by investigating a comprehensive spectrum of omics profiles in immune cells. MethodsWe analysed DNA methylation, transcriptomic and proteomic profiles in hazelnut-stimulated and unstimulated immune cells. ResultsAcross analyses, we identified 80 differentially methylated signatures, 125 differentially expressed genes, and 11 differentially secreted proteins associated with hazelnut allergy. DNA methylation signatures were highly concordant between unstimulated and stimulated conditions, consistent with stable epigenetic remodelling. Key findings implicated ZNF341, associated with a rare monogenic hyper-IgE syndrome, and ARL2, both linked to STAT3-mediated IgE dysregulation. Additionally, we identified a differentially methylated region (DMR) overlapping the T Helper Type 2 Locus Control Region Associated RNA (TH2LCRR) in the cytokine gene cluster, suggesting an epigenetic mechanism contributing to IL-5 and IL-13 upregulation. Antigen stimulation was required to reveal hazelnut-specific transcriptional and proteomic signals. Integration of these data demonstrated that IL-5 expression could distinguish both groups. We identified signals in epithelial barrier genes of the gut and skin (TRIM31, TRIM40, CDSN), activation of the vitamin D pathway (CYP27B1, IL32), and nominate additional signals (PHACTR1, MFHAS1, SPRED2, GALNT5/GALNTL4, NSMCE1-DT) for follow-up. ConclusionOur study confirms type-2 cytokines, Fc{varepsilon}RI, and JAK-STAT signalling and uncovers novel links to monogenic hyper-IgE syndrome, activation of vitamin-D pathways, and gut/skin barrier genes, yielding a catalogue of candidate biomarkers for mechanistic studies and prospective validation. Key messagesO_LIAntigen-specific multi-omics analysis confirms JAK-STAT and Th2 control pathways, with IL-5 emerging as a key marker distinguishing hazelnut-allergic from nonallergic individuals. C_LIO_LIEpigenetic and transcriptomic analysis points to roles for vitamin D metabolism, hyper-IgE-associated genes, and epithelial barrier dysfunction in hazelnut allergy C_LIO_LIThis first antigen-specific methylation and multi-omics discovery study in hazelnut allergy provides candidate pathways and genes to guide future studies C_LI Capsule summaryThis antigen-specific multi-omics study confirms JAK-STAT/Th2 control pathways, pinpoints the IL-5 response as biomarker distinguishing hazelnut allergy, implicates vitamin D metabolism, hyper-IgE genes, and epithelial barrier dysfunction, and delivers additional candidate genes to guide future research.

Measurement of circulating immunoglobulin E (IgE) concentration is helpful for diagnosing and treating asthma and allergic diseases. Identifying gene expression signatures associated with IgE might elucidate novel pathways for IgE regulation. To this end, we performed a discovery transcriptome-wide association study (TWAS) to identify differentially expressed genes associated with circulating IgE levels in whole-blood derived RNA from 5,345 participants in the Framingham Heart Study (FHS) across 17,873 mRNA gene-level transcripts. We identified 216 significant transcripts at a false discovery rate (FDR)< 0.05. We conducted replication using the meta-analysis of two independent external studies: the Childhood Asthma Management Program (n = 610) and the Genetic Epidemiology of Asthma in Costa Rica Study (n = 326); we then reversed the discovery and replication cohorts, which revealed 59 significant genes that bidirectionally replicated. Gene ontology analysis revealed that many of these genes were implicated in immune function pathways, including defense response, inflammatory response, and cytokine production. Mendelian randomization (MR) analysis revealed four genes (CLC, CCDC21, S100A13, and GCNT1) as putatively causal (p< 0.05) regulators of IgE levels. GCNT1 (beta = 1.5, p = 0.01)--which is a top result in the MR analysis of expression in relation to asthma and allergic diseases--plays a role in regulating T helper type 1 (Th1) cell homing, lymphocyte trafficking, and B cell differentiation. Our findings build upon prior knowledge of IgE regulation and provide a deeper understanding of underlying molecular mechanisms. The IgE-associated genes that we identified--particularly those implicated in MR analysis--can be explored as promising therapeutic targets for asthma and IgE-related diseases.

BackgroundEpidemiological studies consistently highlight the adverse impact of pollen on asthma exacerbations. This study investigates the correlation between pollen levels and asthma-related Emergency Department visits across four Andalusian provinces, with a combined population of 3.8 million, from 2017 to 2019. Materials and methodsA bidirectional case-crossover design was applied up to 4 lag days to calculate odds ratios (OR) for admissions, adjusting for daily pollen levels and incorporating meteorological factors and personal information as covariates. ResultsSignificant associations (95% CI) were found between pollen exposure and asthma-related Emergency Department visits, varying by pollen type, region, and lag day. In Almeria, gramineae (1-day lag, OR 1.20); in Huelva, artemisia (1-day lag, OR 1.13), betula (3-day lag, OR 1.26), and olea (1- and 2-day lags, OR 1.20); in Jaen, gramineae (0- and 1-day lags, OR {approx} 9.97), olea (0-4 days, OR {approx} 1.20), and plantago (0-to 2-day lags, OR {approx} 1.20); and in Seville, alternaria (1-4 day lags, OR {approx} 9.96), carex (0-3 day lags, max OR 1.72 at 2 days), olea (0-4 days, OR {approx} 1.20) and urticaceae (same day, OR 1.02). ConclusionThis study provides a comprehensive understanding of pollens role in asthma exacerbations, with specific pollen types showing regional and temporal variation. Findings support further research on regional pollen thresholds and geolocation-based strategies to notify asthma patients. Summary boxWhat do we know about this topic? How does this study impact our current understanding and/or clinical management of this topic?

BackgroundThe immunometabolic mechanisms underlying variable responses to oral immunotherapy (OIT) in patients with IgE-mediated food allergy are unknown. ObjectiveTo identify novel pathways associated with tolerance in food allergy, we used metabolomic profiling to find pathways important for food allergy in multi-ethnic cohorts and responses to OIT. MethodsUntargeted plasma metabolomics data were generated from the VDAART healthy infant cohort (N=384), a Costa Rican cohort of children with asthma (N=1040), and a peanut OIT trial (N=20) evaluating sustained unresponsiveness (SU, protection that lasts after therapy) versus transient desensitization (TD, protection that ends immediately afterwards). Generalized linear regression modeling and pathway enrichment analysis identified metabolites associated with food allergy and OIT outcomes. ResultsCompared with unaffected children, those with food allergy were more likely to have metabolomic profiles with altered histidines and increased bile acids. Eicosanoids (e.g., arachidonic acid derivatives) (q=2.4x10-20) and linoleic acid derivatives (q=3.8x10-5) pathways decreased over time on OIT. Comparing SU versus TD revealed differing concentrations of bile acids (q=4.1x10-8), eicosanoids (q=7.9x10-7), and histidine pathways (q=0.015). In particular, the bile acid lithocholate (4.97[1.93,16.14], p=0.0027), the eicosanoid leukotriene B4 (3.21[1.38,8.38], p=0.01), and the histidine metabolite urocanic acid (22.13[3.98,194.67], p=0.0015) were higher in SU. ConclusionsWe observed distinct profiles of bile acids, histidines, and eicosanoids that vary among patients with food allergy, over time on OIT and between SU and TD. Participants with SU had higher levels of metabolites such as lithocholate and urocanic acid, which have immunomodulatory roles in key T-cell subsets, suggesting potential mechanisms of tolerance in immunotherapy. Key Messages- Compared with unaffected controls, children with food allergy demonstrated higher levels of bile acids and distinct histidine/urocanic acid profiles, suggesting a potential role of these metabolites in food allergy. - In participants receiving oral immunotherapy for food allergy, those who were able to maintain tolerance-even after stopping therapyhad lower overall levels of bile acid and histidine metabolites, with the exception of lithocholic acid and urocanic acid, two metabolites that have roles in T cell differentiation that may increase the likelihood of remission in immunotherapy. Capsule summaryThis is the first study of plasma metabolomic profiles of responses to OIT in individuals with IgE-mediated food allergy. Identification of immunomodulatory metabolites in allergic tolerance may help identify mechanisms of tolerance and guide future therapeutic development. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=125 SRC="FIGDIR/small/24308233v1_ufig1.gif" ALT="Figure 1"> View larger version (40K): org.highwire.dtl.DTLVardef@1d199f3org.highwire.dtl.DTLVardef@1d24661org.highwire.dtl.DTLVardef@abb6corg.highwire.dtl.DTLVardef@96e3ca_HPS_FORMAT_FIGEXP M_FIG C_FIG